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Background: The role of pembrolizumab in the treatment of poor performance status (PS) patients remains unclear., Patients and Methods: We conducted a phase II trial to investigate the efficacy and safety of pembrolizumab as first-line therapy for non-small-cell lung cancer (NSCLC) patients with PSs of 2-3 and programmed cell death ligand 1 (PD-L1) expression ≥ 50%. The primary endpoint of this study was the objective response rate (ORR)., Results: Fourteen patients treated at eight institutions were enrolled. Most patients had PS 2 (12/14; 86%) and others had PS 3 (2/14; 14%). The ORR was 57.1% (95% confidence interval 28.9-82.3%), which met the primary endpoint. The median progression-free survival (PFS) and 1-year PFS rates were 5.8 months and 20.0%, respectively. At the time of data cut-off, one patient had received treatment for more than 1 year; another patient had received treatment for more than 2 years. Nine patients had improved PS with treatment (Wilcoxon signed-rank test, p = 0.003). Two patients had immune-related adverse events ≥ grade 3: grades 5 and 3 elevation in alanine and aspartate aminotransferases. Two PS 3-stage patients were diagnosed with clinically progressive disease prior to initial computed tomography; both died within 2 months., Conclusion: Pembrolizumab was effective for the treatment of NSCLC patients with a poor PS and PD-L1 level ≥ 50%. However, given the poor outcomes of the PS 3 patients, the drug is not indicated for such patients. Adverse events, including liver dysfunction, should be carefully monitored., Registration Id: UMIN000030955., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

The impact of immune checkpoint inhibitors (ICIs) on radiation-induced enterocolitis (RIE) after palliative radiotherapy (PRT) to the bowel has remained to be fully investigated. The aim of the present study was to investigate whether ICIs affect RIE after PRT. For this purpose, 32 lesions (vertebral bone, 13; pelvic bone, 12; adrenal gland, 3; lymph node, 3; liver, 1) in 28 patients with metastatic lung cancer who were treated with both PRT involving the bowel (8-48 Gy; typically 30 Gy in 10 fractions or 20 Gy in 5 fractions) and ICIs between December 2015 and June 2021 were retrospectively reviewed. A total of 12 lesions were treated with ICIs only prior to PRT, 16 received ICIs only after PRT and the remaining 4 received ICIs both prior to and after PRT. The 1-year overall survival rate was 53%. The median PRT dose was 30 Gy (range, 8-48 Gy) in 10 fractions (range, 1-24 fractions). The median interval between PRT and the closest administration of ICIs was 20.5 days (range, 1-212 days). Combination therapy with PRT and ICIs was well tolerated by the majority of patients. However, grade 2 or higher RIE occurred in 6.3% of the patients. In these patients, ICIs were administered within 7 days after completing PRT with 3.6 Gy or a higher-fraction dose (evaluated at the isocenter). There were significant differences in the incidence of RIE between administration of ICIs <7 days after PRT completion and ≥7 days (P=0.05), between <3.6 Gy per fraction and ≥3.6 Gy (P=0.04), and between maximum dose to 2 cc (D2cc) of large bowel <3.3 Gy and D2cc of large bowel ≥3.3 Gy (P=0.02). There was no clear association between the incidence of RIE and any other factors. These results suggest that the administration of ICIs soon after PRT completion and a comparatively high fraction dose may potentially increase the risk of grade 2 or higher RIE., Competing Interests: DH received honoraria from MSD, Ono, Kyowa Hakko Kirin, AstraZeneca, Boehringer Ingelheim, TOWA, Chugai, TAIHO, and Eli Lilly, and received research funding MSD, Chugai, AstraZeneca, Eli Lilly, Pfizer, BMS, Novartis, Kissei and Takeda. TK received honoraria from MSD, Ono, Kyowa Hakko Kirin, AstraZeneca, Boehringer Ingelheim, Chugai, TAIHO, Eli Lilly, Bristol Myers Squibb, Pfizer, Merck Biopharma, Nippon Kayaku, Novartis, Daiichi-Sankyo, AbbVie and Bayer, and received research funding MSD, Kyowa Hakko Kirin, AstraZeneca, Eli Lilly, Pfizer, BMS, Novartis, Kissei, Takeda, Chugai, TAIHO, Bristol-Myers, Merck Biopharma, Daiichi-Sankyo, AbbVie and AMGEN. All other authors declare that they have no competing interests., (Copyright: © Makita et al.)

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., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: JME-001 is a phase II trial assessing the efficacy and safety of cisplatin, pemetrexed, and nivolumab as first-line therapy in malignant pleural mesothelioma (MPM)., Patients and Methods: Patients with untreated, unresectable MPM with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 were included. The primary endpoint is the centrally reviewed objective response rate. The secondary endpoints include (1) response rate assessed by investigators, (2) disease control rate, (3) overall survival, (4) progression-free survival, (5) duration of response, and (6) time to response. Safety and adverse events will also be evaluated. Cisplatin (75 mg/m 2 ), pemetrexed (500 mg/m 2 ), and nivolumab (360 mg/body) were administered intravenously every 3 weeks with a total of 4-6 cycles. If patients did not progress during the combination phase, maintenance therapy with nivolumab was administered until disease progression or unacceptable toxicity. Tissue samples were required and collected for programmed death ligand 1 analysis., Results: Eighteen patients (mean age 69.2 years, 15 men) were enrolled between January 2018 and May 2019. The ECOG PS was 0 in 3 patients and 1 in 15 patients. Fourteen (77.8%; 95% CI 52.4% to 93.6%) patients had an objective response. The disease control rate was 94.4% (95% CI 72.7% to 99.9%). Fourteen (77.8%) patients had partial response (PR), three had stable disease, and one was not evaluable. Tumor shrinkage was observed in 10/14 (71.4%) patients with epithelioid, and 2/2 (100%) patients with sarcomatoid or biphasic histological subtype had PR. Ten (55.6%) patients experienced grade 3 or worse adverse events, including disorder of metabolism or nutrition (33.3%), loss of appetite (27.8%), anemia (16.7%), and hyponatremia (11.1%). No treatment-related deaths occurred., Conclusions: The safety and efficacy of this study strongly support a definitive trial of this combination. Trial registration number UMIN000030892., Competing Interests: Competing interests: TK reports personal fees from Eli Lilly Japan, personal fees from Bristol Myers Squibb, personal fees from Ono Pharmaceutical, during the conduct of the study; grants and personal fees from Taiho Pharmaceutical, grants and personal fees from Kyowa Hakko Kirin, personal fees from AstraZeneca, personal fees from MSD, personal fees from Chugai Pharmaceutical, personal fees from Nippon Boehringer Ingelheim, personal fees from Merck Biopharma, personal fees from Nippon Kayaku, personal fees from Daiichi Sankyo, personal fees from Pfizer Japan, personal fees from Takeda Pharmaceutical, personal fees from Novartis, outside the submitted work. DH reports personal fees from Eli Lilly Japan, grants and personal fees from Bristol Myers Squibb, grants and personal fees from Ono Pharmaceutical, during the conduct of the study; personal fees from Kyowa Hakko Kirin, grants and personal fees from AstraZeneca, personal fees from Nippon Boehringer Ingelheim, grants and personal fees from MSD, personal fees from Taiho Pharmaceutical, grants and personal fees from Chugai Pharmaceutical, grants from Novartis, grants from Kissei Pharmaceutical, grants from Takeda Pharmaceutical, grants from Pfizer Japan, outside the submitted work. KA reports grants and personal fees from Eli Lilly Japan, grants and personal fees from Bristol Myers Squibb, grants and personal fees from Ono Pharmaceutical, during the conduct of the study; grants and personal fees from AstraZeneca, personal fees from Nippon Boehringer Ingelheim, grants and personal fees from MSD, grants from Novartis, outside the submitted work. KH reports grants from Bristol Meyers Squibb, MSD, AstraZeneca, Chugai and Eli Lilly Japan, and honoraria from Eli Lilly Japan, Bristol Meyers Squib, Ono, Pfizer, AstraZeneca, Chugai, Takeda, MSD, Nippon Kayaku, Taiho, and Boehringer Ingelheim. NF reports personal fees from Eli Lilly Japan, grants, personal fees and other from Bristol Myers Squibb, grants, personal fees and other from Ono Pharmaceutical, during the conduct of the study; grants from MSD, personal fees from Chugai, personal fees from Daiichi Sankyo, outside the submitted work. Other authors have stated that they have no conflicts of interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Radiation esophagitis is a critical adverse event that needs to be appropriately managed while administering thoracic irradiation. This trial aimed to investigate whether sodium alginate has preventative effects on esophagitis in patients with non-small-cell lung cancer (NSCLC) receiving concurrent chemoradiotherapy (CRT)., Methods: Patients with untreated stage III NSCLC who were eligible for concurrent CRT were randomly assigned at a 1:1:1 ratio to receive one of the following treatments: initial or late use of oral sodium alginate (arms A and B) or water as control (arm C). The primary endpoint was the proportion of patients developing G3 or worse esophagitis., Results: Overall, 94 patients were randomly assigned between February 2014 and September 2018. The study was prematurely terminated because of slow accrual. The proportions of patients with G3 or worse esophagitis were 12.5%, 9.8%, and 19.4% in arms A, B, and C, respectively. Patients receiving sodium alginate had fewer onsets of G3 esophagitis; however, differences compared with arm C were not significant (A vs. C: p = 0.46; B vs. C: p = 0.28). The rates of grade 3 or worse non-hematologic toxicities besides esophagitis were 29%, 26%, and 43% in arms A, B, and C, respectively. Interestingly, compared with arm C, a low rate of febrile neutropenia was observed in arm A (3.1% vs. 19.4%: p = 0.04)., Conclusions: Sodium alginate did not show significant preventative effects on radiation-induced esophagitis in patients with NSCLC. The frequency of CRT-induced febrile neutropenia was lower in the early use sodium alginate arm., Trial Registration: ClinicalTrials.gov Identifier Registry number: UMIN000013133., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Objectives: It is important to clarify the relationship between irreversible organ damage and the quality of life (QOL) by considering the unique factors of patients with systemic lupus erythematosus (SLE). We aimed to clarify their correlation using SLE-specific QOL assessment tools. We also aimed to identify which type of organ damage is adversely correlated with the QOL., Methods: We conducted a questionnaire-based survey of outpatients with SLE at Kyoto University Hospital and evaluated irreversible organ damage using the SLICC/ACR damage index (SDI). LupusPRO and the SLE symptom checklist (SSC) were employed as SLE-specific QOL tools, and the SF-36v2 was used as a conventional QOL tool. Multiple linear regression analyses were performed to examine the correlations between the total SDI score and each QOL score, and between each SDI item/system score and each QOL score., Results: We analyzed the data of 265 patients. The total SDI score was significantly correlated with physical (PCS) and role/social component summary (RCS) of the SF-36v2, health-related QOL (HRQOL) of LupusPRO, and SSC ( p  < 0.001). Among the SDI items, atrophy/weakness and osteoporosis with fracture/vertebral collapse were negatively correlated with PCS (β = -0.40, p  < 0.001/β = -0.28, p  < 0.001), RCS (β = -0.30, p  < 0.001/β = -0.35, p  < 0.001), and HRQOL (β = -0.34, p  < 0.001/β = -0.31, p  < 0.001), respectively. Among the SDI systems, musculoskeletal damage had higher negative correlations with PCS (β = -0.51, p  < 0.001), RCS (β = -0.29, p  < 0.001), and HRQOL (β = -0.40, p  < 0.001)., Conclusion: We demonstrated the QOL of patients with SLE is negatively correlated with irreversible organ damage. We also revealed musculoskeletal damage is adversely correlated with the health-related QOL, especially the physical and role/social QOL.

Purpose: Neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with treatment outcomes in various cancers; however, the optimal timing to measure NLR is unclear. In this study, "average-NLR" was newly devised, which reflects the NLR throughout the course of radiotherapy, and its usefulness was assessed for stage III non-small cell lung cancer (NSCLC) patients treated with chemoradiotherapy., Materials and Methods: A total of 111 patients who received definitive chemoradiotherapy for unresectable stage III NSCLC were reviewed. Patient/tumor-related factors, treatment-related, and NLR-related factors (average-NLR, pre- and post-radiotherapy NLR, NLR-nadir, NLR-maximum) were assessed using univariate and multivariate analyses., Results: The median follow-up period was 43.8 months among the survivors. In the multivariate analysis, average-NLR and post-radiotherapy NLR were significant factors for the overall survival (OS) (p = 0.016 and 0.028) and distant failure (DF) (p = 0.008 and 0.040). For the patients with low, intermediate, and high average-NLR, the median OS was 41.2, 37.7, and 14.8 months, respectively, and the median DF free time was 52.5, 13.5, and 8.9 months, respectively., Conclusion: Average-NLR and post-radiotherapy NLR were significant factors for the OS and DF. Average-NLR, which was available immediately after the completion of chemoradiotherapy, seemed to be helpful for treatment decisions., (© 2021. The Author(s).)

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., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: MET exon 14 skipping is an oncogenic driver occurring in 3-4% of non-small cell lung cancer (NSCLC). The MET inhibitor tepotinib has demonstrated clinical efficacy in patients with MET exon 14 skipping NSCLC. Here, we present data from Japanese patients in the Phase II VISION study, evaluating the efficacy and safety of tepotinib., Methods: In the open-label, single-arm, Phase II VISION study, patients with advanced/metastatic NSCLC with MET exon 14 skipping received oral tepotinib 500 mg once daily. The primary endpoint was objective response by independent review. Subgroup analyses of Japanese patients were preplanned., Results: As of 1 January 2020, 19 Japanese patients received tepotinib and were evaluated for safety, 15 of whom had ≥9 months' follow-up and were also analysed for efficacy. By independent review, objective response rate (ORR) was 60.0% (95% confidence interval [CI]: 32.3, 83.7), median duration of response was not reached (95% CI: 6.9, not estimable [ne]), and progression-free survival was 11.0 months (95% CI: 1.4, ne). ORR in patients with MET exon 14 skipping identified by liquid biopsy (n = 8) was 87.5% (95% CI: 47.3, 99.7), and by tissue biopsy (n = 12) was 50.0% (95% CI: 21.1, 78.9). Patients' quality of life was maintained with tepotinib treatment. Among patients evaluated for safety, the most common treatment-related adverse events (any grade) were blood creatinine increase and peripheral oedema (12 and nine patients, respectively)., Conclusions: Tepotinib demonstrated robust and durable clinical efficacy in Japanese patients with advanced NSCLC harbouring MET exon 14 skipping, identified by either liquid or tissue biopsy. The main adverse events, blood creatinine increase and peripheral oedema, were manageable., (© The Author(s) 2021. Published by Oxford University Press.)

Objective: The systemic lupus erythematosus (SLE) symptom checklist (SSC) is a patient-reported outcome measure consisting of 38 queries. We translated SSC into Japanese and attempted to validate its usefulness for evaluating the quality of life (QOL) of SLE patients and identify factors that affect QOL., Methods: Data from the Medical Outcomes Study Short-form 36 questionnaire (SF-36), Japanese LupusPRO, the Japanese version of the SSC (SSC-J) questionnaire, SLEDAI-2k, and the physician global assessment (PGA) were obtained on the same day from 226 SLE outpatients of the Kyoto Lupus cohort at Kyoto University Hospital. Relationships between the total scores or each item of SSC-J and SF-36, Japanese LupusPRO, SLEDAI-2k, or PGA were analyzed by Spearman's rank test., Results: The total scores of SSC-J correlated with the scores of SF-36 and Japanese LupusPRO. In each item of SSC-J, all 38 items correlated with the physical component summary and mental component summary of SF-36 as well as the Health-Related QOL (HRQOL) scores of Japanese LupusPRO, but not with the non-HRQOL of LupusPRO. SSC-J scores correlated with age, PGA, and corticosteroid doses, but not with SLEDAI-2k., Conclusions: SSC-J is suitable as a disease-specific QOL assessment tool for SLE.

Background: The efficacy of crizotinib treatment for recurring EML4-ALK-positive non-small cell lung cancer (NSCLC) previously treated with alectinib is unclear. Based on our preclinical findings regarding hepatocyte growth factor/mesenchymal epithelial transition (MET) pathway activation as a potential mechanism of acquired resistance to alectinib, we conducted a phase II trial of the anaplastic lymphoma kinase/MET inhibitor, crizotinib, in patients with alectinib-refractory, EML4-ALK-positive NSCLC., Methods: Patients with ALK-rearranged tumors treated with alectinib immediately before enrolling in the trial received crizotinib monotherapy. The objective response rate was the primary outcome of interest., Results: Nine (100%) patients achieved a partial response with alectinib therapy with a median treatment duration of 6.7 months. Crizotinib was administered with a median treatment interval of 50 (range, 20-433) days. The overall response rate was 33.3% (90% confidence interval [CI]: 9.8-65.5 and 95% CI: 7.5-70.1), which did not reach the predefined criteria of 50%. Two (22%) patients who achieved a partial response had brain metastases at baseline. Progression-free survival (median, 2.2 months) was not affected by the duration of treatment with alectinib. The median survival time was 24.1 months. The most common adverse events were an increased aspartate transaminase/alanine transaminase (AST/ALT) ratio (44%) and appetite loss (33%); one patient developed transient grade 4 AST/ALT elevation, resulting in treatment discontinuation. Other adverse events were consistent with those previously reported; no treatment-related deaths occurred., Conclusions: Although the desired response rate was not achieved, crizotinib monotherapy following treatment with alectinib showed efficacy alongside previously described adverse events., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited., Methods: We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the 'TTF of CRZ' plus the 'TTF of ALEC' if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group., Results: Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P < 0.0001)., Conclusion: The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown., Competing Interests: Conflict of interest statement K.I. reported receiving personal fees from Boehringer Ingelheim, AstraZeneca, Pfizer, Eli Lilly, Chugai Pharmaceutical, Merck Sharp & Dohme (MSD), Ono Pharmaceutical and Taiho Pharmaceutical. T.Y. reported receiving grants from Takeda Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Daiichi Sankyo, Ono Pharmaceutical, Bayer, Astellas and Eli Lilly and receiving personal fees from Takeda Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Daiichi Sankyo, Bayer, Merck Serono, Pfizer, Huya Bioscience, Gilead Sciences and EP-CRSU. H.H. reported receiving grants from MSD, A2 Healthcare Corp., inVentiv Health Japan, Astellas, Daiichi Sankyo, Novartis, AbbVie, Quintiles/IQVIA Services, ICON Japan, Chugai Pharmaceutical, Takeda Pharmaceutical, EP-CRSU CO., GRITSTONE ONCOLOGY, Linical Co., Eli Lilly, Eisai Co., Bristol Myers Squibb company, Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, PAREXEL International Corp., SymBio Pharmaceuticals Limited, Ono Pharmaceutical, Merck Serono Co./Merck Biopharma, AstraZeneca, CMIC Shift Zero, Kissei Pharmaceutical, Kyowa Hakko Kirin, EPS Corporation, Bayer Yakuhin, Syneos Health, EPS International, Pfizer R&D Japan G.K and Otsuka Pharmaceutical and receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Kyorin Pharmaceutical, MSD, Ono Pharmaceutical, Novartis, Pfizer, Shanghai Haihe Biopharm and Taiho Pharmaceutical. Y.H. reported receiving grants from Janssen Pharmaceutical, MSD and Ono Pharmaceutical and receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Eli Lilly, MSD, Novartis, Ono Pharmaceutical and Taiho Pharmaceutical. K.N. reported receiving grants from Boehringer Ingelheim and receiving personal fees from Chugai Pharmaceutical, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Pfizer, Ono Pharmaceutical and Roche Diagnostics. H.K. reported receiving personal fees from Eli Lilly and Taiho Pharmaceutical. Y.O. reported no relevant conflicts of interests. T.Y. reported receiving personal fees from Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, Ono Pharmaceutical, Eli Lilly, Bristol Myers Squibb, Chugai Pharmaceutical, Novartis, Pfizer and MSD. T.S. reported receiving grants from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Boehringer Ingelheim, Novartis, Pfizer, Takeda Pharmaceutical, AbbVie, Bayer Yakuhin, Kissei Pharmaceutical, LOXO Oncology and Merck Serono and receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Boehringer Ingelheim, Novartis, Pfizer, Takeda Pharmaceutical, Astellas, Bristol Myers Squibb, Kyowa Hakko Kirin, Ono Pharmaceutical, Taiho Pharmaceutical, Thermo Fisher Scientific and Precision Medicine Asia Co. Ltd. K.A. reported receiving personal fees from Chugai Pharmaceutical, AstraZeneca, MSD, Bristol Myers Squibb and Ono Pharmaceutical. T.F. reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, MSD, Novartis, Ono Pharmaceutical, Pfizer and Taiho Pharmaceutical. T.K. reported receiving grants from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Bristol Meyers Squibb and Merck Biopharma and receiving personal fees from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Bristol Meyers Squibb, Ono Pharmaceutical, MSD, Pfizer, Kyowa Hakko Kirin, Boehringer Ingelheim, Nippon Kayaku and Novartis. A.N. reported receiving personal fees from MSD, Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Boehringer Ingelheim and Kyowa Kirin. K.T. reported receiving grants from Boehringer Ingelheim, Chugai Pharmaceutical and Ono Pharmaceutical and receiving personal fees from Eli Lilly, Boehringer Ingelheim, Chugai Pharmaceutical, Ono Pharmaceutical, Taiho Pharmaceutical, AbbVie, Pfizer, SRL, MSD, Novartis and Kyowa Kirin. K.H. reported receiving personal fees from AstraZeneca, Eli Lilly, Boehringer Ingelheim, Ono Pharmaceutical, Chugai Pharmaceutical, Pfizer and Taiho Pharmaceutical. T.Y. reported receiving grants from Ono Pharmaceutical and receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, MSD and Boehringer Ingelheim. H.D. reported receiving grants from Chugai Pharmaceutical, Pfizer and Eli Lilly and receiving personal fees from Chugai Pharmaceutical and Boehringer Ingelheim. S.S. reported no relevant conflicts of interests. D.F. reported receiving grants from AstraZeneca and Chugai Pharmaceutical and receiving personal fees from AstraZeneca, Ono Pharmaceutical, Bristol Myers Squibb, Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Boehringer Ingelheim, Eli Lilly and Novartis. M.M. reported receiving personal fees from AstraZeneca, MSD, Ono Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Chugai Pharmaceutical, Shionogi, Taiho Pharmaceutical and Novartis. K.M. reported receiving grants from Boehringer Ingelheim and Eli Lilly and receiving personal fees from Chugai Pharmaceutical and Novartis. T.A. reported no relevant conflicts of interests. A.T. reported no relevant conflicts of interests. S.M. reported receiving personal fees from Chugai Pharmaceutical, Boehringer Ingelheim, MSD, Eli Lilly, AstraZeneca, Ono Pharmaceutical, Taiho Pharmaceutical, Novartis, Bristol Myers Squibb and Kyowa Hakko Kirin. S.W. reported receiving grants from Boehringer Ingelheim and receiving personal fees from Eli Lilly, Pfizer, Novartis Pharma, AstraZeneca, Chugai Pharma, Bristol Meyers Squibb, Boehringer Ingelheim, MSD, Ono Pharmaceutical, Daiichi Sankyo and Taiho Pharmaceutical. H.A. reported receiving grants from Chugai Pharmaceutical and receiving personal fees from Chugai Pharmaceutical, Pfizer and Novartis. O.H. reported receiving grants from GlaxoSmithKline, AstraZeneca, Novartis, Kyorin, Bayer Yakuhin, Boehringer Ingelheim and Daiichi Sankyo and receiving personal fees from GlaxoSmithKline, AstraZeneca, Novartis, Bayer Yakuhin and Boehringer Ingelheim. K.S. reported no relevant conflict of interests. S.H. reported no relevant conflict of interests. K.A. reported no relevant conflict of interests. A.B. reported receiving personal fees from Chugai Pharmaceutical, Pfizer and Novartis. A.K. reported receiving grants from the Japan Society for the Promotion of Science, Boehringer Ingelheim, Chugai Pharmaceutical, Lilly and Ono Pharmaceutical and receiving personal fees from Boehringer Ingelheim, Chugai Pharmaceutical, Lilly, Ono Pharmaceutical, Novartis, Taiho Pharmaceutical and Pfizer. M.O. reported no relevant conflict of interests. K.N. reported receiving grants from MSD, A2 Healthcare Corp., inVentiv Health Japan, Astellas, Daiichi Sankyo, Novartis, AbbVie, Quintiles/IQVIA Services, ICON Japan, Chugai Pharmaceutical, Takeda Pharmaceutical, EP-CRSU CO., GRITSTONE ONCOLOGY, Linical Co., Eli Lilly, Eisai Co., Bristol Myers Squibb company, Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, PAREXEL International Corp., SymBio Pharmaceuticals Limited, Ono Pharmaceutical, Merck Serono Co./Merck Biopharma, AstraZeneca, CMIC Shift Zero, Kissei Pharmaceutical, Kyowa Hakko Kirin, EPS Corporation, Bayer Yakuhin, Syneos Health, EPS International, Pfizer R&D Japan G.K and Otsuka Pharmaceutical; receiving personal fees from AstraZeneca, Nichi-Iko Pharmaceutical, Astellas, Takeda Pharmaceutical, MSD, Taiho Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb company, Boehringer Ingelheim, Eli Lilly, Novartis, SymBio Pharmaceuticals Limited, Pfizer, Chugai Pharmaceutical, Clinical Trials Co., NANZANDO Co., MEDICUS SHUPPAN, Publishers Co., YODOSHA CO., Care Net, Nikkei Business Publications, Reno. Medical, Daiichi Sankyo, KYORIN Pharmaceutical, Thermo Fisher Scientific, Medical Review Co., YOMIURI TELECASTING CORPORATION, Roche Diagnostics, Nippon Kayaku Co., Bayer Yakuhin, Merck Biopharma Co., Medical Mobile Communications Co., AbbVie and 3H Clinical Trial Inc. and receiving consulting and advisor fees from Takeda Pharmaceutical, KYORIN Pharmaceutical, Ono Pharmaceutical, Pfizer and Eli Lilly. N.Y. reported receiving grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Daiichi Sankyo, Ono Pharmaceutical, Astellas, MSD, Pfizer, Takeda, AstraZeneca, Terumo and Toppan and receiving personal fees from Chugai Pharmaceutical, Eli Lilly, MSD, AstraZeneca, Ono Pharmaceutical, Novartis, Pfizer and Boehringer Ingelheim., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Conventional cancer registries are suitable for simple surveillance of cancer patients, including disease frequency and distribution, demographics, and prognosis; however, the collected data are inadequate to clarify comprehensively diverse clinical questions in daily practice., Methods: We constructed an umbrella-type lung cancer patient registry (CS-Lung-003) integrating multiple related prospective observational studies (linked studies) that reflect clinical questions about lung cancer treatment. The primary endpoint of this registry is to clarify daily clinical practice patterns in lung cancer treatment; a key inclusion criterion is pathologically diagnosed lung cancer. Under this registry, indispensable clinical items are detected in advance across all active linked studies and gathered prospectively and systematically to avoid excessive or insufficient data collection. Researchers are to input information mutually, irrespective of the relevance to each researcher's own study. Linked studies under the umbrella of the CS-Lung-003 registry will be updated annually with newly raised clinical questions; some linked studies will be newly created, while others will be deleted after the completion of the analysis. Enrollment began in July 2017., Discussion: We successfully launched the umbrella-type CS-Lung-003 registry. Under this single registry, researchers collaborate on patient registration and data provision for their own and other studies. Thus, the registry will produce results for multiple domains of study, providing answers to questions about lung cancer treatment raised by other researchers. Through such analysis of each linked study, this registry will contribute to the comprehensive elucidation of actual daily practice patterns in lung cancer treatment., Key Points: CS-Lung-003 registry directly integrates multiple linked studies created under the umbrella of this cancer registry to solve various clinical questions regarding daily practice patterns of lung cancer treatment., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

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) (p interaction = 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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Patients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR -mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients' reported outcomes. For patients with NSCLC harboring EGFR -activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients., (© 2020 The Authors.)

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., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The effect of nivolumab and the relation between bone response and tumor control in patients with non-small-cell lung cancer (NSCLC) with bone metastases are not clear. The outcome of nivolumab monotherapy was investigated, and whether the response of bone metastases is useful as an early predictor of tumor control in patients with NSCLC with bone metastases was examined. The participants included 15 patients who received nivolumab monotherapy for NSCLC with bone metastases in our institution between 2015 and 2017. Tumor control was defined using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST1.1). Response of bone metastases was assessed by the MD Anderson response criteria (MDA criteria). Responses according to RECIST1.1 and the MDA criteria were classified as responder (complete response or partial response) and non-responder [progressive disease (PD) or stable disease]. Progression-free survival (PFS) was investigated using the Kaplan-Meier method. With RECIST1.1, the overall response rate was 20%. Multivariate analysis showed that the MDA criteria were the only risk factor for patients with PD (RECIST1.1). Median PFS was 1.9 months, with PFS of 20% at 6 months. Univariate analysis showed that being a non-responder according to the MDA criteria was the only risk factor for PFS. In patients who were responders (MDA criteria) within 3 months, PFS was 83 and 50% at 3 and 6 months, respectively, though all non-responder (MDA criteria) patients converted to PD (RECIST1.1) within 3 months. Response according to RECIST1.1 was significantly correlated with response according to the MDA criteria (P<0.05). In patients who were both responders according to RECIST1.1 and the MDA criteria, time to response with the MDA criteria (1.4-2.0 months) was earlier than with RECIST1.1 (2.8-3.0 months) in all patients. In conclusion, application of the MDA criteria within 2 months of nivolumab monotherapy is useful for early prediction of response and prognosis in patients with NSCLC with bone metastases., (Copyright © 2020, Spandidos Publications.)

Introduction: Cytotoxic agents have immunomodulatory effects, providing a rationale for combining atezolizumab (anti-programmed death-ligand 1 [anti-PD-L1]) with chemotherapy. The randomized phase III IMpower131 study (NCT02367794) evaluated atezolizumab with platinum-based chemotherapy in stage IV squamous NSCLC., Methods: A total of 1021 patients were randomized 1:1:1 to receive atezolizumab+carboplatin+paclitaxel (A+CP) (n = 338), atezolizumab+carboplatin+nab-paclitaxel (A+CnP) (n = 343), or carboplatin+nab-paclitaxel (CnP) (n = 340) for four or six 21-day cycles; patients randomized to the A+CP or A+CnP arms received atezolizumab maintenance therapy until progressive disease or loss of clinical benefit. The coprimary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS) in the intention-to-treat (ITT) population. The secondary end points included PFS and OS in PD-L1 subgroups and safety. The primary PFS (January 22, 2018) and final OS (October 3, 2018) for A+CnP versus CnP are reported., Results: PFS improvement with A+CnP versus CnP was seen in the ITT population (median, 6.3 versus 5.6 mo; hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.60-0.85; p = 0.0001). Median OS in the ITT population was 14.2 and 13.5 months in the A+CnP and CnP arms (HR = 0.88, 95% CI: 0.73-1.05; p = 0.16), not reaching statistical significance. OS improvement with A+CnP versus CnP was observed in the PD-L1-high subgroup (HR = 0.48, 95% CI: 0.29-0.81), despite not being formally tested. Treatment-related grade 3 and 4 adverse events and serious adverse events occurred in 68.0% and 47.9% (A+CnP) and 57.5% and 28.7% (CnP) of patients, respectively., Conclusions: Adding atezolizumab to platinum-based chemotherapy significantly improved PFS in patients with first-line squamous NSCLC; OS was similar between the arms., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: We conducted a subanalysis of data from the multicentre, retrospective observational Nivolumab Japan Real World (CA209-9CR) study to evaluate nivolumab effectiveness and safety in elderly patients (aged ≥75 years) with advanced/metastatic non-small cell lung cancer., Materials and Methods: Medical record data of patients initiating nivolumab treatment between April 2016 and December 2016 were collected using electronic data capture from 23 cancer hospitals in Japan between March 2017 and August 2018. Nivolumab treatment data were collected to investigate the treatment patterns by age group (<75 and ≥75 years), and the effectiveness and safety of nivolumab treatment., Results: Of the 901 patients evaluated, 178 (19.8%) were aged ≥75 years. Overall, patients received a median of five nivolumab treatments regardless of age group. Comparable progression-free survival was observed, with a median of 2.1 months in patients aged <75 years and 2.1 months in patients aged ≥75 years (p=0.5441). No significant differences were found in duration of response, overall response rate or disease control rate between the two age groups. Median overall survival in patients aged <75 and ≥75 years was 14.7 months and 12.3 months, respectively. Grade ≥3 adverse events (AEs) occurred in 29.2% and 28.1% of patients aged <75 and ≥75 years, respectively. Immune-related AEs decreased slightly with increasing age; time to onset and rates of improvement were similar for patients aged <75 and ≥75 years. The most common grade 3-4 AEs were interstitial lung disease in both age groups (4.0% in patients aged <75 years and 2.8% in those aged ≥75 years). Poor performance status was associated with worse outcomes in both age groups., Conclusion: Based on Japanese real-world data, the effectiveness and safety of nivolumab were confirmed regardless of age., Competing Interests: Competing interests: KO reports personal fees from Ono Pharmaceutical Co, Ltd and MSD K.K. outside the submitted work; JS reports personal fees from Bristol-Myers Squibb K.K. and Ono Pharmaceutical CO, Ltd outside the submitted work; HS reports grants from Chugai Pharmaceutical Co, Ltd, AstraZeneca K.K. and MSD K.K. and personal fees from Ono Pharmaceutical Co, Ltd, Nippon Boehringer Ingelheim Co, Ltd and Novartis Pharma K.K. outside the submitted work; HS reports personal fees from Ono Pharmaceutical Co, Ltd and Bristol-Myers Squibb K.K. during the conduct of the study, personal fees from Chugai Pharmaceutical Co, Ltd and MSD K.K. outside the submitted work; OS reports other from Ono Pharmaceutical Co, Ltd during the conduct of the study, personal fees and other from Novartis Pharma K.K., Nippon Boehringer Ingelheim Co, Ltd and AstraZeneca K.K. and other from Kyorin Pharmaceutical Co, Ltd, Bayer Health, Daiichi Sankyo Co, Ltd, GlaxoSmithKline K.K. and Ono Pharmaceutical Co, Ltd outside the submitted work; MY reports personal fees from Chugai Pharmaceutical Co, Ltd, Ono Pharmaceutical Co, Ltd and AstraZeneca K.K. outside the submitted work; MN reports grants and non-financial support from Ono Pharmaceutical Co, Ltd during the conduct of the study, grants and personal fees from Ono Pharmaceutical Co, Ltd, Bristol-Myers Squibb K.K., Pfizer Japan Inc, Chugai Pharmaceutical Co, Ltd, Eli Lilly Japan K.K., Taiho Pharmaceutical Co, Ltd, AstraZeneca K.K., MSD K.K., Novartis Pharma K.K., Takeda Pharmaceutical Co, Ltd and Daiichi Sankyo Healthcare Co, Ltd and grants from Merck Serono Co, Ltd (currently Merck Biopharma Co, Ltd) and personal fees from Nippon Boehringer Ingelheim Co, Ltd outside the submitted work; KA reports grants and personal fees from Ono Pharmaceutical Co, Ltd, Bristol-Myers Squibb K.K., AstraZeneca K.K. and Eli Lilly Japan K.K. and grants from MSD K.K. and Novartis Pharma K.K. outside the submitted work; TK reports grants and personal fees from Ono Pharmaceutical Co, Ltd, AstraZeneca K.K., Taiho Pharmaceutical Co, Ltd, MSD K.K., Novartis Pharma K.K., Nippon Boehringer Ingelheim Co, Ltd, Eli Lilly Japan K.K., Pfizer Japan Inc and Chugai Pharmaceutical Co, Ltd, and grants from Takeda Pharmaceutical Co, Ltd, Regeneron Pharmaceuticals, Inc and Merck Serono Co, Ltd (currently Merck Biopharma Co, Ltd) and personal fees from Teijin Pharma Ltd and Bristol-Myers Squibb K.K. outside the submitted work; SO reports grants and personal fees from Bristol-Myers Squibb K.K. and Ono Pharmaceutical Co, Ltd during the conduct of the study, grants and personal fees from AstraZeneca K.K., Chugai Pharmaceutical Co, Ltd and Taiho Pharmaceutical Co, Ltd and grants from Kyowa Hakko Kirin Co, Ltd (currently Kyowa Kirin Co, Ltd) and Merck Serono Co, Ltd (currently Merck Biopharma Co, Ltd) and personal fees from MSD K.K. and Eli Lilly Japan K.K. outside the submitted work; DF reports personal fees from Ono Pharmaceutical Co, Ltd and Bristol-Myers Squibb K.K. during the conduct of the study, personal fees from AstraZeneca K.K., Taiho Pharmaceutical Co, Ltd, Chugai Pharmaceutical Co, Ltd, MSD K.K., Nippon Boehringer Ingelheim Co, Ltd and Eli Lilly Japan K.K. outside the submitted work; HT reports grants and personal fees from Bristol-Myers Squibb K.K., Eli Lilly Japan K.K., MSD K.K., Taiho Pharmaceutical Co, Ltd, Pfizer Japan Inc, Chugai Pharmaceutical Co, Ltd, Ono Pharmaceutical Co, Ltd, AstraZeneca K.K. and Nippon Boehringer Ingelheim Co, Ltd and grants from Merck Serono Co, Ltd (currently Merck Biopharma Co, Ltd) and personal fees from Novartis Pharma K.K. outside the submitted work; TK reports grants and personal fees from Chugai Pharmaceutical Co, Ltd, AstraZeneca K.K., Eli Lilly Japan K.K. and Bristol-Myers Squibb K.K., and personal fees from Taiho Pharmaceutical Co, Ltd, Ono Pharmaceutical Co, Ltd, MSD K.K., Pfizer Japan Inc, Kyowa Hakko Kirin Co, Ltd (currently Kyowa Kirin Co, Ltd), Nippon Boehringer Ingelheim Co, Ltd, and Nippon Kayaku Co, Ltd and grants from Merck Serono Co, Ltd (currently Merck Biopharma Co, Ltd) outside the submitted work; HS reports other from Mebix, Inc during the conduct of the study, personal fees from AstraZeneca K.K. outside the submitted work; IS reports grants from Nippon Boehringer Ingelheim Co, Ltd during the conduct of the study, grants and personal fees from AstraZeneca K.K., Taiho Pharmaceutical Co, Ltd, Nippon Boehringer Ingelheim Co, Ltd, Ono Pharmaceutical Co, Ltd, MSD K.K, Eli Lilly Japan K.K., Bristol-Myers Squibb K.K. and Chugai Pharmaceutical Co, Ltd and grants from Astellas Pharma Inc, Novartis Pharma K.K. and AbbVie GK, and personal fees from Pfizer Japan Inc outside the submitted work; YO reports grants and personal fees from Ono Pharmaceutical Co, Ltd and Bristol-Myers Squibb K.K. during the conduct of the study, grants and personal fees from AstraZeneca K.K., Chugai Pharmaceutical Co, Ltd, Eli Lilly Japan K.K., Pfizer Japan Inc, MSD K.K., Kyorin Pharmaceutical Co, Ltd, Takeda Pharmaceutical Co, Ltd, Novartis Pharma K.K., Taiho Pharmaceutical Co, Ltd, and AbbVie GK, and personal fees from Celltrion Healthcare Co, Ltd, Amgen Inc, and Nippon Boehringer Ingelheim Co, Ltd, and grants from Kissei Pharmaceutical Co, Ltd, Loxo Oncology, Inc, and Janssen Pharmaceutical K.K. outside the submitted work; HH is an employee of Bristol-Myers Squibb K.K.; NY is an employee of Ono Pharmaceutical Co, Ltd; RM, YHK, OS, KK, HT, KM, TM and TH have nothing to declare., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Background: The effectiveness of bevacizumab monotherapy in elderly patients with non-squamous non-small cell lung cancer (NSCLC) is unclear. The efficacy of the combinations for elderly patients was explored., Methods: Untreated patients (≥75 years; performance status 0-1) with stage IIIB, IV, or recurrent non-squamous NSCLC were included. Patients with epidermal growth factor receptor ( EGFR ) mutation or anaplastic lymphoma kinase ( ALK ) gene rearrangements were eligible even if they received tyrosine kinase inhibitors. Patients were randomized 1:1 to receive docetaxel (50 mg/m 2 ) (DB) or pemetrexed (500 mg/m 2 ) (PB) with bevacizumab (15 m/kg). The primary endpoint was progression-free survival (PFS). Treatment was administered every 3 weeks until disease progression or unacceptable toxicity., Results: Overall, 103 patients (DB: n=51; PB: n=52) were enrolled. In the DB and PB arms, median ages [range] were 78 [75-88] and 79 [75-94] years, respectively; median PFS were 6.1 and 4.6 months, respectively [hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.66-1.61]; and response rates were 43%, and 40%, respectively (P=0.840). Grade ≥3 leukopenia, neutropenia, and fatigue incidences were significantly higher in the DB arm. Febrile neutropenia incidence did not differ significantly (16% vs . 12%, P=0.578). One patient in the PB arm died from a ruptured abdominal aortic aneurysm. Quality of life (QoL) analysis revealed less deterioration in the PB arm., Conclusions: In previously untreated elderly patients with non-squamous NSCLC, PB shows feasibility, better QoL, and promising efficacy in terms of PFS, and an objective response rate for further analysis (UMIN000012786)., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr.2020.03.29). T Kozuki reports grants and personal fees from Chugai Pharmaceutical Co., AstraZeneca, Taiho, Bristol-Myers Squibb, and Eli Lilly Japan, and personal fees from Ono, MSD, Pfizer Japan, Kyowa Hakko Kirin, Nippon Boehringer Ingelheim, Nippon Kayaku and Novartis, and grants from Merck Biopharma, outside the submitted work. NN reports personal fees from MSD, AstraZeneca, Nikkei Business Publications, Eli Lilly Japan, Pfizer Japan, Bristol-Myers Squibb, Matsuyama Association of Obstetricians and Gynecologists, Reno. Medical, Ehime Medical Association, Ehime University Graduate School of Medicine, Quintiles Transnational Japan and grants and personal fees from Kyowa Hakko Kirin, Taiho, Chugai Pharmaceutical Co, Ono, Nippon Boehringer Ingelheim, outside the submitted work. OH reports personal fees and research funding from Novartis Pharma, Boehringer Ingelheim, AstraZeneca, and research funding from Kyorin Pharmaceutical Co., Bayer Health Care, Daiichi Sankyo, GlaxoSmithKline, and Ono, outside the submitted work. NS reports personal fees from Chugai Pharmaceutical Co., Eli Lilly Japan, and Sanofi, during the conduct of the study; personal fees from AstraZeneca, Boehringer Ingelheim, Taiho, Daiichi Sankyo, Ono, Bristol-Myers Squibb, MSD, and Nihon Medi-Physics, outside the submitted work. TH reports personal fees from Boehringer Ingelheim, Hisamitsu Pharmaceutical Co., and GlaxoSmithKline, outside the submitted work. NF reports personal fees from Chugai Pharmaceutical Co. during the conduct of the study; personal fees from Hisamitsu Pharmaceutical Co., Boehringer Ingelheim, Kyorin Pharmaceutical Co., Ono, and Bristol-Myers Squibb outside the submitted work. AB reports personal fees from Chugai Pharmaceutical Co., and Eli Lilly Japan, during the conduct of the study; personal fees from AstraZeneca, Ono, Bristol-Myers Squibb, Pfizer Japan, Boehringer Ingelheim, Chugai Pharmaceutical Co., Novartis Pharma, and Daiichi Sankyo and research funding from AstraZeneca, Ono, Pfizer, and Abbvie outside the submitted work. KT reports grants from Chugai Pharmaceutical Co., grants from Eli Lilly Japan, outside the submitted work. MS reports grants and personal fees from Chugai Pharmaceutical Co., Eli Lilly Japan, during the conduct of the study; grants and personal fees from Pfizer Japan, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Ono, Novartis, and MSD, personal fees from Taiho, and grants from Ignyta, Abbvie, EPS international, and Takeda, outside the submitted work. T Kato reports grants and personal fees from Chugai Pharmaceutical Co., during the conduct of the study; grants and personal fees from Abbvie, AstraZeneca Bristol-Myers Squibb, Chugai Pharmaceutical Co., Eli Lilly, Kyowa Kirin, Merck Biopharma, MSD, Novartis Ono, Pfizer and Taiho, personal fees from Boehringer Ingelheim, Nitto Denko, Sumitomo Dainippon, Takeda, and F. Hoffmann-La Roche, and grants from Astellas, Kyorin Pharmaceutical Co., and Regeneron, outside the submitted work. TS reports grants and personal fee from MSD and Boehringer Ingelheim, personal fees from Nichi-Iko Pharmaceutical Co., AstraZeneca, Chugai Pharmaceutical Co., Daiichi Sankyo, Ono, Bristol-Myers Squibb, Eli Lilly, Novartis, and Taiho outside the submitted work. HO received research funds from Takeda, MSD, Ono, AstraZeneca, Merck Biopharma, Chugai Pharmaceutical Co., Taiho, Bristol-Myers Squibb, Eli Lilly and Daiichi Sankyo outside the submitted work. The other authors have no conflicts of interest to declare., (2020 Translational Lung Cancer Research. All rights reserved.)

Background: Thymic carcinoma is a rare malignant disease and standard treatment for advanced or metastatic thymic carcinoma previously treated with platinum-based chemotherapy has not been established. Lenvatinib is a novel multi-targeted inhibitor of VEGFR, FGFR, RET, c-Kit, and other kinases. The aim of this trial was to assess the activity and safety of lenvatinib as a second-line treatment in thymic carcinoma., Methods: This single-arm, phase 2 trial done in eight institutions in Japan (five cancer centres, two medical university hospitals, and one public hospital) enrolled patients with pathologically confirmed unresectable advanced or metastatic thymic carcinoma that progressed following at least one platinum-based chemotherapy. Key inclusion criteria were age 20 years or older, at least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 24 mg of lenvatinib orally once daily in 4-week cycles until disease progression or occurrence of unacceptable adverse events. The primary endpoint was objective response rate evaluated at the data cutoff date (Feb 22, 2019), by independent central review in the intention-to-treat population. This trial is registered on JMACCT, JMA-IIA00285, and on UMIN-CTR, UMIN000026777., Findings: Between April 21, 2017, and Feb 22, 2018, 42 patients were enrolled and all patients were included in the activity and safety analysis. The median follow-up period was 15·5 months (IQR 13·1-17·5). The objective response rate was 38% (90% CI 25·6-52·0, p<0·0001). 16 (38%) of 42 patients had a partial response and 24 (57%) had stable disease. The most frequent grade 3 treatment-related adverse events were hypertension (27 [64%]) and palmar-plantar erythrodysaesthesia syndrome (three [7%]). No patient died from adverse events., Interpretation: The activity and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma was confirmed. These results suggest that lenvatinib could become a standard treatment option for patients with previously treated advanced or metastatic thymic carcinoma., Funding: Center for Clinical Trials, Japan Medical Association., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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.

Introduction : Platinum-based chemotherapy is the current first-line standard therapy for unresectable malignant pleural mesothelioma (MPM). Recently, immune-checkpoint inhibitors (ICI) have been intensively investigated as treatment options for this disease. Nivolumab, an anti-programmed cell death (PD)-1 agent, was one of the first drugs used and is representative of available ICIs. Areas covered : This review discusses previous relevant reports and current ongoing trials of nivolumab. The efficacy and safety of nivolumab have been investigated mostly in second-line or later treatment settings as both monotherapy and in combination with other ICIs. Particularly, nivolumab monotherapy yielded promising efficacy with an objective response rate of 29% and median overall survival of 17.3 months in salvage settings in the single-arm, Japanese phase 2 trial (MERIT). Notably, the study led to Japanese approval of nivolumab for unresectable recurrent MPM. Several trials with monotherapy or cotherapy with nivolumab have commenced, including randomized trials of nivolumab monotherapy vs. placebo in the salvage setting, and cotherapy with nivolumab and ipilimumab vs. the platinum doublet in the frontline setting. Expert opinion : Nivolumab seems like a reasonable option for unresectable, relapsed MPM despite the lack of randomized trial data. Ongoing pivotal trials will confirm its efficacy.

Papulopustular rash, an acneiform rash, appears on the seborrheic region during the first to second week of treatment with an epidermal growth factor receptor inhibitor (EGFRi). The rash gradually disappears after the fourth week; however, it persists or newly develops in other regions during EGFRi treatment. Because Staphylococcus aureus is frequently isolated from late-phase papulopustular rash, we assessed the incidence of bacterial infection and treatment outcomes of patients with late-phase papulopustular rash. Sixty-four cases treated with an EGFRi over 4 weeks who presented with papulopustular rash were assessed retrospectively. The median duration of EGFR inhibitor treatment was 5 months. Grade 2 and 3 papulopustular rash was observed in 47 and eight cases, respectively. Bacterial culture was performed in 51 cases, 50 of which yielded positive results: methicillin-sensitive S. aureus in 29, methicillin-resistant S. aureus in 14, Staphylococcus species in five, Pseudomonas aeruginosa in three, and other in four cases. Of the S. aureus isolates, 42% were resistant to minocycline and 40% to levofloxacin. After treatment with topical and/or oral antibiotics without topical corticosteroids, the papulopustular rash rapidly improved by an average of 2.9 ± 3.4 weeks. However, use of a combination of antibiotics and a topical corticosteroid prolonged the recovery period to an average of 18.9 ± 11.4 weeks. In conclusion, folliculitis that develops over 4 weeks after the initiation of EGFRi treatment is typically caused by staphylococcal infection. Bacterial culture is necessary due to the high rate of antibiotic resistance. It is important to distinguish late- from early-phase papulopustular rash and to treat using different approaches., (© 2019 Japanese Dermatological Association.)

Objectives: To describe the treatment patterns and determine the effectiveness and safety of nivolumab treatment for non-small cell lung cancer (NSCLC) in real-world setting in Japan., Materials and Methods: Japanese patients with NSCLC who received nivolumab were analyzed retrospectively. Patients who had started nivolumab treatment between April 2016 and December 2016 were enrolled. Information regarding patient demographics and clinical backgrounds, treatment patterns from diagnosis to post-nivolumab treatment, effectiveness and safety of nivolumab treatment and that of treatments just before and after nivolumab treatment, and programmed death-ligand 1 (PD-L1) expression status, if available, were collected. Factors associated with nivolumab effectiveness identified by univariate and multivariate analyses were further investigated for plotting Kaplan-Meier curves of epidermal growth factor receptor (EGFR) gene mutation status, PD-L1 expression status, and Eastern Cooperative Oncology Group performance status (ECOG PS)., Results: In this study, 901 NSCLC patients were enrolled. Nivolumab was used the most as a second line treatment with a median number of nivolumab doses of five. The median overall survival (OS) was 14.6 months, one-year survival rate was 54.3 %, and median progression-free survival (PFS) was 2.1 months. The objective response rate was 20.5 % and disease control rate was 57.4 %. According to multivariate analyses, better OS and PFS were associated with favorable ECOG PS and absence of liver metastasis. Better PFS was observed in patients without EGFR mutation and patients with smoking history. PFS and best overall response in PD-L1 expression subgroups were expression level-dependent. The overall incidence of irAEs was 45.8 %, and the incidence of adverse events of grade 3 or higher was 14.0 %., Conclusion: The real-world effectiveness and safety of nivolumab is consistent with that reported by previous clinical trials and other real-world data. Subgroup analysis showed that ECOG PS, EGFR mutation status, smoking status, and PD-L1 were associated with the effectiveness of nivolumab., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Studies have suggested that chemotherapy after immune checkpoint inhibitors may confer an improved response for non-small cell lung cancer (NSCLC). However, potential selection bias in such studies has not been addressed. We therefore applied propensity score analysis to investigate the efficacy of chemotherapy after PD-1 inhibitor treatment (CAP) compared with chemotherapy alone., Methods: We conducted a retrospective observational cohort study for patients treated at 47 institutions across Japan between April 1, 2014 and July 31, 2017. Eligible patients had advanced or recurrent NSCLC who have undergone chemotherapy. Patients subsequently treated with chemotherapy (docetaxel with or without ramucirumab, S-1 or pemetrexed) either after PD-1 inhibitor therapy (CAP cohort) or alone (control cohort) were included. The primary end point was objective response rate (ORR). Inverse probability weighting (IPW) was applied to adjust for potential confounding factors., Results: A total of 1439 patients (243 and 1196 in the CAP and control cohorts, respectively) was available for unadjusted analysis. Several baseline characteristics-including age, histology, EGFR or ALK genetic alterations, and brain metastasis-differed significantly between the two cohorts. After adjustment for patient characteristics with the IPW method, ORR was 18.9% for the CAP cohort and 11.0% for the control cohort (ORR ratio 1.71; 95% CI 1.19 to 2.46; p=0.004). IPW-adjusted Kaplan-Meier curves showed that median progression-free survival (PFS) for the CAP and control cohorts was 2.8 and 2.7 months (IPW-adjusted HR 0.95; 95% CI 0.80 to 1.12; p=0.55), and median overall survival (OS) was 9.2 and 10.4 months (IPW-adjusted HR 1.05; 95% CI 0.86 to 1.28; p=0.63), respectively., Conclusions: After accounting for selection bias by propensity score analysis, CAP showed a significantly higher ORR compared with chemotherapy alone, with the primary end point of ORR being achieved. However, these results did not translate into a PFS or OS advantage, suggesting that prior administration of PD-1 inhibitors may result in a synergistic antitumor effect with subsequent chemotherapy, but that such an effect is transient. CAP therefore does not appear to achieve durable tumor control or confer a lasting survival benefit., Competing Interests: Competing interests: RK has received lecture fees from Bristol-Myers Squibb. HH has received honoraria from AstraZeneca K.K., Boehringer Ingelheim Japan, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan K.K., MSD K.K., Ono Pharmaceutical, Pfizer Japan, Novartis Pharma K.K., Merck Serono and Taiho Pharmaceutical; and research funding from AbbVie, AC MEDICAL, Astellas Pharma, AstraZeneca K.K., Boehringer Ingelheim Japan, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly Japan K.K., EPS Associates, GlaxoSmithKline K.K., Japan Clinical Research Operations, Kyowa Hakko Kirin, Merck Serono, MSD K.K., Novartis Pharma K.K., Ono Pharmaceutical, Otsuka Pharmaceutical, PAREXEL International, Pfizer Japan, PPD-SNBL K.K., Quintiles Transnational Japan K.K., Taiho Pharmaceutical, Takeda Pharmaceutical and Yakult Honsha. YC has received honoraria from Chugai Pharmaceutical. DF has received lecture fees from Eli Lilly Japan K.K., Boehringer Ingelheim Japan, Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Taiho Pharmaceutical, Novartis Pharma K.K., MSD K.K. and AstraZeneca K.K.; honoraria from Eli Lilly Japan K.K., Ono Pharmaceutical, Bristol-Myers Squibb, Taiho Pharmaceutical and AstraZeneca K.K.; and research funding from AstraZeneca K.K. RT has received honoraria from AstraZeneca K.K., Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan K.K., Kyowa Hakko Kirin, MSD K.K., Boehringer Ingelheim Japan, Nippon Kayaku, Ono Pharmaceutical and Taiho Pharmaceutical. AN has received honoraria from MSD K.K., AstraZeneca K.K. and Chugai Pharmaceutical. TK has received honoraria from Chugai Pharmaceutical, AstraZeneca K.K., Eli Lilly Japan K.K., Taiho Pharmaceutical, Bristol-Myers Squibb, Ono Pharmaceutical, MSD K.K., Pfizer Japan, Kyowa Hakko Kirin, Boehringer Ingelheim Japan, Nippon Kayaku; and research funding from Chugai Pharmaceutical, AstraZeneca K.K., Eli Lilly Japan K.K., Bristol-Myers Squibb, Pfizer Japan and Merck Serono. KT has received honoraria from Chugai Pharmaceutical, AstraZeneca K.K., Boehringer Ingelheim Japan, Eli Lilly Japan K.K., Ono Pharmaceutical. ST has received honoraria from Chugai Pharmaceutical, Novartis Pharma K.K., AstraZeneca K.K. and Taiho Pharmaceutical; and consulting fees from Boehringer Ingelheim Japan and AbbVie. KU has received lecture fees from AstraZeneca K.K., Boehringer Ingelheim Japan, Bristol-Myers Squibb, MSD K.K., Novartis Pharma K.K., Ono Pharmaceutical, Pfizer Japan and Taiho Pharmaceutical. KN has received honoraria from Chugai Pharmaceutical, AstraZeneca K.K., Boehringer Ingelheim Japan, MSD K.K., Bristol-Myers Squibb, Ono Pharmaceutical, Eli Lilly Japan K.K. and Novartis Pharma K.K.; and research funding from Boehringer Ingelheim Japan. OH has received honoraria from Eli Lilly Japan K.K., Novartis Pharma K.K., AstraZeneca K.K. and Boehringer Ingelheim Japan; and research funding from Novartis Pharma K.K., GlaxoSmithKline K.K., Daiichi Sankyo, Bayer Yakuhin, KYORIN Pharmaceutical, Boehringer Ingelheim Japan and Ono Pharmaceutical. YA has received honoraria from AstraZeneca K.K.; and research funding from Chugai Pharmaceutical. NY has received honoraria from AstraZeneca K.K., Boehringer Ingelheim Japan, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan K.K., MSD K.K., Novartis Pharma K.K., Ono Pharmaceutical, Pfizer Japan, Takeda Pharmaceutical and Taiho Pharmaceutical; research funding from Boehringer Ingelheim Japan, Chugai Pharmaceutical, Eli Lilly Japan K.K. and MSD K.K.; and consulting or advisory fees from AstraZeneca K.K., Boehringer Ingelheim Japan, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan K.K., MSD K.K., Novartis Pharma K.K., Ono Pharmaceutical, Pfizer Japan and Takeda Pharmaceutical. KN has received honoraria from Astellas Pharma, AstraZeneca K.K., Bristol-Myers Squibb, Chugai Pharmaceutical, Clinical Trial, Eli Lilly Japan K.K., MSD K.K., Nichi-Iko Pharmaceutical, Boehringer Ingelheim Japan, Novartis Pharma K.K., Ono Pharmaceutical, Pfizer Japan, Reno. Medical K.K. and Sym Bio Pharmaceuticals; research funding from A2 Healthcare, AbbVie, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly Japan K.K., EP-CRSU, GRITSTONE ONCOLOGY, ICON Japan K.K., inVentiv Health Japan, MSD K.K., Linical, Boehringer Ingelheim Japan, Novartis Pharma K.K., Ono Pharmaceutical, PAREXEL International, Pfizer Japan, Quintiles Quintiles, Taiho Pharmaceutical and Takeda Pharmaceutical; and consulting or advisory fees from Astellas Pharma, Takeda Pharmaceutical and Ono Pharmaceutical., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The J-ALEX study compared the efficacy and safety of alectinib with crizotinib in Japanese patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). Superiority in independent review facility (IRF)-assessed progression-free survival (PFS) was demonstrated for alectinib at the second pre-planned interim PFS analysis (data cutoff: December 3, 2015; hazard ratio [HR] 0.34, 99.7 % confidence interval [CI]: 0.17-0.71, P < 0.0001). We report final PFS data and the second pre-planned interim analysis of overall survival (OS) and safety (data cutoff: June 30, 2018)., Methods: Patients aged ≥20 years who were ALK inhibitor-naïve and chemotherapy-naïve, or had received one prior chemotherapy regimen, were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily. The primary end point was IRF-assessed PFS. Secondary end points included OS and safety. All patients entered survival follow-up in July 2018., Results: Median follow-up was 42.4 months for alectinib and 42.2 months for crizotinib. Sustained improvement in IRF-assessed PFS with alectinib was shown (HR 0.37, 95 % CI: 0.26-0.52; median PFS 34.1 months vs 10.2 months crizotinib). At the second interim OS analysis, superiority of alectinib to crizotinib could not be concluded (stratified HR 0.80, 99.8799 % CI: 0.35-1.82, stratified log-rank P = 0.3860; median OS not reached alectinib vs 43.7 months crizotinib). Fewer alectinib-treated patients experienced grade ≥3 adverse events (36.9 % vs 60.6 % crizotinib)., Conclusions: At the final PFS analysis, alectinib continued to demonstrate superiority in IRF-assessed PFS versus crizotinib in ALK-inhibitor-naïve ALK-positive NSCLC, with a favorable safety profile. OS follow-up continues., (Copyright © 2019. Published by Elsevier B.V.)

Background/aim: For immune checkpoint inhibitor (ICI)-pretreated patients, docetaxel and ramucirumab (DOC+RAM) combination therapy may be more effective compared to patients not receiving ICI treatment., Patients and Methods: From June 2013 to July 2018, 39 patients with advanced/recurrent non-small cell lung cancer underwent DOC+RAM therapy. We analyzed the efficacy and safety of DOC+RAM therapy based on the presence (pre-ICI+) or absence (pre-ICI-) of ICI pretreatment history., Results: Of the 39 patients treated with DOC+RAM, we identified 18 (46%) pre-ICI+ patients. Overall response rates for DOC+RAM concerning pre-ICI+ and pre-ICI- patients were 38.9% vs. 19.0%, respectively. Median progression-free survival (PFS) was 5.7 vs. 2.3 months [hazard ratio(HR)=0.36; 95% confidence interval (CI)=0.16-0.80]. Adverse events such as fever, myalgia, arthritis, pleural effusion, and pneumonitis tended to be increased in pre-ICI+ patients., Conclusion: Despite increased toxicity concerns, DOC+RAM therapy in pre-ICI+ patients showed a trend for tumor regression improvement and statistically significant prolongation of PFS., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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/m 2 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., (© 2019 The Authors. Asia-Pacific Journal of Clinical Oncology Published by John Wiley & Sons Australia, Ltd.)

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&#95;e/ctr&#95;view.cgi?recptno=R000019691., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Therapeutic approaches to bronchopleural fistula (BPF) closure after lung resection are surgical or endoscopic interventions. We evaluated therapeutic outcomes to determine the optimal approach. We reviewed 15 patients who had developed BPF after lung resection for thoracic malignant diseases at our institution in the 10 years since 2008. The patients were 11 men and 4 women (mean age 68 years). We performed one pneumonectomy, 6 lobectomies, 7 segmentectomies, and one partial resection for malignant diseases. The median interval from lung resection to the BPF diagnosis was 46 days. The BPF-associated mortality rate was 26.7% (4/15). The rate of successful BPF closure was 66.6% (10/15). The endoscopic and surgical intervention success rates were 14.2% (1/7) and 69.2% (9/13), respectively (p<0.01). Of 5 patients who had failed BPF treatments, 4 died, and one transferred out without BPF closure. The therapeutic outcomes were related to preoperative comorbidities, performance status at the BPF diagnosis, time intervals from lung resection to BPF diagnosis, and presence of active pneumonia. The difference between endoscopic and surgical outcomes was nonsignificant, although the surgical intervention success rate was somewhat higher. The selection of endoscopic or surgical intervention for BPF does not significantly affect therapeutic outcomes., Competing Interests: No potential conflict of interest relevant to this article was reported.

According to rapid development of chemotherapy in advanced non-small cell lung cancer (NSCLC), the Japan Lung Cancer Society has been updated its own guideline annually since 2010. In this latest version, all of the procedure was carried out in accordance with grading of recommendations assessment, development and evaluation (GRADE) system. It includes comprehensive literature search, systematic review, and determination of the recommendation by multidisciplinary expert panel which consisted of medical doctors, pharmacists, nurses, statisticians, and patients from patient advocacy group. Recently, we have had various types of chemotherapeutic drugs like kinase inhibitors or immune-checkpoint inhibitors. Thus, the guideline proposes to categorize patients into three entities: (1) driver oncogene-positive, (2) PD-L1 ≥ 50%, and (3) others. Based on this subgroup, 31 clinical questions were described. We believe that this attempt enables clinicians to choose appropriate treatment easier. Here, we report an English version of the Japan Lung Cancer Society Guidelines 2018 for NSCLC, stages IV.

Blockade of programmed cell death ligand-1 with durvalumab has shown efficacy and safety in large, international studies of patients with advanced solid tumors. A phase 1, non-randomized, open-label multicenter study was initiated to evaluate durvalumab in a Japanese population. The first part of this study used a standard 3 + 3 dose-escalation design to determine the optimal dosing schedule of durvalumab. Primary objective was evaluation of safety and tolerability of durvalumab monotherapy. Secondary objectives were to evaluate maximum tolerated dose (MTD), immunogenicity, pharmacokinetics, and efficacy. Twenty-two patients (median age, 61.5 years; range, 41-76; 64% male) received durvalumab at doses of 1, 3, or 10 mg/kg every 2 weeks (q2w), 15 mg/kg q3w, or 20 mg/kg q4w. Twenty patients discontinued before completing 12 months of treatment as a result of progressive disease and two due to adverse events (AE). The most common treatment-related AE (trAE) were rash (18%) and pruritus (14%); two patients had grade ≥3 trAE including one patient each with hyponatremia and hypothyroidism. No patient experienced a dose-limiting toxicity (DLT) during the DLT evaluation period and the MTD was not identified. There were no AE leading to a fatal outcome during study treatment. Durvalumab showed dose-proportional pharmacokinetics across the 1-20 mg/kg dose range; incidence of positive titers for antidrug antibodies was 9%. One patient with lung cancer had a partial response and disease control rate at 12 weeks was 36%. In conclusion, durvalumab at the doses and regimens evaluated was safe and well tolerated in Japanese patients with advanced solid tumors., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Introduction: Thymic carcinoma (TC) is a rare cancer with a poor prognosis and limited treatment options, especially after relapse., Methods: In this open-label, two-stage, multicentre, single-arm and phase II trial, the main eligibility criteria were unresectable or recurrent TC, an Eastern Cooperative Oncology Group-performance status of 0 or 1, progression after at least one chemo(radio)therapy and no history of autoimmune disease. Nivolumab was administered at a dose of 3 mg/kg every 2 weeks. The primary end-point was response rate (RR) as evaluated by central review using Response Evaluation Criteria In Solid Tumours (RECIST), version 1.1. The planned sample size was 15 for each stage, with a threshold RR of 5%, an expected RR of 20%, one-sided alpha of 5% and power of 80%., Results: Between July 1 and August 16 2016, 15 patients were accrued in the first stage. Response was assessable in all patients, and 13 had squamous histology. Median follow-up time was 14.1 months (range: 2.4-17.5). The median number of nivolumab received was eight (range: 3-33). RR was 0% (95% confidential interval [CI]: 0-21.8). Eleven patients had stable disease (SD) including five patients with SD for 24 or more weeks. Median progression-free survival was 3.8 months (95% CI: 1.9-7.0). Two patients experienced immune-related serious adverse events (grade III aspartate aminotransferase (AST) increase and grade II adrenal insufficiency). Because the early termination criteria (less than one responder) were fulfilled during the first stage, the patient accrual was terminated., Conclusions: Despite the small number of patients, nivolumab was unable to produce tumour shrinkage by RECIST in previously treated unresectable or recurrent TC., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Afatinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), has demonstrated a significant survival benefit over platinum-based chemotherapy in a first-line setting in advanced non-small-cell lung cancer (NSCLC) harboring EGFR exon 19 deletion. In addition, we and other groups have shown there to be favorable progression-free survival (PFS) outcomes, with acceptable toxicity profiles, with bevacizumab and first-generation EGFR-TKI combination therapy. On the basis of the above, we hypothesized that a combination of bevacizumab and afatinib could potentially improve efficacy. In our phase 1 study, a daily 30 mg dose of afatinib and 15 mg/kg intravenous bevacizumab every 3 weeks was well tolerated and was defined as the recommended dose. We have initiated a randomized phase 2 trial comparing afatinib (30 mg daily) and bevacizumab (15 mg/kg every 3 weeks) with afatinib (40 mg daily) alone for nonsquamous NSCLC harboring EGFR common mutations as a first-line therapy. A total of 100 patients will be enrolled onto this study and randomized in a 1:1 ratio. Patients will continue to receive treatment until disease progression or unacceptable toxicity. The primary end point is PFS, and the secondary end points are overall survival, tumor response, and time to treatment failure. The power is greater than 50% under the assumptions of a median PFS of 12 months for the afatinib group and a hazard ratio of 0.6 for the combination group (2-sided α = 0.05). We hypothesize that the combination therapy will be more efficacious than standard therapies for EGFR-mutant NSCLC patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: The phase II JO28638 study evaluated first-line onartuzumab plus erlotinib in patients with MET-positive advanced, metastatic, or post-operative recurrent non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The study was stopped following termination of the global METLung study (OAM4971g), which showed lack of efficacy in the onartuzumab/erlotinib arm. We present immature efficacy and safety data from JO28638., Materials and Methods: Chemotherapy-naïve patients aged ≥ 20 years were enrolled. Patients received onartuzumab (15 mg/kg every 3 weeks) plus erlotinib (150 mg once daily) until progression or unacceptable toxicity. The co-primary endpoints were investigator (INV)-assessed progression-free survival (PFS) and safety. Secondary endpoints: overall response rate (ORR), disease control rate (DCR), overall survival (OS), duration of response (DOR), and pharmacokinetics. Exploratory biomarker analyses were also conducted., Results: 61 patients received treatment. Median age was 67 years and most patients had stage IV NSCLC (71%), MET-IHC score 2 (87%), and exon 19 deletion EGFR mutation (53%). Median PFS (INV) was 8.5 months (95% confidence interval [CI] 6.8-12.4); median OS was 15.6 months (95% CI 15.6-not evaluable); ORR was 68.9% (95% CI 55.7-80.1); median DOR was not reached; DCR was 88.5% (95% CI 77.8-95.3). Pharmacokinetics were similar to previous studies. All patients experienced an adverse event (AE); 26 patients discontinued treatment due to AEs; no grade 5 AEs were reported. No significant correlation was found between biomarkers and efficacy outcomes., Conclusion: The results presented are inconclusive due to the early termination of the study., (Copyright © 2018. Published by Elsevier Ltd.)

[Purpose] The effect of physiotherapy on stooped posture in Parkinson's disease patients remains to be clarified. Therefore, the purpose of this study was to investigate whether comprehensive physiotherapy-based rehabilitation can improve stooped posture in Parkinson's disease patients. [Participants and Methods] The participants were Parkinson's disease patients with stooped posture. Outpatients were assigned to the control group and inpatients to the postural rehabilitation group. The outcomes measured were trunk bending angle, lumbar lordosis, and thoracic kyphosis. Each group was assessed at baseline and 1 month later. [Results] Of 22 participants identified, 20 were included, with 10 participants in the postural rehabilitation group and 10 in the control group. The age in the postural rehabilitation group was significantly greater than that in the control group, while other parameters were comparable in both groups. After the month-long intervention, the trunk bending angle and lumbar lordosis were significantly improved in the postural rehabilitation group compared to the control group. [Conclusion] The results showed improvement in stooped posture in the postural rehabilitation group as compared to the control group. Furthermore, improvement of lumbar lordosis accompanied improvement of stooped posture. These findings suggest that comprehensive physiotherapy-based rehabilitation may improve stooped posture in Parkinson's disease patients.

Although immune checkpoint inhibitors have shown significant survival benefits in the treatment of several cancers, optimal outcomes have been limited to certain subsets of patients. In a previous study, we found that the addition of metformin to nivolumab, an anti-programmed cell death protein 1 (PD-1) antibody, yielded substantial tumor regression in mouse models. Further analysis revealed that the number of tumor-infiltrating CD8 T cells had increased markedly. Based on this result, we have launched an investigator-initiated open-label phase-Ib clinical trial. The objectives of this trial are to investigate the safety, efficacy, and pharmacokinetics of a metformin-nivolumab combination treatment. This study consists of 2 parts. The recommended dose of metformin combined with nivolumab is determined in part 1. The safety and efficacy of the optimal dose of metformin to be delivered in conjunction with nivolumab are examined in part 2. Patient eligibility is based on the following criteria: pathologic diagnosis of refractory/recurrent solid tumor (part 1), and non-small-cell lung cancer or pancreatic cancer refractory to standard primary treatment (part 2); no prior use of immune checkpoint inhibitor; performance status 0 or 1; age ≥ 20 years; and adequate organ function. The primary endpoints are safety in part 1 and safety and pharmacokinetics in part 2. The maximum tolerated dose and recommended dose are determined in part 1 by the 3 + 3 cohort method, and the dose-limiting toxicity evaluation period for each patient is 4 weeks from the start of administration. In part 2, metformin is administered at the optimal dose determined in part 1. Total enrollment is 9 to 18 patients for part 1 and 30 patients for part 2. Enrollment began in 2017, and will be completed by 2019. The University Hospital Medical Information Network registration number for this study is 000028405., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The purpose of this study is to assess the efficacy and safety of combination chemotherapy with cisplatin, pemetrexed, and nivolumab for unresectable malignant pleural mesothelioma (MPM)., Patients and Methods: Patients with untreated, advanced, or metastatic MPM who meet the inclusion and exclusion criteria will be included. A total of 18 patients will be enrolled from 4 Japanese institutions within 1 year. Combination chemotherapy with cisplatin (75 mg/m 2 ), pemetrexed (500 mg/m 2 ), and nivolumab (360 mg/person) is administered every 3 weeks for a total of 4 to 6 cycles. Then, maintenance therapy with nivolumab will be administered until disease progression, unacceptable toxicities, or the patient's condition meets the withdrawal criteria. The primary end point is the centrally reviewed overall response rate. The secondary end points include the disease control rate, overall survival, progression-free survival, and adverse events., Conclusion: This phase II trial evaluating first-line combination chemotherapy for unresectable MPM commenced in January 2018. This is the first prospective trial to evaluate the effect of an anti-programmed death-1 antibody combined with cisplatin and pemetrexed for unresectable MPM., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of our study was to evaluate the efficacy and safety of docetaxel plus ramucirumab with primary prophylactic pegylated (PEG)-granulocyte-colony stimulating factor (G-CSF) for pretreated non-small cell lung cancer (NSCLC)., Results: Sixty-one pretreated NSCLC patients underwent docetaxel plus ramucirumab. Primary prophylactic PEG-G-CSF was performed in 52 (85%) patients (prophylactic group). No febrile neutropenia (FN) (0%) was confirmed in 52 prophylactic group patients, whereas FN was observed in 3 (33%) of 9 non-prophylactic group patients. Among prophylactic group, median lines of prior therapy was 2 (range, 1-9). Median cycles of docetaxel plus ramucirumab was 3 (range, 1-25) (9 and 3 cases moved to ramucirumab and docetaxel monotherapies, respectively). Response rate and disease control rate were 30.8% and 73.1%, respectively. Median progression-free survival was 4.5 (95% confidence interval [CI], 3.0-6.6) months. Median overall survival was 11.4 (95% CI, 8.0-13.9) months. Six (11.5%) patients had grade 3/4 neutropenia. Observed grade 3 (incidence ≥10%) adverse event (AE) was oral mucositis (13.5%). There were no grade 4/5 non-hematological AEs., Conclusions: Our study demonstrated the efficacy and safety of docetaxel plus ramucirumab with PEG-G-CSF in clinical practice. Primary prophylactic PEG-G-CSF could markedly reduce incidence of FN., Methods: We retrospectively reviewed medical records of pretreated NSCLC cases who had received docetaxel plus ramucirumab in our departments., Competing Interests: CONFLICTS OF INTEREST Akito Hata received lecture fee from Chugai, Astra Zeneca, Boeringer Ingelheim, and Eli Lilly. Daijiro Harada has received lecture fees from Ono, Bristol-Myers Squibb, Yakult Honsha, Kyowa Hakko Kirin, AstraZeneca, Nippon Boehringer Ingelheim and Eli Lilly Japan. Toshiyuki Kozuki has received honoraria from Chugai, AstraZeneca, Eli Lilly Japan, Boehringer–Ingelheim, Ono, Bristol-Myers Squibb, Taiho, MSD, Pfizer and Kyowa Hakko Kirin, and research funding from Chugai, AstraZeneca, MSD, and Eli Lilly Japan. Naoyuki Nogami has received honoraria from Astellas, AstraZeneca, Ono, Taiho, Chugai, Eli Lilly, Boehringer Ingelheim and Pfizer. Nobuyuki Katakami received grants from Astra Zeneca, Eisai, Ono, Kyowa Kirin, Shionogi, Daiichi-Sankyo, Taiho, Chugai, Eli Lilly, Boeringer Ingelheim, and Merck Serono, and payment for lectures from Dainippon Sumitomo, Chugai, Boeringer Ingelheim, Astra Zeneca, Eli Lilly, Taiho, Janssen, Novartis, Pfizer, Ono, and Daiichi-Sankyo. The other authors declare no conflicts of interest.

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., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

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, 40mg/day (level 0) and 30mg/day (level -1), were evaluated in combination with 15mg/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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib., Methods: J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen, from 41 study sites in Japan. Patients were randomly assigned (1:1) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status, treatment line, and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was progression-free survival assessed by an independent review facility. The efficacy analysis was done in the intention-to-treat population, and safety analyses were done in all patients who received at least one dose of the study drug. The study is ongoing and patient recruitment is closed. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-132316)., Findings: Between Nov 18, 2013, and Aug 4, 2015, 207 patients were recruited and assigned to the alectinib (n=103) or crizotinib (n=104) groups. At data cutoff for the second interim analysis, 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group, mostly due to lack of efficacy or adverse events. At the second interim analysis (data cutoff date Dec 3, 2015), an independent data monitoring committee determined that the primary endpoint of the study had been met (hazard ratio 0·34 [99·7% CI 0·17-0·71], stratified log-rank p<0·0001) and recommended an immediate release of the data. Median progression-free survival had not yet been reached with alectinib (95% CI 20·3-not estimated) and was 10·2 months (8·2-12·0) with crizotinib. Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib (54 [52%] of 104) than alectinib (27 [26%] of 103). Dose interruptions due to adverse events were also more prevalent with crizotinib (77 [74%] of 104) than with alectinib (30 [29%] of 103), and more patients receiving crizotinib (21 [20%]) than alectinib (nine [9%]) discontinued the study drug because of an adverse event. No adverse events with a fatal outcome occurred in either treatment group., Interpretation: These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study., Funding: Chugai Pharmaceutical Co, Ltd., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Topoisomerase (topo) IIα and IIβ maintain genome stability and are targets for anti-tumor drugs. In this study, we demonstrate that the decatenation checkpoint is regulated, not only by topo IIα, as previously reported, but also by topo IIβ. The decatenation checkpoint is most efficient when both isoforms are present. Regulation of this checkpoint and sensitivity to topo II-targeted drugs is influenced by the C-terminal domain (CTD) of the topo II isoforms and by a conserved non-catalytic tyrosine, Y640 in topo IIα and Y656 in topo IIβ. Deletion of most of the CTD of topo IIα, while preserving the nuclear localization signal (NLS), enhances the decatenation checkpoint and sensitivity to topo II-targeted drugs. In contrast, deletion of most of the CTD of topo IIβ, while preserving the NLS, and mutation of Y640 in topo IIα and Y656 in topo IIβ inhibits these activities. Structural studies suggest that the differential impact of the CTD on topo IIα and topo IIβ function may be due to differences in CTD charge distribution and differential alignment of the CTD with reference to transport DNA. Together these results suggest that topo IIα and topo IIβ cooperate to maintain genome stability, which may be distinctly modulated by their CTDs., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: In Japan, the clinical efficacy of erlotinib monotherapy in epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer was demonstrated in the phase II JO22903 trial, which reported a median progression-free survival of 11.8 months. Here we report final overall survival data from JO22903., Methods: JO22903 (JapicCTI-101085) was a single-arm, multicenter, phase II, open-label, non-randomized study of first-line erlotinib monotherapy in EGFR mutation-positive non-small-cell lung cancer. Eligible patients (≥20 years) with stage IIIB/IV or recurrent non-small-cell lung cancer and confirmed activating mutations of EGFR (exon 19 deletion or L858R point mutation in exon 21) received oral erlotinib 150 mg/day until disease progression or unacceptable toxicity. The primary endpoints were progression-free survival and safety; overall survival was a secondary endpoint., Results: At the final analysis, 102 patients were included in the modified intent-to-treat population and 103 in the safety population. Median follow-up was 32.3 months. Median overall survival was 36.3 months (95 % confidence interval 29.4-not reached). Subgroup analyses of overall survival suggested that the presence of brain metastases was a negative prognostic factor (median overall survival 22.7 months, 95 % confidence interval 19.6-29.4). The impact on overall survival of using versus not using EGFR tyrosine kinase inhibitors in any line of treatment following disease progression was unclear (median 32.8 versus 36.3 months, respectively). No new safety issues were observed., Conclusion: In this survival update, single-agent erlotinib achieved a median overall survival of more than 3 years in patients with EGFR mutation-positive non-small-cell lung cancer., Competing Interests: Noboru Yamamoto received honoraria from AstraZeneca, Eli Lilly, Pfizer and Chugai Pharmaceutical. He also received research funding from Daiichi-Sankyo, Kyowa-Kirin, Chugai Pharmaceutical, Eli Lilly, Takeda, Quintiles, Bristol-Myers Squibb, Astellas, Taiho, Pfizer, Novartis and Eisai. Koichi Goto received research funding from Chugai Pharmaceutical. Makoto Nishio received honoraria from Chugai Pharmaceutical, Boehringer Ingelheim and AstraZeneca. He also received research funding from Chugai Pharmaceutical and AstraZeneca. Kenichi Chikamori received honoraria from Chugai Pharmaceutical. He also received research funding from Chugai Pharmaceutical and Bristol-Myers Squibb. Toyoaki Hida received honoraria from Chugai Pharmaceutical, Taiho, AstraZeneca and Boehringer Ingelheim. He also received research funding from Chugai Pharmaceutical, Taiho, AstraZeneca, Boehringer Ingelheim, Clovis Oncology and Astellas. Makoto Maemondo received honoraria from Chugai Pharmaceutical, AstraZeneca and Boehringer Ingelheim. He also received research funding from Chugai Pharmaceutical, AstraZeneca and Boehringer Ingelheim. Nobuyuki Katakami received honoraria and research funding from Chugai Pharmaceutical. Toshiyuki Kozuki received honoraria from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Pfizer, Kyowa Kirin, Sanofi, Taiho and Roche. He also received research funding from Chugai Pharmaceutical, Bristol-Myers Squibb and Pfizer. Hiroshige Yoshioka received honoraria from Boehringer Ingelheim, Eli Lilly and Chugai Pharmaceutical. He also received research funding from Chugai Pharmaceutical, Novartis, Takeda, Pfizer, Merck-Serono, Eli Lilly and Kyowa Kirin. Takashi Seto received honoraria and lecture fees from Chugai Pharmaceutical. Kosei Tajima is an employee of Chugai Pharmaceutical. Tomohide Tamura received honoraria from Chugai Pharmaceutical, Taiho, Ono, Eli Lilly, Eisai, Yakult Honsha, Boehringer Ingelheim and Bristol-Myers Squibb.

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 patients with HER2+ lung cancers. The major eligibility criteria are as follows: age ≥ 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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: The treatment outcome in elderly patients with limited-disease small-cell lung cancer (LD-SCLC) remains poor. We carried out a phase II trial of split topotecan and cisplatin (TP) therapy and sequential thoracic radiotherapy for elderly LD-SCLC patients as a follow-up to our previous phase I trial., Methods: In total, 30 patients aged 76 years or older, with untreated LD-SCLC were enrolled. Four courses of topotecan (1.0 mg/m(2), days 1-3) and cisplatin (20 mg/m(2), days 1-3) were administered, followed by thoracic radiotherapy (1.8 Gy/day, total of 45 Gy). The primary end point was the overall response rate (ORR)., Results: The trial was terminated early with 22 patients because of slow accrual. Their median age was 79 years. The median number of courses of chemotherapy administered was three, and the actual completion rate of the entire treatment course was 41 %. The ORR was 68 % with a 95 % confidence interval of 47-89 % (15/22 cases). The median progression-free survival and overall survival were 9.1 and 22.2 months, respectively. The main toxicity was myelosuppression, with grades 3-4 neutropenia (96 %), thrombocytopenia (50 %), and febrile neutropenia (32 %)., Conclusions: This regimen produced a favorable survival outcome, despite moderate-to-severe toxicity profiles. Further efforts are necessary to define an optimal regimen for elderly patients with limited SCLC.