Papers - OHASHI Kadoaki

Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer. International journal

Myung-Ju Ahn, Byoung Chul Cho, Enriqueta Felip, Ippokratis Korantzis, Kadoaki Ohashi, Margarita Majem, Oscar Juan-Vidal, Sabin Handzhiev, Hiroki Izumi, Jong-Seok Lee, Rafal Dziadziuszko, Jürgen Wolf, Fiona Blackhall, Martin Reck, Jean Bustamante Alvarez, Horst-Dieter Hummel, Anne-Marie C Dingemans, Jacob Sands, Hiroaki Akamatsu, Taofeek K Owonikoko, Suresh S Ramalingam, Hossein Borghaei, Melissa L Johnson, Shuang Huang, Sujoy Mukherjee, Mukul Minocha, Tony Jiang, Pablo Martinez, Erik S Anderson, Luis Paz-Ares

The New England journal of medicine   2023.10

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BACKGROUND: Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 and CD3, showed promising antitumor activity in a phase 1 trial in patients with previously treated small-cell lung cancer. METHODS: In this phase 2 trial, we evaluated the antitumor activity and safety of tarlatamab, administered intravenously every 2 weeks at a dose of 10 mg or 100 mg, in patients with previously treated small-cell lung cancer. The primary end point was objective response (complete or partial response), as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Overall, 220 patients received tarlatamab; patients had previously received a median of two lines of treatment. Among patients evaluated for antitumor activity and survival, the median follow-up was 10.6 months in the 10-mg group and 10.3 months in the 100-mg group. An objective response occurred in 40% (97.5% confidence interval [CI], 29 to 52) of the patients in the 10-mg group and in 32% (97.5% CI, 21 to 44) of those in the 100-mg group. Among patients with an objective response, the duration of response was at least 6 months in 59% (40 of 68 patients). Objective responses at the time of data cutoff were ongoing in 22 of 40 patients (55%) in the 10-mg group and in 16 of 28 patients (57%) in the 100-mg group. The median progression-free survival was 4.9 months (95% CI, 2.9 to 6.7) in the 10-mg group and 3.9 months (95% CI, 2.6 to 4.4) in the 100-mg group; the estimates of overall survival at 9 months were 68% and 66% of patients, respectively. The most common adverse events were cytokine-release syndrome (in 51% of the patients in the 10-mg group and in 61% of those in the 100-mg group), decreased appetite (in 29% and 44%, respectively), and pyrexia (in 35% and 33%). Cytokine-release syndrome occurred primarily during treatment cycle 1, and events in most of the patients were grade 1 or 2 in severity. Grade 3 cytokine-release syndrome occurred less frequently in the 10-mg group (in 1% of the patients) than in the 100-mg group (in 6%). A low percentage of patients (3%) discontinued tarlatamab because of treatment-related adverse events. CONCLUSIONS: Tarlatamab, administered as a 10-mg dose every 2 weeks, showed antitumor activity with durable objective responses and promising survival outcomes in patients with previously treated small-cell lung cancer. No new safety signals were identified. (Funded by Amgen; DeLLphi-301 ClinicalTrials.gov number, NCT05060016.).

DOI： 10.1056/NEJMoa2307980

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Low frequency of intracranial progression in advanced NSCLC patients treated with cancer immunotherapies. International journal

Naoya Kemmotsu, Kiichiro Ninomiya, Kei Kunimasa, Takamasa Ishino, Joji Nagasaki, Yoshihiro Otani, Hiroyuki Michiue, Eiki Ichihara, Kadoaki Ohashi, Takako Inoue, Motohiro Tamiya, Kazuko Sakai, Youki Ueda, Hiromichi Dansako, Kazuto Nishio, Katsuyuki Kiura, Isao Date, Yosuke Togashi

International journal of cancer   2023.8

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Intracranial metastases are common in nonsmall-cell lung cancer (NSCLC) patients, whose prognosis is very poor. In addition, intracranial progression is common during systemic treatments due to the inability to penetrate central nervous system (CNS) barriers, whereas the intracranial effects of cancer immunotherapies remain unclear. We analyzed clinical data to evaluate the frequency of intracranial progression in advanced NSCLC patients treated with PD-1 blockade therapies compared with those treated without PD-1 blockade therapies, and found that the frequency of intracranial progression in advanced NSCLC patients treated with PD-1 blockade therapies was significantly lower than that in patients treated with cytotoxic chemotherapies. In murine models, intracranial rechallenged tumors after initial rejection by PD-1 blockade were suppressed. Accordingly, long-lived memory precursor effector T cells and antigen-specific T cells were increased by PD-1 blockade in intracranial lesions. However, intracranial rechallenged different tumors are not suppressed. Our results indicate that cancer immunotherapies can prevent intracranial progression, maintaining long-term effects intracranially as well as systemically. If intracranial recurrence occurs during the treatment with PD-1 blockade therapies, aggressive local therapies could be worthwhile.

DOI： 10.1002/ijc.34700

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Clinicogenomic Features and Targetable Mutations in NSCLCs Harboring BRAF Non-V600E Mutations: A Multi-Institutional Genomic Screening Study (LC-SCRUM-Asia). International journal

Tetsuya Sakai, Shingo Matsumoto, Yasuto Ueda, Yuji Shibata, Takaya Ikeda, Atsushi Nakamura, Masahiro Kodani, Kadoaki Ohashi, Naoki Furuya, Hiroki Izumi, Kaname Nosaki, Shigeki Umemura, Yoshitaka Zenke, Hibiki Udagawa, Eri Sugiyama, Kiyotaka Yoh, Koichi Goto

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   2023.8

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INTRODUCTION: BRAF non-V600E mutations occur in 1% to 2% of NSCLCs. Because of their rarity, the clinical backgrounds and outcomes of cytotoxic chemotherapy or immunotherapy remain unclear, and no targeted therapies are approved for BRAF non-V600E-mutant NSCLC. METHODS: In this multi-institutional prospective lung cancer genomic screening project (LC-SCRUM-Asia), we evaluated the clinicogenomic characteristics and therapeutic outcomes of BRAF non-V600E-mutant NSCLC. RESULTS: From March 2015 to November 2021, a total of 11,929 patients with NSCLC were enrolled. BRAF mutations were detected in 380 (3.5%), including the V600E (class I) in 119 (31%) and non-V600E in 261; the non-V600E were functionally classified into class II (122, 32%), class III (86, 23%), and non-classes I to III. Smokers and having concurrent RAS gene family or TP53 mutations were more frequently associated with class II or III than with class I. In patients with class III as compared with class I, the progression-free survival in response to platinum-containing chemotherapies (median, 5.3 versus 11.5 mo, p < 0.01) and the overall survival (median, 14.5 versus 34.8 mo, p < 0.02) were significantly shorter. Furthermore, class IIa mutations were significantly more frequent in our Asian cohort than in previously reported cohorts. The clinicogenomic features associated with class IIa were similar to those associated with class I, and one patient with NSCLC with K601E had a good response to dabrafenib plus trametinib. CONCLUSIONS: Patients with NSCLCs with BRAF non-V600E, especially class III, were associated with poorer therapeutic outcomes than those with V600E. Furthermore, patients with NSCLC with class IIa had distinct clinicogenomic features, and further preclinical and clinical studies are needed to evaluate class IIa mutations as a therapeutic target.

DOI： 10.1016/j.jtho.2023.07.024

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PD-1 blockade augments CD8+ T cell dependent antitumor immunity triggered by Ad-SGE-REIC in Egfr-mutant lung cancer. Reviewed International journal

Takamasa Nakasuka, Kadoaki Ohashi, Kazuya Nishii, Atsuko Hirabae, Sachi Okawa, Nahoko Tomonobu, Kenji Takada, Chihiro Ando, Hiromi Watanabe, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Hiromi Kumon, Yoshinobu Maeda, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands)   178   1 - 10   2023.2

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OBJECTIVES: No immunotherapeutic protocol has yet been established in never-smoking patients with lung cancer harboring driver oncogenic mutations, such as epidermal growth factor receptor (EGFR) mutations. The immunostimulatory effect of Ad-REIC, a genetically engineered adenovirus vector expressing a tumor suppressor gene, reduced expression in immortalized cells (REIC), has been investigated in clinical trials for various solid tumors. However, the immunostimulatory effect of the Ad-REIC in EGFR-mutant lung cancer with a non-inflamed tumor microenvironment (TME) has not been explored. MATERIALS AND METHODS: We used a syngeneic mouse model developed by transplanting Egfr-mutant lung cancer cells into single or double flanks of C57BL/6J mice. Ad-SGE-REIC, a 2nd-generation vector with an enhancer sequence, was injected only into the tumors from one flank, and its antitumor effects were assessed. Tumor-infiltrating cells were evaluated using immunohistochemistry or flow cytometry. The synergistic effects of Ad-SGE-REIC and PD-1 blockade were also examined. RESULTS: Injection of Ad-SGE-REIC into one side of the tumor induced not only a local antitumor effect but also a bystander abscopal effect in the non-injected tumor, located on the other flank. The number of PD-1+CD8+ T cells increased in both injected and non-injected tumors. PD-1 blockade augmented the local and abscopal antitumor effects of Ad-SGE-REIC by increasing the number of CD8+ T cells in the TME of Egfr-mutant tumors. Depletion of CD8+ cells reverted the antitumor effect, suggesting they contribute to antitumor immunity. CONCLUSION: Ad-SGE-REIC induced systemic antitumor immunity by modifying the TME status from non-inflamed to inflamed, with infiltration of CD8+ T cells. Additionally, in Egfr-mutant lung cancer, this effect was enhanced by PD-1 blockade. These findings pave the way to establish a novel combined immunotherapy strategy with Ad-SGE-REIC and anti-PD-1 antibody for lung cancer with a non-inflamed TME.

DOI： 10.1016/j.lungcan.2023.01.018

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Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Reviewed International coauthorship International journal

Vivek Subbiah, Jürgen Wolf, Bhavana Konda, Hyunseok Kang, Alexander Spira, Jared Weiss, Masayuki Takeda, Yuichiro Ohe, Saad Khan, Kadoaki Ohashi, Victoria Soldatenkova, Sylwia Szymczak, Loretta Sullivan, Jennifer Wright, Alexander Drilon

The Lancet. Oncology   23 ( 10 )   1261 - 1273   2022.10

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BACKGROUND: Selpercatinib is a first-in-class, highly selective RET kinase inhibitor with CNS activity that has shown efficacy in RET fusion-positive lung and thyroid cancers. RET fusions occur rarely in other tumour types. We aimed to investigate the efficacy and safety of selpercatinib in a diverse group of patients with RET fusion-positive non-lung or thyroid advanced solid tumours (ie, a tumour-agnostic population). METHODS: LIBRETTO-001 is an ongoing phase 1/2, single-group, open-label, basket trial of selpercatinib in patients aged 18 years and older (or ≥12 years, where permitted by regulatory authorities) with RET-altered cancers. The trial is being conducted at 89 sites in 16 countries; the tumour-agnostic population was enrolled at 30 sites (outpatient and inpatient medical facilities) across eight countries. A prespecified interim analysis of LIBRETTO-001 was planned to investigate the efficacy and safety of selpercatinib in a tumour-agnostic population of patients with RET fusion-positive advanced solid tumours; the data cutoff date was Sept 24, 2021. Eligible patients had disease progression on or after previous systemic therapies or no satisfactory therapeutic options and an Eastern Cooperative Oncology Group performance status of 0-2. Selpercatinib was orally administered in a continuous 28-day cycle. Patients enrolled in the phase 1 dose-escalation portion received between 20 mg once daily or 20-240 mg twice daily; the phase 2 recommended dose was 160 mg twice daily. The primary endpoint was the objective response rate as determined by the independent review committee. The efficacy-evaluable tumour-agnostic population was defined as patients with RET fusion-positive cancer, other than non-small-cell lung cancer and thyroid cancer, who had at least 6 months of follow-up from the first study dose at the time of data cutoff (all responders at the time of data cutoff were followed up for at least 6 months from the onset of response unless they progressed or died earlier). Safety was analysed in the tumour-agnostic population of patients who had been enrolled and received selpercatinib on or before the data cutoff date. This study is registered with ClinicalTrials.gov (NCT03157128) and is still recruiting participants. FINDINGS: Between Dec 4, 2017, and Aug 4, 2021, 45 patients with RET fusion-positive tumour-agnostic cancers were enrolled from the phase 1 dose-escalation and phase 2 dose-expansion cohorts of the trial. 43 (96%) of 45 patients received a starting dose of selpercatinib at the recommended dose of 160 mg twice daily. Of the two patients who did not, one received a dose of 160 mg twice daily via intra-patient dose escalation (as allowed per protocol for patients enrolled in the phase 1 portion of the study at lower doses) and the other patient's starting dose of 120 mg twice daily was never escalated. Of the 41 efficacy-evaluable patients, the objective response rate as per the independent review committee was 43·9% (95% CI 28·5-60·3; 18 of 41 patients). The most common grade 3 or worse treatment-emergent adverse events were hypertension (ten [22%] of 45 patients), increased alanine aminotransferase (seven [16%]), and increased aspartate aminotransferase (six [13%]). Treatment-emergent serious adverse events occurred in 18 (40%) of 45 patients. No treatment-related deaths occurred. INTERPRETATION: Selpercatinib showed clinically meaningful activity in the RET fusion-positive tumour-agnostic population, with a safety profile consistent with that observed in other indications. Comprehensive genomic testing that includes RET fusions will be crucial for identifying patients who might benefit from selpercatinib. FUNDING: Loxo Oncology.

DOI： 10.1016/S1470-2045(22)00541-1

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CD8+ T-cell responses are boosted by dual PD-1/VEGFR2 blockade after EGFR inhibition in Egfr-mutant lung cancer. Reviewed International journal

Kazuya Nishii, Kadoaki Ohashi, Shuta Tomida, Takamasa Nakasuka, Atsuko Hirabae, Sachi Okawa, Jun Nishimura, Hisao Higo, Hiromi Watanabe, Hirohisa Kano, Chihiro Ando, Go Makimoto, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Heiichiro Udono, Yoshinobu Maeda, Katsuyuki Kiura

Cancer immunology research   10 ( 9 )   1111 - 1126   2022.7

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Epidermal growth factor receptor (EGFR) is the most frequently mutated driver oncogene in non-smoking-related, non-small-cell lung cancer (NSCLC). EGFR-mutant NSCLC has a non-inflamed tumor microenvironment (TME), with low infiltration by CD8+ T cells and, thus, immune checkpoint inhibitors, such as anti-programmed cell death-1 (anti-PD-1) have weak anti-tumor effects. Here, we showed that CD8+ T-cell responses were induced by an EGFR-tyrosine kinase inhibitor (TKI) in syngeneic Egfr-mutant NSCLC tumors, which was further pronounced by sequential dual blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2). However, simultaneous triple blockade had no such effect. PD-1/VEGFR2 dual blockade did not exert tumor-inhibitory effects without pre-treatment with the EGFR-TKI, suggesting that treatment schedule is crucial for efficacy of the dual blockade therapy. Pre-treatment with EGFR-TKI increased the CD8+ T-cell/regulatory T-cell (Treg) ratio, while also increasing expression of immunosuppressive chemokines and chemokine receptors, as well as increasing the number of M2-like macrophages, in the TME. Discontinuing EGFR-TKI treatment reversed the transient increase of immunosuppressive factors in the TME. The subsequent PD-1/VEGFR2 inhibition maintained increased numbers of infiltrating CD8+ T cells and CD11c+ dendritic cells. Depletion of CD8+ T cells in vivo abolished tumor growth inhibition by EGFR-TKI alone and the sequential triple therapy, suggesting that EGFR inhibition is a prerequisite for the induction of CD8+ T-cell responses. Our findings could aid in developing an alternative immunotherapy strategy in patients with cancers that have driver mutations and a non-inflamed TME.

DOI： 10.1158/2326-6066.CIR-21-0751

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Identification of targetable kinases in idiopathic pulmonary fibrosis Reviewed

Hisao Higo, Kadoaki Ohashi, Shuta Tomida, Sachi Okawa, Hiromasa Yamamoto, Seiichiro Sugimoto, Satoru Senoo, Go Makimoto, Kiichiro Ninomiya, Takamasa Nakasuka, Kazuya Nishii, Akihiko Taniguchi, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Nobuaki Miyahara, Yoshinobu Maeda, Shinichi Toyooka, Katsuyuki Kiura

Respiratory Research   23 ( 1 )   2022.2

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Abstract

Background

Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF).

Methods

Thirteen samples from five patients with IPF (Cases 1–5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n = 13) and control samples (n = 8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC).

Results

Gene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions.

Conclusions

We performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF.

DOI： 10.1186/s12931-022-01940-y

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Other Link： https://link.springer.com/article/10.1186/s12931-022-01940-y/fulltext.html

MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I. Reviewed International coauthorship International journal

Johannes Brägelmann, Carina Lorenz, Sven Borchmann, Kazuya Nishii, Julia Wegner, Lydia Meder, Jenny Ostendorp, David F Ast, Alena Heimsoeth, Takamasa Nakasuka, Atsuko Hirabae, Sachi Okawa, Marcel A Dammert, Dennis Plenker, Sebastian Klein, Philipp Lohneis, Jianing Gu, Laura K Godfrey, Jan Forster, Marija Trajkovic-Arsic, Thomas Zillinger, Mareike Haarmann, Alexander Quaas, Stefanie Lennartz, Marcel Schmiel, Joshua D'Rozario, Emily S Thomas, Henry Li, Clemens A Schmitt, Julie George, Roman K Thomas, Silvia von Karstedt, Gunther Hartmann, Reinhard Büttner, Roland T Ullrich, Jens T Siveke, Kadoaki Ohashi, Martin Schlee, Martin L Sos

Nature communications   12 ( 1 )   5505 - 5505   2021.9

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Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients.

File： 41467_2021_Article_25728.pdf

DOI： 10.1038/s41467-021-25728-8

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Impact of HER2 expression on EGFR-TKI treatment outcomes in lung tumors harboring EGFR mutations: A HER2-CS study subset analysis. International journal

Kadoaki Ohashi, Kiichiro Ninomiya, Hiroshige Yoshioka, Akihiro Bessho, Takuo Shibayama, Keisuke Aoe, Nobuhisa Ishikawa, Toshiyuki Kozuki, Haruyuki Kawai, Shoichi Kuyama, Seigo Miyoshi, Kazunori Fujitaka, Hideto Obata, Yukari Tsubata, Yoshikazu Awaya, Masaaki Inoue, Koji Inoue, Naokatsu Horita, Hiroyuki Yanai, Katsuyuki Hotta, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands)   150   83 - 89   2020.12

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard treatment for EGFR-mutated non-small-cell lung carcinoma (NSCLC); however, a biomarker to predict their efficacy has not been established. Although human epidermal growth factor receptor-2 (HER2) aberrations constitute a potential mechanism for acquired resistance to EGFR-TKIs, the impact of HER2 on EGFR-TKI treatment outcomes has not been systematically evaluated. In this post-hoc subgroup study, we examined the impact of HER2 on the effect of EGFR-TKIs in patients with NSCLC harboring EGFR mutations. MATERIALS AND METHODS: Of 1126 patients with NSCLC enrolled into a prospective cohort study (HER2-CS study), we analyzed data of 356 (32 %) patients with EGFR-mutant tumors. HER2 protein expression levels were determined by immunohistochemistry (IHC) with the gastric cancer criteria. Patients were divided either to an HER2-P group (HER2-IHC2+/3+) or an HER2-N group (HER2-IHC0/1+). We primarily assessed differences in the time-to-treatment failure (TTF) of EGFR-TKI between the groups. RESULTS: The HER2 scoring was as follows: IHC0 (n = 76, 21 %), IHC1+ (n = 199, 56 %), IHC2+ (n = 72, 20 %), and IHC3+ (n = 9, 3 %). The patients' demographics were similar in the HER2-P and HER2-N groups. The HER2-P group showed a significantly shorter EGFR-TKI TTF than the HER2-N group (hazard ratio [HR]: 1.657, 95 % confidence interval [CI]: 1.076-2.552; median: 13.3 vs. 19.1 months). The magnitude of the negative impact of TTF was especially dependent on performance status (PS). HER2 expression significantly deteriorated the TTF in the subgroup with PS 2 (HR: 5.497, 95 % CI: 1.510-20.02), but not in that with better PS (HR: 1.437, 95 % CI: 0.899-2.298) (pinteraction = 0.015). CONCLUSION: In the current cohort, HER2 protein expression in EGFR-mutant NSCLC may have a negative impact on the effect of EGFR-TKIs, the effect of which was PS dependent.

DOI： 10.1016/j.lungcan.2020.09.024

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Beneficial effect of erlotinib and trastuzumab emtansine combination in lung tumors harboring EGFR mutations. Reviewed International journal

Hiroe Kayatani, Kadoaki Ohashi, Kiichiro Ninomiya, Go Makimoto, Kazuya Nishii, Hisao Higo, Hiromi Watanabe, Hirohisa Kano, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Biochemical and biophysical research communications   532 ( 3 )   341 - 346   2020.11

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Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is the standard therapy for non-small cell lung cancer (NSCLC) harboring EGFR mutations, but the resistance is inevitable. The drug-tolerant persister cancer cells are thought to be involved in the resistance. We recently reported that HER2 expression had a negative impact on time-to-treatment-failure in patients with EGFR mutant NSCLC. In this study, we hypothesized that HER2 might be a potential target for alternative combination therapy in NSCLC harboring EGFR mutations. In vitro study showed that the level of HER2 expression had no correlation with the sensitivity to EGFR-TKI, erlotinib but showed some correlation with HER2-inhibitor, ado-trastuzumab emtansine (T-DM1) in multiple EGFR-mutant lung cancer cell lines. In addition, HER2 expression was increased in persister cancer cells in 11-18 cell line harboring EGFR L858R or HCC827 cell line harboring EGFR exon 19 deletion after the exposure to erlotinib in vitro and in vivo. The combination of erlotinib and T-DM1 showed a superior inhibitory effect on cell proliferation compared with those of the erlotinib or T-DM1 alone in either 11-18 or HCC827 cells in vitro. The combination therapy also induced a significantly greater inhibitory effect on tumor growth in xenograft model in mice transplanted with either 11-18 or HCC827 cells compared with erlotinib alone or T-DM1 alone. No body weight loss was observed in these mice. These results suggested that the combination therapy with EGFR-TKI and T-DM1 might be a potentially promising strategy for treating lung cancer harboring EGFR mutations.

DOI： 10.1016/j.bbrc.2020.07.055

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Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer. Reviewed International journal

Jürgen Wolf, Takashi Seto, Ji-Youn Han, Noemi Reguart, Edward B Garon, Harry J M Groen, Daniel S W Tan, Toyoaki Hida, Maja de Jonge, Sergey V Orlov, Egbert F Smit, Pierre-Jean Souquet, Johan Vansteenkiste, Maximilian Hochmair, Enriqueta Felip, Makoto Nishio, Michael Thomas, Kadoaki Ohashi, Ryo Toyozawa, Tobias R Overbeck, Filippo de Marinis, Tae-Min Kim, Eckart Laack, Anna Robeva, Sylvie Le Mouhaer, Maeve Waldron-Lynch, Banu Sankaran, O Alejandro Balbin, Xiaoming Cui, Monica Giovannini, Mikhail Akimov, Rebecca S Heist

The New England journal of medicine   383 ( 10 )   944 - 957   2020.9

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BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and MET amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation. METHODS: We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with MET-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and MET status (MET exon 14 skipping mutation or MET amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments. RESULTS: A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a MET exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with MET amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with MET amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2. CONCLUSIONS: Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a MET exon 14 skipping mutation, particularly in those not treated previously. The efficacy in MET-amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.).

DOI： 10.1056/NEJMoa2002787

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Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer. Reviewed International journal

Alexander Drilon, Geoffrey R Oxnard, Daniel S W Tan, Herbert H F Loong, Melissa Johnson, Justin Gainor, Caroline E McCoach, Oliver Gautschi, Benjamin Besse, Byoung C Cho, Nir Peled, Jared Weiss, Yu-Jung Kim, Yuichiro Ohe, Makoto Nishio, Keunchil Park, Jyoti Patel, Takashi Seto, Tomohiro Sakamoto, Ezra Rosen, Manisha H Shah, Fabrice Barlesi, Philippe A Cassier, Lyudmila Bazhenova, Filippo De Braud, Elena Garralda, Vamsidhar Velcheti, Miyako Satouchi, Kadoaki Ohashi, Nathan A Pennell, Karen L Reckamp, Grace K Dy, Jürgen Wolf, Benjamin Solomon, Gerald Falchook, Kevin Ebata, Michele Nguyen, Binoj Nair, Edward Y Zhu, Luxi Yang, Xin Huang, Elizabeth Olek, S Michael Rothenberg, Koichi Goto, Vivek Subbiah

The New England journal of medicine   383 ( 9 )   813 - 824   2020.8

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BACKGROUND: RET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown. METHODS: We enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS: In the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event. CONCLUSIONS: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

DOI： 10.1056/NEJMoa2005653

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Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden. Reviewed International journal

Go Makimoto, Kadoaki Ohashi, Shuta Tomida, Kazuya Nishii, Takehiro Matsubara, Hiroe Kayatani, Hisao Higo, Kiichiro Ninomiya, Akiko Sato, Hiromi Watanabe, Hirohisa Kano, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Minoru Takata, Yoshinobu Maeda, Katsuyuki Kiura

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   14 ( 11 )   2009 - 2018   2019.11

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INTRODUCTION: The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples. METHODS: Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing, direct DNA sequencing, and quantitative real-time reverse transcription polymerase chain reaction. RESULTS: ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MNNG HOS transforming gene (MET) gene amplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs in vivo, whereas the third-generation ALK-inhibitor, lorlatinib, diminished tumor growth in vitro and in vivo. Next-generation sequencing indicated high tumor mutation burden and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes. CONCLUSIONS: High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy.

DOI： 10.1016/j.jtho.2019.07.017

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EGFR-TKI acquired resistance in lung cancers harboring EGFR mutations in immunocompetent C57BL/6J mice. Reviewed International journal

Hisao Higo, Kadoaki Ohashi, Go Makimoto, Kazuya Nishii, Kenichiro Kudo, Hiroe Kayatani, Hiromi Watanabe, Hirohisa Kano, Kiichiro Ninomiya, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands)   136   86 - 93   2019.10

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OBJECTIVES: Lung cancers harboring epidermal growth factor receptor (EGFR) mutations inevitably develop resistance to EGFR tyrosine-kinase inhibitors (EGFR-TKIs). Therefore, we sought to establish clinically relevant lung-cancer mouse models to achieve deep remission of cancers. MATERIALS AND METHODS: We previously established two transgenic lung-cancer mouse models harboring human EGFR exon 21 L858R substitution (hLR) and mouse Egfr exon 19 deletion (mDEL) in the C57BL/6 J background. Lung tumors from these two transgenic mouse strains were transplanted subcutaneously into BALB/c-nunu mice or C57BL/6 J mice. RESULTS: The transplanted tumors developed the ability to grow on the subcutaneous tissue, peritoneum, or lung of C57BL/6 J mice. While hLR tumors could grow only in C57BL/6 J mice carrying the transgene, mDEL tumors could grow in wild-type C57BL/6 J mice. The tumors maintained EGFR-dependency, and, thus, the EGFR-TKI gefitinib inhibited tumor growth; however, similar to human lung cancers, hLR and mDEL tumors acquired resistance in 60 and 200 days, respectively, following gefitinib administration. Secondary EGFR T790 M mutation in hLR tumors and secondary Egfr T792I mutation in mDEL tumors developed; however, no MET activation was detected. Accordingly, the third-generation EGFR-TKI osimertinib effectively inhibited gefitinib-resistant tumors in vivo. Furthermore, gefitinib-resistant tumors developed resistance to osimertinib in 100 days. CONCLUSION: These syngeneic lung-cancer mouse models harboring EGFR mutations are suitable for studying the drug-resistance mechanisms and the role of the tumor microenvironment. Further investigation with these mouse models is warranted for developing next-generation treatment strategies for lung cancer.

DOI： 10.1016/j.lungcan.2019.08.019

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Combined effect of cabozantinib and gefitinib in crizotinib-resistant lung tumors harboring ROS1 fusions. Reviewed International journal

Yuka Kato, Kiichiro Ninomiya, Kadoaki Ohashi, Shuta Tomida, Go Makimoto, Hiromi Watanabe, Kenichiro Kudo, Shingo Matsumoto, Shigeki Umemura, Koichi Goto, Eiki Ichihara, Takashi Ninomiya, Toshio Kubo, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Katsuyuki Kiura

Cancer science   109 ( 10 )   3149 - 3158   2018.10

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The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non-small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. In the present study, lung cancer cell lines, HCC78 harboring SLC34A2-ROS1 and ABC-20 harboring CD74-ROS1, were used as cell line-based resistance models. Crizotinib-resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor-receptor tyrosine kinase array and RNA sequence analysis by next-generation sequencing. HCC78R cells showed upregulation of HB-EGF and activation of epidermal growth factor receptor (EGFR) phosphorylation and the EGFR signaling pathway. Recombinant HB-EGF or EGF rendered HCC78 cells or ABC-20 cells resistant to crizotinib. RNA sequence analysis by next-generation sequencing revealed the upregulation of AXL in HCC78R cells. HCC78R cells showed marked sensitivity to EGFR-TKI or anti-EGFR antibody treatment in vitro. Combinations of an AXL inhibitor, cabozantinib or gilteritinib, and an EGFR-TKI were more effective against HCC78R cells than monotherapy with an EGFR-TKI or AXL inhibitor. The combination of cabozantinib and gefitinib effectively inhibited the growth of HCC78R tumors in an in vivo xenograft model of NOG mice. The results of this study indicated that HB-EGF/EGFR and AXL play roles in crizotinib resistance in lung cancers harboring ROS1 fusions. The combination of cabozantinib and EGFR-TKI may represent a useful alternative treatment strategy for patients with advanced NSCLC harboring ROS1 fusion genes.

DOI： 10.1111/cas.13752

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Osimertinib Depletes EGFR T790M in the Spinal Fluid of Patients with Carcinomatous Meningitis of Lung Adenocarcinoma Harboring De Novo EGFR T790M. Reviewed International journal

Satoru Senoo, Kadoaki Ohashi, Kazuya Nishii, Naofumi Hara, Hirohisa Kano, Kiichiro Ninomiya, Yoshinobu Maeda, Katsuyuki Kiura

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   13 ( 8 )   e140-e142   2018.8

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DOI： 10.1016/j.jtho.2018.03.016

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MET or NRAS amplification is an acquired resistance mechanism to the third-generation EGFR inhibitor naquotinib. Reviewed International journal

Kiichiro Ninomiya, Kadoaki Ohashi, Go Makimoto, Shuta Tomida, Hisao Higo, Hiroe Kayatani, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Scientific reports   8 ( 1 )   1955 - 1955   2018.1

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As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimeritnib is the standard treatment for patients with non-small cell lung cancer harboring the EGFR T790M mutation; however, acquired resistance inevitably develops. Therefore, a next-generation treatment strategy is warranted in the osimertinib era. We investigated the mechanism of resistance to a novel EGFR-TKI, naquotinib, with the goal of developing a novel treatment strategy. We established multiple naquotinib-resistant cell lines or osimertinib-resistant cells, two of which were derived from EGFR-TKI-naïve cells; the others were derived from gefitinib- or afatinib-resistant cells harboring EGFR T790M. We comprehensively analyzed the RNA kinome sequence, but no universal gene alterations were detected in naquotinib-resistant cells. Neuroblastoma RAS viral oncogene homolog (NRAS) amplification was detected in naquotinib-resistant cells derived from gefitinib-resistant cells. The combination therapy of MEK inhibitors and naquotinib exhibited a highly beneficial effect in resistant cells with NRAS amplification, but the combination of MEK inhibitors and osimertinib had limited effects on naquotinib-resistant cells. Moreover, the combination of MEK inhibitors and naquotinib inhibited the growth of osimertinib-resistant cells, while the combination of MEK inhibitors and osimertinib had little effect on osimertinib-resistant cells. Clinical assessment of this novel combination (MEK inhibitors and naquotinib) is worth considering in osimertinib-resistant lung tumors.

DOI： 10.1038/s41598-018-20326-z

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Triplet therapy with afatinib, cetuximab, and bevacizumab induces deep remission in lung cancer cells harboring EGFR T790M in vivo. Reviewed

Kudo K, Ohashi K, Makimoto G, Higo H, Kato Y, Kayatani H, Kurata Y, Takami Y, Minami D, Ninomiya T, Kubo T, Ichihara E, Sato A, Hotta K, Yoshino T, Tanimoto M, Kiura K

Molecular oncology   11 ( 6 )   670 - 681   2017.6

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DOI： 10.1002/1878-0261.12063

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Characteristics of Lung Cancers Harboring NRAS Mutations Reviewed

Kadoaki Ohashi, Lecia V. Sequist, Maria E. Arcila, Christine M. Lovly, Xi Chen, Charles M. Rudin, Teresa Moran, David Ross Camidge, Cindy L. Vnencak-Jones, Lynne Berry, Yumei Pan, Hidefumi Sasaki, Jeffrey A. Engelman, Edward B. Garon, Steven M. Dubinett, Wilbur A. Franklin, Gregory J. Riely, Martin L. Sos, Mark G. Kris, Dora Dias-Santagata, Marc Ladanyi, Paul A. Bunn, William Pao

CLINICAL CANCER RESEARCH   19 ( 9 )   2584 - 2591   2013.5

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Purpose: We sought to determine the frequency and clinical characteristics of patients with lung cancer harboring NRAS mutations. We used preclinical models to identify targeted therapies likely to be of benefit against NRAS-mutant lung cancer cells.
Experimental Design: We reviewed clinical data from patients whose lung cancers were identified at six institutions or reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) to harbor NRAS mutations. Six NRAS-mutant cell lines were screened for sensitivity against inhibitors of multiple kinases (i.e., EGFR, ALK, MET, IGF-1R, BRAF, PI3K, and MEK).
Results: Among 4,562 patients with lung cancers tested, NRAS mutations were present in 30 (0.7%; 95% confidence interval, 0.45%-0.94%); 28 of these had no other driver mutations. 83% had adenocarcinoma histology with no significant differences in gender. While 95% of patients were former or current smokers, smoking-related G:C&gt;T:A transversions were significantly less frequent in NRAS-mutated lung tumors than KRAS-mutant non-small cell lung cancer [NSCLC; NRAS: 13% (4/30), KRAS: 66% (1772/2733), P &lt; 0.00000001]. Five of 6 NRAS-mutant cell lines were sensitive to the MEK inhibitors, selumetinib and trametinib, but not to other inhibitors tested.
Conclusion: NRAS mutations define a distinct subset of lung cancers (similar to 1%) with potential sensitivity to MEK inhibitors. Although NRAS mutations are more common in current/former smokers, the types of mutations are not those classically associated with smoking. Clin Cancer Res; 19(9); 2584-91. (C) 2013 AACR.

DOI： 10.1158/1078-0432.CCR-12-3173

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Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor-Resistant Disease Reviewed

Kadoaki Ohashi, Yosef E. Maruvka, Franziska Michor, William Pao

JOURNAL OF CLINICAL ONCOLOGY   31 ( 8 )   1070 - 1080   2013.3

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Purpose
EGFR-mutant lung cancer was first described as a new clinical entity in 2004. Here, we present an update on new controversies and conclusions regarding the disease.
Methods
This article reviews the clinical implications of EGFR mutations in lung cancer with a focus on epidermal growth factor receptor tyrosine kinase inhibitor resistance.
Results
The discovery of EGFR mutations has altered the ways in which we consider and treat non-small-cell lung cancer (NSCLC). Patients whose metastatic tumors harbor EGFR mutations are expected to live longer than 2 years, more than double the previous survival rates for lung cancer.
Conclusion
The information presented in this review can guide practitioners and help them inform their patients about EGFR mutations and their impact on the treatment of NSCLC. Efforts should now concentrate on making EGFR-mutant lung cancer a chronic rather than fatal disease. J Clin Oncol 31:1070-1080. (C) 2013 by American Society of Clinical Oncology

DOI： 10.1200/JCO.2012.43.3912

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Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1 Reviewed

Kadoaki Ohashi, Lecia V. Sequist, Maria E. Arcila, Teresa Moran, Juliann Chmielecki, Ya-Lun Lin, Yumei Pan, Lu Wang, Elisa de Stanchina, Kazuhiko Shien, Keisuke Aoe, Shinichi Toyooka, Katsuyuki Kiura, Lynnette Fernandez-Cuesta, Panos Fidias, James Chih-Hsin Yang, Vincent A. Miller, Gregory J. Riely, Mark G. Kris, Jeffrey A. Engelman, Cindy L. Vnencak-Jones, Dora Dias-Santagata, Marc Ladanyi, William Pao

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   109 ( 31 )   E2127 - E2133   2012.7

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/ BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment.

DOI： 10.1073/pnas.1203530109

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Other Link： http://orcid.org/0000-0002-5180-3933

Optimization of Dosing for EGFR-Mutant Non-Small Cell Lung Cancer with Evolutionary Cancer Modeling Reviewed

Juliann Chmielecki, Jasmine Foo, Geoffrey R. Oxnard, Katherine Hutchinson, Kadoaki Ohashi, Romel Somwar, Lu Wang, Katherine R. Amato, Maria Arcila, Martin L. Sos, Nicholas D. Socci, Agnes Viale, Elisa de Stanchina, Michelle S. Ginsberg, Roman K. Thomas, Mark G. Kris, Akira Inoue, Marc Ladanyi, Vincent A. Miller, Franziska Michor, William Pao

SCIENCE TRANSLATIONAL MEDICINE   3 ( 90 )   2011.7

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Non-small cell lung cancers (NSCLCs) that harbor mutations within the epidermal growth factor receptor (EGFR) gene are sensitive to the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Unfortunately, all patients treated with these drugs will acquire resistance, most commonly as a result of a secondary mutation within EGFR (T790M). Because both drugs were developed to target wild-type EGFR, we hypothesized that current dosing schedules were not optimized for mutant EGFR or to prevent resistance. To investigate this further, we developed isogenic TKI-sensitive and TKI-resistant pairs of cell lines that mimic the behavior of human tumors. We determined that the drug-sensitive and drug-resistant EGFR-mutant cells exhibited differential growth kinetics, with the drug-resistant cells showing slower growth. We incorporated these data into evolutionary mathematical cancer models with constraints derived from clinical data sets. This modeling predicted alternative therapeutic strategies that could prolong the clinical benefit of TKIs against EGFR-mutant NSCLCs by delaying the development of resistance.

DOI： 10.1126/scitranslmed.3002356

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Chemopreventive Effects of Gefitinib on Nonsmoking-Related Lung Tumorigenesis in Activating Epidermal Growth Factor Receptor Transgenic Mice Reviewed

Kadoaki Ohashi, Nagio Takigawa, Masahiro Osawa, Eiki Ichihara, Hiromasa Takeda, Toshio Kubo, Seiki Hirano, Tadashi Yoshino, Minoru Takata, Mitsune Tanimoto, Katsuyuki Kiura

CANCER RESEARCH   69 ( 17 )   7088 - 7095   2009.9

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Twenty-five percent of all lung cancer cases are not attributable to smoking. Epidermal growth factor receptor (EGFR) mutations, which are involved in similar to 50% of nonsmoker lung cancer, are positively correlated with responsiveness to gefitinib, and inversely correlated with smoking history. Activating EGFR mutations play a critical role in the carcinogenesis of nonsmoking-related lung cancer. To investigate the chemopreventive effects of gefitinib on nonsmoking-related lung cancer, we generated transgenic mice expressing EGFR L85SR in type II pneumocytes constitutively using the surfactant protein-C promoter. The transgenic mice invariably developed atypical adenomatous hyperplasia at age 4 weeks and multifocal adenocarcinoma of varying sizes at age 7 weeks. Notably, the expression levels of phosphorylated and total ErbB2, ErbB3, and thyroid transcription factor-1 were elevated in the transgenic mice compared with wild-type controls at age 3 weeks. Administration of gefitinib to 3-week-old transgenic mice for I week before carcinogenesis reduced the amount of phosphorylated EGFR in the lungs of the mice to the baseline level. Gefitinib (5 mg/kg/d; n = 5, 5, and 15) or vehicle (n = 5, 5, and 15) was administered to transgenic mice from age 3 to 8, 13, and 18 weeks, respectively. The numbers of lung tumors in the control and gefitinib-treated groups were 1.75, 5.8, 10.2, and 0 (P &lt; 0.05), respectively. No fatal toxic events occurred in either group, and gefitinib inhibited tumorigenesis completely in this mouse model. These results suggest the utility of molecular targeted chemoprevention against nonsmoking-related lung cancer. [Cancer Res 2009;69(17):7088-95]

DOI： 10.1158/0008-5472.CAN-08-4205

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Induction of lung adenocarcinoma in transgenic mice expressing activated EGFR driven by the SP-C promoter. Reviewed International journal

Kadoaki Ohashi, Kammei Rai, Yoshiro Fujiwara, Masahiro Osawa, Seiki Hirano, Katsuyoshi Takata, Eisaku Kondo, Tadashi Yoshino, Minoru Takata, Mitsune Tanimoto, Katsuyuki Kiura

Cancer science   99 ( 9 )   1747 - 53   2008.9

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To investigate the role of an activating epidermal growth factor receptor (EGFR) mutation in lung cancer, we generated transgenic mice expressing the delE748-A752 mutant version of mouse EGFR driven by the SP-C promoter, which is equivalent to the delE746-A750 mutation found in lung cancer patients. Strikingly, the mice invariably developed multifocal lung adenocarcinomas of varying sizes at between 5 and 6 weeks of age, and they died from tumor progression approximately 2 months later if left untreated. Daily oral administration of the EGFR tyrosine kinase inhibitor (TKI) gefitinib (5 mg/kg/day) reduced the total and phosphorylation levels of EGFR to those in wild-type mouse lung tissue; in addition, it abrogated tumor growth within 1 week and prolonged survival to >30 weeks. Interestingly, phosphorylated ErbB2, ErbB3, and thyroid transcriptional factor-1 increased in the transgenic mice compared with those in wild-type mice. They might play some roles in tumors progression in the transgenic mice. This model will be useful for studying the mechanisms of carcinogenesis, chemoprevention, and acquired resistance to EGFR TKIs in lung cancer patients carrying activating EGFR mutations.

DOI： 10.1111/j.1349-7006.2008.00875.x

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Efficacy of amivantamab, a bi-specific antibody targeting EGFR and MET, in ALK-rearranged non-small-cell lung cancer cell lines. International journal

Tatsuya Nishi, Ayako Morita, Naofumi Hara, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Kammei Rai, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yosuke Togashi, Yoshinobu Maeda, Eiki Ichihara

Lung cancer (Amsterdam, Netherlands)   201   108415 - 108415   2025.3

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BACKGROUND: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are highly effective in treating ALK-rearranged non-small-cell lung cancer (NSCLC). However, at least 40% of patients develop acquired resistance during treatment. Adaptive or acquired resistance to ALK TKIs could be mediated through epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) signaling. Sixteen percent of acquired resistance cases are linked to bypass signaling. METHODS: In this study, we evaluated the effects of amivantamab, a bi-specific antibody targeting both EGFR and MET, on ALK-rearranged NSCLC cells. We investigated the effect of amivantamab on the ALK-rearranged NSCLC cell lines H3122, ABC-19, and ABC-11. RESULTS: Combining alectinib with amivantamab resulted in greater inhibition of cell growth inhibition in H3122 and ABC-19 cells compared to alectinib alone, but not in ABC-11 cells. EGFR TKI erlotinib showed similar efficacy in H3122 and ABC-19 cells, whereas MET TKI tepotinib was ineffective in both, suggesting that the efficacy of amivantamab is through EGFR inhibition. Unlike H3122 and ABC-19 cells, ABC-11 cells were resistant to EGFR/MET signaling inhibition. Interestingly, amivantamab enhanced alectinib efficacy against ABC-11 cells in the presence of peripheral blood mononuclear cells (PBMCs), despite showing no effect alone without PBMCs, suggesting action through non-signal inhibitory mechanisms. Finally, we treated alectinib-resistant cellswith alectinib, with or without amivantamab, and found that amivantamab restored the sensitivity of these cells to alectinib. CONCLUSION: The bi-specific antibody amivantamab, which targets EGFR and MET, enhanced the efficacy of alectinib through both signal and non-signal inhibitory mechanisms in ALK-rearranged NSCLC cells.

DOI： 10.1016/j.lungcan.2025.108415

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High Antigenicity for Treg Cells Confers Resistance to PD-1 Blockade Therapy via High PD-1 Expression in Treg Cells. International journal

Hiroaki Matsuura, Takamasa Ishino, Toshifumi Ninomiya, Kiichiro Ninomiya, Kota Tachibana, Akiko Honobe-Tabuchi, Yoshinori Muto, Takashi Inozume, Youki Ueda, Kadoaki Ohashi, Yoshinobu Maeda, Joji Nagasaki, Yosuke Togashi

Cancer science   2025.2

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Regulatory T (Treg) cells have an immunosuppressive function, and programmed death-1 (PD-1)-expressing Treg cells reportedly induce resistance to PD-1 blockade therapies through their reactivation. However, the effects of antigenicity on PD-1 expression in Treg cells and the resistance to PD-1 blockade therapy remain unclear. Here, we show that Treg cells gain high PD-1 expression through an antigen with high antigenicity. Additionally, tumors with high antigenicity for Treg cells were resistant to PD-1 blockade in vivo due to PD-1+ Treg-cell infiltration. Because such PD-1+ Treg cells have high cytotoxic T lymphocyte antigen (CTLA)-4 expression, resistance could be overcome by combination with an anti-CTLA-4 monoclonal antibody (mAb). Patients who responded to combination therapy with anti-PD-1 and anti-CTLA-4 mAbs sequentially after primary resistance to PD-1 blockade monotherapy showed high Treg cell infiltration. We propose that the high antigenicity of Treg cells confers resistance to PD-1 blockade therapy via high PD-1 expression in Treg cells, which can be overcome by combination therapy with an anti-CTLA-4 mAb.

DOI： 10.1111/cas.70029

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Real-world status of multimodal treatment of Stage IIIA-N2 non-small cell lung cancer in Japan: Results from the SOLUTION study, a non-interventional, multicenter cohort study. International journal

Hidehito Horinouchi, Haruyasu Murakami, Hideyuki Harada, Tomotaka Sobue, Tomohiro Kato, Shinji Atagi, Toshiyuki Kozuki, Takaaki Tokito, Satoshi Oizumi, Masahiro Seike, Kadoaki Ohashi, Tadashi Mio, Takashi Sone, Chikako Iwao, Takeshi Iwane, Ryo Koto, Masahiro Tsuboi

Lung cancer (Amsterdam, Netherlands)   199   108027 - 108027   2024.11

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OBJECTIVES: There is limited consensus on resectability criteria for Stage IIIA-N2 non-small cell lung cancer (NSCLC). We examined the patient characteristics, N2 status, treatment decisions, and clinical outcomes according to the treatment modality for Stage IIIA-N2 NSCLC in Japan. MATERIALS AND METHODS: Patients with Stage IIIA-N2 NSCLC in Japan were consecutively registered in the SOLUTION study between 2013 and 2014. Patients were divided according to treatment (chemoradiotherapy [CRT], surgery + perioperative therapy [neoadjuvant and/or adjuvant therapy], surgery alone). Demographic characteristics, N2 status (number and morphological features), pathological information, and treatments were analyzed descriptively. Overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) were estimated using the Kaplan-Meier method. RESULTS: Of 227 patients registered, 133 underwent CRT, 56 underwent surgery + perioperative therapy, and 38 underwent surgery alone. The physicians reported the following reasons for unresectability for 116 of 133 CRT patients: large number of metastatic lymph nodes (70.7 %), extranodal infiltration (25.0 %), poor surgical tolerance (19.0 %), or other reasons (18.1 %). CRT was more frequently performed in patients whose lymph nodes had an infiltrative appearance (64.3 %) and was the predominant treatment in patients with multiple involved stations (discrete: 60.0 %; infiltrative: 80.4 %). Distant metastasis with/without local progression was found in 50.4 %, 50.0 %, and 36.8 % of patients in the CRT, surgery + perioperative therapy, and surgery alone groups, respectively. The respective 3-year OS and DFS/PFS rates (median values) were as follows: surgery + perioperative therapy-61.9 % (not reached) and 37.1 % (22.4 months; DFS); CRT group-42.2 % (31.9 months) and 26.8 % (12.0 months; PFS); surgery alone group-37.7 % (26.5 months) and 28.7 % (12.6 months; DFS). CONCLUSION: This study has illuminated the real-world decision rules for choosing between surgical and non-surgical approaches in patients with Stage IIIA-N2 NSCLC. Our landmark data could support treatment decision making for using immune checkpoint inhibitors and targeted therapy for driver oncogenes in the perioperative therapy era.

DOI： 10.1016/j.lungcan.2024.108027

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Plain language summary: tarlatamab for patients with previously treated small cell lung cancer. International journal

Myung-Ju Ahn, Byoung Chul Cho, Enriqueta Felip, Ippokratis Korantzis, Kadoaki Ohashi, Margarita Majem, Oscar Juan-Vidal, Sabin Handzhiev, Hiroki Izumi, Jong-Seok Lee, Rafal Dziadziuszko, Jürgen Wolf, Fiona Blackhall, Martin Reck, Jean Bustamante Alvarez, Horst-Dieter Hummel, Anne-Marie C Dingemans, Jacob Sands, Hiroaki Akamatsu, Taofeek K Owonikoko, Suresh S Ramalingam, Hossein Borghaei, Melissa L Johnson, Shuang Huang, Sujoy Mukherjee, Mukul Minocha, Tony Jiang, Pablo Martinez, Erik S Anderson, Luis Paz-Ares

Future oncology (London, England)   1 - 10   2024.11

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WHAT IS THIS SUMMARY ABOUT?: This is a summary of a phase 2 clinical study called DeLLphi-301. The study looked at how effective and safe a medicine called tarlatamab was in participants with small cell lung cancer (SCLC). Participants previously received at least two other treatments for their SCLC. Tarlatamab is a new medicine that locates a protein called DLL3 on the cancer, which allows T cells to attack the cancer. T cells belong to the body's natural defense system known as the immune system. The DeLLphi-301 study separated participants into two groups to receive tarlatamab 10 mg or 100 mg to determine which dose best shrank SCLC with minimal side effects. All participants received a small first dose (1 mg tarlatamab) to decrease the risk of an immune system reaction called cytokine release syndrome (CRS). Tarlatamab was given through the participant's vein once every 2 weeks. This method of administration is known as intravenous (IV) infusion. WHAT WERE THE RESULTS OF THE DELLPHI-301 STUDY?: In the group given 10 mg tarlatamab, 40% of participants responded to treatment (cancer shrank). In the group given 100 mg tarlatamab, 32% of participants responded to treatment (cancer shrank). After taking tarlatamab at either dose, 59% of participants lived for at least 6 months without their cancer growing or getting worse.The most common side effect was CRS, which occurred in 51% of participants in the group given 10 mg tarlatamab and 61% of participants in the group given 100 mg tarlatamab. Other common side effects were decreased appetite, fever, constipation, and anemia. Some participants had a type of immune reaction called immune effector cell-associated neurotoxicity syndrome (ICANS). A small number of participants (3%) stopped taking tarlatamab because of side effects related to tarlatamab. WHAT DO THE RESULTS FROM THE DELLPHI-301 STUDY MEAN?: The study found that tarlatamab given every 2 weeks shrank SCLC in participants with SCLC who received previous treatments. Participants given the 10 mg tarlatamab dose had fewer side effects than those given the 100 mg tarlatamab dose.Clinical Trial Registration: NCT05740566 (DeLLphi-304) (ClinicalTrials.gov).

DOI： 10.1080/14796694.2024.2402152

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A Prompt Diagnosis and Treatment of a Case of Nuclear Protein of the Testis Carcinoma Characterized by a Bronchial Lesion and High Serum Alpha-fetoprotein Level Following Genomic Testing.

Hiroaki Matsuura, Go Makimoto, Naohiro Oda, Kiichiro Ninomiya, Hisao Higo, Masanori Fujii, Kammei Rai, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda

Internal medicine (Tokyo, Japan)   63 ( 19 )   2655 - 2660   2024.10

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Nuclear protein of the testis carcinoma (NUTC) is a rare and aggressive malignancy. We herein report a case of NUTC in the lung characterized by a bronchial lesion and elevated alpha-fetoprotein levels. A 35-year-old Japanese man presented to our institution with suspected advanced lung cancer based on a histological examination. Subsequently, next-generation sequencing (NGS) yielded a positive BRD4-NUTM1 fusion. In addition, positive NUT immunostaining of the lung biopsy specimen confirmed NUTC in the lungs. Systemic chemotherapy and radiotherapy showed a temporary response, with decreased serum alpha-fetoprotein levels. We highlight this case of a prompt diagnosis by NGS of NUTC in a young individual with a rapidly progressing tumor.

DOI： 10.2169/internalmedicine.2938-23

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EGFR変異陽性非小細胞肺癌患者に対するアファチニブ±ベバシズマブ療法のバイオマーカー探索

二宮 貴一朗, 坂井 和子, 大橋 圭明, 石川 暢久, 上月 稔幸, 久山 彰一, 金地 伸拓, 横山 俊秀, 二宮 崇, 堀田 勝幸, 西尾 和人, 木浦 勝行

肺癌   64 ( 5 )   527 - 527   2024.10

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A Case of Single-lung Transplant in a Patient with Mycobacterium avium Pulmonary Disease Successfully Treated with Amikacin Liposome Inhalation Suspension. Reviewed

Taichi Ozeki, Hisao Higo, Hiroki Omori, Shunta Mori, Shin Tanaka, Go Makimoto, Kiichiro Ninomiya, Akihiko Taniguchi, Masanori Fujii, Kentaro Miyoshi, Kammei Rai, Eiki Ichihara, Kadoaki Ohashi, Seiichiro Sugimoto, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Nobuaki Miyahara

Internal medicine (Tokyo, Japan)   2024.9

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A 55-year-old man presented to our hospital with idiopathic pulmonary fibrosis (IPF). He was registered with the Japan Organ Transplant Network the following year due to disease progression. Treatment with clarithromycin, ethambutol, and rifampicin for complications of Mycobacterium avium pulmonary disease was initiated, but sputum conversion could not be achieved. The administration of an amikacin liposome inhalation suspension (ALIS) resulted in sputum conversion, and single-lung transplantation was performed. ALIS therapy was continued after lung transplantation, and no M. avium disease was observed for 15 months. ALIS may cause M. avium pulmonary disease with additional indications for lung transplantation.

DOI： 10.2169/internalmedicine.3854-24

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Concomitant osimertinib and antituberculosis therapy in an elderly patient with EGFR-mutated lung cancer and pulmonary tuberculosis: A case report. International journal

Hiroaki Matsuura, Hisao Higo, Tadahiro Kuribayashi, Akihiko Tamaoki, Takamasa Nakasuka, Mari Uno, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Nobuaki Miyahara, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura, Kadoaki Ohashi

Thoracic cancer   15 ( 17 )   1390 - 1394   2024.6

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The concurrent incidence of lung cancer and tuberculosis is expected to escalate due to the projected growth in the older population. Combination therapy with osimertinib and antituberculosis drugs has not been well-established. We report a case of successful treatment involving the concomitant administration of osimertinib and antituberculosis drugs in an older patient, an 89-year-old female, diagnosed with epidermal growth factor receptor (EGFR)-mutant lung cancer and pulmonary tuberculosis. Accumulating evidence is warranted to develop an optimal treatment strategy for patients with lung cancer and tuberculosis.

DOI： 10.1111/1759-7714.15324

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Phase 2 trial of crizotinib in Japanese patients with advanced NSCLC harboring a MET gene alteration: a Co-MET study.

Kaname Nosaki, Kiyotaka Yoh, Ryo Toyozawa, Hidehito Horinouchi, Masahiro Morise, Kadoaki Ohashi, Haruyasu Murakami, Miyako Satouchi, Jun Sakakibara-Konishi, Seiji Yano, Fumihiko Okumura, Shingo Matsumoto, Mototsugu Shimokawa, Takashi Seto, Koichi Goto

International journal of clinical oncology   2024.5

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BACKGROUND: MET exon 14 skipping mutations occur in 3-4% and MET high amplifications occur in < 1% of patients with non-small-cell lung cancer (NSCLC). Crizotinib, a selective ATP-competitive small-molecule inhibitor of c-Met, ALK, and ROS1 tyrosine kinases, has shown activity in cancer models with various types of MET activation. METHODS: The Co-MET study is a single-arm phase 2 trial to assess the safety and efficacy of crizotinib in MET inhibitor-naïve patients with advanced NSCLC harboring MET exon 14 skipping mutation (cohort 1) or high MET gene copy number of ≥ 7 (cohort 2). The primary endpoint was the objective response rate (ORR) per RECIST v1.1 by independent radiology review in cohort 1. The key secondary endpoints were the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 28 patients (23 in cohort 1 and 5 in cohort 2) were enrolled between March 2018 and February 2020. The primary endpoint was met as the ORR (90% confidence interval: CI) in cohort 1 was 38.1% (20.6-58.3). Median DoR, PFS, and OS (95% CI) were 7.6 (1.9-NE), 5.7 (2.1-11.3), 9.1 (4.0-19.9) months, respectively, in cohort 1. ORR in cohort 2 was 40.0% (18.9-92.4). The safety signals were generally consistent with the known safety profile of crizotinib. CONCLUSIONS: Crizotinib showed a clinical activity similar to that of tepotinib and capmatinib in patients with NSCLC harboring MET exon 14 skipping mutations. CLINICAL TRIAL INFORMATION: UMIN000031623.

DOI： 10.1007/s10147-024-02543-x

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Clinical outcomes in patients with non-small cell lung cancer harboring EGFR Exon20 in-frame insertions in the near-loop and far-loop: Results from LC-SCRUM-Asia. International journal

Masanobu Okahisa, Hibiki Udagawa, Shingo Matsumoto, Terufumi Kato, Hiroshi Yokouchi, Naoki Furuya, Ryota Kanemaru, Ryo Toyozawa, Akihiro Nishiyama, Kadoaki Ohashi, Shingo Miyamoto, Kazumi Nishino, Atsushi Nakamura, Eiji Iwama, Seiji Niho, Hajime Oi, Tetsuya Sakai, Yuji Shibata, Hiroki Izumi, Eri Sugiyama, Kaname Nosaki, Shigeki Umemura, Yoshitaka Zenke, Kiyotaka Yoh, Grace Kah Mun Low, Jianmin Zhuo, Koichi Goto

Lung cancer (Amsterdam, Netherlands)   191   107798 - 107798   2024.5

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OBJECTIVES: In this study, we explored the clinical outcomes of non-small cell lung cancer (NSCLC) patients with EGFR Exon20 in-frame insertions (Exon20ins), and the impact of the location of Exon20ins on these clinical outcomes. MATERIALS AND METHODS: The efficacies of current systemic therapies in NSCLC patients harboring Exon20ins were investigated using a large-scale clinico-genomic database of LC-SCRUM-Asia, and compared with that of amivantamab in the CHRYSALIS trial. RESULTS: Of the 11,397 patients enrolled in LC-SCRUM-Asia, Exon20ins were detected in 189 patients (1.7 %). Treatment with classical EGFR tyrosine-kinase inhibitors (classical TKIs) was associated with a significantly shorter progression-free survival (PFS) in NSCLC patients with Exon20ins as compared with Exon19 deletions and L858R. Post platinum-based chemotherapy, classical TKIs and immune checkpoint inhibitors (ICIs) were associated with a shorter PFS than with docetaxel in patients with Exon20ins (HR [95 % CI]; TKIs vs docetaxel, 2.16 [1.35-3.46]; ICIs vs docetaxel, 1.49 [1.21-1.84]). Patients treated with amivantamab in the CHRYSALIS trial showed a risk reduction in PFS and overall survival as compared with LC-SCRUM-Asia patients treated with docetaxel, classical TKIs, or ICIs. Among the 189 patients, Exon20ins were classified as near-loop or far-loop insertions in 115 (61 %) and 56 (30 %) patients, respectively. Treatment with osimertinib was associated with a longer PFS in patients with Exon20ins in near-loop as compared with far-loop (median, 5.6 vs. 2.0 months; HR [95 % CI], 0.22 [0.07-0.64]). CONCLUSIONS: After platinum-based chemotherapy, classical TKIs and ICIs are less effective in NSCLC patients with Exon20ins, and amivantamab may be a promising targeted therapy. There is a possibility that the location of Exon20ins has an impact on the efficacy of TKIs.

DOI： 10.1016/j.lungcan.2024.107798

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肝切除後の難治性気管支胆汁瘻に対してEndobronchial Watanabe Spigotの挿入が感染制御に有効であった1例

宇野 真梨, 槇本 剛, 藤 智和, 大森 洋樹, 肥後 寿夫, 本倉 優美, 田中 孝明, 森 俊太, 大西 桐子, 二宮 貴一朗, 頼 冠名, 市原 英基, 田端 雅弘, 宮原 信明, 堀田 勝幸, 大橋 圭明

気管支学   46 ( Suppl. )   S337 - S337   2024.5

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Clinical characteristics of patients treated with immune checkpoint inhibitors in EGFR-mutant non-small cell lung cancer: CS-Lung-003 prospective observational registry study. International journal

Tadahiro Kuribayashi, Kadoaki Ohashi, Kazuya Nishii, Kiichiro Ninomiya, Yukari Tsubata, Nobuhisa Ishikawa, Masahiro Kodani, Nobuhiro Kanaji, Masahiro Yamasaki, Kazunori Fujitaka, Shoichi Kuyama, Nagio Takigawa, Nobukazu Fujimoto, Tetsuya Kubota, Masaaki Inoue, Keiichi Fujiwara, Shingo Harita, Ichiro Takata, Kenji Takada, Sachi Okawa, Katsuyuki Kiura, Katsuyuki Hotta

Journal of cancer research and clinical oncology   150 ( 2 )   89 - 89   2024.2

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PURPOSE: Immune checkpoint inhibitors (ICIs) are ineffective against epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). This study aimed to investigate the clinical characteristics of patients who were treated or not treated with ICIs, and of those who benefit from immunotherapy in EGFR-mutant NSCLC. METHODS: We analyzed patients with unresectable stage III/IV or recurrent NSCLC harboring EGFR mutations using a prospective umbrella-type lung cancer registry (CS-Lung-003). RESULTS: A total of 303 patients who met the eligibility criteria were analyzed. The median age was 69 years; 116 patients were male, 289 had adenocarcinoma, 273 had major mutations, and 67 were treated with ICIs. The duration of EGFR-TKI treatment was longer in the Non-ICI group than in the ICI group (17.1 vs. 12.7 months, p < 0.001). Patients who received ICIs for more than 6 months were categorized into the durable clinical benefit (DCB) group (24 patients), and those who received ICIs for less than 6 months into the Non-DCB group (43 patients). The overall survival in the DCB group exhibited longer than the Non-DCB group (69.3 vs. 47.1 months), and an equivalent compared to that in the Non-ICI group (69.3 vs. 68.9 months). Multivariate analysis for time to next treatment (TTNT) of ICIs showed that a poor PS was associated with a shorter TTNT [hazard ratio (HR) 3.309; p < 0.001]. Patients who were treated with ICIs and chemotherapy combination were associated with a longer TTNT (HR 0.389; p = 0.003). In addition, minor EGFR mutation was associated with a long TTNT (HR 0.450; p = 0.046). CONCLUSION: ICIs were administered to only 22% of patients with EGFR-mutated lung cancer, and they had shorter TTNT of EGFR-TKI compared to other patients. ICI treatment should be avoided in EGFR mutated lung cancer with poor PS but can be considered for lung cancer with EGFR minor mutations. Pathological biomarker to predict long-term responders to ICI are needed.

DOI： 10.1007/s00432-024-05618-4

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Protracted coronavirus disease 2019 after chimeric antigen receptor-T cell therapy successfully treated with sequential multidrug therapy. International journal

Masahiro Yamashita, Hisao Higo, Nobuharu Fujii, Chiaki Matsumoto, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Kammei Rai, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Nobuaki Miyahara

Respiratory medicine case reports   51   102104 - 102104   2024

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A 56-year-old woman who received CD19 chimeric antigen receptor-T cell therapy for refractory diffuse large B-cell lymphoma developed severe coronavirus disease 2019 (COVID-19) and was treated with nirmatrelvir/ritonavir in April 2022. However, she experienced persistent fatigue and cough and fever in June. Computed tomography revealed bilateral ground-glass opacities (GGO), and the patient was treated with corticosteroids for organizing pneumonia after COVID-19. Partial improvement was observed, but new GGO appeared despite corticosteroid therapy. Genome analysis of severe acute respiratory syndrome coronavirus 2 detected Omicron variant BA.1.1.2, which was prevalent at the time of initial infection. The patient was diagnosed with protracted COVID-19 and was treated with remdesivir, molnupiravir, nirmatrelvir/ritonavir, and tixagevimab/cilgavimab. These treatments appeared to contribute to the improvement of protracted COVID-19.

DOI： 10.1016/j.rmcr.2024.102104

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[Survival Mechanisms of Drug Tolerant Persister Cancer Cells against Targeted Anticancer Drugs].

Masataka Taoka, Go Makimoto, Kadoaki Ohashi

Gan to kagaku ryoho. Cancer & chemotherapy   50 ( 12 )   1239 - 1245   2023.12

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Persister cells constitute a subset of cancer cells that exhibit resistance to anticancer therapies. They evade anticancer drug-induced cell death by slowing down the cell cycle and transiently adapting to the drugs through multiple pathways. Subsequently, these persister cells function as reservoirs, leading cancer cells towards diverse and irreversible mechanisms of drug resistance. The causes of treatment resistance in persister cells have been reported to be primarily epigenetic changes, rather than irreversible genetic mutations. Acquisition of stem-like features, epithelial-to-mesenchymal transition, alterations in survival and apoptosis signaling, changes in metabolism, variations in the tumor microenvironment, and acquisition of immune escape mechanisms are reported to be involved in the survival of persister cells. Although various therapeutic interventions have been explored for each of these aspects, few have been clinically applied. In this article, we place a particular emphasis on EGFR lung cancer and persister cells. We discuss the reasons why EGFR tyrosine kinase inhibitors fail to achieve curative outcomes and consider the biological characteristics of persister cells. We also review an overview of potential therapeutic strategies to overcome persister cell-induced resistance.

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Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK-rearranged non-small cell lung cancer. International journal

Chihiro Ando, Eiki Ichihara, Tatsuya Nishi, Ayako Morita, Naofumi Hara, Kenji Takada, Takamasa Nakasuka, Hiromi Watanabe, Hirohisa Kano, Kazuya Nishii, Go Makimoto, Takumi Kondo, Kiichiro Ninomiya, Masanori Fujii, Toshio Kubo, Kadoaki Ohashi, Ken-Ichi Matsuoka, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Cancer science   114 ( 11 )   4343 - 4354   2023.11

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Gilteritinib is a multitarget tyrosine kinase inhibitor (TKI), approved for the treatment of FLT3-mutant acute myeloid leukemia, with a broad range of activity against several tyrosine kinases including anaplastic lymphoma kinase (ALK). This study investigated the efficacy of gilteritinib against ALK-rearranged non-small cell lung cancers (NSCLC). To this end, we assessed the effects of gilteritinib on cell proliferation, apoptosis, and acquired resistance responses in several ALK-rearranged NSCLC cell lines and mouse xenograft tumor models and compared its efficacy to alectinib, a standard ALK inhibitor. Gilteritinib was significantly more potent than alectinib, as it inhibited cell proliferation at a lower dose, with complete attenuation of growth observed in several ALK-rearranged NSCLC cell lines and no development of drug tolerance. Immunoblotting showed that gilteritinib strongly suppressed phosphorylated ALK and its downstream effectors, as well as mesenchymal-epithelial transition factor (MET) signaling. By comparison, MET signaling was enhanced in alectinib-treated cells. Furthermore, gilteritinib was found to more effectively abolish growth of ALK-rearranged NSCLC xenograft tumors, many of which completely receded. Interleukin-15 (IL-15) mRNA levels were elevated in gilteritinib-treated cells, together with a concomitant increase in the infiltration of tumors by natural killer (NK) cells, as assessed by immunohistochemistry. This suggests that IL-15 production along with NK cell infiltration may constitute components of the gilteritinib-mediated antitumor responses in ALK-rearranged NSCLCs. In conclusion, gilteritinib demonstrated significantly improved antitumor efficacy compared with alectinib against ALK-rearranged NSCLC cells, which can warrant its candidacy for use in anticancer regimens, after further examination in clinical trial settings.

DOI： 10.1111/cas.15958

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CDK4/6 signaling attenuates the effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer. International journal

Naofumi Hara, Eiki Ichihara, Hirohisa Kano, Chihiro Ando, Ayako Morita, Tatsuya Nishi, Sachi Okawa, Takamasa Nakasuka, Atsuko Hirabae, Masaya Abe, Noboru Asada, Kiichiro Ninomiya, Go Makimoto, Masanori Fujii, Toshio Kubo, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Translational lung cancer research   12 ( 10 )   2098 - 2112   2023.10

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BACKGROUND: Epidermal growth factor receptor (EGFR) mutations, such as exon 19 deletion and exon 21 L858R, are driver oncogenes of non-small cell lung cancer (NSCLC), with EGFR tyrosine kinase inhibitors (TKIs) being effective against EGFR-mutant NSCLC. However, the efficacy of EGFR-TKIs is transient and eventually leads to acquired resistance. Herein, we focused on the significance of cell cycle factors as a mechanism to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC before the emergence of acquired resistance. METHODS: Using several EGFR-mutant cell lines, we investigated the significance of cell cycle factors to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC. RESULTS: In several EGFR-mutant cell lines, certain cancer cells continued to proliferate without EGFR signaling, and the cell cycle regulator retinoblastoma protein (RB) was not completely dephosphorylated. Further inhibition of phosphorylated RB with cyclin-dependent kinase (CDK) 4/6 inhibitors, combined with the EGFR-TKI osimertinib, enhanced G0/G1 cell cycle accumulation and growth inhibition of the EGFR-mutant NSCLC in both in vitro and in vivo models. Furthermore, residual RB phosphorylation without EGFR signaling was maintained by extracellular signal-regulated kinase (ERK) signaling, and the ERK inhibition pathway showed further RB dephosphorylation. CONCLUSIONS: Our study demonstrated that the CDK4/6-RB signal axis, maintained by the MAPK pathway, attenuates the efficacy of EGFR-TKIs in EGFR-mutant NSCLC, and targeting CDK4/6 enhances this efficacy. Thus, combining CDK4/6 inhibitors and EGFR-TKI could be a novel treatment strategy for TKI-naïve EGFR-mutant NSCLC.

DOI： 10.21037/tlcr-23-99

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Cutaneous toxicity with subepidermal blisters and dyskeratosis following administration of pemetrexed in a patient with nivolumab-induced psoriasis and linear IgA bullous dermatosis. International journal

Sayuri Yokomizo, Tomoko Miyake, Yoshio Kawakami, Kadoaki Ohashi, Hiroshi Koga, Norito Ishii, Shin Morizane

The Journal of dermatology   2023.9

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DOI： 10.1111/1346-8138.16974

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Severe Cytokine Release Syndrome and Immune Effector Cell-associated Neurotoxicity Syndrome in a Man Receiving Immune Checkpoint Inhibitors for Lung Cancer: A Case Report.

Takaaki Tanaka, Masataka Taoka, Go Makimoto, Kiichiro Ninomiya, Hisao Higo, Masanori Fujii, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda

Internal medicine (Tokyo, Japan)   2023.9

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A 55-year-old man with stage IV lung adenocarcinoma was treated with cisplatin, pemetrexed, nivolumab, and ipilimumab. Approximately 100 days after treatment initiation, he became disoriented and presented to the emergency department with a high fever. Blood tests revealed liver and kidney dysfunctions. Subsequently, the patient developed generalized convulsions that required intensive care. He was clinically diagnosed with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Organ damage was gradually controlled with immunosuppressive drugs, including steroids, and the patient was discharged. Successful treatment is rare in patients with CRS, including ICANS, during immune checkpoint inhibitor treatment for solid tumors.

DOI： 10.2169/internalmedicine.2429-23

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Pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous non-small-cell lung cancer in KEYNOTE-407. International journal

Shunichi Sugawara, Kentaro Tanaka, Fumio Imamura, Nobuyuki Yamamoto, Makoto Nishio, Kyoichi Okishio, Tomonori Hirashima, Hiroshi Tanaka, Tatsuro Fukuhara, Yasuharu Nakahara, Takayasu Kurata, Nobuyuki Katakami, Morihito Okada, Hidehito Horinouchi, Hibiki Udagawa, Kazuo Kasahara, Miyako Satouchi, Hideo Saka, Takaaki Tokito, Yukio Hosomi, Keisuke Aoe, Kazuma Kishi, Kadoaki Ohashi, Takuma Yokoyama, Noriaki Adachi, Kazuo Noguchi, Paul Schwarzenberger, Terufumi Kato

Cancer science   114 ( 8 )   3330 - 3341   2023.8

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The global phase III KEYNOTE-407 (NCT02775435) trial showed that pembrolizumab plus chemotherapy prolonged overall and progression-free survival (OS/PFS) versus placebo plus chemotherapy in patients with metastatic squamous non-small-cell lung cancer (NSCLC). We present outcomes of patients from Japan enrolled in KEYNOTE-407. Patients were randomized 1:1 to receive pembrolizumab 200 mg or placebo with paclitaxel 200 mg/m2 every 3 weeks (Q3W) or nab-paclitaxel 100 mg/m2 (weekly) plus carboplatin area under the concentration-time curve of 6 mg/mL/min Q3W for four cycles, followed by pembrolizumab or placebo Q3W for a total of 35 cycles. Primary end-points were OS and PFS per RECIST version 1.1 by blinded independent central review. Fifty patients were randomized at Japanese sites (pembrolizumab plus chemotherapy, n = 22; placebo plus chemotherapy, n = 28). Median follow-up time at data cut-off (May 9, 2019) was 15.1 (range, 0.5-24.0) months. Median OS (95% confidence interval [CI]) was 17.3 (12.5-not reached) versus 11.0 (8.6-19.5) months in the pembrolizumab plus chemotherapy versus placebo plus chemotherapy group (hazard ratio [HR] 0.56; 95% CI, 0.27-1.15). Median PFS (95% CI) was 8.3 (6.1-13.0) versus 7.2 (3.9-8.8) months (HR 0.65; 95% CI, 0.35-1.23). Grade 3-5 adverse events (AEs) occurred in 86% and 75% of patients, respectively. There were three fatal AEs, two of which were treatment-related (one from each treatment group, pneumonitis and pulmonary hemorrhage). Efficacy and safety outcomes were consistent with the global study and support the use of pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous NSCLC.

DOI： 10.1111/cas.15816

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COVID-19 Vaccine-Associated Lymphadenopathy Mimicking Regrowth of Axillary Lymph Node Metastasis of Lung Adenocarcinoma. Reviewed

Taku Noumi, Hiromi Watanabe, Kiichiro Ninomiya, Kadoaki Ohashi, Eiki Ichihara, Toshio Kubo, Go Makimoto, Yuka Kato, Masanori Fujii, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Hotta, Katsuyuki Kiura

Acta medica Okayama   76 ( 5 )   593 - 596   2022.10

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We encountered a woman with re-enlarged axillary lymph nodes during a computed tomography (CT) scan for surveillance of lung adenocarcinoma with axillary lymph node metastasis at the initial diagnosis that had shrunk with standard chemotherapy. We first suspected cancer recurrence and considered a change in the chemotherapeutic regimen. However, after careful history taking regarding the timing of her Coronavirus Disease 2019 (COVID-19) vaccination, and subsequent careful, close follow-up, radiological shrinkage suggested a strictly benign cause. Especially in lung cancer with a medical history of axillary lymph node involvement, cliniciansshould be aware that vaccine-associated lymphadenopathy can mimic cancer recurrence and sometimesprompt serious misjudgment regarding a current treatment course and strategy.

DOI： 10.18926/AMO/64041

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RET融合遺伝子陽性の非小細胞肺癌患者に対するセルペルカチニブの有効性・安全性 国際共同第1/2相試験における日本人コホートの解析結果 Reviewed

西尾 誠人, 大江 裕一郎, 大橋 圭明, 豊澤 亮, 里内 美弥子, 関根 信幸, 森 丈治, 江夏 総太郎, 後藤 功一

癌と化学療法   49 ( 6 )   669 - 675   2022.6

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Language：Japanese   Publisher：(株)癌と化学療法社  

目的:セルペルカチニブは選択性が高く強力なRET阻害剤である。2017年から実施中の多施設共同、非盲検、国際共同第1/2相試験(LIBRETTO-001試験、NCT03157128)の2020年3月30日カットオフデータを用いて、RET融合遺伝子陽性非小細胞肺癌(NSCLC)患者の日本人集団データを評価した。方法:第2相推奨用量(160mg、1日2回、経口、1サイクル28日間)の安全性を日本人患者で確認後、LIBRETTO-001試験の第2相での日本人患者の登録を開始した。主要評価項目は独立評価委員会判定による奏効率(RECIST v1.1)とした。結果:コホート1ではプラチナ製剤などの化学療法やPD-1PD-L1免疫療法による治療歴がある44名、コホート2では治療歴がない4名の日本人NSCLC患者を解析対象とした。コホート1で有効性評価が可能な(投与開始後に少なくとも2回、画像評価に相当する期間を観察する機会があった)38名での奏効率(95%信頼区間)は55.3%(38.3%、71.4%)であった(完全奏効1名、部分奏効20名)。コホート2で評価可能な患者は1名のみで、奏効は認められなかった。発現割合の最も高い有害事象はALT増加で、次いでAST増加、下痢であった。結論:セルペルカチニブは日本人のRET融合遺伝子陽性のNSCLC患者に対しても有効性が期待でき、安全性プロファイルも既報告と大きく異ならないことが示された。(著者抄録)

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J00296&link_issn=&doc_id=20220621410012&doc_link_id=%2Fab8gtkrc%2F2022%2F004906%2F013%2F0669b0675%26dl%3D3&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2022%2F004906%2F013%2F0669b0675%26dl%3D3&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_4.gif

Massive hemoptysis in a post-operative patient with recurrent lung cancer successfully treated by the combination therapy of Endobronchial Watanabe Spigot and bronchial artery embolization

Masataka Taoka, Go Makimoto, Noriyuki Umakoshi, Kiichiro Ninomiya, Hisao Higo, Yuka Kato, Masanori Fujii, Toshio Kubo, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Respiratory Medicine Case Reports   38   101669 - 101669   2022

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.rmcr.2022.101669

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Successful and Prompt Treatment with Tepotinib for Lung Adenocarcinoma Harboring MET Exon 14 Skipping Mutation Combined with Lung Abscess Formation: A Case Report. Reviewed International journal

Go Makimoto, Atsushi Shimonishi, Kadoaki Ohashi, Kiichiro Ninomiya, Hisao Higo, Yuka Kato, Masanori Fujii, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Case reports in oncology   15 ( 2 )   494 - 498   2022

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Language：English  

Tepotinib, the novel MET-tyrosine kinase inhibitor, shows an antitumor effect for patients with non-small-cell lung cancer (NSCLC) harboring MET exon 14 skipping mutation. In January 2022, the AmoyDx® Pan Lung Cancer polymerase chain reaction Panel (AmoyDx® panel), which had a shorter turnaround time than the conventional test, was launched in Japan as a tepotinib companion test. We report a patient with an advanced MET-mutant NSCLC promptly diagnosed using the AmoyDx® panel and successfully treated with tepotinib. Although the patient's performance status (PS) worsened due to the rapid tumor progression and lung abscess formation, the tumor shrank immediately after tepotinib treatment with marked PS improvement.

DOI： 10.1159/000524326

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Deciphering the clinical features of heterogeneous stage III non-small cell lung cancer in Japanese real-world clinical practice: expanded cohort of the SOLUTION study Reviewed International journal

Haruyasu Murakami, Hidehito Horinouchi, Hideyuki Harada, Tomotaka Sobue, Tomohiro Kato, Shinji Atagi, Toshiyuki Kozuki, Takaaki Tokito, Satoshi Oizumi, Masahiro Seike, Kadoaki Ohashi, Tadashi Mio, Takashi Sone, Masahisa Jinushi, Masahiro Tsuboi

Lung Cancer   165   152 - 163   2021.12

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

OBJECTIVES: To evaluate the actual treatment patterns with respective outcomes and the patient characteristics of stage III non-small cell lung cancer (NSCLC) in Japan. MATERIALS AND METHODS: Patients (aged ≥20 years at diagnosis) who were diagnosed with stage III NSCLC between January 2013 and December 2014 and underwent surgery, chemoradiotherapy (CRT), chemotherapy (CT), or radiotherapy (RT) at 11 institutions in Japan were consecutively registered in this retrospective, observational study (SOLUTION; UMIN000031385). Study measures included patient characteristics, first-line treatments, overall survival (OS), progression-free survival, objective response rate, and incidence of radiation-related adverse events. RESULTS: The study population comprised 744 patients. The tumors were classified as stage IIIA and IIIB in 58.9% and 41.1% of patients, respectively. The tumors were considered resectable at diagnosis in 25.0% of patients. First-line treatments were surgery (20.0%), CRT (46.1%), CT (22.2%), and RT (11.7%). The median OS (mOS) in the overall population was 25.4 months and the 3-year OS rate was 38.7%. Among the four first-line treatment cohorts, OS most favored the surgery cohort: mOS was 43.4 months and the 3-year OS rate was 53.8%. Prognostic factors for OS in each treatment modality were analyzed using multivariable analysis and included the following: age, performance status, and histological type for the surgery cohort; sex, histological type, and primary lesion location (lower lobe) for the CRT cohort; and performance status and clinical stage for the RT cohort. The timing of peak incidence of pneumonitis from the start of first-line treatment was 18-20 and 12-14 weeks in the CRT and RT cohorts, respectively. CONCLUSION: Patients with clinical stage III NSCLC received a variety of treatments selected to the clinical background and tumor status, and we clarified the outcome and prognostic factors. These findings will be a useful reference for future studies evaluating newly introduced treatments for stage III NSCLC.

DOI： 10.1016/j.lungcan.2021.12.005

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Triple therapy with osimertinib, bevacizumab and cetuximab in EGFR-mutant lung cancer with HIF-1α/TGF-α expression. Reviewed International journal

Kazuya Nishii, Kadoaki Ohashi, Hiromi Watanabe, Go Makimoto, Takamasa Nakasuka, Hisao Higo, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Oncology letters   22 ( 3 )   639 - 639   2021.9

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

Osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is the standard treatment for patients with lung cancer harboring EGFR T790M; however, acquired resistance is inevitable due to genetic and epigenetic changes in cancer cells. In addition, a recent randomized clinical trial revealed that the combination of osimertinib and bevacizumab failed to exhibit superior progression-free survival compared with osimertinib alone. The present study aimed to investigate the effect of triple therapy with osimertinib, bevacizumab and cetuximab in xenograft tumors with different initial tumor volumes (conventional model, 200 mm3 and large model, 500 mm3). The results demonstrated that osimertinib significantly inhibited tumor growth in both the conventional and large models; however, maximum tumor regression was attenuated in the large model in which hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor-α (TGF-α) expression levels increased. Although the combination of osimertinib and bevacizumab exerted a greater inhibitory effect on tumor growth compared with osimertinib in the conventional model, the effect of this combination therapy was attenuated in the large model. TGF-α attenuated sensitivity to osimertinib in vitro; however, this negative effect was counteracted by the combination of osimertinib and cetuximab, but not osimertinib and bevacizumab. In the large xenograft tumor model, the triple therapy induced the greatest inhibitory effect on tumor growth compared with osimertinib alone and its combination with bevacizumab. Clinical trials of the triple therapy are required for patients with lung cancer with EGFR mutations and HIF-1α/TGF-α.

DOI： 10.3892/ol.2021.12900

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Pulmonary Aspergilloma and Allergic Bronchopulmonary Aspergillosis Following the 2018 Heavy Rain Event in Western Japan: A Case Report.

Eri Ando, Takamasa Nakasuka, Toshio Kubo, Akihiko Taniguchi, Kiichiro Ninomiya, Yuka Kato, Eiki Ichihara, Kadoaki Ohashi, Kammei Rai, Katsuyuki Hotta, Masaomi Yamane, Nobuaki Miyahara, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan)   61 ( 3 )   379 - 383   2021.8

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A 16-year-old boy with asthma participated in recovery volunteer work following the 2018 heavy rains in Japan. One month later, he experienced chest pain and dyspnea. Chest computed tomography revealed a cavity with a fungal ball, and Aspergillus fumigatus was detected in his bronchoalveolar lavage fluid. He was treated with voriconazole, but new consolidations appeared rapidly. He also experienced allergic bronchopulmonary aspergillosis. After prednisolone prescription, the consolidations improved; however, his asthma worsened. He underwent partial lung resection to avoid allergens, and his symptoms improved. We must recognize cases of infection after a disaster, especially in patients with chronic respiratory diseases.

DOI： 10.2169/internalmedicine.7124-21

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Survival of chemo-naïve patients with EGFR mutation-positive advanced non-small cell lung cancer after treatment with afatinib and bevacizumab: updates from the Okayama Lung Cancer Study Group Trial 1404. Reviewed International journal

Takashi Ninomiya, Naoyuki Nogami, Toshiyuki Kozuki, Daijiro Harada, Toshio Kubo, Kadoaki Ohashi, Eiki Ichihara, Shoichi Kuyama, Kenichiro Kudo, Akihiro Bessho, Makoto Sakugawa, Nobukazu Fujimoto, Keisuke Aoe, Daisuke Minami, Keisuke Sugimoto, Nobuaki Ochi, Nagio Takigawa, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Japanese journal of clinical oncology   51 ( 8 )   1269 - 1276   2021.8

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BACKGROUND: In a phase I study, afatinib (30 mg/body daily) plus bevacizumab (15 mg/kg every 3 weeks) was well tolerated and showed favourable outcomes in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer. Herein, we report the 2-year progression-free survival, overall survival and safety profile of these patients. METHODS: Chemo-naïve patients with EGFR-mutant advanced non-small-cell lung cancer were enrolled. One group of patients received 40 mg afatinib daily and 15 mg/kg bevacizumab every 3 weeks (level 0) until disease progression or severe toxicity. Another group of patients received 30 mg afatinib daily and the same dose of bevacizumab (level 1). Dose-limiting toxicity was the primary endpoint, whereas long-term progression-free survival, overall survival and tolerability were secondary endpoints. Survival rates were estimated using the Kaplan-Meier method. RESULTS: The study included 19 patients (level 0: 5; level - 1: 14). Until the data cut-off date, seven patients continued the treatment, whereas 12 discontinued due to disease progression (n = 5) or toxicity (n = 7). The median PFS was 24.2 months, while the median overall survival was not reached. All patients developed adverse effects. Diarrhoea and skin rash were frequently observed as severe adverse events (grade 3). A secondary EGFR mutation (T790M) was detected in two patients after progression. CONCLUSIONS: Prolonged follow-up revealed that combination therapy with afatinib and bevacizumab might improve survival outcomes in EGFR-mutant advanced non-small-cell lung cancer patients and seems to be promising. TRIAL REGISTRATION: UMIN000015944.

DOI： 10.1093/jjco/hyab084

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SHP2 Inhibition Enhances the Effects of Tyrosine Kinase Inhibitors in Preclinical Models of Treatment-naïve ALK-, ROS1-, or EGFR-altered Non-small Cell Lung Cancer. International journal

Hirohisa Kano, Eiki Ichihara, Hiromi Watanabe, Kazuya Nishii, Chihiro Ando, Takamasa Nakasuka, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Kammei Rai, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Molecular cancer therapeutics   20 ( 9 )   1653 - 1662   2021.6

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After molecular-targeted therapy, some cancer cells may remain that are resistant to therapies targeting oncogene alterations, such as those in the genes encoding the EGFR and anaplastic lymphoma kinase (ALK) as well as c-ros oncogene 1 (ROS1). The mechanisms underlying this type of resistance are unknown. In this article, we report the potential role of Src homology 2 domain-containing phosphatase 2 (SHP2) in the residual cells of ALK/ROS1/EGFR-altered non-small cell lung cancer (NSCLC). Molecular-targeted therapies failed to inhibit the ERK signaling pathway in the residual cells, whereas the SHP2 inhibitor SHP099 abolished their remaining ERK activity. SHP099 administered in combination with molecular-targeted therapy resulted in marked growth inhibition of cancer cells both in vitro and in vivo Thus, treatment combining an SHP2 inhibitor and a tyrosine kinase inhibitor may be a promising therapeutic strategy for oncogene-driven NSCLC.

DOI： 10.1158/1535-7163.MCT-20-0965

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A case of dramatic reduction in cancer-associated thrombus following initiation of pembrolizumab in patient with a poor performance status and PD-L1+ lung adenocarcinoma harboring CCDC6-RET fusion gene and NF1/TP53 mutations. Reviewed International journal

Takamasa Nakasuka, Kadoaki Ohashi, Hiromi Watanabe, Toshio Kubo, Shingo Matsumoto, Koichi Goto, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands)   156   1 - 4   2021.6

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: Pembrolizumab is a standard treatment for non-small cell lung cancer (NSCLC) with high-PD-L1 expression; however, its effect is dismal in patients with poor physical condition. Additionally, the effect of immunotherapy is generally limited in NSCLC harboring driver mutations such asEGFR, ALK, or RET gene aberrations. RESULTS: We report the beneficial effect of pembrolizumab in a patient with poor performance status and PD-L1+ lung adenocarcinoma with theCCDC6-RET fusion gene and co-occurring NF1/TP53 mutations, complicated by multiple cancer-associated thrombi and respiratory failure. CONCLUSIONS: Further studies are warranted to establish the role of co-occurring NF1/TP53 mutations as a positive predictive biomarker for pembrolizumab in NSCLC harboring RET fusion genes.

DOI： 10.1016/j.lungcan.2021.03.022

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A novel osimertinib-resistant human lung adenocarcinoma cell line harbouring mutant EGFR and activated IGF1R. Reviewed International journal

Go Makimoto, Kiichiro Ninomiya, Toshio Kubo, Ryota Sunami, Yuka Kato, Eiki Ichihara, Kadoaki Ohashi, Kammei Rai, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Japanese journal of clinical oncology   51 ( 6 )   956 - 965   2021.5

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OBJECTIVE: A third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, is the standard treatment for patients with non-small cell lung cancer harbouring mutant EGFR. Unfortunately, these patients inevitably acquire resistance to EGFR-TKI therapies, including osimertinib. However, the mechanism associated with this resistance remains unclear. METHODS: A 63-year-old Japanese female with lung adenocarcinoma underwent right upper lobectomy (pT1bN2M0 pStage IIIA, EGFR Ex21 L858R). She manifested post-operative tumour recurrence with multiple lung metastases 8 months later and began gefitinib treatment. The lung lesions re-grew 15 months later, and EGFR T790M mutation was detected in the lung metastasis re-biopsy. She was administered osimertinib; however, it relapsed with pleural effusion 16 months later. We isolated cells from the osimertinib-resistant pleural effusion to establish a novel cell line, ABC-31. RESULTS: Although the EGFR L858R mutation was detected in ABC-31 cells, the T790M mutation was lost. ABC-31 cells were resistant to EGFR-TKIs, including osimertinib. Phospho-receptor tyrosine kinase array revealed activation of the insulin-like growth factor 1 receptor (IGF1R), whereas overexpression of the IGF1R ligand, IGF2, induced IGF1R activation in ABC-31 cells. Combination therapy using EGFR-TKIs and IGF1R inhibitor acted synergistically in vitro. She was re-administered osimertinib since EGFR-TKIs and IGF1R inhibitor combination therapy was impossible in clinical practice. This had a slight and short-lived effect. CONCLUSIONS: Taken together, we have successfully established a new osimertinib-resistant lung adenocarcinoma cell line with activated IGF1R. These ABC-31 cells will help develop novel therapeutic strategies for patients with lung adenocarcinoma resistant to specific treatment via IGF1R activation.

DOI： 10.1093/jjco/hyab048

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VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene-driven non-small-cell lung cancers. Reviewed International journal

Hiromi Watanabe, Eiki Ichihara, Hiroe Kayatani, Go Makimoto, Kiichiro Ninomiya, Kazuya Nishii, Hisao Higo, Chihiro Ando, Sachi Okawa, Takamasa Nakasuka, Hirohisa Kano, Naofumi Hara, Atsuko Hirabae, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Cancer science   112 ( 5 )   1853 - 1864   2021.5

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Molecular agents targeting the epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene-driven non-small-cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti-vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti-tumor effects of these agents in xenograft mouse models of EGFR-, ALK-, or ROS1-altered NSCLC. The numbers of CD31-positive blood vessels were significantly lower in the tumors of mice treated with an anti-VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR-, ALK-, or ROS1-altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti-tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti-tumor effects of molecular targeted agents in various oncogene-driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti-VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene-driven NSCLC.

DOI： 10.1111/cas.14801

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Capmatinib in Japanese patients with MET exon 14 skipping-mutated or MET-amplified advanced NSCLC: GEOMETRY mono-1 study. Reviewed International journal

Takashi Seto, Kadoaki Ohashi, Shunichi Sugawara, Makoto Nishio, Masayuki Takeda, Keisuke Aoe, Sanae Moizumi, Satoshi Nomura, Takeshi Tajima, Toyoaki Hida

Cancer science   112 ( 4 )   1556 - 1566   2021.4

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MET mutations leading to exon 14 skipping (METΔex14) are strong molecular drivers for non-small-cell lung cancer (NSCLC). Capmatinib is a highly potent, selective oral MET inhibitor that showed clinically meaningful efficacy and a manageable safety profile in a global phase II study (GEOMETRY mono-1, NCT02414139) in patients with advanced METΔex14-mutated/MET-amplified NSCLC. We report results of preplanned analyses of 45 Japanese patients according to MET status (METΔex14-mutated or MET-amplified) and line of therapy (first- [1L] or second-/third-line [2/3L]). The starting dose was 400 mg twice daily. The primary endpoint was the objective response rate (ORR) assessed by a blinded independent review committee. A key secondary endpoint was duration of response (DOR). Among METΔex14-mutated patients, in the 1L group, one patient achieved partial response (DOR of 4.24 months) and the other had stable disease. In the 2/3L group, the ORR was 36.4% (95% confidence interval [CI] 10.9%-69.2%), median DOR was not evaluable, and progression-free survival was 4.70 months. One patient (2/3L group) showed partial resolution of brain lesions per independent neuroradiologist review. In MET-amplified patients with a MET gene copy number of ≥10, the ORR was 100% (2/2 patients) in the 1L group and 45.5% (5/11 patients) in the 2/3L group, with DOR of 8.2 and 8.3 months, respectively. Common treatment-related adverse events among the 45 Japanese patients were blood creatinine increased (53.3%), nausea (35.6%), and oedema peripheral (31.1%); most were grade 1/2 severity. In conclusion, capmatinib was effective and well tolerated by Japanese patients with METΔex14/MET-amplified NSCLC, consistent with the overall population.

DOI： 10.1111/cas.14826

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Marginal Zone Lymphoma and Lung Adenocarcinoma with an EGFR Exon 19 E746-S752del Mutation in a Patient with IgG4-related Disease. Reviewed

Sachi Okawa, Kammei Rai, Nobuharu Fujii, Yuka Gion, Kiichiro Ninomiya, Yuka Kato, Akihiko Taniguchi, Toshio Kubo, Ichihara Eiki, Kadoaki Ohashi, Nobuaki Miyahara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan)   60 ( 17 )   2831 - 2837   2021.3

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A 68-year-old man presented with a solid mass at the left renal pelvis and ureter with multiple systemic lymphadenopathies and a mass with a cavity in the right lower lobe of the lung. While a transbronchial lung biopsy revealed no malignancy, a biopsy of the renal pelvis showed marginal zone lymphoma with polyclonal IgG4-positive cells. The serum IgG4 level and presence of a bilateral orbital mass suggested Mikulicz disease.The lesions shrank following the administration of steroids. A rebiopsy confirmed lung adenocarcinoma, and its background showed IgG4-positive cells a year later. IgG4-related diseases require careful follow-up because they can be complicated by malignancy.

DOI： 10.2169/internalmedicine.6470-20

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Comparison of bronchoscopy and computed tomography-guided needle biopsy for re-biopsy in non-small cell lung cancer patients. Reviewed International journal

Hirohisa Kano, Toshio Kubo, Kiichiro Ninomiya, Eiki Ichihara, Kadoaki Ohashi, Kammei Rai, Katsuyuki Hotta, Masahiro Tabata, Takao Hiraki, Susumu Kanazawa, Yoshinobu Maeda, Katsuyuki Kiura

Respiratory investigation   59 ( 2 )   240 - 246   2021.3

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BACKGROUND: New therapeutic drugs have been developed for non-small cell lung cancer (NSCLC), and the prognosis of advanced NSCLC patients has improved. However, resistance to these drugs is a concern, and re-biopsy is necessary to determine the mechanism of drug resistance. There are many reports about the protocols for re-biopsy, including techniques such as bronchoscopy and computed tomography-guided needle biopsy (CTNB); however, there is no consensus on which method is optimal. Therefore, we retrospectively reviewed the bronchoscopy and CTNB re-biopsies conducted at our hospital. METHODS: We retrospectively analyzed 79 cases of re-biopsies with bronchoscopy or CTNB in patients with NSCLC from January 2014 to December 2016 at our institute. RESULTS: Forty-nine cases of bronchoscopy and 30 cases of CTNB were taken for re-biopsy. The diagnostic rates of bronchoscopy and CTNB were 83.7% and 100%, respectively (p = 0.023). The complication rates of bronchoscopy and CTNB were 18.4% and 36.7%, respectively (p = 0.11), with a statistically significant difference in the incidence of pneumothorax (0% vs. 23.3%, respectively; p < 0.01). Pneumothorax required drainage in 6.7% of all CTNB cases. There were no fatalities in either group. CONCLUSIONS: CTNB showed a higher diagnostic rate; however, it was associated with a higher rate of complications such as pneumothorax. Hence, the optimal modality must be determined individually for each patient.

DOI： 10.1016/j.resinv.2020.12.001

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Randomized study comparing mannitol with furosemide for the prevention of cisplatin-induced renal toxicity in non-small cell lung cancer: The OLCSG1406 trial. Reviewed International journal

Go Makimoto, Katsuyuki Hotta, Isao Oze, Kiichiro Ninomiya, Masamoto Nakanishi, Naofumi Hara, Hirohisa Kano, Hiromi Watanabe, Yusuke Hata, Kazuya Nishii, Takamasa Nakasuka, Junko Itano, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Eiki Ichihara, Daisuke Minami, Akiko Sato, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Asia-Pacific journal of clinical oncology   17 ( 1 )   101 - 108   2021.2

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AIM: Evidence is lacking on the best standard method for forced diuresis to prevent cisplatin-induced nephrotoxicity. We compared the cisplatin-induced nephrotoxicity prevention effect of furosemide or mannitol in patients with advanced non-small cell lung cancer. METHODS: Patients with advanced non-small cell lung cancer suitable to receive cisplatin-containing regimen were randomly assigned to receive furosemide or mannitol with appropriate hydration. The primary endpoint was the proportion of ≥ grade 1 serum creatinine elevation in the first cycle. RESULTS: The trial was terminated early with 44 (22 per arm) of the planned 66 patients because of slow accrual. Patients' characteristics were well balanced with median baseline creatinine clearance of 98.0 and 95.1 mL/min in the furosemide and mannitol arms, respectively. In the first cycle, two (9%) and four (18%) patients developed grade 1 creatinine elevation (P = .66), respectively, despite no ≥ grade 2 toxicity. The median times to develop the worst creatinine score were 10 and 8 days, respectively. For all cycles, median times to recover to grade 0 were 56 and 20 days, respectively. The furosemide arm was characterized by relatively high urine output after cisplatin administration (900 vs 550 mL/h), low frequency of unplanned additional hydration (14% vs 32%), and high incidence of hyponatremia (18% and 5%) compared with the mannitol arm. Both arms showed similar progression-free survival and overall survival. CONCLUSION: The preventive effect of the two forced diuretics on cisplatin-induced nephrotoxicity was not significantly different. However, the two diuretics have some distinct types of clinical presentations.

DOI： 10.1111/ajco.13423

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Phase 1/2 study of alectinib in RET-rearranged previously-treated non-small cell lung cancer (ALL-RET). Reviewed International journal

Shinji Takeuchi, Noriko Yanagitani, Takashi Seto, Yoshihiro Hattori, Kadoaki Ohashi, Masahiro Morise, Shingo Matsumoto, Kiyotaka Yoh, Koichi Goto, Makoto Nishio, Shizuko Takahara, Takahiro Kawakami, Yasuhito Imai, Kenichi Yoshimura, Azusa Tanimoto, Akihiro Nishiyama, Toshinori Murayama, Seiji Yano

Translational lung cancer research   10 ( 1 )   314 - 325   2021.1

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Background: Rearranged during transfection (RET) rearrangements occur in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib administered at doses of 300 mg and 600 mg twice daily (BID) is approved for. ALK: rearranged NSCLC in Japan and other countries, respectively. Since alectinib has activity against RET, we conducted a phase (P) 1/2 study of alectinib to determine its activity in Japanese patients with. RET: rearranged NSCLC. Methods: This study was a single-arm, open-label, multi-institutional P1/2 trial. Previously treated patients with RET-rearranged NSCLC, screened by nation-wide network (LC-SCRUM-Japan), were recruited. In P1, alectinib (600 or 450 mg BID) was administered following a 3+3 design and its safety was assessed. During P2, alectinib was administered at the recommended dose (RD) determined in P1. The primary endpoint was the objective response rate (ORR) in RET inhibitor-naïve patients treated with the RD of alectinib. Results: Thirty-four patients were administered alectinib. In cohort 1 (600 mg BID) of P1, we observed 5 dose-limiting toxicities (DLTs), including grade 3 rash and thromboembolic event, in 3 of 6 patients. In cohort 2 (450 mg BID), we observed no DLTs in 3 patients. Pharmacokinetic analysis revealed that AUC0-10 to 600 mg BID was higher than that previously reported in global trials. We determined 450 mg BID as the RD for P2. In 25 RET inhibitor-naïve patients, one achieved an objective response (4%) and 13 achieved disease control at 8 weeks (52%). The median progression-free survival (PFS) was 3.4 months (95% CI, 2.0-5.4), while the median overall survival was 19.0 months (5.4-NE). We observed grade 3 adverse events (AEs) (4%) including pneumonitis in P2. Conclusions: Alectinib exerts limited activity against RET-rearranged NSCLC. Further investigation to elucidate the mechanisms underlying sensitivity and resistance of RET inhibitors is required to improve outcomes for these patients.

DOI： 10.21037/tlcr-20-549

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Immune checkpoint inhibitor efficacy and safety in older non-small cell lung cancer patients. Reviewed International journal

Toshio Kubo, Hiromi Watanabe, Kiichiro Ninomiya, Kenichiro Kudo, Daisuke Minami, Etsuko Murakami, Nobuaki Ochi, Takashi Ninomiya, Daijiro Harada, Masayuki Yasugi, Eiki Ichihara, Kadoaki Ohashi, Kammei Rai, Keiichi Fujiwara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Japanese journal of clinical oncology   50 ( 12 )   1447 - 1453   2020.12

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OBJECTIVES: Immune checkpoint inhibitors offer longer survival than chemotherapy in several clinical trials for advanced non-small cell lung cancer. In subset analyses of clinical trials, immune checkpoint inhibitors extended survival in patients aged ≥65 years, but the effects in patients aged ≥75 years are controversial. We performed multicenter, collaborative and retrospective analyses of immune checkpoint inhibitor efficacy and safety in non-small cell lung cancer patients aged ≥75 years. METHODS: We retrospectively studied 434 advanced non-small cell lung cancer patients who received immune checkpoint inhibitors from December 2015 to December 2017, and retrospectively applied the Geriatric (G) 8 screening tool with medical records. RESULTS: Of the 434 patients who received immune checkpoint inhibitors, 100 were aged ≥75 years. Five patients with performance status 3 were omitted from the final analysis. Immune checkpoint inhibitors were given as a first-line treatment to 20 patients. The objective response rates, median progression-free survival rates and median survival times were 35.0%, 6.1 months and 10.7 months for first-line treatment, and 20.0%, 2.9 months and 14.7 months for second- or later-line treatments, respectively. The median modified G8 score was 11.0. The median survival time was longer in the high modified G8 (≥12.0) group than in the low modified G8 (≤11.0) group (18.7 vs. 8.7 months; P = 0.02). Likewise, the median survival time was 15.5 months (performance status 0-1) vs. 3.2 months (performance status 2) (P < 0.01). The grade ≥ 2 immune-related adverse events incidence was 36.8%. CONCLUSIONS: In this study, immune checkpoint inhibitors were effective and tolerable for patients aged ≥75 years. The modified G8 screening tool and performance status were associated with the outcome of older non-small cell lung cancer patients treated with immune checkpoint inhibitors.

DOI： 10.1093/jjco/hyaa152

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Detection of epidermal growth factor receptor mutations in exhaled breath condensate using droplet digital polymerase chain reaction. Reviewed International journal

Kazuya Nishii, Kadoaki Ohashi, Tomoki Tamura, Kiichiro Ninomiya, Takehiro Matsubara, Satoru Senoo, Hirohisa Kano, Hiromi Watanabe, Naohiro Oda, Go Makimoto, Hisao Higo, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Hiromasa Yamamoto, Shuta Tomida, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Katsuyuki Kiura

Oncology letters   20 ( 6 )   393 - 393   2020.12

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The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor (EGFR), is essential for determining treatment strategies for advanced non-small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube™ method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC-ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54-81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post-operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC-ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC-ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC-ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult.

DOI： 10.3892/ol.2020.12256

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Anaplastic Lymphoma Kinase Fusion: A Review of Therapeutic Drugs and Treatment Strategies. Reviewed

Go Makimoto, Kadoaki Ohashi, Yoshinobu Maeda, Katsuyuki Kiura

Acta medica Okayama   74 ( 5 )   371 - 379   2020.10

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The prognosis of advanced non-small cell lung cancer (NSCLC) patients has improved in recent decades, especially for patients with an oncogenic driver mutation. Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are effective for patients with the echinoderm microtubule-associated protein-like 4-ALK fusion gene. Several ALK-TKIs have been established: the first-generation ALK-TKI, crizotinib; second-generation ALK-TKIs, alectinib and ceritinib; and third-generation ALK-TKI, lorlatinib. Some ALK-TKIs are effective for tumors that are resistant to other ALK-TKIs; however, as is known in epidermal growth factor receptormutant lung cancer, tumor resistance is inevitable. ALK-positive NSCLCs acquire resistance via various mechanisms, making it a heterogeneous disease. Therefore, it is necessary to develop next-generation treatment strategies, such as the use of next-generation ALK-TKIs for secondary mutations, or combination therapies with ALK-TKIs and other TKIs. In this review, we summarize the development and use of ALK-TKIs, prior pivotal clinical trials, and resistance mechanisms.

DOI： 10.18926/AMO/60796

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Real-world outcomes of chemoradiotherapy for unresectable Stage III non-small cell lung cancer: The SOLUTION study. Reviewed International journal

Hidehito Horinouchi, Shinji Atagi, Satoshi Oizumi, Kadoaki Ohashi, Tomohiro Kato, Toshiyuki Kozuki, Masahiro Seike, Takashi Sone, Tomotaka Sobue, Takaaki Tokito, Hideyuki Harada, Tadashi Maeda, Tadashi Mio, Ikue Shirosaka, Kana Hattori, Eisei Shin, Haruyasu Murakami

Cancer medicine   9 ( 18 )   6597 - 6608   2020.9

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There are limited real-world data on the treatment practices, outcomes, and safety of chemoradiotherapy (CRT) alone in potential candidates for immune checkpoint inhibitors (ICI) for unresectable non-small cell lung cancer (NSCLC). In this study, we analyzed the safety and efficacy of CRT in patients who underwent CRT and would satisfy the key eligibility criteria for maintenance therapy with durvalumab (eg, no progression after CRT) in real-world settings (m-sub) for unresectable Stage III NSCLC between 1 January 2013 and 31 December 2015 at 12 sites in Japan. The m-sub comprised 214 patients with a median follow-up of 31.6 months (range 1.9-65.8 months). Median overall survival (OS) and progression-free survival (PFS) from completing CRT were 36.4 months (95% confidence interval [CI] 28.1 months to not reached) and 9.5 months (95% CI 7.7-11.7 months), respectively. Consolidation chemotherapy did not influence OS or PFS. Median PFS was 16.9 vs 9.1 months in patients with vs without epidermal growth factor receptor (EGFR) mutations, with PFS rates of ~20% at 3-4 years. Pneumonitis was the most common adverse event (according to MedDRA version 21.0J), and about half of events were grade 1. Pneumonitis mostly occurred 10-24 weeks after starting CRT, peaking at 18-20 weeks. Esophagitis and dermatitis generally occurred from 0 to 4 weeks, peaking at 2-4 weeks after starting CRT. Pericarditis was rare and occurred sporadically. In conclusion, the results of the m-sub provide real-world insight into the outcomes of CRT, and will be useful for future evaluations of ICI maintenance therapy after CRT.

DOI： 10.1002/cam4.3306

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Pilot evaluation of a HER2 testing in non-small-cell lung cancer. Reviewed International journal

Katsuyuki Hotta, Hiroyuki Yanai, Kadoaki Ohashi, Kiichiro Ninomiya, Hiromi Nakashima, Hiroe Kayatani, Minoru Takata, Katsuyuki Kiura

Journal of clinical pathology   73 ( 6 )   353 - 357   2020.6

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AIMS: HER2-positivity pattern in the specimens of immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) has been hardly reported in non-small-cell lung cancer (NSCLC). METHODS: We evaluated the characteristics of HER2-positivity pattern in formalin-fixed paraffin-embedded samples using IHC and FISH in 15 patients enrolled in a larger prospective cohort study to survey a HER2-positive NSCLC. RESULTS: As for the immunostaining pattern, most specimens (79%) demonstrated incomplete or mixed-typed membranous immunoreactivity with heterogeneity, resembling that observed in gastric cancer rather than breast cancer. Concordance between IHC-positivity and FISH-positivity was 87.5% according to the criteria for breast cancer scoring system. On application of the gastric cancer scoring system to the examined tumours, the IHC score increased in the seven (43.8%) specimens, and the concordance between IHC positivity and FISH positivity rose to 93.8%. CONCLUSIONS: In our pilot series, the pattern of IHC reactivity closely resembled that observed in gastric cancer rather than breast cancer. TRIAL REGISTRATION NUMBER: 000017003.

DOI： 10.1136/jclinpath-2019-206204

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Phase II, open-label, multicenter trial of crizotinib in Japanese patients with advanced non-small cell lung cancer harboring a MET gene alteration: Co-MET study. Reviewed International journal

Mototsugu Shimokawa, Kaname Nosaki, Takashi Seto, Kadoaki Ohashi, Masahiro Morise, Hidehito Horinouchi, Jun Sakakibara, Haruyasu Murakami, Seiji Yano, Miyako Satouchi, Shingo Matsumoto, Koichi Goto, Kiyotaka Yoh

Trials   21 ( 1 )   298 - 298   2020.3

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BACKGROUND: MET-deregulated non-small cell lung cancer represents an urgent clinical need because of the lack of specific therapies. Although recent studies have suggested a potential role for crizotinib in patients harboring MET gene alterations, no conclusive data are currently available. Therefore, we designed the Co-MET study, a single-arm phase II study to assess the efficacy and safety of crizotinib in patients with advanced non-small cell lung cancers harboring MET gene alterations. METHODS: Co-MET is an open-label, multi-center, single-arm, phase II trial to assess the safety and efficacy of oral crizotinib in patients with advanced non-small cell lung cancer harboring MET exon 14 skipping mutation (cohort 1) or a high MET gene copy number of ≥ 7 (cohort 2). We will identify MET gene alterations using RT-PCR and/or next-generation sequencing. Oral crizotinib 250 mg BID will be administered until disease progression or unacceptable toxicity. A radiology committee will review tumor scans according to the RECIST criteria. The primary endpoint is the objective response rate. Assuming a null hypothesis of 20% objective response rate and an alternative hypothesis of 50% objective response rate for cohort 1, and a one-sided alpha error of 0.05 and 80% power based on the exact binomial distribution, the required number of evaluable patients is 19. We set the exploratory sample size for cohort 2 at 10 patients. DISCUSSION: The results of this study are expected to provide evidence regarding the usefulness of oral crizotinib for advanced MET exon 14 skipping mutation-positive or MET high gene copy number-positive non-small cell lung cancer. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry as UMIN000031623 on 3 March 2018.

DOI： 10.1186/s13063-020-4221-7

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Successful Re-administration of Osimertinib in Osimertinib-induced Interstitial Lung Disease with an Organizing Pneumonia Pattern: A Case Report and Literature Review. Reviewed

Junko Itano, Hisao Higo, Kadoaki Ohashi, Go Makimoto, Kazuya Nishii, Katsuyuki Hotta, Nobuaki Miyahara, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan)   59 ( 6 )   823 - 828   2020.3

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Osimertinib is the standard therapy for epidermal-growth-factor-receptor (EGFR)-mutant lung cancers. We herein report a case of osimertinib-induced interstitial lung disease (OsiILD) with an organizing pneumonia (OP) pattern and provide a literature-based review. Six months after osimertinib administration, a 75-year-old woman with right pleural carcinomatosis developed ILD with an OP pattern. After salvage chemotherapy, osimertinib with corticosteroid was successfully re-administered. A literature review suggested that 1) OsiILD with an OP pattern was rare but should be recognized, and 2) re-administration of osimertinib in OsiILD was successful in select patients. A criterion that determines whether a patient would benefit from re-administration is warranted.

DOI： 10.2169/internalmedicine.3689-19

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Influence of age on the efficacy of immune checkpoint inhibitors in advanced cancers: a systematic review and meta-analysis. Reviewed International journal

Kiichiro Ninomiya, Isao Oze, Yuka Kato, Toshio Kubo, Eiki Ichihara, Kammei Rai, Kadoaki Ohashi, Toshiyuki Kozuki, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura, Katsuyuki Hotta

Acta oncologica (Stockholm, Sweden)   59 ( 3 )   249 - 256   2020.3

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Background: Immune checkpoint inhibitors (ICIs) represent a paradigm shift in the development of cancer treatment. However, it remains to be clarified whether the benefits that they confer differ according to patient age. We conducted a systematic review and meta-analysis to assess age differences in the benefits of ICI treatment.Methods: We systematically searched the PubMed database for randomised controlled trials of ICIs, including PD-1, PD-L1 and CTLA-4 inhibitors across multiple cancer types, such as melanoma, lung cancer and gastric cancer. We extracted trials including hazard ratios (HRs) for death stratified by patient age (cut-off age, 65 years). The primary objective of this study was to assess the difference in ICI efficacy between younger and older patients. We calculated pooled HRs and 95% confidence intervals (CIs) for younger and older cancer patients, and assessed data heterogeneity.Results: We identified 3999 studies in our search. Of these, 24 eligible randomised trials, including a total of 8157 (57%) younger and 6104 (43%) older cancer patients, fulfilled the criteria for our study and were thus further analysed. The pooled HRs of the younger and older patients were 0.76 (95% CI: 0.69-0.84) and 0.80 (95% CI: 0.71-0.86), respectively; the difference in ICI efficacy between younger and older cancer patients was not significant (p = .82). Regarding the PD-1 and PD-L1 inhibitors, the survival benefit was similar in both age groups (HR: 0.74; p = .96), whereas for the CTLA-4 inhibitors, there tended to be less survival benefit for older versus younger patients (HR: 0.90 and 0.77, respectively; p = .26).Conclusions: The survival benefit conferred by ICI was not age-dependent, amongst patients aged 65 years or younger. However, age-dependent benefits may vary amongst different types of ICIs.

DOI： 10.1080/0284186X.2019.1695062

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A Long-term Response to Nivolumab in a Case of PD-L1-negative Lung Adenocarcinoma with an EGFR Mutation and Surrounding PD-L1-positive Tumor-associated Macrophages. Reviewed

Hiromi Watanabe, Kadoaki Ohashi, Kazuya Nishii, Keisuke Seike, Go Makimoto, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan)   58 ( 20 )   3033 - 3037   2019.10

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Anti-programmed cell death 1 (PD-1) antibodies have poor efficacy in epidermal growth factor receptor (EGFR)-mutated lung cancer. We herein report a 72-year-old man with programmed cell death-ligand 1 (PD-L1)-negative lung adenocarcinoma harboring an EGFR mutation that responded to nivolumab for more than 2 years. A pathological examination revealed infiltration of CD8-positive lymphocytes and macrophages expressing CD68, CD206, and PD-L1 into the PD-L1-negative tumor; CD206 expression is a marker of immunosuppressive tumor-associated macrophages (TAMs). The presence of PD-L1-positive TAMs in the tumor environment might be a predictor of a positive response to anti-PD-1 antibodies.

DOI： 10.2169/internalmedicine.2875-19

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Patients' preferences and perceptions of lung cancer treatment decision making: results from Okayama lung cancer study group trial 1406. Reviewed International journal

Makimoto G, Hotta K, Oze I, Ninomiya K, Nakanishi M, Hara N, Kano H, Watanabe H, Hata Y, Nishii K, Nakasuka T, Itano J, Ninomiya T, Kubo T, Ohashi K, Ichihara E, Minami D, Sato A, Tabata M, Maeda Y, Kiura K

Acta oncologica (Stockholm, Sweden)   59 ( 3 )   1 - 5   2019.10

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DOI： 10.1080/0284186X.2019.1679880

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Programmed cell death-ligand 1 expression and efficacy of cisplatin-based chemotherapy in lung cancer: A sub-analysis of data from the two Okayama Lung Cancer Study Group prospective feasibility studies. Reviewed International journal

Kazuya Nishii, Katsuyuki Hotta, Kiichiro Ninomiya, Yuka Kato, Eiki Ichihara, Kadoaki Ohashi, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Respiratory investigation   57 ( 5 )   460 - 465   2019.9

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BACKGROUND: Cisplatin-based chemotherapy remains the mainstay treatment for advanced lung cancer; however, it remains controversial whether the efficacy of chemotherapy can be modulated by the immune-checkpoint status. In this study, we investigated the relationship between programmed cell death-ligand 1 (PD-L1) expression status and the efficacy of cisplatin-based chemotherapy by using individual patient data and pathological specimens obtained during our two previously performed prospective studies on the feasibility of short-term low-volume hydration in patients with advanced lung cancer who received cisplatin-based chemotherapy. METHODS: Among 91 patients who participated in the two aforementioned trials, those with assessable tumor specimens were included in this sub-analysis. PD-L1 expression levels were determined using immunohistochemical staining, while the Response Evaluation Criteria in Solid Tumors, version 1.1, were used for determining treatment efficacy. RESULTS: Thirty-two patients were investigated. PD-L1 expression was observed in 8 patients (25.0%; the PD-L1-positive group), with 2 exhibiting a PD-L1 expression of 50% or more. None of the patients in the PD-L1-positive group responded to treatment, while the overall response rate in the PD-L1-negative group was 20.8% (5 of 24; P = 0.296). Both the progression-free survival and overall survival rates were worse in the PD-L1-positive group than in the PD-L1-negative group (3.7 vs. 5.9 months [P = 0.018] and 5.8 vs. 37.3 months [P = 0.070], respectively). CONCLUSION: PD-L1 expression was negatively correlated with survival in patients receiving cisplatin-based chemotherapy.

DOI： 10.1016/j.resinv.2019.04.004

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The effect and safety of immune checkpoint inhibitor rechallenge in non-small cell lung cancer. Reviewed International journal

Hiromi Watanabe, Toshio Kubo, Kiichiro Ninomiya, Kenichiro Kudo, Daisuke Minami, Etsuko Murakami, Nobuaki Ochi, Takashi Ninomiya, Daijiro Harada, Masayuki Yasugi, Eiki Ichihara, Kadoaki Ohashi, Keiichi Fujiwara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Japanese journal of clinical oncology   49 ( 8 )   762 - 765   2019.8

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INTRODUCTION: Immune checkpoint inhibitors (ICIs) have demonstrated long survival for the treatment of advanced non-small cell lung cancer (NSCLC). However, the effect and safety of ICI rechallenge have not been fully evaluated. The aim of this study was to investigate the efficacy and safety of ICI rechallenge in NSCLC patients. METHODS: We defined 'rechallenge' as re-administration of ICIs for patients who were previously treated with ICIs and discontinued treatment for any reason, and received subsequent chemotherapy. We retrospectively analyzed the histories of 434 patients with advanced NSCLC who received ICIs from December 2015 to December 2017 at seven centers. RESULTS: A total of 317 patients discontinued the ICI treatment, and 14 patients (4.4%) received ICI rechallenge. All 14 patients discontinued the first ICI due to disease progression. Eight patients received the same kind of ICIs, and six patients received different ICIs. Median progression-free survival and overall survival were 1.5 months [95% confidence interval (CI): 0.8-2.6] and 6.5 months [95% CI: 1.4-19.0], respectively. The objective response rate was 7.1%, and the disease control rate was 21.4%. Two of three patients who achieved at least a stable disease, received radiotherapy between the first and second ICIs. Adverse events were not significantly different compared with the first ICIs. CONCLUSIONS: In this study, the effect of ICI rechallenge was limited. Careful consideration of the administration of ICI rechallenge is necessary. This report involved a small number of cases, so further large prospective studies are warranted to confirm the efficacy of ICI rechallenge and to investigate predictive markers to identify a patient population in which ICI rechallenge is effective.

DOI： 10.1093/jjco/hyz066

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A phase I/II trial of weekly nab-paclitaxel for pretreated non-small-cell lung cancer patients without epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangement. Reviewed International journal

Daijiro Harada, Toshiyuki Kozuki, Naoyuki Nogami, Akihiro Bessho, Shinobu Hosokawa, Nobuaki Fukamatsu, Katsuyuki Hotta, Kadoaki Ohashi, Toshio Kubo, Hiroshige Yoshioka, Toshihide Yokoyama, Naoyuki Sone, Shoichi Kuyama, Kenichiro Kudo, Masayuki Yasugi, Nagio Takigawa, Isao Oze, Katsuyuki Kiura

Asia-Pacific journal of clinical oncology   15 ( 4 )   250 - 256   2019.8

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AIM: We investigated the efficacy, safety and optimal schedule of nanoparticle albumin-bound paclitaxel monotherapy as second- or third-line treatment for non-small-cell lung cancer patients without epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement. METHODS: Patients with pretreated advanced non-small-cell lung cancer without epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement were included. The patients were administered 100 mg/m2 of nanoparticle albumin-bound paclitaxel on days 1, 8, 15 and 22 (level 0) or on days 1, 8 and 15 (level -1) every 4 weeks during phase I of the trial. The primary endpoint was objective response rate. The estimated objective response rate was 15% and the threshold was 5% with an α error of 0.05 and β error of 0.2 in phase II. RESULTS: The recommended schedule was determined as level -1 in phase I. The characteristics of the 55 patients enrolled in phase II were as follows: median age = 66 years, male/female = 40/15, second/third line = 34/21 and adenocarcinoma/squamous cell carcinoma/large cell carcinoma/others = 34/17/2/2. Objective response rate was 7.3% (95% confidence interval, 2.0-17.6%). Median progression-free survival was 3.4 months. Treatment-related grade 3 or 4 toxicities were neutropenia (36.4%), febrile neutropenia (5.5%) and pulmonary infection (3.6%). Three patients had grade 2 pneumonitis and one treatment-related death occurred due to adult respiratory distress syndrome. CONCLUSION: This study failed to meet predefined primary endpoints for pretreated patients with advanced non-small-cell lung cancer without epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement.

DOI： 10.1111/ajco.13147

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A Prospective Cohort Study to Define the Clinical Features and Outcome of Lung Cancers Harboring HER2 Aberration in Japan (HER2-CS STUDY). Reviewed International journal

Kiichiro Ninomiya, Tae Hata, Hiroshige Yoshioka, Kadoaki Ohashi, Akihiro Bessho, Shinobu Hosokawa, Nobuhisa Ishikawa, Masahiro Yamasaki, Takuo Shibayama, Keisuke Aoe, Toshiyuki Kozuki, Shingo Harita, Yutaka Ueda, Toshi Murakami, Nobukazu Fujimoto, Hiroyuki Yanai, Shinichi Toyooka, Minoru Takata, Katsuyuki Hotta, Katsuyuki Kiura

Chest   156 ( 2 )   357 - 366   2019.8

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BACKGROUND: Human epidermal growth factor 2 (HER2) is a potential driver oncogene. Although HER2-targeted precision therapy has been tested in non-small cell lung cancer (NSCLC), the demographic characteristics of HER2-positive NSCLC have not been systematically defined. METHODS: Patients with pathologically confirmed stage IIIB/IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, were prospectively registered. HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays were performed to screen patients. HER2 mutations were identified by using direct gene sequencing. The aim of this study was to clarify the frequency, characteristics, and outcome of HER2-positive NSCLC. HER2 was defined as positive if the tumor harbored IHC3+, IHC2+/FISH+, or exon 20 insertion mutations. RESULTS: Of the 1,126 tumors screened, 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 epidermal growth factor receptor wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775-G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female patients had HER2-mutant tumors more frequently, whereas both IHC3+ and IHC2+/FISH+ tumors were detected more often in male subjects and smokers. Patients with an HER2-aberrant tumor had a significantly worse prognosis than those with epidermal growth factor receptor-positive and anaplastic lymphoma kinase-positive tumors, possibly due to the low proportion that received HER2-targeted therapies (n = 15 [26%]) and low response rates of 0% and 14% in patients with HER2-overexpressing and HER2-mutant tumors, respectively. CONCLUSIONS: This prospective large-scale cohort study is the first to show comprehensively the frequency and clinical demographic characteristics of those with HER2-positive advanced lung tumors in detail, providing critical historical data for future drug development against HER2-positive NSCLC. Future treatment strategies would be developed stratified according to the types of HER2 aberrations. TRIAL REGISTRY: UMIN Registration No. 000017003; URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000019691.

DOI： 10.1016/j.chest.2019.01.011

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Beneficial Effect of Osimertinib Readministration in Non-small-cell Lung Cancer Harboring an Epidermal Growth Factor Receptor (EGFR) Mutation with a History of Acquired Resistance to Osimertinib. Reviewed

Go Makimoto, Kadoaki Ohashi, Satoru Senoo, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan)   58 ( 11 )   1625 - 1627   2019.6

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We herein report a case of the beneficial effect of osimertinib readministration in non-small-cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation. A 69-year-old non-smoking woman was diagnosed with advanced NSCLC harboring an EGFR exon19 deletion and T790M. She was treated with osimertinib for two years but eventually acquired resistance. After 1.5 years of salvage chemotherapies, osimertinib was re-administered. She has been effectively and safely treated with osimertinib readministration for over 10 months. A prospective study is warranted to evaluate the efficacy and safety of osimertinib readministration in NSCLC with EGFR mutations.

DOI： 10.2169/internalmedicine.2152-18

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Re-administration of osimertinib in osimertinib-acquired resistant non-small-cell lung cancer. Reviewed International journal

Eiki Ichihara, Katsuyuki Hotta, Kiichiro Ninomiya, Toshio Kubo, Kadoaki Ohashi, Kammei Rai, Hisaaki Tanaka, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands)   132   54 - 58   2019.6

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BACKGROUND: Osimertinib is a tyrosine kinase inhibitor (TKI) that is an essential agent for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). However, there is no established strategy for treatment following acquired resistance to this agent. One potential strategy for treating acquired resistance to EGFR TKIs is re-administration, which has been evaluated mainly using first- or second-generation EGFR TKIs. However, no clinical data are available with which to determine the significance of re-administration of osimertinib, a third-generation EGFR TKI. The aim of this study was to evaluate the efficacy of re-administering osimertinib to patients who had acquired resistance to this agent. PATIENTS AND METHODS: We reviewed the medical records of consecutive patients with advanced NSCLC harboring EGFR-activating mutations and secondary T790M, who had undergone osimertinib re-administration to treat acquired resistance. RESULTS: Seventeen patients were re-administered osimertinib after acquiring resistance to osimertinib. Of these, two received osimertinib to treat carcinomatous meningitis without any measurable lesion. Responses were evaluated in the remaining 15 patients. The objective response and disease control rates were 33% and 73%, respectively. Tumor shrinkage by osimertinib re-administration was associated with that due to initial osimertinib treatment (r = 0.585, 95% confidence interval [CI]: 0.104-0.844). In the remaining two patients without measurable lesions, one exhibited improved clinical symptoms following osimertinib re-administration. The median progression-free survival (PFS) time of all 17 patients was 4.1 months (95% CI: 1.9-6.7). The toxicity of re-administration was low, without interruption of the treatment due to adverse events (AEs). Most patients had grade 2 AEs or lower. CONCLUSIONS: Re-administration of osimertinib for EGFR-mutant NSCLC yielded modest activity with tolerable toxicity.

DOI： 10.1016/j.lungcan.2019.02.021

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Chemoradiotherapy for locally advanced lung cancer patients with interstitial lung abnormalities. Reviewed International journal

Hisao Higo, Toshio Kubo, Satoko Makimoto, Go Makimoto, Hiroki Ihara, Yoshihisa Masaoka, Takashi Ninomiya, Eiki Ichihara, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Nagio Takigawa, Yoshinobu Maeda, Katsuyuki Kiura

Japanese journal of clinical oncology   49 ( 5 )   458 - 464   2019.5

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INTRODUCTION: Although chemoradiotherapy for locally advanced lung cancer has the potential for cure, treatment is avoided in patients with interstitial lung disease because of the risk for severe radiation pneumonitis. Interstitial lung abnormalities (ILA) can be evaluated using high-resolution computed tomography (HRCT) to assess interstitial changes. In this study, we retrospectively examined the feasibility and efficacy of chemoradiotherapy for locally advanced lung cancer patients with ILA. METHODS: Patients who underwent chemoradiotherapy for locally advanced lung cancer at Okayama University Hospital between 2012 and 2015 were reviewed retrospectively. HRCT prior to treatment was evaluated by one pulmonologist and two radiologists using a sequential reading method. RESULTS: Of the 77 patients enrolled in this study, ILA was present in 25 (32.5%) and indeterminate ILA in 24 patients; 28 patients did not have ILA. Desaturation at rest (SpO2 < 95%) and honeycombing on HRCT were not observed in ILA patients. Only one patient with ILA had a low vital capacity (%VC < 80%). Severe radiation pneumonitis (≥Grade 2) occurred in 36.0% of the patients with ILA, but it was controllable; Grade 4 or 5 was not observed. Multivariate analysis showed that >25% of the lung volume receiving >20 Gy was risk factors of severe radiation pneumonitis, but ILA was not. The 2-year survival rates of patients with and without ILA were 56.8% and 74.1%, respectively, but the difference was not significant (P = 0.33). CONCLUSIONS: Chemoradiotherapy was feasible and effective in some patient population with ILA without desaturation, low VC and honeycombing on HRCT.

DOI： 10.1093/jjco/hyz016

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A case of axillary lymphadenitis caused by Mycobacterium intracellulare in an immunocompetent patient. Reviewed International journal

Itano J, Ohashi K, Senoo S, Oda N, Nishii K, Taniguchi A, Miyahara N, Maeda Y, Kiura K

Respiratory medicine case reports   28   100947 - 100947   2019

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Axillary lymphadenitis caused by non-tuberculous mycobacteria is rare and has been reported in immunocompromised hosts. Herein, we report the case of a 67-year-old man without immunodeficiency who developed right axillary lymphadenitis caused by Mycobacterium intracellulare and showed a small nodular shadow in the left pulmonary apex. Biopsy of the right axillary lymph node revealed several epithelioid granulomas, and the culture of the lymph node aspirate yielded Mycobacterium intracellulare. The lymph node lesion and left lung apex shadow resolved spontaneously after careful outpatient monitoring. This case suggests that axillary lymphadenitis could be caused by Mycobacterium intracellulare in an immunocompetent patient.

DOI： 10.1016/j.rmcr.2019.100947

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Long-term spontaneous remission with active surveillance in IgG4-related pleuritis: A case report and literature review. Reviewed International journal

Go Makimoto, Kadoaki Ohashi, Kohei Taniguchi, Junichi Soh, Akihiko Taniguchi, Nobuaki Miyahara, Shinichi Toyooka, Tadashi Yoshino, Yoshinobu Maeda, Katsuyuki Kiura

Respiratory medicine case reports   28   100938 - 100938   2019

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Pleural effusion is a relatively rare feature of IgG4-related disease (IgG4-RD). Here, we report a case of a 72-year-old woman who presented with pleural effusion. Although the pleural adenosine deaminase level was increased, surgical biopsy of the pleura and left inguinal lymph node indicated that the effusion was due to IgG4-RD. Active surveillance was initiated because serum IgG4 and pleural effusion naturally decreased and then completely disappeared. The patient has shown no recurrence for >4 years. This case suggests that pleural biopsy can be used to distinguish IgG4-RD from tuberculosis; moreover, some cases with pleural effusion could improve without treatment.

DOI： 10.1016/j.rmcr.2019.100938

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Randomized Phase II Study Comparing Mannitol with Furosemide for the Prevention of Renal Toxicity Induced by Cisplatin-based Chemotherapy with Short-term Low-volume Hydration in Advanced Non-small Cell Lung Cancer: The OLCSG1406 Study Protocol. Reviewed

Makimoto G, Ichihara E, Hotta K, Ninomiya K, Oze I, Minami D, Ninomiya T, Kubo T, Ohashi K, Tabata M, Maeda Y, Kiura K

Acta medica Okayama   72 ( 3 )   319 - 323   2018.6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Although cisplatin-based chemotherapy shows a survival advantage compared to carboplatin for treating advanced non-small cell lung cancer, high-volume hydration and a long infusion time are necessary to avoid nephrotoxicity, and cisplatin-based chemotherapy has been difficult to administer in outpatient settings. A low-volume hydration method using mannitol or furosemide as forced diuresis was recently introduced, but there are no dear conclusions regarding which agent should be used. We describe our ongoing randomized phase II trial (the OLCSG1406 Study) evaluating the efficacy of forced diuresis. This study will clarify whether mannitol or furosemide is more suitable in cisplatin-based chemotherapy with low-volume hydration.

DOI： 10.18926/AMO/56080

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Clinical significance of repeat rebiopsy in detecting the EGFR T790M secondary mutation in patients with non-small cell lung cancer. Reviewed International journal

Ichihara E, Hotta K, Kubo T, Higashionna T, Ninomiya K, Ohashi K, Tabata M, Maeda Y, Kiura K

Oncotarget   9 ( 50 )   29525 - 29531   2018.6

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Background: Osimertinib is an essential drug to treat non-small-cell lung cancer (NSCLC) harboring the epidermal growth factor receptor (EGFR) T790M mutation, and rebiopsy is necessary to detect this mutation. However, the significance of repeat rebiopsy in NSCLC patients whose first rebiopsy was T790M-negative remains unclear. We used a retrospective cohort to clarify this issue. Methods: We reviewed the medical records of patients with NSCLC harboring EGFR mutations who underwent EGFR tyrosine kinase inhibitor (TKI) treatment at Okayama University Hospital between January 2015 and January 2017. Results: Of 102 patients with EGFR-mutant NSCLC, 55 underwent rebiopsy after acquired resistance to prior EGFR TKIs. Pre-existing activating EGFR mutations were found in all 55 rebiopsied samples. Of the 55 samples, 25 were T790M-positive (45%). Among the remaining 30 patients (T790M-negative on the first rebiopsy), 21 underwent additional rebiopsies following interval therapy. Of the 21 patients, 11 were T790M-positive on the second rebiopsy and 1 on the third. We also evaluated the efficacy of osimertinib in patients who needed a repeat rebiopsy to detect the T790M mutation. Osimertinib showed good activity with an objective response rate of 50%. Conclusions: Repeat rebiopsy increases the ability to detect a secondary mutation (T790M) in EGFR.

DOI： 10.18632/oncotarget.25705

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Second primary cancer in survivors of locally advanced non-small cell lung cancer treated with concurrent chemoradiation followed by surgery Reviewed

Go Makimoto, Toshio Kubo, Isao Oze, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Junichi Soh, Shinichi Toyooka, Kuniaki Katsui, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

Japanese Journal of Clinical Oncology   48 ( 3 )   287 - 290   2018.3

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The standard treatment for patients with locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT), but surgical resection following induction CRT can extend overall survival in a select population. However, patients who survive longer are at risk of developing a second primary cancer (SPC). This is the first report to determine the incidence of SPC in survivors with LA-NSCLC after trimodal therapy. Between October 1997 and October 2013, 112 Stage III NSCLC patients underwent trimodal therapy in our hospital. The 5-year overall survival rate was 71.8%. SPC developed in 10 of the 112 patients 0.60-15.0 (median 5.49) years after initiating CRT. The observed incidence of SPC was 1.8 per 100 patient-years. Although trimodal therapy can prolong patient survival, the estimated incidence of SPC does not increase. A large prospective study with a longer follow-up time is required to determine the effects of trimodal therapy, including the development of SPC.

DOI： 10.1093/jjco/hyy003

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A Phase II Study of Trastuzumab Emtansine in HER2-Positive Non–Small Cell Lung Cancer Reviewed

Katsuyuki Hotta, Keisuke Aoe, Toshiyuki Kozuki, Kadoaki Ohashi, Kiichiro Ninomiya, Eiki Ichihara, Toshio Kubo, Takashi Ninomiya, Kenichi Chikamori, Daijiro Harada, Naoyuki Nogami, Taizo Hirata, Shiro Hinotsu, Shinichi Toyooka, Katsuyuki Kiura

Journal of Thoracic Oncology   13 ( 2 )   273 - 279   2018.2

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Trastuzumab emtansine (T-DM1), an anti–erb-b2 receptor tyrosine kinase 2 (HER2) antibody-drug conjugate, has been shown to significantly improve survival in HER2-positive breast cancer. We report a phase II trial of T-DM1 monotherapy in relapsed NSCLC with documented HER2 positivity (an immunohistochemistry [IHC] score of 3+, both an IHC score of 2+ and fluorescence in situ hybridization positivity, or exon 20 mutation). This study was terminated early because of limited efficacy. The demographic characteristics in the 15 assessable patients were as follows: median age, 67 years
male sex, 47%
performance status of 0 to 1, 80%
HER2 status IHC 3+, 33%
HER status IHC 2+/fluorescence in situ hybridization–positive, 20%
and exon 20 mutation, 47%. The median number of delivered cycles was 3 (range 1–11). One patient achieved a partial response with an objective response rate of 6.7% (90% confidence interval: 0.2–32.0). With a median follow-up time of 9.2 months, the median progression-free survival time and median survival time were 2.0 and 10.9 months, respectively. Grade 3 or 4 adverse events included thrombocytopenia (40%) and hepatotoxicity (20%) without any treatment-related deaths. T-DM1 had a limited efficacy for HER2-positive NSCLC in our cohort. Applying the concept of precision medicine to tumors appears challenging
thus, additional molecular approaches are warranted.

DOI： 10.1016/j.jtho.2017.10.032

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Potential influence of interleukin-6 on the therapeutic effect of gefitinib in patients with advanced non-small cell lung cancer harbouring EGFR mutations Reviewed

Tomoki Tamura, Yuka Kato, Kadoaki Ohashi, Kiichiro Ninomiya, Go Makimoto, Hiroko Gotoda, Toshio Kubo, Eiki Ichihara, Takehiro Tanaka, Koichi Ichimura, Yoshinobu Maeda, Katsuyuki Hotta, Katsuyuki Kiura

Biochemical and Biophysical Research Communications   495 ( 1 )   360 - 367   2018.1

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Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a key therapy used for patients with EGFR-mutant non-small cell lung cancer (NSCLC), some of whom do not respond well to its therapy. Cytokine including IL-6 secreted by tumour cells is postulated as a potential mechanism for the primary resistance or low sensitivity to EGFR-TKIs. Fifty-two patients with advanced EGFR-mutant NSCLC who had received gefitinib were assessed retrospectively. The protein expression of IL-6 in the tumour cells was assessed by immunostaining and judged as positive if ≥ 50 of 100 tumour cells stained positively. Of the 52 patients, 24 (46%) and 28 (54%) were defined as IL-6-postitive (group P) and IL-6-negative (group N), respectively. Group P had worse progression-free survival (PFS) than that of group N, which was retained in the multivariate analysis (hazard ratio: 2.39
95 %CI: 1.00–5.68
p &lt
0.05). By contrast, the PFS after platinum-based chemotherapy did not differ between groups P and N (p = 0.47). In cell line-based model, the impact of IL-6 on the effect of EGFR-TKIs was assessed. The combination of EGFR-TKI and anti-IL-6 antibody moderately improved the sensitivity of EGFR-TKI in lung cancer cell with EGFR mutation. Interestingly, suppression of EGFR with EGFR-TKI accelerated the activation of STAT3 induced by IL-6. Taken together, tumour IL-6 levels might indicate a subpopulation of EGFR-mutant NSCLC that benefits less from gefitinib monotherapy.

DOI： 10.1016/j.bbrc.2017.10.175

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Other Link： http://orcid.org/0000-0002-5180-3933

A phase I trial of afatinib and bevacizumab in chemo-naïve patients with advanced non-small-cell lung cancer harboring EGFR mutations: Okayama Lung Cancer Study Group Trial 1404 Reviewed

Takashi Ninomiya, Naoyuki Nogami, Toshiyuki Kozuki, Daijiro Harada, Toshio Kubo, Kadoaki Ohashi, Shoichi Kuyama, Kenichiro Kudo, Akihiro Bessho, Nobuaki Fukamatsu, Nobukazu Fujimoto, Keisuke Aoe, Takuo Shibayama, Keisuke Sugimoto, Nagio Takigawa, Katsuyuki Hotta, Katsuyuki Kiura

Lung Cancer   115   103 - 108   2018.1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ireland Ltd  

Objective In advanced epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC), treatment with afatinib, a second-generation EGFR-tyrosine kinase inhibitor (TKI), confers a significant survival benefit over platinum-based chemotherapy. The first-generation EGFR-TKIs gefitinib and erlotinib in combination with bevacizumab have improved progression-free survival. We hypothesized that the combination of afatinib with bevacizumab would further improve efficacy, and conducted a phase I trial to test this hypothesis. Materials and methods Untreated patients with advanced EGFR-mutant NSCLC were enrolled. The primary endpoint was safety. Two doses of afatinib, 40 mg/day (level 0) and 30 mg/day (level −1), were evaluated in combination with 15 mg/kg bevacizumab every 3 weeks. Optimal dosing was determined by dose-limiting toxicity (DLT), with the concentration at which ≤4 of 12 patients experienced toxicity considered the recommended dose. Results Nineteen patients were enrolled (level 0:5, level −1:14). Three of the five patients at level 0 experienced a DLT, which indicated that this dose was unfeasible. Three patients at level −1 developed a DLT of grade 3 non-hematological toxicity, which was soon resolved. Grade 3 or worse adverse events were experienced by all five patients at dose level 0 (diarrhea in 2, skin rash in 1, hypoxia in 1, and paronychia in 1), and by three patients at level −1 (diarrhea in 2 and anorexia in 1). Among 16 evaluable patients, 1 had a complete response, 12 had partial responses, and 0 had progressive disease. Conclusion Afatinib plus bevacizumab (level −1) was well tolerated and showed evidence of favorable disease control. This combination therapy may represent a potent therapeutic option for patients with EGFR-mutant NSCLC.

DOI： 10.1016/j.lungcan.2017.11.025

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A phase II trial of carboplatin plus S-1 for elderly patients with advanced non-small-cell lung cancer with wild-type epidermal growth factor receptor: The Okayama Lung Cancer Study Group Trial 1202 Reviewed

Shoichi Kuyama, Nobuaki Ochi, Akihiro Bessho, Katsuyuki Hotta, Genyo Ikeda, Daizo Kishino, Toshio Kubo, Daijiro Harada, Nobukazu Fujimoto, Masamoto Nakanishi, Takahiro Umeno, Toshiaki Okada, Kenichi Chikamori, Tomoko Yamagishi, Kadoaki Ohashi, Eiki Ichihara, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

LUNG CANCER   112   188 - 194   2017.10

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Introduction: S-1 is an oral fluoropyrimidine-based combination of tegafur, gimeracil, and oteracil potassium. Although the combination of S-1 with carboplatin is a first-line chemotherapy regimen for advanced non-small cell lung cancer (NSCLC), the efficacy and safety of the regimen in the elderly remain unknown.
Methods: The patient inclusion criteria were previously untreated advanced NSCLC, wild-type epidermal growth factor receptor, aged 70 years or more, and a performance status (PS) of 0-2. The patients received oral S-1 (40 mg/m(2), twice daily) for 2 weeks and carboplatin (area under the curve: 5) on day 1 every 4 weeks as induction treatment. After four induction cycles, S-1 alone (40 mg/m(2), twice daily) was administered for 2 weeks every 4 weeks as a maintenance therapy until disease progression. The primary endpoint was the overall response rate (ORR), which was expected to exceed 20%, and the secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and the toxicity profile. The associations between clinical outcomes and expression of genes such as thymidylate synthase and thymidine phosphorylase in the tumors were evaluated.
Results: Thirty-three patients were enrolled between March 2013 and June 2015. The median age was 78 (range 70-89) years, and 51.5% had a PS of 0. The ORR was 30.3% (95% confidence interval (CI): 14.6-46.0) and the DCR 57.6% (95% CI: 40.7-74.4). Grade 3/4 toxicities included thrombocytopenia (42.4%), neutropenia (33.3%), and anemia (27.3%). There was one treatment-related death due to aspiration pneumonia following febrile neutropenia. The median PFS and OS were 134 days (95% CI: 79-173) and 479 days (95% CI: 250-571), respectively. Low thymidine phosphorylase expression was associated with the DCR (P &lt; 0.01).
Conclusion: This study met the predesigned primary endpoint, and the regimen seems to be a favorable treatment option.

DOI： 10.1016/j.lungcan.2017.08.010

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Discomfort during bronchoscopy performed after endobronchial intubation with fentanyl and midazolam: a prospective study Reviewed

Daisuke Minami, Nagio Takigawa, Hirohisa Kano, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

JAPANESE JOURNAL OF CLINICAL ONCOLOGY   47 ( 5 )   434 - 437   2017.5

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Endobronchial intubation with fentanyl and midazolam might be recommended for an invasive bronchoscopic procedure.Although endobronchial intubation during a bronchoscopic examination is useful for invasive procedures, it is not routine practice in Japan. The present study evaluated discomfort due to endobronchial intubation using fentanyl and midazolam sedation during bronchoscopy.
Thirty-nine patients were enrolled prospectively from November 2014 to September 2015 at Okayama University Hospital. Fentanyl (20 A mu g) was administered to the patients just before endobronchial intubation, and fentanyl (10 A mu g) and midazolam (1 mg) were added as needed during the procedure. A questionnaire survey was administered 2 h after the examination. In the questionnaire, patient satisfaction was scored using a visual analog scale as follows: excellent (1 point), good (2 points), normal (3 points), uncomfortable (4 points) and very uncomfortable (5 points). An additional question ('Do you remember the bronchoscopic examination?') was also asked. Predefined parameters (blood pressure, heart rate, oxygen saturation and complications) were recorded.
The enrolled patients included 22 males and 17 females; their median age was 70 (range: 28-88) years. The patients received a mean dose of 47.9 A mu g of fentanyl (range: 30-90 A mu g) and 2.79 mg of midazolam (range: 1-7 mg). In total, 28 patients (71.7%) agreed to undergo a second bronchoscopic examination; the mean levels of discomfort and for the re-examination were 2.07 points each. About 41% of the patients remembered the bronchoscopic examination. No severe complications were reported.
Endobronchial intubation using fentanyl and midazolam sedation during an invasive bronchoscopic procedure might be recommended.
UMIN000015578 in the UMIN Clinical Trials Registry.

DOI： 10.1093/jjco/hyx022

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Optimal method for quantitative detection of plasma EGFR T790M mutation using droplet digital PCR system Reviewed

Ken Suzawa, Hiromasa Yamamoto, Kadoaki Ohashi, Shinsuke Hashida, Shuta Tomida, Toshio Kubo, Yuho Maki, Junichi Soh, Kazunori Tsukuda, Katsuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka

ONCOLOGY REPORTS   37 ( 5 )   3100 - 3106   2017.5

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Though patients with EGFR mutations are initially responsive to EGFR-tyrosine kinase inhibitors (TKIs), most tumors ultimately acquire resistance to EGFR-TKIs. The most frequently reported mechanism is EGFR T790M mutation. In this study, using a droplet digital PCR (ddPCR) system, we assessed optimal conditions for a mutation detection assay for EGFR T790M obtained from circulating cell-free DNA (cfDNA) in plasma. The advantages of locked nucleic acids (LNA) probe, short amplicon size, and blocking oligo using peptide nucleic acids (PNA) were assessed using control DNAs from cell lines to improve the sensitivity of mutation detection. T790M alleles were then analyzed using ddPCR in 59 plasma samples from 24 NSCLC patients with EGFR mutations, and compared to the T790M status which were determined thorough re-biopsies. The assessment of the optimal assay method revealed that the assay using the short amplicon can efficiently detect more fragmented-DNA. The LNA probe and PNA clamp contributed better separation between positive and negative droplets. This PNA-LNA-ddPCR clamp method can detect mutant alleles in the sample with a mutant allele content of 0.01%. In clinical plasma samples, T790M alleles were detected via ddPCR with a sensitivity of 42.8% and specificity of 97.3%. We established a highly-sensitive detection assay for the T790M allele using the PNA-LNA-ddPCR clamp method. ddPCR is a promising method for detecting non-invasive T790M mutation.

DOI： 10.3892/or.2017.5567

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Trastuzumab Emtansine in HER2+Recurrent Metastatic Non-Small-Cell Lung Cancer: Study Protocol Reviewed

Kadoaki Ohashi, Katsuyuki Hotta, Taizo Hirata, Keisuke Aoe, Toshiyuki Kozuki, Kiichiro Ninomiya, Hiroe Kayatani, Hiroyuki Yanai, Shinichi Toyooka, Shiro Hinotsu, Minoru Takata, Katsuyuki Kiura

CLINICAL LUNG CANCER   18 ( 1 )   92 - 95   2017.1

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The treatment outcome has been unsatisfactory for patients with non small-cell lung cancer (NSCLC) refractory to standard first-line chemotherapy. Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with a vinca alkaloid, has been approved for clinical use in HER2+ breast cancer in many countries. Approximately 5% of NSCLC tumors possess HER2 alterations, and T-DM1 has shown excellent antitumor effects against HER2+ lung cancer cell lines in preclinical models. Therefore, we hypothesized that T-DM1 could significantly inhibit the growth of HER2+ lung cancers. We have launched a nonrandomized phase II trial of T-DM1 monotherapy for patientg with HER2+ lung cancers. The major eligibility criteria are as follows: age &gt;= 20 years, pathologically diagnosed NSCLC with documented HER2 positivity (immunohistochemistry 3+, both immunohistochemistry 2+ and fluorescence in situ hybridization positive, or exon 20 insertion mutation), and previous chemotherapy. Thirty patients will receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate. This trial will provide information on whether T-DM1 monotherapy is effective against HER2+ lung cancer. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.cllc.2016.06.014

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Safety And Discomfort During Bronchoscopy Performed Under Sedation With Fentanyl And Midazolam: A Prospective Study Reviewed

D. Minami, N. Takigawa, T. Ninomiya, T. Kubo, E. Ichihara, K. Ohashi, A. Sato, K. Hotta, T. Shibayama, N. Miyahara, M. Tabata, A. Kanehiro, K. Kiura

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE   195 ( 9 )   871 - 874   2017

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DOI： 10.1093/jjco/hyw083

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Potential influence of being overweight on the development of hepatic dysfunction in Japanese patients with EGFR-mutated non-small cell lung cancer undergoing gefitinib monotherapy: the Okayama Lung Cancer Study Group experience Reviewed

Naohiro Oda, Katsuyuki Hotta, Hiroshige Yoshioka, Kenichiro Kudo, Eiki Ichihara, Yuka Kato, Kiichiro Ninomiya, Daisuke Minami, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Akiko Sato, Nagio Takigawa, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

CANCER CHEMOTHERAPY AND PHARMACOLOGY   78 ( 5 )   941 - 947   2016.11

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Being overweight has been reported to induce hepatic dysfunction during cytotoxic chemotherapy. Severe hepatic dysfunction can also be observed during gefitinib monotherapy, leading to interrupted or discontinued treatment. However, whether being overweight is a risk factor during gefitinib therapy is unknown.
We retrospectively reviewed 183 Japanese patients with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor-na &lt; ve non-small cell lung cancer (NSCLC) harboring EGFR mutations, who received gefitinib monotherapy between July 2007 and February 2014. We defined being overweight as having a body mass index (BMI) aeyen 25 kg/m(2) and assessed its potential relationship with aeyengrade 2 hepatic dysfunction.
The patient demographics were as follows: 114 women; median age 72 years (range 42-95 years); BMI aeyen 25 kg/m(2), n = 32; performance status 0-1, n = 136; stage IIIB/IV, n = 141; and major EGFR mutations, n = 171. Hepatic dysfunction aeyengrade 2 during the gefitinib therapy was observed in 44 (24.0 %) patients, 22 (50.0 %) of whom interrupted or discontinued treatment. The median duration from gefitinib administration to the development of hepatic dysfunction was 56 days (range 6-1,352 days). Overweight patients were more likely to develop hepatic dysfunction aeyengrade 2 compared to non-overweight patients according to a multivariate analysis adjusted for several confounding factors (hazard ratio 2.24; 95 % confidence interval 1.01-4.95; p = 0.046).
These results suggest that being overweight may induce hepatic dysfunction during gefitinib monotherapy in Japanese patients with EGFR-mutated NSCLC.

DOI： 10.1007/s00280-016-3146-z

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Protocol Design for the Bench to Bed Trial in Alectinib-Refractory Non-Small-Cell Lung Cancer Patients Harboring the EML4-ALK Fusion Gene (ALRIGHT/OLCSG1405) Reviewed

Hideko Isozaki, Katsuyuki Hotta, Eiki Ichihara, Nagio Takigawa, Kadoaki Ohashi, Toshio Kubo, Takashi Ninomiya, Kiichiro Ninomiya, Naohiro Oda, Hiroshige Yoshioka, Hirohisa Ichikawa, Masaaki Inoue, Ichiro Takata, Takuo Shibayama, Shoichi Kuyama, Keisuke Sugimoto, Daijiro Harada, Shingo Harita, Toshiaki Sendo, Mitsune Tanimoto, Katsuyuki Kiura

CLINICAL LUNG CANCER   17 ( 6 )   602 - 605   2016.11

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Based on our preclinical study results, which showed that the activation of the hepatocyte growth factor/MET pathway is a potential mechanism of acquired resistance to alectinib, we launched the ALRIGHT (OLCSG1405 [alectinib-refractory nonesmall-cell lung cancer patients harboring the EML4-ALK fusion gene]), a phase II trial of the anaplastic lymphoma kinase (ALK)/MET inhibitor crizotinib in patients with nonesmall-cell lung cancer refractory to alectinib and harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene. Patients with ALK-rearranged tumors who have developed disease progression during alectinib treatment will receive crizotinib monotherapy until disease progression or the occurrence of unacceptable toxicity. The primary endpoint is set as the objective response rate, assuming that a response in 50% of eligible patients will indicate potential usefulness and that 15% would be the lower limit of interest (1-sided a of 0.05, b of 0.20). The estimated accrual number of patients is 9. The secondary endpoints include progression-free survival, overall survival, adverse events, and patient-reported outcomes. We will also take tissue samples before crizotinib monotherapy to conduct an exploratory analysis of ALK and hepatocyte growth factor/MET expression levels and gene alterations (eg, mutations, amplifications, and translocations). We will obtain information regarding whether crizotinib, which targets not only ALK, but also MET, can truly produce efficacy with acceptable safety profiles in ALK(+) non-small-cell lung cancer even in the alectinibrefractory setting. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.cllc.2016.05.005

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Safety and discomfort during bronchoscopy performed under sedation with fentanyl and midazolam: a prospective study Reviewed

Daisuke Minami, Nagio Takigawa, Hiromi Watanabe, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

JAPANESE JOURNAL OF CLINICAL ONCOLOGY   46 ( 9 )   871 - 874   2016.9

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Objective: Although sedation with fentanyl and midazolam during bronchoscopic examination is widely accepted in the USA and Europe, it is not routine practice in Japan. The objective of the present study was to evaluate sedation with fentanyl and midazolam during bronchoscopy.
Methods: Thirty-seven patients were enrolled prospectively between November 2014 and July 2015 at Okayama University Hospital. Fentanyl (20 mu g) was administered to the patients just before the examination, and fentanyl (10 mu g) and midazolam (1mg) were added as needed during the procedure. A questionnaire was administered 2 hours after the examination. In the questionnaire, patient satisfaction was scored using a visual analog scale as follows: great (1 point), good (2 points), normal (3 points), uncomfortable (4 points) and very uncomfortable (5 points). An additional question ('Do you remember the bronchoscopic examination?') was also used. Predefined matters for investigation (e.g. blood pressure, heart rate, oxygen saturation and complications) were recorded.
Results: The enrolled patients included 13 males and 24 females; the median age was 67 (range: 31-87) years. The patients received a median dose of fentanyl of 45.4 mu g (range: 30-100 mu g) and midazolam of 2.56 mg (range: 1-10 mg). Twenty-six patients (70.2%) agreed to undergo a second bronchoscopic examination, and the average levels of discomfort and re-examination were 2.02 points for each. Only 37.8% of the patients remembered the bronchoscopic examination. No severe complications were reported.
Conclusions: Sedation with fentanyl and midazolam during bronchoscopic examination should be recommended for use in Japan.

DOI： 10.1093/jjco/hyw083

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Activating alternative receptor tyrosine kinases induced alectinib-resistance in ALK rearranged non-small cell lung cancer cells Reviewed

Hideko Isozaki, Eiki Ichihara, Masayuki Yasugi, Nagio Takigawa, Kadoaki Ohashi, Toshio Kubo, Takashi Ninomiya, Nobuaki Ochi, Daisuke Minami, Kenichiro Kudo, Yuka Kato, Hiroe Kayatani, Tomoki Tamura, Kiichiro Ninonniya, Toshio Higo, Tsuyoshi Makimoto, Akiko Sato, Katsuyuki Hotta, Kunio Matsumoto, Toshiaki Sendo, Mitsune Tanimoto, Katsuyuki Kiura

CANCER RESEARCH   76   2016.7

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DOI： 10.1158/1538-7445.AM2016-2103

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Endobronchial ultrasound-guided transbronchial needle aspiration of hilar and mediastinal lymph nodes detected on F-18-fluorodeoxyglucose positron emission tomography/computed tomography Reviewed

Daisuke Minami, Nagio Takigawa, Naohiro Oda, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Mitsumasa Kaji, Mitsune Tanimoto, Katsuyuki Kiura

JAPANESE JOURNAL OF CLINICAL ONCOLOGY   46 ( 6 )   529 - 533   2016.6

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Endobronchial ultrasound-guided transbronchial needle aspiration is of diagnostic value in hilar/mediastinal (N1/N2) lymph node staging. We assessed the utility of endobronchial ultrasound-guided transbronchial needle aspiration in lung cancer patients with N1/N2 lymph nodes detected on F-18-fluorodeoxyglucose positron emission tomography/computed tomography.
Fifty lung cancer patients with N1/N2 disease on F-18-fluorodeoxyglucose positron emission tomography/computed tomography underwent endobronchial ultrasound-guided transbronchial needle aspiration for pathological lymph nodes between November 2012 and April 2015. The diagnostic performance of endobronchial ultrasound-guided transbronchial needle aspiration, lymph node site and size, number of needle passes and complications were evaluated retrospectively from patients' medical records. Malignancy was defined as a maximum standardized uptake value (SUVmax) &gt; 2.5.
The median longest diameter of the 61 lymph nodes (29 subcarinal, 21 right lower paratracheal, 6 left lower paratracheal, 4 right hilar and 1 upper paratracheal) was 23.4 mm (range: 10.4-45.7); the median number of needle passes was 2 (range: 1-5). There were no severe complications. A definitive diagnosis was made by endobronchial ultrasound-guided transbronchial needle aspiration in 39 patients (31 adenocarcinomas, 3 small-cell carcinomas, 2 squamous-cell carcinomas, 3 large-cell neuroendocrine carcinomas). In the remaining 11 patients, the diagnosis was indefinite: insufficient endobronchial ultrasound-guided transbronchial needle aspiration material was collected in two patients and non-specific lymphadenopathy was confirmed by endobronchial ultrasound-guided transbronchial needle aspiration or thoracotomy in the other nine patients. The mean lymph node SUVmax was 7.09 (range: 2.90-26.9) and was significantly higher in true-positive than in false-positive nodes (P &lt; 0.05, t-test). Non-specific lymphadenopathy was diagnosed by expert visual interpretation of F-18-fluorodeoxyglucose positron emission tomography/computed tomography images in five of the nine patients.
Endobronchial ultrasound-guided transbronchial needle aspiration accurately diagnoses N1/N2 disease detected on F-18-fluorodeoxyglucose positron emission tomography/computed tomography.

DOI： 10.1093/jjco/hyw023

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Non-Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases. Reviewed International journal

Hideko Isozaki, Eiki Ichihara, Nagio Takigawa, Kadoaki Ohashi, Nobuaki Ochi, Masayuki Yasugi, Takashi Ninomiya, Hiromichi Yamane, Katsuyuki Hotta, Katsuya Sakai, Kunio Matsumoto, Shinobu Hosokawa, Akihiro Bessho, Toshiaki Sendo, Mitsune Tanimoto, Katsuyuki Kiura

Cancer research   76 ( 6 )   1506 - 16   2016.3

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Crizotinib is the standard of care for advanced non-small cell lung cancer (NSCLC) patients harboring the anaplastic lymphoma kinase (ALK) fusion gene, but resistance invariably develops. Unlike crizotinib, alectinib is a selective ALK tyrosine kinase inhibitor (TKI) with more potent antitumor effects and a favorable toxicity profile, even in crizotinib-resistant cases. However, acquired resistance to alectinib, as for other TKIs, remains a limitation of its efficacy. Therefore, we investigated the mechanisms by which human NSCLC cells acquire resistance to alectinib. We established two alectinib-resistant cell lines that did not harbor the secondary ALK mutations frequently occurring in crizotinib-resistant cells. One cell line lost the EML4-ALK fusion gene, but exhibited increased activation of insulin-like growth factor-1 receptor (IGF1R) and human epidermal growth factor receptor 3 (HER3), and overexpressed the HER3 ligand neuregulin 1. Accordingly, pharmacologic inhibition of IGF1R and HER3 signaling overcame resistance to alectinib in this cell line. The second alectinib-resistant cell line displayed stimulated HGF autocrine signaling that promoted MET activation and remained sensitive to crizotinib treatment. Taken together, our findings reveal two novel mechanisms underlying alectinib resistance that are caused by the activation of alternative tyrosine kinase receptors rather than by secondary ALK mutations. These studies may guide the development of comprehensive treatment strategies that take into consideration the various approaches ALK-positive lung tumors use to withstand therapeutic insult.

DOI： 10.1158/0008-5472.CAN-15-1010

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Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration Of Hilar And Mediastinal Lymph Nodes Detected On 18f-Fluorodeoxyglucose Positron Emission Tomography/computed Tomography

D. Minami, N. Takigawa, Y. Kato, T. Ninomiya, T. Kubo, K. Ohashi, K. Hotta, T. Shibayama, N. Miyahara, M. Tabata, A. Kanehiro, M. Tanimoto, K. Kiura

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE   193 ( 6 )   529 - 533   2016

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DOI： 10.1093/jjco/hyw023

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Downregulation of TBXAS1 in an iron-induced malignant mesothelioma model Reviewed

Daisuke Minami, Nagio Takigawa, Yuka Kato, Kenichiro Kudo, Hideko Isozaki, Shinsuke Hashida, Daijiro Harada, Nobuaki Ochi, Masanori Fujii, Toshio Kubo, Kadoaki Ohashi, Akiko Sato, Takehiro Tanaka, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Mitsune Tanimoto, Katsuyuki Kiura

CANCER SCIENCE   106 ( 10 )   1296 - 1302   2015.10

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Malignant mesothelioma is an aggressive and therapy-resistant neoplasm arising from mesothelial cells. Evidence suggests that the major pathology associated with asbestos-induced mesothelioma is local iron overload. In the present study, we induced iron-induced mesothelioma in rats based on previous reports. Ten Wistar rats were given ferric saccharate and nitrilotriacetate i.p. for 5 days a week. Five of the ten rats exhibited widespread mesotheliomas in the peritoneum and tunica vaginalis. The tumor cells showed positive immunostaining for calretinin, wilms tumor-1, podoplanin and the oxidative DNA marker 8-hydroxy-2-deoxyguanosine. In three of the five rats with mesothelioma, array-based comparative genomic hybridization analysis identified a common chromosomal deletion mapped to the chromosomal 4q31 locus, which encompasses the TBXAS1 gene. Downregulation of the TBXAS1 gene was confirmed using quantitative PCR. TBXAS1 gene expression was also reduced in three of four human malignant pleural mesothelioma cell lines compared with normal bronchial epithelial cells. Immunohistochemistry revealed that TBXAS1 expression was weakly positive and positive in five and three out of eight human malignant mesothelioma samples, respectively. In conclusion, TBXAS1 gene expression was downregulated in rats with iron-induced mesothelioma. The relationship between iron overload and TBXAS1 downregulation should be pursued further.

DOI： 10.1111/cas.12752

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Endobronchial ultrasound-guided transbronchial biopsy with or without a guide sheath for diagnosis of lung Cancer Reviewed

Daisuke Minami, Nagio Takigawa, Daisuke Morichika, Toshio Kubo, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

Respiratory Investigation   53 ( 3 )   93 - 97   2015.5

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Background: Endobronchial ultrasound-guided transbronchial biopsy with a guide sheath (EBUS-GS) is widely used for diagnosing lung cancers
however, the diagnostic yield varies widely. This study aimed to assess the efficiency of EBUS-GS. Methods: We retrospectively evaluated the results of 110 patients who underwent transbronchial biopsy (TBB) for diagnosis of peripheral lung cancer. Bronchoscopy with and without EBUS-GS was performed in 60 (group A) and 50 patients (group B), respectively
their medical records were examined, and results from the two groups were compared by using the unpaired Student t-test. Results: The diagnostic sensitivity for lung cancer was 83.3% in group A and 68% in group B ( P=0.066) while using at least one of the following procedures: TBB, cytological brushing, and bronchial washing. The diagnostic sensitivity for lesions ≥20. mm was 86.4% in group A and 76.7% in group B ( P=0.263). Moreover, the diagnostic sensitivity for lesions 10-20. mm was 60% in group A and 14.2% in group B ( P=0.0004)
the diagnostic sensitivity with TBB alone was 63.3% in group A and 44% in group B ( P=0.043). The diagnostic sensitivity with TBB alone for lesions ≥20. mm was 70.2% in group A and 44.8% in group B ( P=0.051). Moreover, the diagnostic sensitivity for lesions 10-20. mm in size was 45% in group A and 14.2% in group B with TBB alone ( P=0.115). Conclusion: EBUS-GS with TBB, brushing, and bronchial washing is effective in diagnosing lung cancers sized &lt
20. mm.

DOI： 10.1016/j.resinv.2014.10.003

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Magnitude of the Benefit of Progression-Free Survival as a Potential Surrogate Marker in Phase 3 Trials Assessing Targeted Agents in Molecularly Selected Patients with Advanced Non-Small Cell Lung Cancer: Systematic Review Reviewed

Katsuyuki Hotta, Yuka Kato, Natasha Leighl, Nagio Takigawa, Rabab Mohamed Gaafar, Hiroe Kayatani, Taizo Hirata, Kadoaki Ohashi, Toshio Kubo, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

PLOS ONE   10 ( 3 )   2015.3

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Background
In evaluation of the clinical benefit of a new targeted agent in a phase 3 trial enrolling molecularly selected patients with advanced non-small cell lung cancer (NSCLC), overall survival (OS) as an endpoint seems to be of limited use because of a high level of treatment crossover for ethical reasons. A more efficient and useful indicator for assessing efficacy is needed.
Methods and Findings
We identified 18 phase 3 trials in the literature investigating EGFR-tyrosine kinase inhibitor (TKIs) or ALK-TKIs, now approved for use to treat NSCLC, compared with standard cytotoxic chemotherapy (eight trials were performed in molecularly selected patients and ten using an "all-comer" design). Receiver operating characteristic analysis was used to identify the best threshold by which to divide the groups. Although trials enrolling molecularly selected patients and all-comer trials had similar OS-hazard ratios (OS-HRs) (0.99 vs. 1.04), the former exhibited greater progression-free survival-hazard ratios (PFS-HR) (mean, 0.40 vs. 1.01; P &lt; 0.01). A PFS-HR of 0.60 successfully distinguished between the two types of trials (sensitivity 100%, specificity 100%). The odds ratio for overall response was higher in trials with molecularly selected patients than in all-comer trials (mean: 6.10 vs. 1.64; P &lt; 0.01). An odds ratio of 3.40 for response afforded a sensitivity of 88% and a specificity of 90%.
Conclusion
The notably enhanced PFS benefit was quite specific to trials with molecularly selected patients. A PFS-HR cutoff of similar to 0.6 may help detect clinical benefit of molecular targeted agents in which OS is of limited use, although desired threshold might differ in an individual trial.

DOI： 10.1371/journal.pone.0121211

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[Appropriate use of granulocyte-colony stimulating factor]. Reviewed

Ohashi K, Kiura K

Nihon rinsho. Japanese journal of clinical medicine   73 Suppl 2   336 - 40   2015.2

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Everolimus prolonged survival in transgenic mice with EGFR-driven lung tumors Reviewed

Masayuki Yasugi, Nagio Takigawa, Nobuaki Ochi, Kadoaki Ohashi, Daijiro Harada, Takashi Ninomiya, Toshi Murakami, Yoshihiro Honda, Eiki Ichihara, Mitsurte Tartimoto, Katsuyuki Kiura

EXPERIMENTAL CELL RESEARCH   326 ( 2 )   201 - 209   2014.8

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Everolimus is an orally administered mTOR inhibitor. The effect, and mechanism of action, of everolimus on lung cancers with an epidermal growth factor receptor (EGFR) mutation remain unclear. Four gefitinib-sensitive and -resistant cell lines were used in the present work. Growth inhibition was determined using the MTT assay. Transgenic mice carrying the EGFR L858R mutation were treated with everolimus (10 mg/kg/day), or vehicle alone, from 5 to 20 weeks of age, and were then sacrificed. To evaluate the efficacy of everolimus in prolonging survival, everolimus (10 mg/kg/day) or vehicle was administered from 5 weeks of age. The four cell lines were similarly sensitive to everolimus. Expression of phosphorylated (p) mTOR and pS6 were suppressed upon treatment with everolimus in vitro, whereas the pAKT level increased. The numbers of lung tumors with a long axis exceeding 1 mm in the everolimus-treated and control groups were 1.9 +/- 0.9 and 9.4 +/- 3.2 (t-test, p&lt;0.001), respectively. pS6 was suppressed during everolimus treatment. Although apoptosis and autophagy were not induced in everolimus-treated EGFR transgenic mice, angiogenesis was suppressed. The median survival time in the everolimus-treated group (58.0 weeks) was significantly longer than that in the control group (31.2 weeks) (logrank test, p&lt;0.001). These findings suggest that everolimus had an indirect effect on tumor formation by inhibiting angiogenesis and might be effective to treat lung tumors induced by an activating EGFR gene mutation. (C) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.yexcr.2014.04.012

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Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC Reviewed

Annette O. Walter, Robert Tjin Tham Sjin, Henry J. Haringsma, Kadoaki Ohashi, Jing Sun, Kwangho Lee, Aleksandr Dubrovskiy, Matthew Labenski, Zhendong Zhu, Zhigang Wang, Michael Sheets, Thia St Martin, Russell Karp, Dan van Kalken, Prasoon Chaturvedi, Deqiang Niu, Mariana Nacht, Russell C. Petter, William Westlin, Kevin Lin, Sarah Jaw-Tsai, Mitch Raponi, Terry Van Dyke, Jeff Etter, Zoe Weaver, William Pao, Juswinder Singh, Andrew D. Simmons, Thomas C. Harding, Andrew Allen

CANCER DISCOVERY   3 ( 12 )   1404 - 1415   2013.12

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Patients with non-small cell lung cancer (NSCLC) with activating EGF receptor (EGFR) mutations initially respond to first-generation reversible EGFR tyrosine kinase inhibitors. However, clinical efficacy is limited by acquired resistance, frequently driven by the EGFR(T790M) mutation. CO-1686 is a novel, irreversible, and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR, including T790M, while exhibiting minimal activity toward the wild-type (WT) receptor. Oral administration of CO-1686 as single agent induces tumor regression in EGFR-mutated NSCLC tumor xenograft and transgenic models. Minimal activity of CO-1686 against the WT EGFR receptor was observed. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of additional mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial-mesenchymal transition and demonstrated increased sensitivity to AKT inhibitors. These results suggest that CO-1686 may offer a novel therapeutic option for patients with mutant EGFR NSCLC.
SIGNIFICANCE: We report the preclinical development of a novel covalent inhibitor, CO-1686, that irreversibly and selectively inhibits mutant EGFR, in particular the T790M drug-resistance mutation, in NSCLC models. CO-1686 is the first drug of its class in clinical development for the treatment of T790M-positive NSCLC, potentially offering potent inhibition of mutant EGFR while avoiding the on-target toxicity observed with inhibition of the WT EGFR. (C) 2013 AACR.

DOI： 10.1158/2159-8290.CD-13-0314

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Lower gefitinib dose led to earlier resistance acquisition before emergence of T790M mutation in epidermal growth factor receptor-mutated lung cancer model. Reviewed International journal

Hiromi Hayakawa, Eiki Ichihara, Kadoaki Ohashi, Takashi Ninomiya, Masayuki Yasugi, Saburo Takata, Katsuya Sakai, Kunio Matsumoto, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

Cancer science   104 ( 11 )   1440 - 6   2013.11

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Non-small-cell lung cancers with epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs); however, unlike cytotoxic agents, it is generally accepted that minimal doses of drugs inhibiting target molecules are sufficient when molecular-targeted agents, including EGFR-TKIs, are used. Thus, any utility of higher doses remains unclear. We compared low-dose (15 mg/kg) gefitinib therapy with high-dose (50 mg/kg) therapy using an EGFR-mutated lung cancer xenograft model. Both gefitinib doses induced tumor shrinkage, but tumors regrew in the low-dose group within 1 month, whereas tumors in the high-dose group did not. Neither the T790M mutation nor MET amplification was apparent in regrown tumors. We also compared outcomes after two doses of gefitinib (5 and 25 mg/kg) in a transgenic EGFR-mutated lung cancer mouse model. In line with the results obtained using the xenograft model, both gefitinib doses completely inhibited tumor growth, but tumors treated with the lower dose of gefitinib developed earlier drug resistance. In conclusion, a low gefitinib dose caused tumors to become drug-resistant prior to acquisition of the T790M mutation or MET amplification in EGFR-mutated models of lung cancer. This suggests that it is important to optimize the EGFR-TKI dose for treatment of EGFR mutation-associated lung cancer. Gefitinib may need to be given at a dose greater than the minimum required for inhibition of target molecules.

DOI： 10.1111/cas.12284

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Next-generation sequencing of paired tyrosine kinase inhibitor-sensitive and -resistant EGFR mutant lung cancer cell lines identifies spectrum of DNA changes associated with drug resistance Reviewed

Peilin Jia, Hailing Jin, Catherine B. Meador, Junfeng Xia, Kadoaki Ohashi, Lin Liu, Valentina Pirazzoli, Kimberly B. Dahlman, Katerina Politi, Franziska Michor, Zhongming Zhao, William Pao

GENOME RESEARCH   23 ( 9 )   1434 - 1445   2013.9

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Somatic mutations in kinase genes are associated with sensitivity of solid tumors to kinase inhibitors, but patients with metastatic cancer eventually develop disease progression. In EGFR mutant lung cancer, modeling of acquired resistance (AR) with drug-sensitive cell lines has identified clinically relevant EGFR tyrosine kinase inhibitor (TKI) resistance mechanisms such as the second-site mutation, EGFR T790M, amplification of the gene encoding an alternative kinase, MET, and epithelial mesenchymal transition (EMT). The full spectrum of DNA changes associated with AR remains unknown. We used next-generation sequencing to characterize mutational changes associated with four populations of EGFR mutant drug-sensitive and five matched drug-resistant cell lines. Comparing resistant cells with parental counterparts, 18-91 coding SNVs/Indels were predicted to be acquired and 1-27 were lost; few SNVs/indels were shared across resistant lines. Comparison of two related parental lines revealed no unique coding SNVs/indels, suggesting that changes in the resistant lines were due to drug selection. Surprisingly, we observed more CNV changes across all resistant lines, and the line with EMT displayed significantly higher levels of CNV changes than the other lines with AR. These results demonstrate a framework for studying the evolution of AR and provide the first genome-wide spectrum of mutations associated with the development of cellular drug resistance in an oncogene-addicted cancer. Collectively, the data suggest that CNV changes may play a larger role than previously appreciated in the acquisition of drug resistance and highlight that resistance may be heterogeneous in the context of different tumor cell backgrounds.

DOI： 10.1101/gr.152322.112

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Vandetanib is effective in EGFR-mutant lung cancer cells with PTEN deficiency Reviewed

Hiromasa Takeda, Nagio Takigawa, Kadoaki Ohashi, Daisuke Minami, Itaru Kataoka, Eiki Ichihara, Nobuaki Ochi, Mitsune Tanimoto, Katsuyuki Kiura

Experimental Cell Research   319 ( 4 )   417 - 423   2013.2

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The effectiveness of vandetanib, an agent that targets RET, VEGFR and EGFR signaling, against EGFR-mutant lung cancer cells with PTEN loss was investigated. Two EGFR mutant non-small cell lung cancer (NSCLC) cell lines, PC-9 (PTEN wild type) and NCI-H1650 (PTEN null), were used. We transfected an intact PTEN gene into H1650 cells and knocked down PTEN expression in PC-9 cells using shRNA. The effectiveness of gefitinib and vandetanib was assessed using a xenograft model. While PC-9 cells were more resistant to vandetanib than gefitinib, H1650 cells were more sensitive to vandetanib than gefitinib. Both gefitinib and vandetanib suppressed the activation of EGFR and MAPK in H1650 cells, although phosphorylated AKT levels were not affected. In an H1650 cell xenograft model, vandetanib was also more effective than gefitinib. Although PTEN-transfected H1650 cells did not show restoration of sensitivity to gefitinib in vitro, the xenograft tumors responded to gefitinib and vandetanib. Knockdown of PTEN in PC-9 cells caused resistance to gefitinib. In conclusion, vandetanib might be effective in NSCLC with EGFR mutations that lack PTEN expression. The contribution of PTEN absence to vandetanib activity in NSCLC cells harboring EGFR mutations should be further examined. © 2012 Elsevier Inc.

DOI： 10.1016/j.yexcr.2012.12.018

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JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation Reviewed

Daijiro Harada, Nagio Takigawa, Nobuaki Ochi, Takashi Ninomiya, Masayuki Yasugi, Toshio Kubo, Hiromasa Takeda, Eiki Ichihara, Kadoaki Ohashi, Saburo Takata, Mitsune Tanimoto, Katsuyuki Kiura

CANCER SCIENCE   103 ( 10 )   1795 - 1802   2012.10

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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as gefitinib and erlotinib, are effective for non-small cell lung cancer with activating EGFR mutations. However, even in patients with an initial dramatic response to such a drug, acquired resistance develops after 612 similar to months. A secondary mutation of T790M in EGFR and amplification of the MET gene account for this resistance; however, the mechanism(s) of approximately 30% of acquired resistance cases remain unknown. We established an erlotinib-resistant lung cancer cell line named PC-9/ER3 that harbors an EGFR mutation after continuously exposing PC-9 cells to erlotinib. PC-9/ER3 cells were 136-fold more resistant to erlotinib than the parental cells. Although the PC-9/ER3 cells did not carry the T790M mutation or MET amplification and had similar levels of phosphorylated (p) STAT3, pJAK2 increased in the resistant cells. It was found in the present study that 312 similar to h of exposure to erlotinib in both cell lines did not affect pJAK2 expression, but did result in increased pSTAT3 expression. pAkt in PC-9/ER3 cells was less suppressed than in PC-9 cells, although pEGFR and pMAPK were markedly suppressed in both cell lines. The combined treatment of erlotinib plus a JAK2 inhibitor (JSI-124) suppressed pAkt in PC-9/ER3 cells. Similarly, the combination of erlotinib plus JSI-124 or siRNA against JAK2 restored sensitivity to erlotinib in PC-9/ER3 cells. The combination of erlotinib plus JSI-124 was also effective for reducing PC-9/ER3 tumors in a murine xenograft model. Our results suggest that the activation of JAK2 partially accounts for acquired erlotinib resistance.(Cancer Sci, doi: 10.1111/j.1349-7006.2012.02363.x, 2012)

DOI： 10.1111/j.1349-7006.2012.02363.x

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HER2 Amplification: A Potential Mechanism of Acquired Resistance to EGFR Inhibition in EGFR-Mutant Lung Cancers That Lack the Second-Site EGFR(T790M) Mutation Reviewed

Ken Takezawa, Valentina Pirazzoli, Maria E. Arcila, Caroline A. Nebhan, Xiaoling Song, Elisa de Stanchina, Kadoaki Ohashi, Yelena Y. Janjigian, Paula J. Spitzler, Mary Ann Melnick, Greg J. Riely, Mark G. Kris, Vincent A. Miller, Marc Ladanyi, Katerina Politi, William Pao

CANCER DISCOVERY   2 ( 10 )   922 - 933   2012.10

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EGF receptor (EGFR)-mutant lung cancers eventually become resistant to treatment with EGFR tyrosine kinase inhibitors (TKI). The combination of EGFR-TKI afatinib and anti-EGFR antibody cetuximab can overcome acquired resistance in mouse models and human patients. Because afatinib is also a potent HER2 inhibitor, we investigated the role of HER2 in EGFR-mutant tumor cells. We show in vitro and in vivo that afatinib plus cetuximab significantly inhibits HER2 phosphorylation. HER2 overexpression or knockdown confers resistance or sensitivity, respectively, in all studied cell line models. FISH analysis revealed that HER2 was amplified in 12% of tumors with acquired resistance versus only 1% of untreated lung adenocarcinomas. Notably, HER2 amplification and EGFR(T790M) were mutually exclusive. Collectively, these results reveal a previously unrecognized mechanism of resistance to EGFR-TKIs and provide a rationale to assess the status and possibly target HER2 in EGFR-mutant tumors with acquired resistance to EGFR-TKIs.

DOI： 10.1158/2159-8290.CD-12-0108

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STAT3 expression in activating EGFR-driven adenocarcinoma of the lung Reviewed

Saburo Takata, Nagio Takigawa, Yoshihiko Segawa, Toshio Kubo, Kadoaki Ohashi, Toshiyuki Kozuki, Norihiro Teramoto, Motohiro Yamashita, Shinichi Toyooka, Mitsune Tanimoto, Katsuyuki Kiura

LUNG CANCER   75 ( 1 )   24 - 29   2012.1

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Bronchioloalveolar carcinoma (BAC) pattern is often seen at the margin of invasive adenocarcinomas. We investigated EGFR signaling abnormalities involved in the progression of adenocarcinoma. Fifty tumors were obtained from patients who underwent surgery for lung adenocarcinoma seen as dense areas in ground glass opacity on computed tomography. Six, 18, and 26 tumors &lt;1 cm, 1-2 cm, and &gt;= 2 cm in diameter, respectively, were analyzed. Of the 24 tumors &lt;= 2 cm in diameter, nine were preinvasive and 15 were invasive. EGFR, pAKT, and pMAPK were overexpressed in the center of the adenocarcinoma compared to the BAC component (p &lt; 0.01) by immunohistochemistry, while pSTAT3 expression was reversed (p = 0.017). In the tumors &lt;= 2 cm in diameter, pSTAT3 expression in the central area was higher in preinvasive tumors than in invasive tumors (p = 0.005). pSTAT3 was identified in the BAC component of 88% of the EGFR mutant (n = 17) and 82% of the wild-type tumors (n = 33). Transgenic mice expressing delE748-A752 EGFR and two lung cancer cell lines (PC-9 mutant and A549 wild-type EGFR) were also investigated. In transgenic mice, pSTAT3 was overexpressed in the BAC component around the adenocarcinoma center. Two lung cancer cell lines that overexpressed pSTAT3 were equally sensitive to a JAK2/STAT3 inhibitor (JSI-124). The role of STAT3 in the progression of adenocarcinoma should be further pursued. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2011.05.015

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Ruptured Littoral Cell Angiosarcoma Causing Hemoperitoneum Reviewed

Hiromichi Yamane, Kadoaki Ohashi, Toshimitsu Suwaki, Nagio Takigawa

INTERNAL MEDICINE   51 ( 3 )   337 - 338   2012

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Language：English   Publisher：JAPAN SOC INTERNAL MEDICINE  

DOI： 10.2169/internalmedicine.51.6663

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A new target for therapy in squamous cell carcinoma of the lung. Reviewed

Ohashi K, Pao W

Cancer Discovery   2011.1

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DOI： 10.1158/2159-8274.CD-11-0069.

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Effect of gefitinib on N-nitrosamine-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induced lung tumorigenesis in A/J mice Reviewed

Daizo Kishino, Katsuyuki Kiura, Nagio Takigawa, Hideki Katayama, Shoichi Kuyama, Ken Sato, Toshiaki Okada, Kadoaki Ohashi, Mitsune Tanimoto

LUNG CANCER   65 ( 3 )   284 - 289   2009.9

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Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). N-Nitrosamine-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent carcinogen found in tobacco smoke, induces lung tumors in A/J mice. NNK induces cellular transformation resulting in the over-expression of EGFP. Accordingly, EGFR may be a target for cancer prevention. In this study, we investigated the effect of gefitinib on NNK-induced tumorigenesis and the carcinogenicity of gefitinib in A/J mice.
A total of 180 four-week-old female A/J mice were randomly divided into six groups: group 1 (controls), treated with deionized water; group 2, treated with 5 mg/kg p.o. gefitinib; group 3, treated with 50 mg/kg p.o. gefitinib (to test the carcinogenicity of gefitinib); group 4 (controls for NNK treatment), treated with deionized water; group 5, treated with 5 mg/kg p.o. gefitinib; and group 6, treated with 50 mg/kg p.o. gefitinib and injected with NNK once at 8 weeks of age to test the chemopreventive activity of gefitinib. Gefitinib was given once a day, 5 days a week by gavage, beginning at 4 weeks of age and continuing for 26 weeks. All mice were sacrificed at 30 weeks of age. The multiplicities of the NNK-induced lung tumors were significantly suppressed in a dose-dependent manner. Gefitinib had no effect on body weight at a low dose. The administration of gefitinib alone for 26 weeks did not induce tumorigenesis; instead, it significantly suppressed the incidence of spontaneous tumors in the mice, in contrast with other anticancer agents. Gefitinib did not induce lung fibrosis when compared with control mice by Azan-Mallory staining. Our results suggest that gefitinib has a weak but significant chemopreventive effect with no carcinogenicity or pulmonary toxicity in A/J mice. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2008.11.021

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Effects of Vandetanib on Lung Adenocarcinoma Cells Harboring Epidermal Growth Factor Receptor T790M Mutation In vivo Reviewed

Eiki Ichihara, Kadoaki Ohashi, Nagio Takigawa, Masahiro Osawa, Atsuko Ogino, Mitsune Tanimoto, Katsuyuki Kiura

CANCER RESEARCH   69 ( 12 )   5091 - 5098   2009.6

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Vandetanib is a novel multitarget tyrosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), with additional inhibition of epidermal growth factor receptor (EGFR) and rearranged during transfection receptor signaling, which has shown promising results in clinical trials for advanced non-small cell lung cancer. However, the mechanisms of acquired resistance to vandetanib remain unclear. Therefore, we established in vitro vandetanib-resistant PC-9/VanR cells from PC-9, a vandetanib-sensitive lung adenocarcinoma cell line, by chronic exposure to this agent. PC-9/VanR cells were 50-fold more resistant to vandetanib than PC-9 cells in vitro. Compared with PC-9 cells, PC-9/VanR cells showed emergence of an EGFR T790M mutation, moderately elevated MET amplification, and similar VEGFR-2 inhibition by vandetanib. Note that phospho-MET in PC-9/VanR was suppressed following EGFR inhibition by an irreversible EGFR-TKI, indicating that MET signaling of PC-9/VanR was dependent on EGFR signaling and that MET amplification was not the primary mechanism of resistance to vandetanib. In contrast to the in vitro experiment, vandetanib effectively inhibited the growth of PC-9/VanR tumors in an in vivo xenograft model through the antiangiogenesis effects of VEGFR-2 inhibition. In conclusion, the multitarget TKI vandetanib induced or selected for the EGFR T790M mutation as observed previously with highly selective EGFR-TKIs. However, vandetanib retained significant efficacy in vivo against xenografts harboring the T790M mutation, providing a strong scientific rationale for investigating vandetanib in clinical settings where acquired resistance through emergence of EGFR T790M mutations limits the effectiveness of highly selective EGFR-TKIs. [Cancer Res 2009;69(12):5091-8]

DOI： 10.1158/0008-5472.CAN-08-4204

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Radiation necrosis mimicking progressive brain metastasis in a patient with non-small cell lung cancer Reviewed

Kadoaki Ohashi, Kastuyuki Kiura, Nagio Takigawa, Shigeki Umemura, Naruhito Kondo, Mistuhiro Takemoto, Kensuke Onoda, Motoi Aoe, Masahiro Tabata, Mistune Tanimoto

JOURNAL OF THORACIC ONCOLOGY   2 ( 8 )   762 - 763   2007.8

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Authorship：Lead author   Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1097/JTO.0b013e31811f3abb

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Combination of SN-38 with gefitinib or imatinib overcomes SN-38-resistant small-cell lung cancer cells Reviewed

Nagio Takigawa, Masami Takeyama, Toshiyuki Kozuki, Takuo Shibayama, Akiko Hisamoto, Katsuyuki Kiura, Atsuhiko Tada, Katsuyuki Hotta, Shigeki Umemura, Kadoaki Ohashi, Yoshiro Fujiwara, Saburo Takata, Eiki Ichihara, Masahiro Osawa, Masahiro Tabata, Mitsune Tanimoto, Kiyoshi Takahashi

ONCOLOGY REPORTS   17 ( 5 )   983 - 987   2007.5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

Irinotecan is one of the effective anticancer agents for small-cell lung cancer (SCLC) and 7-ethyl-10-hydroxycampthothecin (SN-38) is an active metabolite of irinotecan. Gefitinib and imatinib are tyrosine kinase inhibitors which have clinical activities in several malignancies and they are also potent inhibitors of breast cancer resistance protein (BCRP) transporter, which confers the resistance of topoisomerase I inhibitors including SN-38 and topotecan. The cytotoxicity of SN-38, gefitinib and imatinib for the SN38-resistant cells (SBC-3/SN-38) from human SCLC cells, SBC-3, was evaluated using AlamarBlue assay. The drug concentration required to inhibit the growth of tumor cells by 50% (IC50) for 96-h exposure was used to evaluate the cytotoxicity. BCRP expression was determined by Western blotting and immunofluorescence staining. Intracellular topotecan accumulation was evaluated by flow cytometry. No differences were observed in the IC50 values (mean +/- SD) of the tyrosine kinase inhibitors between the SBC-3 cells and the SBC-3/SN-38 cells: 15 +/- 1.6 and 12 +/- 2.8 mu M of gefitinib, respectively; 15 +/- 0.51 and 14 +/- 3.9 mu M of imatinib, respectively. The SBC-3/SN-38 was 9.5-fold more resistant to SN-38 than the parental SBC-3. The SBC-3/SN-38 restored sensitivity to SN-38 when combined with 8 mu M gefitinib or 8 mu M imatinib, even though the IC50 values of SN-38 combined with gefitinib or imatinib in the SBC-3 cells did not change. BCRP was equally overexpressed in the SBC-3/SN-38 with and without gefitinib or imatinib. In addition, the BCRP expression on the SBC-3/SN-38 cell membrane with and without gefitinib seemed to be equal. Gefitinib increased intracellular accumulation of topotecan in the SBC-3/SN-38 cells. Gefitinib or imatinib reversed SN-38-resistance in these SCLC cells, possibly due to intracellular accumulation of SN-38 without any change in BCRP quantity. Irinotecan with gefitinib or imatinib might be effective for SCLC refractory to irinotecan.

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Successful treatment of a patient with gastric and duodenal metastases from large cell carcinoma of the lung with carboplatin and gemcitabine Reviewed

Kadoaki Ohashi, Katsuyuki Kiura, Nagio Takigawa, Takaaki Mizushima, Hideo Ino, Masahiro Tabata, Hiroshi Ueoka, Mitsune Tanimoto

ANTICANCER RESEARCH   26 ( 6C )   4695 - 4696   2006.11

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

A 62-year-old man with large cell carcinoma of the lung underwent a right upper lobectomy and four months later demonstrated a relapse in the stomach and duodenum. He received systemic chemotherapy consisting of carboplatin and gemcitabine. After the first cycle of chemotherapy, the duodenal lesion disappeared, however, the gastric lesion demonstrated no response. Considering the risk of bleeding or perforation, a partial gastroduodenal resection was therefore performed. Subsequently, he received adjuvant chemotherapy with the same regimen. He has since been doing well for 24 months after the recurrence. Although the prognosis for patients with gastrointestinal metastases from lung cancer tends to be extremely poor, treatment with chemotherapy and a metastasectomy have resulted in this patient, achieving a long survival.

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Double mutation and gene copy number of EGFR in gefitinib refractory non-small-cell lung cancer Reviewed

Masaki Tokumo, Shinichi Toyookaa, Shuji Ichihara, Kadoaki Ohashi, Kazunori Tsukuda, Kouichi Ichimura, Masahiro Tabata, Katsuyuki Kiura, Motoi Aoe, Yoshifumi Sano, Hiroshi Date, Nobuyoshi Shimizu

LUNG CANCER   53 ( 1 )   117 - 121   2006.7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Mutations of the epidermal growth factor receptor (EGFR) gene have been reported in non-small-cell tung cancer (NSCLC), especially in patients with adenocarcinoma and never smokers. Some common somatic mutations in EGFR, including deletion mutations in exon 19 and leucine-to-arginine substitution at amino acid position 858 (L858R) in exon 21, have been examined for their ability to predict sensitivity to gefitinib or erlotinib, which are selective EGFR tyrosine kinase inhibitors (EGFR-TKIs). On the other hand, reports have shown that the threonine-to-methyonine substitution at amino acid position 790 (T790M) in exon 20 is related to gefitinib resistance. Some studies have indicated that high copy numbers of the EGFR gene may be a more effective molecular predictor to responsiveness and prolonged survival in patients treated with EGFR-TKIs. Here, we describe two NSCLC patients with the L858R mutation who did not respond to gefitinib. Case 1 harbored both the T790M and L858R mutations, and fluorescence in situ hybridization showed EGFR gene amplification. Case 2 harbored both the L858R and aspartic acid-to-thyrosine substitution at amino acid position 761 in exon 19 of EGFR mutations and had a high polysomy status for EGFR. In these two cases, tumors showed resistance to gefitinib treatment despite the presence of EGFR L858R mutation and increased copy number. Our findings encourage further molecular analysis to elucidate the relationship between the EGFR status, including mutations and amplifications, and the responsiveness of NSCLC to gefitinib. (c) 2006 Elsevier Ireland Ltd. All. rights reserved.

DOI： 10.1016/j.lungcan.2006.04.008

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