Faculty Profiles - ICHIHARA Eiki

Papers - ICHIHARA Eiki

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Utility of immune checkpoint inhibitors in non-small-cell lung cancer patients with poor performance status. International journal

Hirohisa Kano, Eiki Ichihara, Daijiro Harada, Koji Inoue, Hiroe Kayatani, Shinobu Hosokawa, Daizo Kishino, Kazuhiko Watanabe, Nobuaki Ochi, Naohiro Oda, Naofumi Hara, Kiichiro Ninomiya, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Cancer science 111 ( 10 ) 3739 - 3746 2020.10

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

Most clinical trials of non-small-cell lung cancer (NSCLC) exclude patients with poor ECOG performance status (PS). Thus, the efficacy of immune checkpoint inhibitors (ICIs) in patients with poor PS remains unclear. Herein, we used data from a retrospective cohort to assess the potential clinical benefits of ICIs in NSCLC patients with poor PS. Data from NSCLC patients who received ICI monotherapy at 9 institutions between December 2015 and May 2018 were retrospectively analyzed. After excluding 4 patients who lacked PS data, a total of 527 ICI-treated patients, including 79 patients with PS 2 or higher, were used for our analyses. The progression-free survival (PFS) and overall survival (OS) of patients with PS 2 or higher were significantly shorter compared with those of PS 0-1 patients (median PFS, 4.1 vs 2.0 months; P < .001 and median OS, 17.4 vs 4.0 months; P < .001). Among NSCLC patients with programmed cell death protein-ligand 1 (PD-L1) expression of 50% or higher who were treated with pembrolizumab as first-line therapy, the median PFS times of patients with PS 2 and 0-1 were 7.3 and 8.1 months, respectively. There was no significant difference in PFS between patients with PS 2 and 0-1 (P = .321). Although poor PS was significantly associated with worse outcomes in NSCLC patients treated with ICIs, pembrolizumab as a first-line treatment in NSCLC patients expressing high levels of PD-L1 could provide a clinical benefit, even in patients with PS 2.

DOI： 10.1111/cas.14590

Association between Histological Types and Enhancement of Dynamic CT for Primary Lung Cancer.

Shogo Fukuma, Takayoshi Shinya, Junichi Soh, Ryuichiro Fukuhara, Nanako Ogawa, Fumiyo Higaki, Takehiro Tanaka, Eiki Ichihara, Takao Hiraki, Shinichi Toyooka, Susumu Kanazawa

Acta medica Okayama 74 ( 2 ) 129 - 135 2020.4

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

The aim of this study was to explore enhancement patterns of different types of primary lung cancers on 2-phase dynamic computed tomography (CT). This study included 217 primary lung cancer patients (141 adenocarcinomas [ADs], 48 squamous cell carcinomas [SCCs], 20 small cell lung carcinomas [SCLCs], and 8 others) who were examined using a 2-phase dynamic scan. Regions of interest were identified and mean enhancement values were calculated. After excluding the 20 SCLCs because these lesions had different clinical stages from the other cancer types, the mean attenuation values and subtractions between phases were compared between types of non-small cell lung carcinomas (NSCLCs) using the Kruskal-Wallis test. Late phase attenuation and attenuation of the late minus unenhanced phase (LMU) of SCCs were significantly higher than those of ADs (p<0.05). To differentiate SCC and AD in the late phase, a threshold of 80.21 Hounsfield units (HU) gave 52.9% accuracy. In LMU, a threshold of 52.16 HU gave 59.3% accuracy. Dynamic lung CT has the potential to aid in differentiating among NSCLC types.

DOI： 10.18926/AMO/58271

Pembrolizumab-induced hypothyroidism caused reversible increased serum creatinine levels: a case report. International journal

Natsumi Matsuoka, Kenji Tsuji, Eiki Ichihara, Takayuki Hara, Kazuhiko Fukushima, Kishio Toma, Shinji Kitamura, Kenichi Inagaki, Hitoshi Sugiyama, Jun Wada

BMC nephrology 21 ( 1 ) 113 - 113 2020.3

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

BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of patients with advanced malignancies. On the other hand, these drugs might cause immune-related adverse events (irAEs) including endocrinopathies and nephropathies. Thyroid dysfunction is one of the most common irAEs. For ICIs-induced nephropathies, most cases are due to tubulointerstitial nephritis, which might require steroid treatment. Here, we report a patient with non-small cell lung cancer treated with ICI who developed increased serum creatinine (s-Cr) levels due to ICIs-induced hypothyroidism. CASE PRESENTATION: A 57-year-old Asian man with refractory non-small cell lung cancer under ICIs therapy (pembrolizumab, an anti-programmed cell death-1 monoclonal antibody) developed increased s-Cr levels 5 months after the pembrolizumab initiation. His laboratory data, renal biopsy, and Gallium-67 scintigraphy findings denied pembrolizumab-induced tubulointerstitial nephritis. His renal function was correlated with thyroid function. Despite the increase of s-Cr levels, serum cystatin C levels were normal, which could be explained by the hypothyroidism. Levothyroxine treatment improved renal function as well as thyroid function. Then pembrolizumab was resumed, and both his thyroid and renal function remained normal level. Ultimately, we concluded that the increased s-Cr levels were caused by pembrolizumab-induced hypothyroidism. CONCLUSION: All clinicians involved in ICI treatment need to recognize the possible increase in s-Cr levels caused by ICIs-induced hypothyroidism, and we propose monitoring serum cystatin C levels to differentiate ICIs-induced hypothyroidism from tubulointerstitial nephritis before invasive renal biopsies or steroid treatment, which are recommended by the prescribing information for pembrolizumab, are performed.

DOI： 10.1186/s12882-020-01775-z

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

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

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

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

Acta oncologica (Stockholm, Sweden) 59 ( 3 ) 324 - 328 2020.3

Managing Lung Cancer with Comorbid Interstitial Pneumonia.

Eiki Ichihara, Nobuaki Miyahara, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 59 ( 2 ) 163 - 167 2020.1

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

Systemic therapy for advanced non-small cell lung cancer (NSCLC) has dramatically changed in the latest 15 years. Molecular-targeted therapy has brought about an era of precision medicine, and immune checkpoint inhibitors have brought hope for a cure for advanced NSCLC. In the wake of this remarkable advancement, lung cancer with comorbid interstitial pneumonia (IP) has been completely left behind, as most clinical trials exclude patients with comorbid IP. IP, especially idiopathic pulmonary fibrosis (IPF), is often accompanied by lung cancer, and acute exacerbation can develop during various cancer therapies, including surgery, radiotherapy and pharmacotherapy. In this review, we focus on the clinical questions concerning pharmacotherapy in cases of advanced lung cancer with comorbid IP and discuss what we can do with the currently available data.

DOI： 10.2169/internalmedicine.3481-19

The impact of body mass index on the efficacy of anti-PD-1/PD-L1 antibodies in patients with non-small cell lung cancer. International journal

Eiki Ichihara, Daijiro Harada, Koji Inoue, Ken Sato, Shinobu Hosokawa, Daizo Kishino, Kazuhiko Watanabe, Nobuaki Ochi, Naohiro Oda, Naofumi Hara, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands) 139 140 - 145 2020.1

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

OBJECTIVES: Body mass index (BMI) is reported to be associated with the efficacy of immune checkpoint inhibitors (ICIs) in solid tumors such as melanomas. However, it remains unclear whether such a relationship exists in non-small cell lung cancer (NSCLC) treated with programmed cell death protein 1 (PD-1)/ programmed death-ligand 1(PD-L1) inhibitors. The purpose of this study was to investigate the relationship between BMI and the efficacy of ICI treatment in patients with advanced NSCLC. MATERIALS AND METHODS: The medical records of NSCLC patients who received PD-1/PD-L1 antibody monotherapy at nine institutions between December 2015 and May 2018 were reviewed retrospectively. The effect of BMI was investigated in two cohorts. Cohort 1 included patients with NSCLCs with high PD-L1 expression (≥ 50 %) treated with pembrolizumab as first-line therapy, and cohort 2 included patients with NSCLCs treated with nivolumab/pembrolizumab/atezolizumab as second- or later-line treatment. RESULTS: A total of 513 from nine institutions were analyzed (84 in cohort 1, 429 in cohort 2). Using a BMI cut-off value of 22 kg/m2, which is an ideal BMI in our country (high BMI:22.0 and low BMI:22.0), there was no significant difference in the PFS or OS between the high and low BMI patients in cohort 1. However, in cohort 2, survival was significantly longer in patients with a high versus low BMI (PFS: 3.7 vs. 2.8 months, p = 0.036; OS: 15.4 vs. 13.5 months, p = 0.021). CONCLUSION: BMI was significantly associated with the efficacy of ICIs in patients with NSCLC treated with second- or later-line PD-1/PD-L1 inhibitors in our cohort.

DOI： 10.1016/j.lungcan.2019.11.011

Summary of the Japanese Respiratory Society statement for the treatment of lung cancer with comorbid interstitial pneumonia. International journal

Takashi Ogura, Nagio Takigawa, Keisuke Tomii, Kazuma Kishi, Yoshikazu Inoue, Eiki Ichihara, Sakae Homma, Kazuhisa Takahashi, Hiroaki Akamatsu, Satoshi Ikeda, Naohiko Inase, Tae Iwasawa, Yuichiro Ohe, Hiromitsu Ohta, Hiroshi Onishi, Isamu Okamoto, Kazumasa Ogawa, Kazuo Kasahara, Hiroki Karata, Takumi Kishimoto, Yuka Kitamura, Akihiko Gemma, Hirotsugu Kenmotsu, Hiroyuki Sakashita, Susumu Sakamoto, Katsutoshi Sekine, Yuichi Takiguchi, Yuji Tada, Shinichi Toyooka, Yuko Nakayama, Yasuhiko Nishioka, Koichi Hagiwara, Masaki Hanibuchi, Junya Fukuoka, Yuji Minegishi, Toyoshi Yanagihara, Nobuyuki Yamamoto, Hiromasa Yamamoto, Mina Gaga, Kwun M Fong, Charles A Powell, Katsuyuki Kiura

Respiratory investigation 57 ( 6 ) 512 - 533 2019.11

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

Dramatic progress in targeted therapy and immunotherapy has been changing clinical practices in lung cancer. With the accumulation of clinical practice, it has become clear that pre-existing interstitial pneumonia (IP) could be a risk factor for drug-induced lung injury, which has enhanced awareness regarding the difficulty in treating lung cancer with comorbid IP. Unfortunately, there is only low-grade evidence in the field of lung cancer with comorbid IP, because almost all clinical trials exclude such patients. There have been very few specialized clinical trials for patients with lung cancer and underlying IPs thus far. Therefore, it is necessary to treat such cases empirically or to give up on the treatment itself. Considering these circumstances, establishing how to treat lung cancer with comorbid IP is an urgent issue. This paper is a summary of the official statement reported by the Diffuse Lung Disease/Thoracic Oncology Assembly and the Japanese Respiratory Society (JRS) in 2017, which attempts to approach lung cancer with comorbid IP systematically.

DOI： 10.1016/j.resinv.2019.06.001

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

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

Granulation Tissue-induced Pseudo-relapse During Nivolumab Treatment in Advanced Non-small Cell Lung Cancer

Chihiro Ando, Eiki Ichihara, Hirohisa Kano, Yoshitaka Iwamoto, Atsuko Hirabae, Takamasa Nakasuka, Yoshinobu Maeda, Katsuyuki Kiura

IN VIVO 33 ( 6 ) 2113 - 2115 2019.11

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

Atypical tumor responses such as pseudo-progression or hyper-progression sometimes occur during immune check point inhibitor therapy. Distinct from both responses, we experienced a case of non-small cell lung cancer (NSCLC) with a pseudo-relapse, in which development of granulation mimicked cancer relapse during nivolumab therapy. A male with advanced NSCLC started nivolumab as a second-line therapy. After 15 cycles of nivolumab with a complete response, tumor markers started increasing and positron-emission computed tomography indicated a hot spot in the sigmoid colon. Laparoscopic segmental sigmoid colon resection revealed granulation tissue without any relapse of malignant cells. The results showed that even if radiographical tumor progression is found during immune therapy, histological confirmation should be considered.

DOI： 10.21873/invivo.11711

KEYNOTE-189試験における日本人転移性NSCLC患者に対するpembrolizumab+pemetrexed/platinum併用療法(Pembrolizumab Plus Pemetrexed-Platinum for Metastatic NSCLC Among Japanese Patients in KEYNOTE-189)

野上尚之, Horinouchi Hidehito, Saka Hideo, Nishio Makoto, Tokito Takaaki, Takahashi Toshiaki, Kasahara Kazuo, Hattori Yoshihiro, Ichihara Eiki, Adachi Noriaki, Noguchi Kazuo, Souza Fabricio, Kurata Takayasu

肺癌 59 ( 6 ) 540 - 540 2019.11

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. 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

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

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

Efficacy of afatinib treatment for lung adenocarcinoma harboring exon 18 delE709_T710insD mutation. International journal

Yoshitaka Iwamoto, Eiki Ichihara, Naofumi Hara, Takamasa Nakasuka, Chihiro Ando, Takahiro Umeno, Atsuko Hirabae, Yoshinobu Maeda, Katsuyuki Kiura

Japanese journal of clinical oncology 49 ( 8 ) 786 - 788 2019.8

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Exon 18 delE709_T710insD is an extremely rare mutation in epidermal growth factor receptor (EGFR) in non-small-cell lung cancer (NSCLC); the efficacy of EGFR tyrosine kinase inhibitors against this mutation remains unclear. In this case report, we report a case of NSCLC harboring EGFR exon 18 delE709_T710insD that was not detected by a commercially available assay, but was detected by a next-generation sequencing cancer panel. A 56-year old female patient with advanced NSCLC was diagnosed as EGFR-mutation-negative using the PNAClamp method. ALK rearrangement was also absent and she received cytotoxic chemotherapies. Clinical characteristics, including adenocarcinoma histology and no history of smoking, implied the presence of a driver mutation, so a next-generation-sequencing Oncomine® Cancer Research Panel was conducted in the patient's clinical course and the EGFR exon 18 delE709_T710insD mutation was detected. The patient started afatinib as sixth-line treatment and her pulmonary lesion significantly decreased in size. Afatinib was continued for 7 months until disease progressed.

DOI： 10.1093/jjco/hyz086

Primary Resistance to Alectinib Was Lost after Bevacizumab Combined Chemotherapy in ALK-Rearranged Lung Adenocarcinoma. International journal

Takamasa Nakasuka, Eiki Ichihara, Go Makimoto, Yoshinobu Maeda, Katsuyuki Kiura

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 14 ( 8 ) e168-e169 - E169 2019.8

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

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

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

Chemoradiotherapy for locally advanced lung cancer patients with interstitial lung abnormalities. 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

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC CLINICAL ONCOLOGY

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

Chemoradiotherapy for locally advanced lung cancer patients with interstitial lung abnormalities

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

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 (SpO(2) < 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

Significance of re-biopsy of histological tumor samples in advanced non-small-cell lung cancer in clinical practice.

Katsuyuki Hotta, Kiichiro Ninomiya, Eiki Ichihara, Katsuyuki Kiura

International journal of clinical oncology 24 ( 1 ) 41 - 45 2019.1

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

The significance of evaluating oncogenes, including EGFR mutations, ALK abnormalities, and PD-L1 expression has become broadly recognized with recent advances in molecular biology. It is now extremely important to investigate tumor oncogene status in each patient at the initial diagnosis. By contrast, the significance of conducting a re-biopsy in the salvage setting has not been systematically reviewed. This review reports that the significance of a re-biopsy varies depending on the clinical situation.

DOI： 10.1007/s10147-018-1344-x

A phase II trial of EGFR-TKI readministration with afatinib in advanced non-small-cell lung cancer harboring a sensitive non-T790M EGFR mutation: Okayama Lung Cancer Study Group trial 1403. International journal

Naohiro Oda, Kastuyuki Hotta, Kiichiro Ninomiya, Daisuke Minami, Eiki Ichihara, Toshi Murakami, Toshihide Yokoyama, Hirohisa Ichikawa, Kenichi Chikamori, Nagio Takigawa, Nobuaki Ochi, Shingo Harita, Yoshinobu Maeda, Katsuyuki Kiura

Cancer chemotherapy and pharmacology 82 ( 6 ) 1031 - 1038 2018.12

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

PURPOSE: The aim of this study was to evaluate the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) readministration using afatinib in patients with non-small-cell lung cancer (NSCLC) with a sensitive non-T790M EGFR mutation who had received cytotoxic chemotherapy after acquiring resistance to EGFR-TKIs. METHODS: Eligible patients had EGFR-mutant tumors resistant to first- or second-generation EGFR-TKIs and an EGFR-TKI-free period with cytotoxic agents. Confirmation of absence of the T790M mutation was required before registration. Afatinib (40 mg/body) was administered daily. The primary endpoint was progression-free survival (PFS). We assumed estimated and threshold PFS times of 3.3 and 1 months, with an α of 0.05 and β of 0.1, respectively. RESULTS: Twelve patients were enrolled from December 2014 to May 2017. The objective response rate and disease control rate were 17% and 84%, respectively. The median PFS time was 4.2 months (95% confidence interval [CI] 2.0-5.8), which met the pre-defined primary endpoint. The median overall survival was 11.6 months (95% CI 9.2-not reached). Grade 3 or worse adverse events included diarrhea (25%), elevated creatinine levels (8%), and hypokalemia (8%), without any treatment-related deaths. CONCLUSION: EGFR-TKI readministration with afatinib for sensitive EGFR-mutant NSCLC without T790M after resistance to a first- or second-generation EGFR-TKI yielded modest activity with tolerable toxicity. It might be one of the treatment options in patients who do not possess T790M tumors, although further studies in this patient setting are warranted.

DOI： 10.1007/s00280-018-3694-5

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