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Background: In CheckMate 9LA, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy regardless of tumor PD-L1 expression or histology. We report updated efficacy and safety in all randomized patients with a minimum 4-year follow-up and an exploratory treatment-switching adjustment analysis in all treated patients who received chemotherapy and subsequent immunotherapy., Methods: Adults with stage IV/recurrent non-small cell lung cancer (NSCLC), no sensitizing EGFR/ALK alterations, and ECOG performance status ≤1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy (four cycles, with optional maintenance pemetrexed for the nonsquamous population). Assessments included OS, progression-free survival, and objective response rate. Exploratory analyses included efficacy by tumor PD-L1 expression and histology and in patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events (TRAEs), and a treatment-switching adjustment analysis using inverse probability of censoring weighting., Results: With a 47.9-month minimum follow-up for OS, nivolumab plus ipilimumab with chemotherapy continued to prolong OS over chemotherapy in all randomized patients (HR 0.74, 95% CI 0.63 to 0.87; 4-year OS rate: 21% versus 16%), regardless of tumor PD-L1 expression (HR (95% CI): PD-L1<1%, 0.66 (0.50 to 0.86) and ≥1%, 0.74 (0.60 to 0.92)) or histology (squamous, 0.64 (0.48 to 0.84) and non-squamous, 0.80 (0.66 to 0.97)). In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy due to TRAEs (n=61), the 4-year OS rate was 41%. With treatment-switching adjustment for the 36% of patients receiving subsequent immunotherapy in the chemotherapy arm, the estimated HR of nivolumab plus ipilimumab with chemotherapy versus chemotherapy was 0.66 (95% CI 0.55 to 0.80). No new safety signals were observed., Conclusions: In this 4-year update, patients treated with nivolumab plus ipilimumab with chemotherapy continued to have long-term, durable efficacy benefit over chemotherapy regardless of tumor PD-L1 expression and/or histology. A greater estimated relative OS benefit was observed after adjustment for subsequent immunotherapy use in the chemotherapy arm. These results further support nivolumab plus ipilimumab with chemotherapy as a first-line treatment for patients with metastatic/recurrent NSCLC, including those with tumor PD-L1<1% or squamous histology, populations with high unmet needs., Competing Interests: Competing interests: DPC has received consulting fees from Arcus Biosciences, Bristol Myers Squibb, BMS KK, Boehringer Ingelheim, Curio Science, Daiichi Sankyo, Genentech/Roche, GI Therapeutics (Intellisphere), GSK, Janssen, Merck, Mirati, Novartis, Novocure, OncoCyte, OncoHost, Roche China, and Seattle Genetics; and has participated on the advisory board of Amgen, Arcus Biosciences, AstraZeneca, Merck, Flame Biosciences, Gritstone Oncology, Cantargia (PPD), Daiichi Sankyo, EMD Serono GSK, Lilly, Regeneron, Sanofi, and Seattle Genetics and the data safety monitoring board of EORTC, AbbVie, and Lilly. T-EC has received honoraria from Astellas Pharma, Janssen, MSD, Merck Serono, Amgen, Roche, Pfizer, Sanofi Genzyme, Servier, Ipsen, AstraZeneca, Lilly, Novartis, Boehringer Ingelheim, and Bristol Myers Squibb; and has participated on a data safety monitoring board or advisory board of Astellas Pharma, Janssen, MSD, Merck Serono, Amgen, Roche, Pfizer, Sanofi Genzyme, Servier, Ipsen, AstraZeneca, Lilly, Novartis, Boehringer Ingelheim, and Bristol Myers Squibb. MS has received funding from Bristol Myers Squibb, MSD, Merck Serono, Pfizer, GSK, Roche, Bayer, Astellas, Amgen, Gilead, Tesaro, Clovis, Eli Lilly, Novartis, Regeneron, AbbVie, AstraZeneca, PharmaMar, Mylan, Samsung Pharmaceuticals, Bioven, BeiGene, and Daiichi Sankyo. OJ-V has received grants from AstraZeneca Spain, honoraria from Bristol Myers Squibb, Roche/Genentech, MSD Oncology, AstraZeneca/MedImmune, and Takeda; has served as a consultant for Bristol Myers Squibb, Lilly, Takeda, AstraZeneca Spain, and Janssen Oncology, and has received travel support from Takeda, AstraZeneca/MedImmune. NR has received honoraria from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GSK, Hoffmann-La Roche, Janssen, Lilly, MSD, Merck, Pfizer, Symphogen, and Takeda; travel support from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, Hoffmann-La Roche, and Takeda; and has participated on a data safety monitoring board or advisory board for Merck and Symphogen. BZ has received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GSK, Janssen-Cilag, MSD and Roche. AA has received consulting fees from Boehringer Ingelheim and Roche, provided expert testimony for Bristol Myers Squibb, Novartis, and Sandoz, and received travel support from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Roche, and Sanofi. LP-A has received grants or contracts from MSD, AstraZeneca, Pfizer, and Bristol Myers Squibb; consulting fees from Lilly, MSD, Roche, PharmaMar, Merck KGaA (Darmstadt, Germany), AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, Bristol Myers Squibb, Mirati, GSK, Janssen, Takeda, and Daichii Sankyo; honoraria from AstraZeneca, Janssen, Merck, and Mirati; and has participated on a data safety monitoring board or advisory board for Altum Sequencing and Genomica. SL has received consulting fees from AstraZeneca, Boehringer Ingelheim, Hutchinson MediPharma, Simcere, ZaiLab, GenomiCare, Roche, and Hanosh, and honoraria from AstraZeneca, Roche, and Hanosh. TJ has received consulting fees from Roche, Merck, MSD, Puma, AstraZeneca, Bristol Myers Squibb, Amgen, Gilead, and Specialised Therapeutics; and honoraria from AstraZeneca. XZ holds stock in Bristol Myers Squibb. IS has received consulting fees from Bristol Myers Squibb. JRP holds stock in Bristol Myers Squibb. AL holds stock in Bristol Myers Squibb. MR has received consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, BeiGene, Lilly, Mirati, MSD, Merck, Novartis, Pfizer, Sanofi, Regeneron, Roche, Takeda, and Samsung Bioepis; honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, BeiGene, Lilly, Mirati, MSD, Merck, Novartis, Pfizer, Sanofi, Regeneron, Roche, Takeda, and Samsung Bioepis; travel support from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, BeiGene, Lilly, Mirati, MSD, Merck, Novartis, Pfizer, Sanofi, Regeneron, Roche, Takeda, and Samsung Bioepis; and has participated on a data safety monitoring board or advisory board for Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, BeiGene, Lilly, Mirati, MSD, Merck, Novartis, Pfizer, Sanofi, Regeneron, Roche, Takeda, and Samsung Bioepis. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. 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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.

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.)

Background: A phase II study was conducted in order to determine the tumor efficacy and tolerance of alternating chemotherapy for extensive-stage small cell lung cancer (ED-SCLC)., Patients and Methods: Twenty patients with previously-untreated ED-SCLC were enrolled in the study. At least four courses of chemotherapy consisting of alternation of two drug combinations were given: alternating cycles of amrubicin and cisplatin with weekly administration of irinotecan and cisplatin at 3- or 4-week intervals., Results: The overall response rate was 85.0% (17/20). The median duration of overall survival and progression-free survival were 359 days and 227 days, respectively. Hematological toxicity was the main adverse event. Grade 3 or 4 neutropenia, thrombocytopenia and anemia were observed in 20 (100%), 4 (20%) and 6 (30%) patients, respectively. With regard to non-hematological adverse events, grade 3 or 4 anorexia, diarrhea, febrile neutropenia and infection were observed in 5 (25%), 2 (10%), 2 (10%) and 2 (10%) patients, respectively. No treatment-related death occurred during either regimen., Conclusion: The novel alternating non-cross-resistant chemotherapy was probably active against ED-SCLC and had acceptable toxicities. Further evaluation of this treatment for ED-SCLC in randomized phase III trials is warranted.

Background: A phase II study was conducted to determine the tumor efficacy and tolerance of alternating chemotherapy in extensive-stage small-cell lung cancer (ED-SCLC)., Patients and Methods: Thirty-six patients with previously untreated ED-SCLC were enrolled in the study. At least four courses of chemotherapy consisting of alternation of two drug combinations were given: alternating cycles of etoposide and carboplatin (EC) with weekly administration of irinotecan and cisplatin (IP) at 3- or 4-week intervals., Results: The overall response rate was 81.8%. The median duration of survival and progression-free survival were 314 days and 144 days, respectively. Hematological toxicity was the main adverse event. Grade 3 or 4 neutropenia, thrombocytopenia and anemia were observed in 69.2, 25.6 and 23.1% of the patients, respectively. Severe diarrhea (10.8%) was remarkable during the IP regimen., Conclusion: This novel alternating chemotherapy for patients with ED-SCLC showed moderate tumor efficacy and an acceptable safety profile.

The main purpose of tumor classification is to distinguish clear differences such as deciding treatment or showing a peculiar characteristic. In the treatment of lung cancer, the standard for treatment selection is to make the important classification of small cell lung cancer(SCLC)and non-small cell lung cancer(NSCLC). This is based on the fact that with a clinical-pathology difference and treatment reactivity, the prognosis differs between SCLC and NSCLC. In the 21st century, it has become insufficient to choose a treatment only by the classification of NSCLC with the advent of gefitinib a molecular target drug. Thus, treatment must be chosen in terms of the presence or absence of adenocarcinoma, an ethnic group, gender, a smoking history, and also the gene mutation. Moreover, it was reported by ASCO in 2008 that efficacy of pemetrexed is low for non-squamous cell carcinoma. From now on, not the NSCLC classification, but further detailed classification is needed to choose a treatment. Treatment selection in terms of the individual will be possible with ongoing study.