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BACKGROUND: It is unknown whether combined chemoradiotherapy improves overall survival in elderly patients with locally advanced non-small-cell lung cancer (NSCLC). The aim of this study was to assess whether radiotherapy plus carboplatin results in longer survival than radiotherapy alone in elderly patients with NSCLC. METHODS: This was a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Patients older than 70 years with unresectable stage III NSCLC were randomly assigned to chemoradiotherapy (60 Gy plus concurrent low-dose carboplatin [30 mg/m(2) per day, 5 days a week for 20 days]) or radiotherapy alone, using a minimisation method with biased-coin assignment balancing on Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1 vs 2), stage (IIIA vs IIIB), and institution. The primary endpoint was overall survival, which was analysed for the eligible population and stratified by ECOG performance status, stage, and institution. The trial was stopped early as a result of the second planned interim analysis. This study is registered with UMIN Clinical Trials Registry, number C000000060, and ClinicalTrials.gov, number NCT00132665. FINDINGS: 200 patients were enrolled from Sept 1, 2003 to May 27, 2010: 100 in the chemoradiotherapy group and 100 in the radiotherapy group. The second planned interim analysis was done 10 months after completion of patient accrual. At this time, median follow-up for censored cases was 19·4 months (IQR 10·3-33·5). In accordance with the prespecified stopping rule, the JCOG data and safety monitoring committee recommended early publication of this trial because the difference in overall survival favoured the chemoradiotherapy group. Median overall survival for the chemoradiotherapy and radiotherapy alone groups were 22·4 months (95% CI 16·5-33·6) and 16·9 months (13·4-20·3), respectively (hazard ratio 0·68, 95·4% CI 0·47-0·98, stratified log-rank test one-sided p value=0·0179). More patients had grade 3-4 haematological toxic effects in the chemoradiotherapy group than in the radiotherapy alone group, including leucopenia (61 [63·5%] vs none), neutropenia (55 [57·3%] vs none), and thrombocytopenia (28 [29·2%] vs two [2·0%]). Grade 3 infection was more common with chemoradiotherapy (12 patients [12·5%]) than with radiotherapy (four patients [4·1%]). Incidences of grade 3-4 pneumonitis and late lung toxicity were similar between groups. There were seven treatment-related deaths: three of 100 patients (3·0%) in the chemoradiotherapy group and four of 100 (4·0%) in the radiotherapy group. INTERPRETATION: For a select group of elderly patients with locally advanced NSCLC, combination chemoradiotherapy provides a clinically significant benefit over radiotherapy alone, and should be considered for this population. FUNDING: Ministry of Health, Labour, and Welfare of Japan. [ABSTRACT FROM AUTHOR]

Background: To elucidate the treatment and surgery outcomes with or without perioperative therapies in Japanese patients with clinical stage III non-small cell lung cancer (NSCLC) in real-world settings., Methods: We performed subset analyses of the SOLUTION study, a multicenter, noninterventional, observational study of Japanese patients diagnosed with clinical stage III NSCLC, for those who started first-line treatment (surgery±perioperative therapy) between January 2013 and December 2014 (study registration: UMIN000031385). Follow-up data were obtained using medical records from diagnosis to March 1, 2018., Results: Of 149 eligible patients, 67 underwent surgery alone (median age 71 years) and 82 underwent surgery+perioperative therapy (median age 63 years). Lung resection was performed in 137 patients and the others underwent exploratory thoracotomy or other procedures. Perioperative therapies included adjuvant therapy only (n = 41), neoadjuvant therapy only (n = 24), and neoadjuvant+adjuvant therapy (n = 17). The median overall survival (OS) and 3-year OS rate were 29.3 months and 44.0%, respectively, in patients who underwent surgery alone, and not reached and 61.1%, respectively, in patients who underwent surgery+perioperative therapy. The 3-year progression-free survival (PFS) and disease-free survival (DFS) rates were 42.4% and 47.1%, respectively, in patients who underwent surgery+perioperative therapy and 28.5% and 28.9%, respectively, in patients who underwent surgery alone. In multivariable Cox regression, perioperative therapy was associated with improved OS (hazard ratio [95% confidence interval] 0.49 [0.29-0.81]), PFS (0.62 [0.39-0.96]), and DFS (0.62 [0.39-0.97]) versus surgery alone., Conclusions: Our study suggested that perioperative therapy may be associated with better survival among patients undergoing surgical treatment of clinical stage III NSCLC., (© 2024 Astrazeneca and The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Tepotinib is a highly selective MET tyrosine kinase inhibitor (TKI) that has demonstrated robust and durable clinical activity in patients with MET exon 14 (METex14) skipping non-small-cell lung cancer (NSCLC). In the Phase II VISION study, patients received oral tepotinib 500 mg once daily. The primary endpoint was an objective response by an independent review committee (IRC) according to RECIST v1.1 criteria. The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Here we report the analysis of the efficacy and safety of tepotinib in all Japanese patients with advanced METex14 skipping NSCLC from VISION (n = 38) with >18 months' follow-up. The median age of the Japanese patients was 73 years (range 63-88), 39.5% of patients were ≥75 years old, 68.4% were male, 55.3% had a history of smoking, 76.3% had adenocarcinoma, and 10.5% of patients had known brain metastases at baseline. Overall, the objective response rate (ORR) was 60.5% (95% confidence interval (CI): 43.4, 76.0) with a median DOR of 18.5 months (95% CI: 8.3, not estimable). ORR in treatment-naïve patients (n = 18) was 77.8% (95% CI: 52.4, 93.6), and in patients aged ≥75 years (n = 15), ORR was 73.3% (95% CI: 44.9, 92.2). The most common treatment-related adverse event (AE) with any grade was blood creatinine increase (65.8%), which resolved following tepotinib discontinuation. Other common treatment-related AEs were peripheral edema (60.5%), hypoalbuminemia (34.2%), diarrhea (28.9%), and nausea (15.8%). In summary, tepotinib demonstrated robust and durable clinical activity irrespective of age or therapy line, with a manageable safety profile in Japanese patients with METex14 skipping NSCLC enrolled in VISION., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

In the open-label, phase III CheckMate 816 study (NCT02998528), neoadjuvant nivolumab plus chemotherapy demonstrated statistically significant improvements in event-free survival (EFS) and pathological complete response (pCR) versus chemotherapy alone in patients with resectable non-small-cell lung cancer (NSCLC). Here we report efficacy and safety outcomes in the Japanese subpopulation. Patients with stage IB-IIIA, resectable NSCLC were randomized 1:1 to nivolumab plus chemotherapy or chemotherapy alone for three cycles before undergoing definitive surgery within 6 weeks of completing neoadjuvant treatment. The primary end-points (EFS and pCR) and safety were assessed in patients enrolled at 16 centers in Japan. Of the Japanese patients randomized, 93.9% (31/33) in the nivolumab plus chemotherapy arm and 82.9% (29/35) in the chemotherapy arm underwent surgery. At 21.5 months' minimum follow-up, median EFS was 30.6 months (95% confidence interval [CI], 16.8-not reached [NR]) with nivolumab plus chemotherapy versus 19.6 months (95% CI, 8.5-NR) with chemotherapy; hazard ratio, 0.60 (95% CI, 0.30-1.24). The pCR rate was 30.3% (95% CI, 15.6-48.7) versus 5.7% (95% CI, 0.7-19.2), respectively; odds ratio, 7.17 (95% CI, 1.44-35.85). Grade 3/4 treatment-related adverse events were reported in 59.4% versus 42.9% of patients, respectively, with no new safety signals identified. Neoadjuvant nivolumab plus chemotherapy resulted in longer EFS and a higher pCR rate versus chemotherapy alone in Japanese patients, consistent with findings in the global population. These data support nivolumab plus chemotherapy as a neoadjuvant treatment option in Japanese patients with resectable NSCLC., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: This study evaluated the efficacy and safety of the combination chemotherapy of docetaxel plus S-1 in patients with previously treated non-small cell lung cancer (NSCLC) compared to docetaxel alone., Methods: Patients with previously treated NSCLC were randomly assigned to docetaxel alone (arm A) or a combination of docetaxel and S-1 (arm B) for a maximum of four cycles. The primary endpoint was overall survival (OS)., Results: The study was terminated early because of poor accrual. The number of patients evaluated were 74 and 77 in arm A and arm B, respectively. The median OS was 9.8 months (95% confidence interval [CI]: 6.8-15.2) and 12.3 months (95% CI: 9.2-14.5) in arms A and B, respectively. In arms A and B, the median progression-free survival was 3.5 months (95% CI: 2.7-4.0) and 4.1 months (95% CI: 3.2-4.7), respectively. No statistically significant difference was observed in OS (hazard ratio [HR]: 0.984, 95% CI: 0.682-1.419, p = 0.4569) or progression-free survival (HR: 0.823, 95% CI: 0.528-1.282, p = 0.0953). The major toxicity was myelosuppression. The incidence of grade 3 or more neutropenia was higher in arm A than in arm B (44.6% vs. 35.1%). However, the incidence of grade 3 or more febrile neutropenia and infection with neutropenia (12.2% vs. 22.1%) was more frequently observed in arm B., Conclusions: The prematurely terminated study did not show the benefit of two cytotoxic agents over single-agent therapy for previously treated NSCLC patients., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Objectives: Opioids are often administered for cancer-related pain relief. However, few reports have evaluated the association between opioids and immune checkpoint inhibitor treatment for patients with non-small-cell lung cancer (NSCLC). The aim of this retrospective study was to reveal the effect of opioids on the prognosis of patients harbouring NSCLC treated with nivolumab., Methods: The medical records of consecutive patients with NSCLC receiving nivolumab at our institution were retrospectively reviewed. We collected clinical data at the time of nivolumab treatment initiation. Propensity score matching (PSM) was performed to minimise potential selection bias. We compared clinical outcomes with and without baseline opioid use., Results: Of the 296 patients identified in the study, after PSM, 38 cases with opioid use and matched 38 cases without opioid use were selected. The overall response rate was significantly lower in patients with opioid use than in those without (2.63%, 95% CI 0.47% to 13.49%, vs 21.05%, 95% CI 11.07% to 36.35%; p=0.0284). The median progression-free survival in patients with opioid use was significantly shorter than that in patients without (1.17, 95% CI 0.93 to 1.73 months, vs 2.07 95% CI 1.23 to 4.73 months; p=0.002). The median overall survival in patients with opioid use was significantly shorter than that in patients without (4.20, 95% CI 2.53 to 6.20 months, vs 9.57, 95% CI 2.23 to not reached months; p=0.018)., Conclusions: Patients with NSCLC receiving regular opioid administration at nivolumab treatment initiation had a worse nivolumab treatment outcome than patients without opioid use., Competing Interests: Competing interests: YT reports grants and personal fees from Ono Pharmaceutical and Bristol-Myers Squibb and personal fees from Chugai Pharmaceutical and AstraZeneca, all outside the submitted work. AT reports grants and personal fees from Ono Pharmaceutical, Bristol-Myers Squibb and AstraZeneca and personal fees from Chugai Pharmaceutical, Eli Lilly Japan, Taiho Pharmaceutical, MSD, Pfizer, and Boehringer Ingelheim, all outside the submitted work. YA reports personal fees from Daiichi Sankyo Company and Taiho Pharmaceutical, all outside the submitted work. AT reports personal fees from Daiichi Sankyo, Shionogi, Mundipharma, Kirin-Kyowa, and Kracie, all outside the submitted work. SA reports grants and personal fees from Ono Pharmaceutical, Bristol-Myers Squibb, Pfizer, Taiho Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Eli Lilly, and Boehringer Ingelheim and grants from Yakult Pharmaceutical Industry and MSD, all outside the submitted work. The remaining authors have no disclosures., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), such as erlotinib, are standard-of-care for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC), but most patients progress within 1 year. Previously, we demonstrated that erlotinib plus bevacizumab (EB) improved progression-free survival (PFS) in patients with EGFR -positive non-squamous NSCLC in the randomized JO25567 study. To understand this effect, we conducted comprehensive exploratory biomarker analyses., Methods: Using blood and tissue specimens from patients enrolled in the JO25567 study, angiogenesis-related serum factors, plasma vascular endothelial growth factor-A (pVEGFA), angiogenesis-related gene polymorphisms, and messenger RNAs (mRNAs) in tumor tissue were analyzed. Interactions between potential predictors and treatment effect on PFS were analyzed in a Cox model. Continuous variable predictors were evaluated by multivariate fractional polynomial interaction methodology and subpopulation treatment effect pattern plotting (STEPP)., Results: Overall, 152 patients treated with EB or erlotinib alone (E) were included in the analysis. Among 26 factors analyzed in 134 baseline serum samples, high follistatin and low leptin were identified as potential biomarkers for worse and better outcomes with EB, with interaction P values of 0.0168 and 0.0049, respectively. Serum concentrations of 12 angiogenic factors were significantly higher in patients with high follistatin. Low pVEGFA levels related to better outcomes with EB, interaction P=0.033. VEGF-A165a was the only predictive tissue mRNA, showing a similar trend to pVEGFA. No valid results were obtained in 13 polymorphisms of eight genes., Conclusions: EB treatment showed better treatment outcomes in patients with low pVEGFA and serum leptin, and limited efficacy in patients with high serum follistatin., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-632/coif). TH serves as an unpaid editorial board member of Translational Lung Cancer Research from January 2022 to December 2023. MN reports receiving grants and personal fees from AstraZeneca, Amgen, MSD, Taiho Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Novartis, Pfizer, Bristol-Myers Squibb, and Merck Biopharma; personal fees from Ono Pharmaceutical, Boehringer Ingelheim, and Janssen Pharmaceutical; and grants from Daiichi-Sankyo. SA reports grants from AstraZeneca, Eli Lilly, Ono, Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, MSD, Chugai Pharmaceutical, Merck, and F. Hoffmann-La Roche; and honoraria from Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, Sawai Pharmaceutical, Novartis Pharma, AstraZeneca, Ono, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Hisamitsu, MSD, Kyowa Hakko Kirin, Merck, and Thermo Fisher Scientific. KG reports receiving research grants from Amgen Astellas BioPharma, Amgen, AstraZeneca, Bayer Yakuhin, Ltd., Bristol-Myers Squibb K.K., Boehringer Ingelheim Japan, Inc., Blueprint Medicines Corporation, Daiichi-Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Haihe Biopharma Co., Ltd., Ignyta, Inc., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Life Technologies Japan Ltd., Loxo Oncology, Inc., Medical & Biological Laboratories Co., Ltd., Merck Biopharma Co., Ltd., Merus N.V., MSD K.K., NEC Corporation, Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sumitomo Dainippon Pharma Co., Ltd., Spectrum Pharmaceuticals, Inc., Sysmex Corporation, Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Turning Point Therapeutics, Inc.; honoraria from Amgen Inc., AstraZeneca K.K., Bayer HealthCare Pharmaceuticals Inc., Boehringer Ingelheim Japan, Inc., Bristol-Myers Squibb K.K., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Guardant Health Inc., Janssen Pharmaceutical K.K., Kyowa Kirin Co., Ltd., Life Technologies Japan Ltd., Medpace Japan K.K., Merck Biopharma Co., Ltd., MSD K.K., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Taiho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. YH reports receiving payment/honoraria from Chugai Pharmaceutical, AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Bristol-Myers Squibb, Kyowa Kirin, and Ono Pharmaceutical. TS reports receiving institutional funding from AbbVie, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Kissei Pharmaceutical, MSD, Novartis Pharma, Pfizer Japan, Takeda Pharmaceutical; honoraria from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Covidien Japan, Daiichi Sankyo, Eli Lilly Japan, Kyowa Hakko Kirin, MSD, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, Takeda Pharmaceutical, and Towa Pharmaceutical; and is an employee of Precision Medicine Asia. TH reports receiving research grants from Chugai Pharmaceutical, AstraZeneca, Nippon Boehringer Ingelheim, Pfizer, Eli Lilly, Takeda Bio, Novartis Pharma, Ono Pharmaceutical, Daiichi-Sankyo, Merck Serono, Dainippon Sumitomo Pharma, Bristol-Myers Squibb, and Eisai. Kazuhiko Nakagawa reports receiving honoraria from Chugai Pharmaceutical, AstraZeneca, Nippon Boehringer Ingelheim, and Eli Lilly. HY reports research grants from Chugai Pharmaceutical, Boehringer Ingelheim, and Nippon Kayaku; consulting fees from Delta Fly Pharma; honoraria from Eli Lilly, Chugai Pharmaceutical, Boehringer Ingelheim, Delta Fly Pharma, AstraZeneca, BMS, MSD, Ono Pharmaceutical, Merck Biopharma, Nippon Kayaku, Taiho Pharmaceutical, Otsuka Pharmaceutical, Takeda Pharmaceutical, Novartis Pharmaceutical, Amgen, Nipro Pharma, Kyowa Kirin, and Pfizer. NN reports receiving honoraria from Chugai Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, AstraZeneca, and Nippon Boehringer Ingelheim. MM reports receiving honoraria from Chugai Pharmaceutical and AstraZeneca; research grants and honoraria from Nippon Boehringer Ingelheim. IO reports receiving payment/honoraria from Chugai Pharmaceutical. Noboru Yamamoto reports receiving research grants from Chugai Pharmaceutical, Taiho Pharmaceutical, Eisai, Eli Lilly, Quintiles, Astellas Pharma, Bristol-Myers Squibb, Novartis, Daiichi-Sankyo, Pfizer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, Ono Pharmaceutical Co., Ltd., Takeda, Janssen Pharma, MSD, Merck, GSK, Sumitomo Dainippon, Chiome Bioscience Inc, Otsuka, Carna Bioscienes, Genmab, and Shionogi; honoraria from Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Pfizer, Eli Lilly, Bristol-Myers Squibb, Sysmex, and Eisai; and consulting fees from Eisai, Otsuka, Takeda, Boehringer Ingelheim, and Cimic. YI and KT are employees of Chugai Pharmaceutical. MF reports receiving honoraria from Eisai and Chugai Pharmaceutical. Nobuyuki Yamamoto reports receiving grants from MSD K.K., AstraZeneca, Ono Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd., Taiho Pharmaceutical., Takeda, Chugai Pharmaceutical Co., Ltd., Pfizer, Amgen, Janssen Pharmaceutical K.K., Toppan Printing, Terumo, and Boehringer Ingelheim; consulting fees from AstraZeneca, Daiichi-Sankyo, Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Boehringer Ingelheim, Novartis, Bristol-Myers Squibb, Nippon Kayaku, Life Technologies Japan, Ltd., Amgen, Guardant Health Japan, and Janssen Pharmaceutical K.K.; honoraria from MSD, AstraZeneca, Ono Pharmaceutical, Thermo Fisher Scientific, Daiichi-Sankyo, Taiho Pharmaceutical, Takeda, Chugai Pharmaceutical, Eli Lilly Japan K.K., Boehringer Ingelheim, Novartis, Pfizer, Bristol-Myers Squibb, Nippon Kayaku, GSK K.K., Sanofi K.K., Hisamitsu Pharmaceutical, and Merck Biopharma; and participated on a data safety monitoring board/advisory board for MSD K.K., AstraZeneca, Ono Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, Eli Lilly Japan K.K., Boehringer Ingelheim, and Pfizer. Kazuto Nishio reports receiving grants from Nippon Boehringer Ingelheim, West Japan Oncology Group, Thoracic Oncology Research Group, North East Japan Study Group, Clinical Research Support Center Kyushu, Nichirei Biosciences Inc., and Eli Lilly Japan; consulting fees from SymBio Pharmaceuticals, Solasia Pharma, Eli Lilly Japan, and Otsuka Pharmaceutical; honoraria for lectures from Boehringer Ingelheim Japan, AstraZeneca, Chugai, Novartis Pharma, Eisai, MSD, Bristol-Myers Squibb, Ono Pharmaceutical, Pfizer, Sanofi, Guardant Health, Eli Lilly Japan, Amgen, Merck Biopharma, Roche Diagnostics, Yakult Honsha, Takeda Pharmaceutical, Fujirebio, and Janssen Pharmaceutical. All authors report receiving funding from Chugai Pharmaceutical Co., Ltd. The authors have no other conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

Background: Previous trials suggest that older adults with non-small cell lung cancer (NSCLC) derive benefit from platinum doublet combination therapy, but its superiority is controversial. Although geriatric assessment variables are used to assess the individual risk of severe toxicity and clinical outcomes in older patients, the standard first-line treatment is still debated. Therefore, we aimed to identify the risk factors for clinical outcomes in older patients with NSCLC., Methods: Patients aged ≥75 years with advanced NSCLC treated at any of 24 National Hospital Organization institutions completed a pre-first-line chemotherapy assessment, including patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables. We evaluated whether these variables were the risk factors for progression-free survival (PFS) and overall survival (OS)., Results: A total of 148 patients with advanced NSCLC were treated with combination therapy (n = 90) or monotherapy (n = 58). Median PFS was 5.3 months and OS was 13.6 months. We identified that hypoalbuminemia (hazard ratio [HR] 2.570, 95% confidence interval [CI]: 1.117-5.913, p = 0.0264) was a risk factor for PFS and monotherapy (HR 1.590, 95% CI: 1.070-2.361, p = 0.0217), lactate dehydrogenase (HR 3.682, 95% CI: 1.013-13.39, p = 0.0478), and high C-reactive protein (HR 2.038, 95% CI: 1.141-3.642, p = 0.0161) were risk factors for OS. The median OS was significantly longer in patients treated with combination therapy than in those who received monotherapy (16.5 months vs. 10.3 months; HR 0.684, 95% CI: 0.470-0.995, p = 0.0453)., Discussion: Platinum doublet combination therapy may be beneficial in older patients with NSCLC. Identification of risk factors will assist in the development of a personalized treatment strategy., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Introduction: In the CAPITAL study, a randomized phase 3 study, wherein carboplatin plus nab-paclitaxel treatment was compared with docetaxel treatment for older patients with squamous-cell lung cancer, the former became the new standard of care for such patients. Our study aimed to evaluate whether the efficacy of second-line immune checkpoint inhibitors (ICIs) affected the primary analysis of overall survival (OS)., Methods: Herein, we performed a post hoc analysis of the impact of second-line ICIs on OS, safety in each group of participants aged more than 75 years, and intracycle nab-paclitaxel skip status., Results: Patients were randomly allocated to the carboplatin plus nab-paclitaxel (nab-PC) arm (n = 95) or the docetaxel (D) arm (n = 95). Of these patients, 74 of 190 (38.9%) were transferred to ICIs for second-line treatment (nab-PC arm: 36, D arm: 38). A survival benefit was numerically observed only for patients for whom first-line therapy was terminated owing to disease progression (median OS [nab-PC arm]: with and without ICIs, 321 and 142 d, respectively; median OS [D arm]: with and without ICIs, 311 and 256 d, respectively). The OS among patients who received ICI after adverse events was similar in the two arms. In the D arm, a significantly higher frequency of grade greater than or equal to 3 adverse events was observed among patients aged more than or equal to 75 years (86.2%) than among those aged less than 75 years (65.6%, p  = 0.041), including a significantly higher frequency of neutropenia (84.6% versus 62.5%, p  = 0.032); no such differences were observed in the nab-PC arm., Conclusions: We found that second-line ICI treatment seemed to have a little impact on OS., (© 2023 The Authors.)

Background: Nab-paclitaxel (nab-PTX) has better transfer to tumor tissue than cremophor-based paclitaxel. It suggests that the optimum dose of nab-PTX might be lower than the dose and schedule that is widely used. We designed a randomized phase II trial to examine the clinical utility and safety of nab-PTX in patients with previously treated advanced non-small cell lung cancer (NSCLC)., Methods: Patients were randomly allocated (1:1) to receive nab-PTX monotherapy at 100 mg/m 2 (group A) or 70 mg/m 2 (group B). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs)., Results: Finally, 81 patients were randomized. Similar results were observed in both groups for PFS (3.75 vs. 3.71 months), OS (13.50 vs. 16.13 months), or ORR (20.5% vs. 23.1%). The incidences of grade 3 or worse AEs were 57.5% in group A and 41.5% in group B. The proportion of serious side effects was 10.0% in group A and 4.9% in group B., Conclusion: Both standard dose and low dose of nab-PTX monotherapy are active for previously treated NSCLC patients with better safety profile. Therefore, nab-PTX 70 mg/m 2 dose and schedule in the trial would be a reasonable option., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease implicated as an independent risk factor for lung cancer. However, optimal treatment for advanced lung cancer with IPF remains to be established. We performed a randomised phase 3 trial (J-SONIC) to assess the efficacy and safety of nintedanib plus chemotherapy (experimental arm) compared with chemotherapy alone (standard-of-care arm) for advanced nonsmall cell lung cancer (NSCLC) with IPF., Methods: Chemotherapy-naïve advanced NSCLC patients with IPF were allocated to receive carboplatin (area under the curve of 6 on day 1) plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) (100 mg·m -2 on days 1, 8 and 15) every 3 weeks with or without nintedanib (150 mg twice daily, daily). The primary end-point was exacerbation-free survival (EFS)., Results: Between May 2017 and February 2020, 243 patients were enrolled. Median EFS was 14.6 months in the nintedanib plus chemotherapy group and 11.8 months in the chemotherapy group (hazard ratio (HR) 0.89, 90% CI 0.67-1.17; p=0.24), whereas median progression-free survival was 6.2 and 5.5 months, respectively (HR 0.68, 95% CI 0.50-0.92). Overall survival was improved by nintedanib in patients with nonsquamous histology (HR 0.61, 95% CI 0.40-0.93) and in those at GAP (gender-age-physiology) stage I (HR 0.61, 95% CI 0.38-0.98). Seven (2.9%) out of 240 patients experienced acute exacerbation during study treatment., Conclusions: The primary end-point of the study was not met. However, carboplatin plus nab-paclitaxel was found to be effective and tolerable in advanced NSCLC patients with IPF. Moreover, nintedanib in combination with such chemotherapy improved overall survival in patients with nonsquamous histology., Competing Interests: Conflict of interest: K. Otsubo has received honoraria from Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, Boehringer Ingelheim, ONO Pharmaceutical, AstraZeneca, Novartis, Merck and Thermo Fisher Scientific. H. Kenmotsu has received grants from Chugai Pharmaceutical, Novartis, Daiichi Sankyo, AstraZeneca and Loxo Oncology; and honoraria from Chugai Pharmaceutical, ONO Pharmaceutical, Boehringer Ingelheim, Eli Lilly, Kyowa Kirin, Bristol-Myers Squibb, MSD, Novartis, Daiichi Sankyo, AstraZeneca, Pfizer and Taiho Pharmaceutical. Y. Minegishi has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, ONO Pharmaceutical, Taiho Pharmaceutical and Chugai Pharmaceutical. H. Horinouchi has received grants from MSD, AbbVie, AstraZeneca, Bristol-Myers Squibb, ONO Pharmaceutical, Merck, Daiichi Sankyo, Janssen, Genomic Health, Chugai Pharmaceutical, Roche and Novartis; honoraria from AstraZeneca, MSD, Eli Lilly, ONO Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Roche, Kyowa Kirin and Novartis; and fees for membership of an advisory board from Roche, AstraZeneca, Eli Lilly, Chugai Pharmaceutical, Roche, ONO Pharmaceutical, Bristol-Myers Squibb and MSD. T. Kato received grants from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Merck, MSD, Novartis, ONO Pharmaceutical, Pfizer and Regeneron; honoraria from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Merck, MSD, Novartis, Pfizer and Boehringer Ingelheim; fees for membership of an advisory board from AbbVie, AstraZeneca, Daiichi Sankyo, MSD, Merck, Amgen, Chugai Pharmaceutical, Eli Lilly, Novartis and Nippon Kayaku; and fees for membership of an independent data monitoring committee from Chugai Pharmaceutical, Taiho Pharmaceutical, Takeda and ONO Pharmaceutical. E. Ichihara has received grants from Eli Lilly and MSD; and honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Bristol-Myers Squibb, Novartis, ONO Pharmaceutical, Taiho Pharmaceutical, Takeda and Chugai Pharmaceutical. M. Kondo has received consulting fees from Takeda; and honoraria from Chugai Pharmaceutical, Eli Lilly, Pfizer, AstraZeneca, ONO Pharmaceutical, Bristol-Myers Squibb and MSD. S. Atagi has received grants from AstraZeneca, Eli Lilly, ONO Pharmaceutical, Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, MSD, Chugai Pharmaceutical, Merck and Roche; and honoraria from AstraZeneca, Eli Lilly, ONO Pharmaceutical, Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Hisamitsu Pharmaceutical, MSD, Chugai Pharmaceutical, Kyowa Kirin, Merck, Novartis and Thermo Fisher Scientific. M. Tamiya has received grants and honoraria from Boehringer Ingelheim. S. Ikeda has received grants from AstraZeneca and Chugai Pharmaceutical; and honoraria from Chugai Pharmaceutical, ONO Pharmaceutical, Boehringer Ingelheim, Eli Lilly, Bristol-Myers Squibb, AstraZeneca, Pfizer and Taiho Pharmaceutical. H. Hayashi has received reports grants from AstraZeneca, Astellas, MSD, ONO Pharmaceutical, Boehringer Ingelheim, Novartis, Pfizer, Bristol-Myers Squibb, Eli Lilly, Chugai Pharmaceutical, Daiichi Sankyo, Merck, Takeda, Taiho Pharmaceutical, SymBio Pharmaceuticals, AbbVie, inVentiv Health Japan, ICON Japan, Gritsone Oncology, Parexel, Kissei Pharmaceutical, EPS Corporation, Syneos Health, Pfizer R&D Japan, A2 Healthcare, IQVIA, EP-CRSU, Eisai, CMIC Shift Zero, Kyowa Kirin, Bayer Yakuhin, EPS and Otsuka Pharmaceutical; consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Pfizer, Shanghai Haihe Biopharm, Takeda and Merck; and honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Kyorin, Merck, Ltd, MSD, Novartis, ONO Pharmaceutical, Taiho Pharmaceutical and Takeda. Y. Kimura has received honoraria from AstraZeneca, Boehringer Ingelheim and Taiho Pharmaceutical. Y. Kondoh has received honoraria from Asahi Kasei Pharma, Shionogi, Boehringer Ingelheim, AstraZeneca, Eisai, Kyorin, Mitsubishi Tanabe Pharma and Novartis; and fees for membership of a data safety monitoring board or an advisory board from Asahi Kasei Pharma, Shionogi, Boehringer Ingelheim, Janssen, Healios, Chugai Pharmaceutical and Taiho Pharmaceutical. M. Kusumoto has received grants from Canon medical systems; and honoraria from AstraZeneca and Daiichi Sankyo. N. Yamamoto has received honoraria from MSD, AstraZeneca, ONO Pharmaceutical, Thermo Fisher Scientific, Daiichi Sankyo, Taiho Pharmaceutical, Takeda, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Novartis, Pfizer, Bristol-Myers Squibb, Nippon Kayaku, GlaxoSmithKline, Sanofi, Hisamitsu Pharmaceutical and Merck; and fees for membership of a data safety monitoring board or an advisory board from MSD, AstraZeneca, ONO Pharmaceutical, Taiho Pharmaceutical, Takeda, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Novartis, Pfizer, Bristol-Myers Squibb, Life Technologies Japan, Nippon Kayaku, Amgen, Guardant Health and Janssen. K. Nakagawa has received grants from Takeda, Taiho Pharmaceutical, SymBio Pharmaceuticals, AbbVie, ICON, Parexel, Kissei Pharmaceutical, EPS, Syneos Health, Pfizer R&D Japan, A2 Healthcare, IQVIA, Eisai, CMIC Shift Zero, Kyowa Kirin, Bayer Yakuhin, Otsuka Pharmaceutical, PRA Health Sciences, Covance, Medical Research Support, Sanofi, PPD-SNBL, Japan Clinical Research Operations, Sysmex, Mochida Pharmaceutical and GlaxoSmithKline; honoraria from AstraZeneca, Chugai Pharmaceutical, Takeda, Roche, MSD, Eli Lilly, Nippon Kayaku, ONO Pharmaceutical, Astellas, Bayer Yakuhin, Merck, Nanzando, Daiichi Sankyo, Novartis, Kyowa Kirin, Medical Mobile Communications, Yomiuri Telecasting Corporation, Nikkei Business Publications, Boehringer Ingelheim, Medicus Shuppan, Taiho Pharmaceutical, Pfizer, AbbVie, Bristol-Myers Squibb, CareNet, Amgen, Medical Review, Yodosha, 3H Clinical Trial, Thermo Fisher Scientific, Hisamitsu Pharmaceutical, Nichi-Iko Pharmaceutical and Kyorin; and payment for expert testimony from Astellas, Takeda, Eli Lilly, Pfizer, Kyorin and ONO Pharmaceutical. Y. Nakanishi has received grants from ONO Pharmaceutical; and honoraria from MSD, ONO Pharmaceutical, AstraZeneca, Pfizer and Boehringer Ingelheim. I. Okamoto has received grants from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, ONO Pharmaceutical, MSD, Eli Lilly, Astellas, Bristol-Myers Squibb, Novartis, Chugai Pharmaceutical, Pfizer and AbbVie; consulting fees from AstraZeneca, Bristol-Myers Squibb and AbbVie; and honoraria from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, ONO Pharmaceutical, MSD, Eli Lilly, Bristol-Myers Squibb, Novartis, Chugai Pharmaceutical and Pfizer. All other authors declare no competing interests., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Introduction: Previous studies have developed risk stratification schemas to assess systemic therapy toxicity. However, it is controversial which geriatric assessment variables should be used to assess the individual risk of severe treatment-associated toxicity in older adult patients., Materials and Methods: Patients aged ≥70 years with advanced non-small cell lung cancer (NSCLC) treated at 24 National Hospital Organization institutions completed a pre-first-line systemic therapy assessment, including patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables. Patients were followed through one cycle of systemic therapy to assess grade 3 (severe) to grade 5 (death) adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0., Results: In total, 348 advanced NSCLC patients with a median age of 76 years (range, 70 to 95 years) joined this prospective study. Severe adverse events ≥grade 3 occurred in 136 patients (39.1%). Predictors of hematologic toxicity were treatment variables, body mass index, body weight loss, and limitation in daily living due to dementia. These predictors provided the predictive model of hematologic toxicity ≥grade 3; 0 point (22.2%), 1 point (33.8%), 2 points (59.6%), ≥3 points (73.3%). Sex, daily living independence level, and lactate dehydrogenase levels were associated with non-hematologic toxicity ≥grade 3 in multivariate analysis. A scoring system using these predictors distinguished the risk levels of non-hematologic toxicity ≥grade 3; 0 point (6.6%), 1 point (12.2%), 2 points (39.0%), 3 points (75.0%)., Discussion: A stratification using individual extracted risk factors may be useful to predict the vulnerability to systemic therapy in older adult NSCLC patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Gefitinib (G) is a recommended molecular-targeted agent for elderly patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Docetaxel (Doc) and pemetrexed (Pem) have similar efficacies, and either is often used as the sole agent during treatment. The efficacy of continuing G after progressive disease (PD) develops has been reported. It remains unclear whether the continuation of G in combination with a single cytotoxic agent beyond PD is beneficial for elderly patients. Here, we conducted a randomized phase II study to assess the efficacy and safety of cytotoxic chemotherapy with G for elderly patients with progressive EGFR-mutant NSCLC., Methods: Elderly patients with EGFR-mutant NSCLC with PD previously treated with G were enrolled. Patients received Pem 500 mg/m or Doc 60 mg/m every 21 days and were randomly assigned to receive chemotherapy with 250 mg G (G+ Doc/Pem arm) or without G (Doc/Pem arm) until further disease progression or unacceptable toxicity., Results: This trial was terminated early owing to slow accrual. A group of 22 patients underwent analysis. The primary endpoint, progression-free survival (PFS), was significantly longer in the G + Doc/Pem arm (median: 1.6 months vs. 5.6 months, hazard ratio = 0.40, 95% CI: 0.16-0.99, p = 0.0391). Adverse events ≥ grade 3 were more frequent in the G + Doc/Pem arm (45.5% vs. 90.9%, p = 0.032)., Conclusions: Patients on G and Pem or Doc beyond PD showed a longer PFS than those on single-agent chemotherapy; however, it was associated with increased toxicity., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: In the phase III ADAURA trial, adjuvant treatment with osimertinib versus placebo, with/without prior adjuvant chemotherapy, resulted in a statistically significant and clinically meaningful disease-free survival benefit in completely resected stage IB-IIIA EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). We report health-related quality of life (HRQoL) outcomes from ADAURA., Patients and Methods: Patients randomized 1:1 received oral osimertinib 80 mg or placebo for 3 years or until recurrence/discontinuation. HRQoL (secondary endpoint) was measured using the Short Form-36 (SF-36) health survey at baseline, 12, and 24 weeks, then every 24 weeks until recurrence or treatment completion/discontinuation. Exploratory analyses of SF-36 score changes from baseline until week 96 and time to deterioration (TTD) were performed in the overall population (stage IB-IIIA; N = 682). Clinically meaningful changes were defined using the SF-36 manual., Results: Baseline physical/mental component summary (PCS/MCS) scores were comparable between osimertinib and placebo (range, 46-47) and maintained to Week 96, with no clinically meaningful differences between arms; difference in adjusted least squares (LS) mean [95% confidence intervals (CI), -1.18 (-2.02 to -0.34) and -1.34 (-2.40 to -0.28), for PCS and MCS, respectively. There were no differences between arms for TTD of PCS and MCS; HR, 1.17 (95% CI, 0.82-1.67) and HR, 0.98 (95% CI, 0.70-1.39), respectively., Conclusions: HRQoL was maintained with adjuvant osimertinib in patients with stage IB-IIIA EGFRm NSCLC, who were disease-free after complete resection, with no clinically meaningful differences versus placebo, further supporting adjuvant osimertinib as a new treatment in this setting. See related commentary by Patil and Bunn, p. 2204., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Cancer cachexia is a syndrome characterized by anorexia and decreased body weight. This study evaluated the efficacy and safety of anamorelin, an orally active, selective ghrelin receptor agonist, in patients with cancer cachexia and a low body mass index (BMI)., Methods: This multicenter, open-label, single-arm study enrolled Japanese patients with non-small cell lung cancer or gastrointestinal cancer with cancer cachexia (BMI < 20 kg/m 2 , involuntary weight loss > 2% in the last 6 months, and anorexia). Patients were administered 100 mg of anamorelin once daily for up to 24 weeks. The primary end point was a composite clinical response (CCR) at 9 weeks, which was defined as an increase in body weight of ≥5% from the baseline, an increase of ≥2 points in the score of the 5-item Anorexia Symptom Scale of the Functional Assessment of Anorexia/Cachexia Therapy, and being alive., Results: One hundred two patients were eligible and enrolled. The means and standard deviations for age and BMI were 71.0 ± 8.2 years and 17.47 ± 1.48 kg/m 2 , respectively. The CCR rate at 9 weeks was 25.9% (95% confidence interval [CI], 18.3%-35.3%), which met the primary end point with a lower 95% CI exceeding the prespecified minimum of 8%. Improvements in body weight and anorexia were durable and were accompanied by improvements in patients' global impression of change for appetite/eating-related symptoms and overall condition. Adverse drug reactions occurred in 37 of 101 treated patients (36.6%), with the most common being glycosylated hemoglobin increases, constipation, and peripheral edema., Conclusions: Anamorelin improved body weight and anorexia-related symptoms in patients with cancer cachexia and a low BMI with durable efficacy and favorable safety and tolerability., Lay Summary: Anamorelin is a drug that stimulates appetite and promotes weight gain. This clinical trial was aimed at determining its efficacy and safety in Japanese cancer patients with a low body mass index and cachexia, a syndrome associated with anorexia and weight loss. Anamorelin was found to improve body weight and anorexia-related symptoms in these patients, and these effects were durable for up to 24 weeks. Moreover, anamorelin was generally well tolerated. These findings suggest that anamorelin is a valuable treatment option for patients with cancer cachexia and a low body mass index., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

The association between non-small cell lung cancer histology and programmed death-ligand 1 expression remains controversial. We retrospectively analyzed histological dependence of the programmed death-ligand 1 expression by a multiple regression analysis of 356 non-small cell lung cancer patients. The programmed death-ligand 1 expression patterns of adenocarcinoma were consistent with a pathological predominant growth pattern as a reference to papillary adenocarcinoma: minimally invasive adenocarcinoma[partial regression coefficient (B), 0.17; 95% confidence interval, 0.05-0.59], lepidic adenocarcinoma (B, 0.46; 95% confidence interval, 0.23-0.90), acinar adenocarcinoma (B, 1.98; 95% confidence interval, 1.05-3.76) and solid adenocarcinoma (B, 5.11; 95% confidence interval, 2.20-11.9). In histology other than adenocarcinoma, the programmed death-ligand 1 expression tended to be high with poor differentiation: adenosquamous carcinoma (B, 4.17; 95% confidence interval, 1.05-16.6), squamous cell carcinoma (B, 4.32; 95% confidence interval, 2.45-7.62) and pleomorphic carcinoma (B, 13.0; 95% confidence interval, 4.43-38.2). We showed quantitatively that the programmed death-ligand 1 expression in non-small cell lung cancer tended to be clearly histology-dependent, with more poorly differentiated histology showing a higher expression., (© The Author(s) 2021. Published by Oxford University Press.)

Objective: Ramucirumab (RAM) plus Docetaxel (DOC) is one of the standard treatments after first-line treatment failure in patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the efficacy and safety of RAM plus DOC in older patients. We aimed to clarify these and elucidate the prognostic factors., Materials and Methods: In this multicenter retrospective study, conducted at four medical facilities in Japan, we evaluated the efficacy and safety data for two groups (<65 and ≥ 65 years). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and log-rank test. Multivariate analysis was performed to reveal the prognostic factors for better PFS and OS. Patient characteristics and adverse events (AEs) in both groups were compared using the Mann-Whitney's U and Fisher's exact tests for categorical variables., Results: A total of 237 patients were included, of whom 43% (n = 103), and 57% (n = 134) were aged <65, and ≥ 65 years. Median OS was 12.2 (95% CI: 9.4-15.0), and 14.8 months (95% CI: 10.8-18.8), respectively, and there were no significant differences between the groups (p = 0.534). Multivariate analysis identified DOC dose reduction (none vs performed, HR: 2.66, 95% CI: 1.62-4.35, p < 0.001) as an independent prognostic factor for OS in older patients, and a similar result was shown for the PFS. Grade ≥ 3 all AEs were identified in 42.7% and 56.7% of younger and older patients, respectively, and there was a significant difference between the groups (p = 0.033); however, the difference between the groups disappeared with primary DOC dose reduction (p = 0.526)., Conclusion: The efficacy of RAM plus DOC administration in older, pretreated patients with advanced NSCLC was comparable to those of younger patients, whereas RAM plus DOC should be cautiously administered to older patients because of severe toxicity. Moreover, appropriate DOC dose reduction may be recommended for increased survival benefit and safety in such patients., Competing Interests: Declaration of Competing Interest A. T. reported grants and personal fees from AstraZeneca, Ono Pharmaceutical, and Bristol-Myers Squibb, and personal fees from Eli Lilly Japan, Chugai Pharmaceutical, Boehringer Ingelheim, MSD, Pfizer, Taiho Pharmaceutical, and Kissei Pharmaceutical. S. A. reported grants and personal fees from AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb, Eli Lilly Japan, Boehringer Ingelheim, MSD, Pfizer, Taiho Pharmaceutical, Chugai Pharmaceutical, and Merck Pharmaceutical; grants from F. Hoffmann-La Roche, and personal fees from Kyowa Hakko Kirin and Hisamitsu Pharmaceutical. M. T. reported grants and personal fees from Boehringer Ingelheim, Ono Pharmaceutical, and Bristol-Myers Squibb, and personal fees from AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, MSD, Taiho Pharmaceutical, and Asahi Kasei Pharmaceutical. H. S. reported personal fees from AstraZeneca, Chugai Pharmaceutical, and MSD. The remaining authors declare that they have no conflict of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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.)

Patients with uncommon EGFR- mutated non-small-cell lung cancer (NSCLC) demonstrated lower clinical efficacy of first-generation EGFR-tyrosine kinase inhibitors compared with patients harboring common EGFR- mutated NSCLC. The US FDA has approved afatinib for uncommon EGFR mutation positive NSCLC based on the pooled analysis in the first- or second-line setting. Osimertinib has limited evidence in the small sample sizes of phase 2 studies in any-line settings. The aim of the present single-arm, multicenter, phase 2 study is to evaluate the efficacy of osimertinib for previously untreated NSCLC. The primary end point is to assess the overall response to osimertinib. The secondary end points include disease control rate, progression-free survival, duration of time-to-treatment failure, overall survival and safety. Clinical trial registration: jRCTs071200002.

Background: Nivolumab, an immune checkpoint inhibitor (ICI), has changed the treatment paradigm for advanced non-small cell lung cancer (NSCLC). However, factors associated with long-term survival in NSCLC patients treated with ICIs remain unknown. This study aimed to evaluate patient characteristics and clinical laboratory changes related to long-term survival in NSCLC patients treated with nivolumab, using real-world data., Methods: We retrospectively reviewed the medical records of consecutive patients with advanced NSCLC with Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤1 treated with nivolumab. We defined patients with overall survival (OS) ≥3 years as long-term survivors. We evaluated the differences in patient characteristics and tumor response between nonlong-term survivors and long-term survivors and performed univariate and multivariate analyses of factors associated with long-term survival., Results: Out of 213 patients with advanced NSCLC treated with nivolumab, 162 patients with ECOG-PS ≤1 were included in the study. Young age, ECOG-PS 0, absolute neutrophil count decrease, lymphocyte percentage increase, and neutrophil-to-lymphocyte ratio (NLR) change (ΔNLR) <1 were significantly associated with long-term survival. Long-term survivors had significantly higher response and disease control rates than nonlong-term survivors. Multivariate analysis showed that ΔNLR <1 was significantly associated with long-term survival. Further, OS was significantly different between the PS 0 and PS 1 groups (median OS: 32.0 months vs. 10.6 months) and the nonincreasing NLR and increasing NLR groups (median OS: 20.8 months vs. 5.7 months)., Conclusions: ΔNLR <1 was a significant long-term survival factor compared to ΔNLR ≥1 in advanced NSCLC patients treated with nivolumab., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: To investigate the efficacy of gefitinib as an adjuvant therapy for non-small-cell lung cancer patients with EGFR mutation., Patients and Methods: IMPACT (WJOG6410L; University Hospital Medical Information Network Clinical Trials Registry: UMIN000006252), a randomized, open-label, phase III study, included patients with completely resected pathologic stage II-III non-small-cell lung cancer harboring EGFR mutations (exon 19 deletion or L858R) during September 2011 to December 2015. Patients were randomly assigned to receive gefitinib (250 mg once daily) for 24 months or cisplatin (80 mg/m 2 on day 1) plus vinorelbine (25 mg/m 2 on days 1 and 8; cis/vin) once every 3 weeks for four cycles. The primary end point was disease-free survival (DFS)., Results: Overall, 234 patients were randomly assigned. Among 232 eligible patients (116 each; excluding two who withdrew consent), the median DFS was 35.9 and 25.1 months in the gefitinib and cis/vin groups, respectively. However, Kaplan-Meier curves crossed around 4 years after surgery with no statistically significant difference (stratified log-rank P = .63; hazard ratio by stratified Cox proportional hazards model = 0.92; 95% CI, 0.67 to 1.28). Overall survival (OS) was also not different (stratified log-rank P = .89; hazard ratio = 1.03; 95% CI, 0.65 to 1.65), with the 5-year OS rates being 78.0% and 74.6% in the gefitinib and cis/vin groups, respectively. Treatment-related deaths occurred in 0 and three patients in the gefitinib and cis/vin groups, respectively., Conclusion: Although adjuvant gefitinib appeared to prevent early relapse, it did not prolong DFS or OS. However, similar DFS and OS may justify adjuvant gefitinib in the selected patient subsets, especially those deemed ineligible for platinum-doublet adjuvant therapy; however, this was not a noninferiority trial., Competing Interests: Hirohito TadaHonoraria: Chugai Pharma Tetsuya MitsudomiHonoraria: AstraZeneca, Pfizer, Boehringer Ingelheim, Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharma, Taiho Pharmaceutical, Lilly, Novartis, MSD K.K., Kyowa Hakko Kirin, Amgen, Daiichi-Sankyo, Guardant Health, Ethicon, Thermofisher Scientific Biomarkers, Merck KGaA, Janssen Oncology, TakedaConsulting or Advisory Role: AstraZeneca, Pfizer, Boehringer Ingelheim, Chugai Pharma, Ono Pharmaceutical, MSD Oncology, Lilly, Novartis, Amgen, Daiichi Sankyo, Thermo Fisher ScientificResearch Funding: Boehringer Ingelheim (Inst), AstraZeneca (Inst), Pfizer (Inst), Chugai Pharma (Inst), Ono Pharmaceutical (Inst), Taiho Pharmaceutical (Inst), Sanofi/Aventis (Inst), Daiichi Sankyo (Inst), MSD K.K. (Inst), Kyowa Hakko Kirin (Inst) Toshihiro MisumiSpeakers' Bureau: Chugai Pharma, AstraZeneca Kenji SugioHonoraria: AstraZeneca, Chugai PharmaResearch Funding: Covidien Japan, Lilly Japan Masahiro TsuboiHonoraria: AstraZeneca Japan, Chugai Pharma, Taiho Pharmaceutical, Teijin Pharma, Johnson & Johnson, Novartis, MSD K.K., Ono Pharmaceutical, Bristol Myers Squibb Japan, MedtronicResearch Funding: Boehringer Ingelheim (Inst), Merck (Inst) Isamu OkamotoHonoraria: Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD Oncology, Chugai Pharma, AstraZeneca, Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Lilly JapanConsulting or Advisory Role: Lilly Japan, Bristol Myers Squibb Japan, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, PfizerResearch Funding: AstraZeneca (Inst), Taiho Pharmaceutical (Inst), Boehringer Ingelheim (Inst), Ono Pharmaceutical (Inst), MSD Oncology (Inst), Lilly (Inst), Astellas Pharma (Inst), AbbVie (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Takeda (Inst), Chugai/Roche (Inst) Shunichi SugawaraHonoraria: AstraZeneca, Chugai Pharma, Nippon Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Ono Pharmaceutical, MSD K.K., Yakult Honsha, Kyowa Kirin Shinji AtagiHonoraria: Chugai Pharma, MSD K.K., Ono Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Lilly Japan, Pfizer, Bristol Myers Squibb Japan, Hisamitsu Pharmaceutical, Kyowa Hakko Kirin, Merck, Novartis, Thermo Fisher ScientificResearch Funding: MSD K.K. (Inst), Chugai Pharma (Inst), Ono Pharmaceutical (Inst), AstraZeneca (Inst), Taiho Pharmaceutical (Inst), Boehringer Ingelheim (Inst), Lilly Japan (Inst), Pfizer (Inst), Bristol Myers Squibb Japan (Inst), Roche (Inst), Merck (Inst) Toshiaki TakahashiHonoraria: AstraZeneca KK, Chugai Pharma, Lilly Japan, Ono Pharmaceutical, MSD K.K., Pfizer, Boehringer Ingelheim, Roche, Takeda Pharmaceutical Co Ltd, Yakult HonshaResearch Funding: AstraZeneca KK (Inst), Lilly Japan (Inst), Chugai Pharma (Inst), Ono Pharmaceutical (Inst), MSD K.K. (Inst), Pfizer (Inst), Amgen (Inst), Boehringer Ingelheim (Inst) Hidetoshi HayashiHonoraria: Ono Pharmaceutical, Bristol Myers Squibb Japan, Lilly, Taiho Pharmaceutical, Boehringer Ingelheim, AstraZeneca Japan, Chugai Pharma, Pfizer, MSD, Novartis, Merck SeronoConsulting or Advisory Role: Lilly, AstraZeneca, Boehringer Ingelheim, Chugai Pharma, Pfizer, Merck Serono, Shanghai HaiHe Pharmaceutical, Bristol Myers Squibb, Daiichi Sankyo/UCB JapanResearch Funding: Ono Pharmaceutical, Boehringer Ingelheim, AstraZeneca, AbbVie (Inst), AC Medical (Inst), Astellas Pharma (Inst), Bristol Myers Squibb (Inst), Daiichi Sankyo (Inst), Eisai (Inst), Lilly Japan (Inst), EPS Associates Co, Ltd (Inst), GlaxoSmithKline (Inst), Japan Clinical Research Operations (Inst), Kyowa Hakko Kirin (Inst), Merck Serono (Inst), Novartis (Inst), Otsuka (Inst), Parexel (Inst), Pfizer (Inst), PPD-SNBL (Inst), Quintiles Inc (Inst), Taiho Pharmaceutical (Inst), Takeda (Inst), Yakult Honsha (Inst)Patents, Royalties, Other Intellectual Property: Sysmex Morihito OkadaSpeakers' Bureau: Taiho Pharmaceutical, Johnson & Johnson, Covidien, Lilly, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, CSL BehringResearch Funding: Taiho Pharmaceutical (Inst), Nippon Kayaku (Inst), Chugai Pharma (Inst), Covidien (Inst), Johnson & Johnson (Inst), Daiichi Sankyo (Inst), Yakult Honsha (Inst), Lilly Japan (Inst), Nihon Medi-Physics (Inst), Pfizer (Inst), Mochida Pharmaceutical Co Ltd. (Inst), Shionogi (Inst), Ono Pharmaceutical (Inst), Kyowa Hakko Kirin (Inst) Hiroshige YoshiokaHonoraria: Lilly, Chugai Pharma, Boehringer Ingelheim, Taiho Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Ono Pharmaceutical, MSD K.K., Novartis, Kyowa Kirin Co, Ltd, Daiichi Sankyo, Nippon Kayaku, Delta-Fly Pharma, PfizerConsulting or Advisory Role: Delta-Fly Pharma Kazuhisa TakahashiSpeakers' Bureau: AstraZeneca Ichiro YoshinoHonoraria: Johnson & Johnson, Pfizer, Chugai Pharma, Taiho Pharmaceutical, Shionogi, Astra Zeneca, Intuitive Surgical, Daiichi Sankyo, Boehringer Ingelheim, Covidien/MedtronicConsulting or Advisory Role: Astra Zeneca, Intuitive Surgical, Covidien/MedtronicResearch Funding: Chugai Pharma (Inst), Taiho Pharmaceutical (Inst), Pfizer (Inst), Shionogi (Inst) Kazuhiko NakagawaHonoraria: AstraZeneca KK, Ono Pharmaceutical, Chugai Pharma, Nippon Boehringer Ingelheim, Lilly, Pfizer, Bristol Myers Squibb, Novartis, CareNet, Taiho Pharmaceutical, Yodosha, Nikkei Business Publications, Inc, Kyorin, Takeda, Medical Review Co, Ltd, MSD K.K., AbbVie, Merck, Roche Diagnostics, Bayer Yakuhin, Nippon Kayaku, Amgen, Kyowa Kirin Co, Ltd, Medical Mobile Communications Co, Ltd, 3H Clinical Trial, Astellas Pharma, Yomiuri Telecasting Corporation, Medicus Shuppan, publishers Co, Ltd, Thermo Fisher Scientific, Hisamitsu Pharmaceutical Co, Inc, Nichi-iko, Nanzando Co, Ltd, Daiichi Sankyo Co, LtdConsulting or Advisory Role: Pfizer, Kyorin Pharmaceutical Co, Ltd, Lilly Japan, Ono Pharmaceutical, Astellas Pharma, TakedaResearch Funding: Chugai Pharma (Inst), Ono Pharmaceutical (Inst), Daiichi Sankyo (Inst), Eisai (Inst), Pfizer (Inst), Takeda (Inst), Nippon Boehringer Ingelheim (Inst), Taiho Pharmaceutical (Inst), Bristol Myers Squibb (Inst), AbbVie (Inst), Lilly (Inst), Parexel International Corp. (Inst), A2 Healthcare (Inst), Novartis (Inst), IQvia (Inst), SymBio Pharmaceuticals (Inst), AstraZeneca KK (Inst), Kissei Pharmaceutical (Inst), EPS Holdings (Inst), Bayer Yakuhin (Inst), MSD K.K. (Inst), Pfizer (Inst), Otsuka (Inst), Syneos Health (Inst), EPS International (Inst), PRA Health Sciences (Inst), PPD-SNBL (Inst), Covance (Inst), GlaxoSmithKline K.K. (Inst), Sysmex (Inst), Mochida Pharmaceutical Co Ltd. (Inst), Japan Clinical Research Operations (Inst), Sanofi (Inst), Medical Research Support (Inst), ICON (Inst), CMIC (Inst), Kyowa Kirin Co, Ltd (Inst)No other potential conflicts of interest were reported.

Background: In Japan, docetaxel, a cytotoxic monotherapy, is the standard drug administered to older patients with advanced non-small-cell lung cancer (NSCLC). Carboplatin plus nab-paclitaxel has shown a high objective response rate in patients with squamous histology and was suggested to improve overall survival in patients aged 70 years and older. The CAPITAL trial aimed to assess the safety and efficacy of carboplatin plus nab-paclitaxel versus docetaxel as first-line therapy for patients aged 70 years and older with advanced squamous NSCLC., Methods: This multicentre, open-label, randomised, phase 3 trial was carried out at 92 medical institutions in Japan. Eligible patients were aged 70 years and older, had advanced squamous NSCLC with no previous systemic chemotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Using an electronic data capture system, patients were randomly assigned (1:1) to intravenous carboplatin (area under the concentration-time curve of 6 mg/mL per min for 30 min) on day 1 of a 21-day cycle and intravenous nab-paclitaxel (100 mg/m 2 for 60 min) on days 1, 8, and 15 every 3 weeks or intravenous docetaxel (60 mg/m 2 for 60 min) on day 1 every 3 weeks. Randomisation was computer-generated per participant and stratified by ECOG performance status, clinical stage, sex, age, and institution. The primary endpoint was overall survival, measured in the full analysis set and defined as the time from registration to the date of death due to any cause. Safety was assessed in all patients who received at least one dose of the trial treatment. This trial is registered with the UMIN Clinical Trials Registry, UMIN000019843, and the Japan Registry of Clinical Trials, jRCTs041180110. After the planned interim analysis in Aug 3, 2020, the independent data monitoring committee recommended that the trial be stopped early. This report represents the final analysis., Findings: Between Feb 24, 2016, and Aug 11, 2020, 196 patients were enrolled and were randomly assigned to the carboplatin plus nab-paclitaxel group (n=98) or the docetaxel group (n=98). Of these patients, four (carboplatin plus nab-paclitaxel group, n=3; docetaxel group, n=1) did not receive any treatment and two patients in the docetaxel group were excluded from the full analysis set. Median overall survival in the full analysis set was 16·9 months (95% CI 12·6-25·4) in the carboplatin plus nab-paclitaxel group and 10·9 months (8·5-12·4) in the docetaxel group (hazard ratio 0·52 [90% CI 0·38-0·70]; p=0·0003). Grade 3-4 adverse events occurred in 79 (83%) patients in the carboplatin plus nab-paclitaxel group and 77 (79%) patients in the docetaxel group (p=0·63). The most common grade 3-4 adverse events in the carboplatin plus nab-paclitaxel group and the docetaxel group were leukopenia (44 [46%] vs 55 [57%]; p=0·20), neutropenia (60 [63%] vs 75 [77%]; p=0·046), febrile neutropenia (nine [10%] vs 19 [20%]; p=0·073), and anaemia (37 [39%] vs two [2%]; p<0·0001). Serious treatment-related adverse events of all grades occurred in 13 (14%) patients in the carboplatin plus nab-paclitaxel group and 11 (11%) patients in the docetaxel group. Treatment-related deaths occurred in two (2%; respiratory failure n=1, visceral arterial ischaemia n=1) patients in the carboplatin plus nab-paclitaxel group and one (1%; sepsis) patient in the docetaxel group., Interpretation: Our study showed that overall survival was longer with carboplatin plus nab-paclitaxel than with docetaxel, suggesting that carboplatin plus nab-paclitaxel can be used as standard first-line treatment for patients aged 70 years and older with advanced squamous NSCLC., Funding: Taiho Pharmaceutical., Competing Interests: Declaration of interests YK reports grants from Taiho Pharmaceutical, during the conduct of the study; and grants and personal fees from MSD, personal fees from AstraZeneca, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, Boehringer Ingelheim, and Ono Pharmaceutical, outside the submitted work. SI reports grants and personal fees from Ono Pharmaceutical; and personal fees from Chugai Pharmaceutical, AstraZeneca, MSD, Bristol Myers Squibb, Taiho Pharmaceutical, and Daiichi Sankyo, outside the submitted work. HS reports grants from Taiho Pharmaceutical, during the conduct of the study; grants and personal fees from AstraZeneca, MSD, Ono Pharmaceutical; and personal fees from Boehringer Ingelheim, Chugai Pharma, and Kyorin, outside the submitted work. AK reports grants from Taiho Pharmaceutical, during the conduct of the study; and personal fees from Bayer Yakuhin, outside the submitted work. SA reports grants from the National Cancer Center Research and Development Fund (26-A-22, 29-A-15, 2020-A-13) and Taiho Pharmaceutical, during the conduct of the study; grants and personal fees from AstraZeneca, Ono Pharmaceutical, Taiho, Boehringer Ingelheim, Pfizer, Bristol Myers Squibb, MSD, Eli Lilly, Chugai, and Merck; grants and non-financial support from F Hoffmann-La Roche; and personal fees from Hisamitsu, Kyowa Hakko Kirin, Novartis Pharma, and Thermo Fisher Scientific, outside the submitted work. YT reports grants and personal fees from Taiho Pharmaceutical, during the conduct of the study; grants and personal fees from Eli Lilly, Ono Pharmaceutical, Chugai Pharmaceutical, MSD, and Takeda; grants from Daiichi Sankyo and Kyowa-Hakko Kirin; and personal fees from Novartis, Boehringer Ingelheim, and AstraZeneca, outside the submitted work. AI reports personal fees from AstraZeneca, Eli Lilly, Boehringer Ingelheim, Pfizer, Chugai Pharmaceutical, MSD, and Daiichi Sankyo, outside the submitted work. TK reports personal fees from AstraZeneca, MSD, Eli Lilly, Chugai, Ono Pharmaceutical, Bristol Myers Squibb, and Boehringer Ingelheim; grants from AstraZeneca, MSD, Ono Pharmaceuticals, Eli Lilly, and Takeda, outside the submitted work. IO reports grants from Boehringer Ingelheim, during the conduct of the study; grants and personal fees from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD Oncology, Eli Lilly, Bristol Myers Squibb, and Chugai Pharma; grants from Astellas Pharma, Novartis, and AbbVie; and personal fees from Pfizer, outside the submitted work. MY reports grants and personal fees from Chugai Pharmaceutical; and grants from Daiichi Sankyo, MSD, and Pfizer Japan, outside the submitted work. MS reports grants and personal fees from Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Boehringer Ingelheim, and Eli Lilly Japan; and personal fees from AstraZeneca, outside the submitted work. MA reports grants from Kyowa Kirin, outside the submitted work. KK reports grants and personal fees from Ono Pharmaceutical and Boehringer Ingelheim; and personal fees from Chugai, MSD, AstraZeneca, Eli Lilly, Daiichi Sankyo, Bristol Myers Squibb, Kyowa Hakko Kirin, and Taiho, outside the submitted work. MT reports grants and personal fees from AstraZeneca, Chugai Pharmaceutical, Covidien Japan, Eli Lilly Japan, Kyowa Hakko Kirin, MSD, Nippon Boehringer Ingelheim, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, and Taiho Pharmaceutical; personal fees from Bristol Myers Squibb, Johnson & Johnson, and Nippon Kayaku; and grants from KM Biologics, outside the submitted work. TS reports grants and personal fees from Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, MSD, Novartis Pharma, Pfizer Japan, and Takeda Pharmaceutical; grants from AbbVie, Kissei Pharmaceutical, LOXO Oncology, and Merck Biopharma; and personal fees from AstraZeneca, Bristol Myers Squibb, Covidien Japan, Kyowa Hakko Kirin, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, Thermo Fisher Scientific, and Precision Medicine Asia, outside the submitted work. NY reports grants and personal fees from MSD, Chugai Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Takeda Pharmaceutical, Eli Lilly Japan, Boehringer Ingelheim, Novartis, Pfizer, and AstraZeneca; and personal fees from Thermo Fisher Scientific, Bristol Myers Squibb, Life Technologies, Nippon Kayaku, and Merk Biopharma; grants from Astellas Pharma, Tsumura & Co, Shionogi, AbbVie, Amgen, Kyorin Pharmaceutical, Eisai, Terumo, Toppan Printing, and TOSOH, outside the submitted work. AG reports personal fees from Taiho, Nihon Kayaku, AstraZeneca, Chugai, Ono Pharmaceutical, and Boehringer Ingelheim, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or greater evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). The hazard ratio (HR) for progression-free survival by independent central review (data cut-off date, 10 July 2017) was 0.25 (95% confidence interval [CI], 0.10-0.64; one-sided, nominal P = .001). The HR for overall survival (data cut-off date, 15 February 2019) was 0.39 (95% CI, 0.17-0.91; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 patients (52%) and four patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or greater. The trial is registered with ClinicalTrials.gov: NCT02142738., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objectives: The study was designed to investigate the safety of ramucirumab administered in combination with erlotinib or osimertinib for patients with untreated EGFR-mutated non-small cell lung cancer (NSCLC) and asymptomatic brain metastases, a patient subgroup in which these regimens have remained untested., Materials and Methods: This phase 1b study (RELAY-Brain) consisted of two cohorts with three patients each. Patients with asymptomatic brain metastases received ramucirumab every 2 weeks plus either daily oral erlotinib or osimertinib until disease progression or intolerable toxicity. The primary objective was to assess dose-limiting toxicity (DLT), defined as central nervous system (CNS) hemorrhage of grade ≥ 2., Results: Six patients were enrolled. Neither DLT nor serious or unexpected adverse events were observed. One treatment-related adverse event of grade ≥ 3 (hypertension of grade 3) was apparent. Common adverse events were generally manageable. The median number of ramucirumab administrations was 18.5 (range, 13 to 31), and there were no detected episodes of CNS hemorrhage. Five of the six patients showed an objective systemic response. Although only one patient had a measurable CNS lesion at baseline, a confirmed intracranial partial response was observed., Conclusion: Ramucirumab in combination with erlotinib or osimertinib showed safety for EGFR-mutated NSCLC with brain metastases., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Although information on the PD-L1 expression and EGFR mutations in non-small cell lung cancer (NSCLC) is important for therapeutic strategies, the effect of these factors on postoperative recurrence and the association between each factor have remained unclear. We retrospectively assessed the PD-L1 expression and EGFR mutations in 280 NSCLC patients, and analyzed the associations by multivariate analyses. The hazard ratio (HR) of postoperative recurrence in cases with high (≥ 50%) PD-L1 expression regarding negative expression was 4.83 (95% confidence interval [CI] 1.51-15.5). The HR for the PD-L1 expression, considered a continuous variable, was 1.016 (95% CI 1.01-1.03). The HRs in cases with EGFR major and minor mutations were 0.42 (95% CI 0.14-1.25) and 0.63 (95% CI 0.18-2.15), respectively. The high PD-L1 (≥ 50%) expression was significantly associated with exon 21 L858R mutation (Ex21) of EGFR (odds ratio, 0.10; 95% CI 0.01-0.87). The risk of postoperative recurrence increased 1.016-fold for every 1% increase in the PD-L1 expression, and a marked increase in risk was observed for expression levels of ≥ 50%. Whereas EGFR mutations were not an independent risk factor. The high PD-L1 (≥ 50%) expression was negatively associated with Ex21. These findings may help identify NSCLC patients with an increased risk of postoperative recurrence., (© 2021. The Author(s).)

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.)

Objectives Vascular endothelial growth factor plays an important role in the pathogenesis of malignant pleural effusion (MPE). We previously showed the efficacy of bevacizumab (Bev) plus carboplatin (CBDCA)/paclitaxel (PTX) in the treatment of non-small lung cell cancer (NSCLC) with MPE. However, the toxicities were a little severe, and the efficacy was not satisfied sufficiently. Therefore, we conducted a phase II study for NSCLC with MPE to evaluate the efficacy and safety of Bev plus CBDCA/nab-PTX, which is a new combination therapy. Methods Chemotherapy-naive non-squamous (SQ) NSCLC patients with MPE participated in the study. A single aspiration (not allowing chest tube drainage) was allowed before chemotherapy. Patients received a maximum of six cycles of Bev (15 mg/kg, day1) plus CBDCA (AUC 6, day1)/nab-PTX (100 mg/m 2 , day1, 8) every 3 weeks followed by Bev (15 mg/kg, day1) plus nab-PTX (100 mg/m 2 , day1, 8) every 3 weeks without disease progression or unacceptable severe toxicities. The primary endpoint was objective response rate (ORR). Results The study enrollment was ceased because of suspension of the registration period (as scheduled) after 12 of 20 planned patients were treated successfully between March 2014 and February 2018. The ORR was 58.3 % (95 % CI, 27.7-84.8 %), and the disease control rate was 100 % (95 % CI, 73.5-100 %). Eight patients received maintenance therapy. Median progression-free and overall survival times were 14.4 and 26.9 months, respectively. Most patients experienced hematological toxicities, including ≥ grade 3 neutropenia and anemia; none experienced severe bleeding events and grade 5 toxicities. Conclusion The combination of Bev plus CBDCA/nab-PTX, a novel combination, might have efficacy with acceptable toxicities in chemotherapy-naïve non-SQ NSCLC patients with MPE.Trial Registration University Hospital Medical Information Network in Japan (UMIN) Clinical Trials Registry (No. UMIN000013329) registered on 4th March 2014., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background: Atezolizumab combined with bevacizumab plus platinum-based chemotherapy is a standard treatment for advanced non-squamous non-small-cell lung cancer (nsNSCLC). We aimed to determine the most effective platinum-based combination, such that future studies with atezolizumab can be conducted to further improve patient outcomes., Methods: This phase 2 study enrolled treatment-naïve patients with advanced or recurrent nsNSCLC who were randomly assigned to either cisplatin (75 mg/m 2 ) + pemetrexed (500 mg/m 2 ) + bevacizumab (15 mg/kg) (CisPemBev) followed by maintenance PemBev (N=132) or carboplatin (area under the concentration-time curve of 6 mg/mL/min) + paclitaxel (200 mg/m 2 ) + bevacizumab (15 mg/kg) (CarPacBev) followed by maintenance Bev (N=67). The primary endpoint was progression-free survival (PFS, by central review). Secondary endpoints included overall survival (OS) and overall response rate (ORR). Adverse events (AEs) were evaluated for safety. This study was designed with the point estimate of the hazard ratio (HR) for PFS calculated based on an expected HR <0.830 with a probability ≥80%., Results: The HR for PFS (CisPemBev/CarPacBev) was 0.825 [95% confidence interval (CI), 0.600-1.134, median PFS, 7.6 vs . 7.0 months]. Because the observed point estimate of the HR for PFS was <0.830, the primary endpoint was met, and CisPem doublet therapy was deemed to be more effective than CarPac in terms of PFS. Median OS was 23.4 months for CisPemBev and 21.6 months for CarPacBev (HR 0.845; 95% CI, 0.583-1.242). The ORR was 57% for CisPemBev and 55% for CarPacBev. Both CisPemBev and CarPacBev were well tolerated; grade ≥3 AEs were reported in 67% and 82% of patients, respectively., Conclusions: CisPem combined with Bev was more effective in improving PFS compared with CarPacBev in patients with advanced nsNSCLC. CisPemBev was also well tolerated by this patient population. A study to evaluate the efficacy of atezolizumab plus CisPemBev is warranted., Trial Registration: University hospital Medical Information Network Clinical Trial Registry (ID: UMIN000013354)., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-240). SW, FT, MS, HY, TY and KG have received honoraria from Chugai Pharmaceutical Co., Ltd. SA and KG have received research funds from Chugai Pharmaceutical Co., Ltd. FT, MS and TY have received scholarship endowments from Chugai Pharmaceutical Co., Ltd. The authors have no other conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

The most frequent mechanism of resistance after 1st/2nd-generation (G) epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is secondary point mutation Thr790Met (T790M) in EGFR. Afatinib followed by osimertinib (Afa group) may provide better outcomes for T790M-positive non-small cell lung cancer (NSCLC) than 1st-G EGFR-TKI followed by osimertinib (1st-G group). We studied 111 consecutive NSCLC patients with T790M mutation treated with osimertinib after progression following 1st/2nd-G EGFR-TKI between March 28, 2016 and March 31, 2018. We analyzed the ratio of T790M to EGFR-activating mutation (T790M ratio) in post EGFR-TKI resistance re-biopsy tissue using droplet digital polymerase chain reaction. And investigated whether afatinib purified the T790M mutation more than 1st-G EGFR-TKI. Among 60 patients with preserved re-biopsy tissue, we analyzed 38 having adequate DNA content. The response rate in Afa group was 81.8% (n = 11) and 1st-G group was 85.2% (n = 27). The mean T790M ratio in total population was 0.3643. The ratio in those with response to osimertinib was significantly higher than in the non-responders (0.395, 0.202; p = 0.0231) and was similar in Afa and 1st-G group (0.371, 0.362; p = 0.9693). T790M ratio significantly correlated with osimertinib response and was similar between the 1st/2nd-G EGFR-TKIs in 1st/2nd-G EGFR-TKI-refractory tumors.

Background: Osimertinib is a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits EGFR activating and EGFR T790M resistance mutations. Osimertinib was found to be more effective than first-generation EGFR-TKIs in patients with previously untreated advanced non-small-cell lung cancer (NSCLC) harboring EGFR-positive mutations in a prior phase III trial. Osimertinib is, therefore, one of the most important standard therapies for EGFR mutation-positive patients. However, there are few reports about osimertinib resistance mechanisms in first-line EGFR-TKI therapy. Understanding first-line osimertinib resistance mechanisms is essential for future therapeutic strategies in patients with NSCLC with EGFR-positive mutations. To clarify the resistance mechanisms of first-line osimertinib, we proposed to analyze circulating tumor (ct) deoxyribonucleic acid (DNA) by the ultra-sensitive next-generation sequencing method., Patients and Methods: We aim to collect ctDNA samples from patients with the following key inclusion criteria: histologically or cytologically proven NSCLC, activating EGFR mutation-positive, planned treatment with first-line osimertinib, and written informed consent. Patients with comorbidities, who are deemed unsuitable for participation by an attending physician, would be excluded. We plan to enroll 180 cases and estimate a final analysis of 120 cases following registration and 2-year observation. ctDNA samples are collected at osimertinib treatment initiation, 3 and 12 months later, and disease progression. The key primary endpoint is to clarify the incidence and ratio of osimertinib resistance. The key secondary endpoint is to examine how the quantity of osimertinib resistance-associated mutations detected in ctDNA at treatment initiation influences disease progression., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Undifferentiated pleomorphic sarcoma (UPS) is a new disease in the World Health Organization's classification of tumors of soft tissue and bone published in 2013. Primary mediastinal UPS is rare, especially with pleural effusion. Herein, we describe the pathological findings of pleural effusion followed by mediastinal UPS, which was initially misdiagnosed as epithelial malignant pleural mesothelioma (MPM). The cytopathological findings of the pleural effusion cell block often contribute to the diagnosis of various malignant tumors. However, these findings may lead to misdiagnosis of highly invasive mediastinal tumors such as UPS. A biopsy for primary mediastinal lesions should be performed because MPM rarely mimics mediastinal tumors with pleural effusion., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)