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Background: Recognizing rare molecular variants of driver mutations poses a challenge in precision oncology, particularly for treatment of non-small cell lung cancer (NSCLC). In this study, we aimed to determine whether Oncomine Dx Target Test Multi-CDx System (ODxTT), the most widely used genetic test for NSCLC in Japan, potentially overlooks druggable EGFR mutations., Materials and Methods: Among 418 patients who underwent molecular testing using ODxTT at our hospital, 267 were diagnosed with adenocarcinoma. No mutations were reported in 82 of these cases. For these 82 cases, we searched for EGFR mutations in exons 18-21 by examining the binary alignment map file. Once a mutation was identified, its pathological significance was evaluated using the ClinVar database to determine whether ODxTT had overlooked any actionable EGFR mutations., Results: Mutations in EGFR exons 19 and 18 were identified in six and four cases, respectively. Three, six, and none of these variants were detectable using the Cobas EGFR Mutation Test v2, Lung Cancer Compact Panel, and Amoy Dx, respectively. Of the 10 patients, five were subsequently treated with EGFR TKI; three showed partial response, one had stable disease, and one had progressive disease., Conclusions: ODxTT failed to identify 10 actionable EGFR mutations, accounting for 12.2% (10/82) of the cases initially reported as not carrying actionable mutations. Therefore, comprehensive genomic profiling should be actively performed early in cases with high clinical suspicion of EGFR mutations., (© 2025 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

The perioperative treatments for non-small cell lung cancer (NSCLC) should control both local and microscopic systemic disease, because the survival of patients with NSCLC who underwent surgical resection alone has been dismal except in stage IA patients. One way to improve surgical outcome is the administration of chemotherapy before or after the surgical procedure. During the last two decades, many clinical studies have focused on developing optimal adjuvant or neoadjuvant cisplatin-based chemotherapy regimens that can be combined with surgical treatment and/or radiotherapy. Based on the results of those clinical studies, multimodality therapy has been considered to be an appropriate treatment approach for locally advanced NSCLC patients. When nodal involvement is discovered postoperatively, adjuvant cisplatin-based chemotherapy has conferred an overall survival benefit. More recently, neoadjuvant and/or adjuvant use of immunotherapy adding to the cisplatin-based chemotherapy has been revealed to improve survival of the patients with locally advanced NSCLC in many large-scale clinical trials; although, optimal treatment strategies are still evolving., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Previous reports indicated still low implementation rates of multigene testing for advanced non-small cell lung cancer (NSCLC) in Japan., Methods: This is a retrospective study launched at the initiative of lung cancer patients. Patients with stage IV NSCLC from January 2019 to December 2022 were investigated for testing of 8 actionable oncogenic drivers with targeted therapies available as of 2022., Results: A total of 15,719 patients were included. Between 2019 and 2022, the percentage of patients who were not tested for any actionable oncogenic drivers remained the same, ranging from 21.5% to 33.1%. However, since late 2021, the percentage of patients tested for five or more actionable oncogenic drivers has increased. Across hospital categories and regions, the number of actionable oncogenic drivers tested was similar., Conclusions: This patient-initiated national survey in Japan reveals the recent nationwide increase in testing rates for actionable oncogenic drivers in Advanced NSCLC., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: The optimal region of lymph node dissection (LND) during segmentectomy in patients with small peripheral non-small cell lung cancer requires clarification. Through a supplemental analysis of the Japan Clinical Oncology Group (JCOG) 0802/West Japan Oncology Group (WJOG) 4607L, we investigated the associated factors, distribution, and recurrence pattern of lymph node metastases (LNMs) and proposed the optimal LND region., Methods: Of the 1106 patients included in the JCOG0802/WJOG4607L, 1056 patients with LNDs were included in this supplemental analysis. We investigated the distribution and recurrence pattern of LNMs along with the radiologic findings (with ground-glass opacity, part-solid tumor; without ground-grass opacity component, pure-solid tumor)., Results: The radiologic findings were the only significant factor for LNMs. Of 533 patients with part-solid tumors, 8 (1.5%) had LNMs. Further, only 3 (0.5%) patients had pN2 disease, and no patients had interlobar LNMs from nonadjacent segments. Of the 523 patients with pure-solid tumors, 55 (10.5%) had LNMs, and 28 (5.4%) had pN2 disease. Five patients had metastases to nonadjacent interlobar lymph nodes (LNs). Two (2.0%) patients with S6 tumors had upper mediastinal LNMs. In addition, the incidence of mediastinal LN recurrence in patients with S6 lung cancer was greater in those who underwent selective LND than those who underwent systematic LND (P = .0455)., Conclusions: Nonadjacent interlobar and mediastinal LND have little impact on pathologic nodal staging in patients with part-solid tumors. In contrast, selective LND is recommended at least for patients with pure-solid tumors., Competing Interests: Conflict of Interest Statement H.Y. reported honoraria from Eli Lilly, Chugai, Boehringer Ingelheim, Nippon Kayaku, Astra Zeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Ono, Merck Biopharma, Taiho, Otsuka, Takeda, Novartis, Amgen, Nipro Pharma, Kyowa Kirin, and Pfizer (payments were made to the author) and consulting fees from Delta Fly Pharma (payments were made to the author). M.T. reported participation on a Data Safety Monitoring Board or Advisory Board, Chugai Pharmaceutical Co, Ltd. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Immune-related adverse events (irAEs) have been found to predict PD-L1 inhibitor efficacy in metastatic NSCLC. However, the relation of irAEs to clinical outcome for nonmetastatic NSCLC has remained unknown., Methods: In this multicenter prospective study of Stage III NSCLC treated with PACIFIC regimen, the relation of irAEs to PFS was evaluated by 8-week landmark analysis to minimise lead-time bias as well as by multivariable analysis adjusted for baseline factors. irAEs were categorised as mild or nonmild according to whether they were treated with systemic steroid., Results: Median PFS was 16.0 months, not reached, and 9.7 months for patients without (85 cases) or with mild (21 cases) or nonmild (21 cases) irAEs, respectively. Multivariable analysis indicated that nonmild irAEs were associated with poor PFS, with HRs of 3.86 (95% CI, 1.31-11.38) compared with no irAEs and 11.58 (95% CI, 2.11-63.63) compared with mild irAEs. This pattern was consistent after irAE grade, the number of durvalumab doses and immune profiles (PD-L1 score, CD8 + tumour-infiltrating lymphocyte density, and tumour mutation burden) were taken into consideration., Conclusions: The development of mild irAEs might predict a better survival outcome, whereas immunosuppressive steroid-treated irAEs were associated with a worse outcome, regardless of baseline clinical and immune profiles., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: The phase III CheckMate 722 trial (ClinicalTrials.gov identifier: NCT02864251) evaluated nivolumab plus chemotherapy versus chemotherapy in patients with epidermal growth factor receptor ( EGFR )-mutated metastatic non-small-cell lung cancer (NSCLC) after disease progression on EGFR tyrosine kinase inhibitors (TKIs)., Methods: Patients with disease progression after first- or second-generation EGFR TKI therapy (without EGFR T790M mutation) or osimertinib (with/without T790M mutation) were randomly assigned 1:1 to nivolumab (360 mg once every 3 weeks) plus platinum-doublet chemotherapy (once every 3 weeks) or platinum-doublet chemotherapy alone (once every 3 weeks) for four cycles. Primary end point was progression-free survival (PFS). Secondary end points included 9- and 12-month PFS rates, overall survival (OS), objective response rate (ORR), and duration of response (DOR)., Results: Overall, 294 patients were randomly assigned. At final analysis (median follow-up, 38.1 months), PFS was not significantly improved with nivolumab plus chemotherapy versus chemotherapy (median, 5.6 v 5.4 months; hazard ratio [HR], 0.75 [95% CI, 0.56 to 1.00]; P = .0528), with 9- and 12-month PFS rates of 25.9% versus 19.8%, and 21.2% versus 15.9%, respectively. Post hoc PFS subgroup analyses showed a trend favoring nivolumab plus chemotherapy in patients with tumors harboring sensitizing EGFR mutations (HR, 0.72 [95% CI, 0.54 to 0.97]), one line of previous EGFR TKI (0.72 [95% CI, 0.54 to 0.97]), or both (0.64 [95% CI, 0.47 to 0.88]). Median OS was 19.4 months with nivolumab plus chemotherapy versus 15.9 months with chemotherapy, while ORR was 31.3% versus 26.7%, and median DOR was 6.7 versus 5.6 months, respectively. Grade 3/4 treatment-related adverse events occurred in 44.7% and 29.4% of patients treated with nivolumab plus chemotherapy and chemotherapy alone, respectively., Conclusion: Nivolumab plus chemotherapy did not significantly improve PFS versus chemotherapy in patients with EGFR- mutated metastatic NSCLC previously treated with EGFR TKIs. No new safety signals were identified.

BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.

Background: DESTINY-Lung01 is a multicentre, open-label, phase 2 study evaluating the antitumour activity and safety of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpressing or HER2 (ERBB2)-mutant unresectable or metastatic non-small-cell lung cancer (NSCLC). The results of the HER2-mutant cohort (cohort 2) have been reported elsewhere. Herein, we report the primary analysis of cohorts 1 and 1A, which aimed to evaluate the activity and safety of trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg in patients with HER2-overexpressing NSCLC., Methods: Patients aged 18 years or older with unresectable or metastatic (or both unresectable and metastatic) non-squamous NSCLC who had relapsed following or were refractory to standard treatment or for whom no standard treatment was available, with an HER2 immunohistochemistry score of 3+ or 2+ (without known HER2 mutations) and an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled at 20 specialist hospitals in France, Japan, the Netherlands, Spain, and the USA. Patients were assigned to cohorts sequentially, first to cohort 1, to receive trastuzumab deruxtecan 6·4 mg/kg (cohort 1), then to cohort 1A, to receive trastuzumab deruxtecan 5·4 mg/kg, both administered intravenously once every 3 weeks. The primary endpoint was confirmed objective response rate by independent central review and was assessed in the full analysis set, which included all patients who signed an informed consent form and were enrolled in the study. Safety was assessed in all enrolled patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT03505710, and is ongoing (closed to recruitment)., Findings: Between Aug 27, 2018, and Jan 28, 2020, 49 patients were enrolled in cohort 1 (median age 63·0 years [IQR 58·0-68·0], 30 [61%] male, 19 [39%] female, and 31 [63%] White), and from June 16 to Dec 9, 2020, 41 patients were enrolled in cohort 1A (median age 62·0 years [IQR 56·0-66·0], 22 [54%] male, 19 [46%] female, and 31 [76%] White). As of data cutoff (Dec 3, 2021), the median treatment duration was 4·1 months (IQR 1·4-7·1) in cohort 1 and 5·5 months (1·4-8·7) in cohort 1A, and median follow-up was 12·0 months (5·4-22·4) in cohort 1 and 10·6 months (4·5-13·5) in cohort 1A. Confirmed objective response rate by independent central review was 26·5% (95% CI 15·0-41·1; 13 of 49, all partial responses) in cohort 1 and 34·1% (20·1-50·6; 14 of 41; two complete responses and 12 partial responses) in cohort 1A. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (12 [24%] of 49 in cohort 1, none in cohort 1A), pneumonia (six [12%] and two [5%], respectively), fatigue (six [12%] and three [7%], respectively), and disease progression (six [12%] and four [10%], respectively). Drug-related treatment-emergent adverse events of grade 3 or worse occurred in 26 (53%) of 41 patients in cohort 1 and nine (22%) of 49 patients in cohort 1A. Drug-related serious adverse events were reported in ten (20%) patients and three (7%) patients, respectively. Deaths due to treatment-emergent adverse events occurred in ten (20%) patients in cohort 1 (disease progression in six (12%) patients and bronchospasm, hydrocephalus, respiratory failure, and pneumonitis in one [2%] patient each), and in seven (17%) patients in cohort 1A (due to disease progression in four (10%) patients and dyspnoea, malignant neoplasm, and sepsis in one (2%) patient each). One death due to a treatment-emergent adverse event was determined to be due to study treatment by the investigator, which was in cohort 1 (pneumonitis). Independent adjudication of interstitial lung disease or pneumonitis found that drug-related interstitial lung disease or pneumonitis occurred in ten (20%) patients in cohort 1 (two [4%] grade 1, five [10%] grade 2, and three [6%] grade 5) and two (5%) patients in cohort 1A (one [2%] grade 2 and one [2%] grade 5). An additional patient in cohort 1A had grade 4 pneumonitis after the data cutoff, which was subsequently adjudicated as drug-related grade 5 interstitial lung disease or pneumonitis., Interpretation: Given the low antitumour activity of existing treatment options in this patient population, trastuzumab deruxtecan might have the potential to fill a large unmet need in HER2-overexpressing NSCLC. Our findings support further investigation of trastuzumab deruxtecan in patients with HER2-overexpressing NSCLC., Funding: Daiichi Sankyo and AstraZeneca., Competing Interests: Declaration of interests EFS has received provision of study materials (drug) and clinical trial funding (to their institution) from Daiichi Sankyo; consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Janssen, MSD, Roche Sanofi, and Takeda; speaker payment or honoraria from Boehringer Ingelheim and Daiichi Sankyo; and participated on a data safety monitoring board for Daiichi Sankyo. EF has received consulting fees from Amgen, AstraZeneca, Bayer, Bergenbio, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F Hoffmann–La Roche, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Pfizer, Sanofi, and Takeda; speaker payment or honoraria from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, F Hoffmann–La Roche, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, Peervoice, Pfizer, Sanofi, Takeda, and Touch Oncology; grants or contracts from Fundación Merck Salud, Merck Healthcare, and Oncology Innovation; and has other financial interests in Grífols. DU has received consulting fees from AstraZeneca, Daiichi Sankyo, Jazz Pharmaceuticals, and Sanofi. MN has received consulting fees from Caris Life Sciences; speaker payment or honoraria from AstraZeneca, Blueprint Medicine, Daiichi Sankyo, EMD Serono, Genentech, Janssen, Lilly, Mirati, Novartis, Pfizer, and Takeda; and support for meeting attendance or travel from AnHeart Therapeutics. KN has received consulting fees from Eli Lilly Japan and Ono Pharmaceuticals; speaker payment or honoraria from Amgen, AstraZeneca, Bayer Yakuhin, Bristol Myers Squibb, Care Net, Chugai Pharmaceutical, CMIC, CMIC ShiftZero, Daiichi Sankyo, Eli Lilly Japan, Incyte Biosciences Japan, Janssen Pharmaceuticals, Japan Clinical Research Operations, Kyowa Kirin, Medical Mobile Communications, Medical Review, Merck Biopharma, MSD, Life Technologies Japan, Neo Communication, Nikkei Business Publications, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, Taiyo Pharma, Takeda Pharmaceutical, Yodosha, and 3H Clinical Trial; grants or contracts from Amgen, Ascent Development Services, Astellas Pharma, AstraZeneca, Bayer Yakuhin, Bristol Myers Squibb, Chugai Pharmaceutical, CMIC, Daiichi Sankyo, Eisai, Eli Lilly Japan, EP-CRSU, EPS Corporation, GlaxoSmithKline, IQVIA Services Japan, Janssen Pharmaceutical, Japan Clinical Research Operations, Kissei Pharmaceutical, Kobayashi Pharmaceutical, Labcorp Development Japan (Covance Japan), Mebix, Medical Research Support, Mochida Pharmaceutical, MSD, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Parexel International, Pfizer Japan, Pfizer R&D Japan, PPD-SNBL, Sanofi, Shionogi, SRL, SymBio Pharmaceuticals, Syneos Health Clinical, Sysmex Corporation, Taiho Pharmaceutical, and Takeda Pharmaceutical; and holds a patent with Daiichi Sankyo. LP-AR has received consulting fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Lilly, Daiichi Sankyo, GlaxoSmithKline, Janssen, Merck, Mirati, MSD, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, and Takeda; speaker payment or honoraria from AstraZeneca, Janssen, Merck, and Mirati; and grants and contracts from AstraZeneca, Bristol Myers Squibb, MSD, and Pfizer. JMP has received consulting fees from AstraZeneca, Blueprint Medicines, Jazz Pharmaceuticals, and Silverback Therapeutics. BTL has received grants or contracts from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Jiangsu Hengrui Pharmaceuticals, Lilly, and National Institutes of Health (Cancer Center Support Grant P30 CA008748 and Research Project Grant R01CA249666); support for meeting attendance or travel from Amgen; holds a patent with Memorial Sloan Kettering Cancer Center; and has a leadership or fiduciary role in Asia Society Policy Institute Cure4Cancer and Bloomberg New Economy International Cancer Coalition. DP has received consulting fees from AstraZeneca, AbbVie, AnHeart Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Novartis, Roche, Pfizer, MSD Oncology, Celgene, BeiGene, Samsung, Janssen, Jazz Pharmaceuticals, Pierre Fabre, Seagen, Gilead Sciences, and Sanofi; speaker payment or honoraria from Prime Oncology and PeerVoice; and research grants paid to his institution from AstraZeneca/MedImmune, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi/Aventis, Taiho Pharmaceutical, Daiichi Sankyo, AbbVie, Janssen, Pierre Fabre, and Seagen. CB has received consulting fees from AstraZeneca, Boehringer, Daiichi Sankyo, Guardant, Jansen, Pfizer, Regeneron, Silverback, Takeda, and TurningPoint; and grants or contracts from AbbVie, AstraZeneca, Blueprint, Daiichi Sankyo, Jansen, Lilly, Loxo, Nuvalent, Pfizer, Rain Therapeutics, Spectrum, and TurningPoint. YG has received speaker payment or honoraria from Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Eli Lilly, Merck, MSD, Novartis, Ono, Pfizer, Taiho, and Thermo Fisher Scientific; grants or contracts from AbbVie, AZK, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Kyorin, Novartis, Ono, Pfizer, and Preferred Network; participated in advisory boards for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Guardant Health, Illumina, MSD, Novartis, Ono Pharmaceutical, Pfizer, and Taiho; and has a leadership or fiduciary role in Cancer Net Japan and the Japan Association of Medical Translation for Cancer. HM has received speaker payment or honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb Japan, Chugai Pharma, Daiichi Sankyo, Eisai, Lilly Japan, MSD, Nihonkayaku, Novartis, Ono Pharmaceutical, Pfizer, Takeda, and Taiho Pharmaceutical; grants or contracts from AbbVie, AstraZeneca, Bayer, Chugai Pharma, IQVIA, and Takeda; and participated in advisory boards for Amgen, Chugai Pharma, Daiichi Sankyo, GAIA BioMedicine, and Taiho Pharmaceutical. AS has received speaker payment and honoraria from HMP Global and MJH Life Sciences; grants or contracts from AstraZeneca, BioAtla, Daiichi Sankyo, Eli Lily, Genentech, Genmab, Memgen, Mersana, Novartis, and Turning Point Therapeutics; and participated in advisory boards for Daiichi Sankyo, Eli Lilly, and Zymeworks. KP and ZT are employees of Daiichi Sankyo. AT, WF, YC, and QY are employees of Daiichi Sankyo and hold stocks, stock options, or have other financial interest in Daiichi Sankyo. PAJ has received consulting fees from AbbVie, Accutar Biotech, Allorion Therapeutics, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Chugai Pharmaceuticals, Daiichi Sankyo, Duality, Eli Lilly, Esai, Frontier Medicines, Hongyun Biotechnology, Merus, Mirati Therapeutics, Monte Rosa, Novartis, Nuvalent, Pfizer, Roche/Genentech, Scorpion Therapeutics, SFJ Pharmaceuticals, Silicon Therapeutics, Syndax, Takeda Oncology, Transcenta, and Voronoi; grants and contracts from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Puma Biotechnology, Revolution Medicines, and Takeda Oncology; holds patents and royalties or licenses with LabCorp; and reports holding stocks or stock options in Gatekeeper Pharmaceuticals., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Efficacy of necitumumab [recombinant human monoclonal antibody that blocks the ligand binding epidermal growth factor receptor (EGFR)] in patients with squamous (SQ) non-small-cell lung cancer (NSCLC) has been confirmed in two randomized clinical trials (SQUIRE and JFCM). This study evaluated the association between efficacy and initial skin toxicity with necitumumab treatment by analyzing pooled data from two clinical trials (SQUIRE and JFCM)., Materials and Methods: Data of 635 patients with SQ-NSCLC (intent-to-treat population) treated with necitumumab plus gemcitabine and cisplatin (N + GC) were pooled from two clinical trials (SQUIRE and JFCM). The relationship between skin toxicities developed by the end of the second cycle and efficacy was evaluated. Efficacy endpoints included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Univariate and multivariate analyses were carried out for these endpoints., Results: OS and ORR were associated with skin toxicity, whereas PFS was not. Patients with grade ≥2 or grade 1 skin toxicity had significantly longer OS compared to patients without skin toxicity (grade 0) in the N + GC group [median = 15.0 (grade ≥2); 12.7 (grade 1); 9.4 (grade 0) months; hazard ratio (HR) = 0.51 (grade ≥2 to grade 0); 95% confidence interval (CI) 0.40-0.64, P < 0.001 and HR = 0.64 (grade 1 to grade 0); 95% CI 0.52-0.80, P < 0.001]. In multivariate analysis, OS was significantly associated with skin toxicity., Conclusions: A significant association was found between necitumumab-induced skin toxicity and efficacy. These results are consistent with the previously reported association between other EGFR inhibitors-induced skin toxicity and efficacy., Competing Interests: Disclosure SW reports receiving personal fees from Novartis Pharma, Chugai Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, AstraZeneca, Bristol-Myers Squibb, MSD, and Daiichi Sankyo. HY reports receiving personal fees from Delta Fly Pharma, Chugai Pharmaceutical, MSD, AstraZeneca, Boehringer Ingelheim, Taiho Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Novartis Pharma, Kyowa Kirin, Nippon Kayaku, Eli Lilly, Otsuka Pharmaceutical, Daiichi Sankyo, Amgen, Pfizer, and Nipro Pharma. HS reports receiving personal fees from Merck, Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, and AstraZeneca. KH reports receiving grants from MSD, AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Bristol-Myers Squibb, and AbbVie; and personal fees from Pfizer, AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Takeda Pharmaceutical, MSD, Bristol-Myers Squibb, Ono Pharmaceutical, Taiho Pharmaceutical, and Boehringer Ingelheim. MT reports receiving grants from Chugai Pharmaceutical, Ono Pharmaceutical, and Pfizer. KY reports personal fees from Healios, Chugai Pharmaceutical, AstraZeneca, and Bristol-Myers Squibb. SS reports receiving personal fees from MSD, Nippon Kayaku, Chugai Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, Taiho Pharmaceutical, Eli Lilly, Novartis Pharma, Kyowa Kirin, Yakult Honsha, Takeda Pharmaceutical, Pfizer, Merck, Amgen, AbbVie, Otsuka Pharmaceutical, Thermo Fisher Scientific, and Towa Pharmaceutical. YT reports receiving grants from Ono Pharmaceutical, AstraZeneca, MSD, AbbVie, Bristol-Meyers Squib, Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Boehringer Ingelheim, Eisai, Nippon Kayaku, and Takeda Pharmaceutical; and personal fees from Ono Pharmaceutical, AstraZeneca, Bristol-Meyers Squib, Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Boehringer Ingelheim, Eisai, MSD, Takeda Pharmaceutical, Amgen, Novartis Pharma, Merck BioPharma, and Kyowa Kirin. YH reports receiving personal fees from AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Kyowa Kirin, Nippon Kayaku, Takeda Pharmaceutical, Eisai, Novartis Pharma, and Pfizer. KT reports receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Kyowa Kirin, MSD, and Taiho Pharmaceutical. SN reports receiving grants from AstraZeneca, Merck BioPharma, Chugai Pharmaceutical, and GlaxoSmithKline; and personal fees from AstraZeneca, Ono Pharmaceutical, Chugai Pharmaceutical, Pfizer, Eli Lilly, Takeda Pharmaceutical, Merck BioPharma, Boehringer Ingelheim, Taiho Pharmaceutical, Novartis Pharma, Daiichi Sankyo, KYORIN Pharmaceutical, and MSD. MN reports receiving personal fees from Ono Pharmaceutical, Bristol-Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Astellas Pharma, Boehringer Ingelheim, MSD, Novartis Pharma, Daiichi Sankyo Healthcare, Taiho Pharmaceutical, and Merck Serono. TK reports receiving grants from AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Haihe Biopharma, Merck, MSD, Novartis Pharma, Pfizer, Regeneron Pharmaceuticals, Takeda Pharmaceutical, and Turning Point Therapeutics; and personal fees from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutical, Merck, MSD, Novartis Pharma, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda Pharmaceutical. TT reports receiving grants from AstraZeneca, Amgen, Boehringer Ingelheim, Merck Biopharma, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, MSD, and Pfizer; and personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, MSD, Pfizer, Boehringer Ingelheim, Roche Diagnostics, Takeda Pharmaceutical, and Yakult Honsha. HE reports receiving personal fees from Nippon Kayaku. MA reports receiving personal fees from Nippon Kayaku. NY reports receiving grants from Boehringer Ingelheim, Taiho Pharmaceutical, Chugai Pharmaceutical, Shionogi Pharma, Eli Lilly, Daiichi Sankyo, Tsumura, Nippon Kayaku, Asahikasei-pharma, AstraZeneca, Janssen Pharmaceutical, Sanofi, Amgen, Novartis Pharma, Astellas Pharma, MSD, Eisai, Bristol-Myers Squibb, AbbVie, and Tosoh; and personal fees from MSD, AstraZeneca, Amgen, Ono Pharmaceutical, Otsuka Pharmaceutical, Guardant Health, Tsumura, Kyowa Kirin, KYORIN Pharmaceutical, GlaxoSmithKline, Sanofi, Daiichi Sankyo, Taiho Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Nippon Kayaku, Boehringer Ingelheim, Novartis Pharma, Pfizer, Bristol-Myers Squibb, Miyarisan Pharmaceutical, Merck, and Janssen Pharmaceutical. YO reports receiving grants from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, KYORIN Pharmaceutical, Sumitomo Pharma, Pfizer, Taiho Pharmaceutical, Novartis Pharma, Takeda Pharmaceutical, Kissei Pharmaceutical, Daiichi Sankyo, and Janssen Pharmaceutical; and personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Yakuhin, Pfizer, MSD, Taiho Pharmaceutical, Nippon Kayaku, Kyowa Kirin, and Eisai. KN reports receiving grants from AstraZeneca, MSD, Ono Pharmaceutical, Boehringer Ingelheim, Novartis Pharma, Pfizer, Bristol-Myers Squibb, Eli Lilly, Chugai Pharmaceutical, Daiichi Sankyo, Merck Biopharma, PAREXEL International, PRA HEALTHSCIENCES, EPS, Kissei Pharmaceutical, EPS International, Taiho Pharmaceutical, PPD-SNBL, SymBio Pharmaceuticals, IQVIA Services, SYNEOS HEALTH CLINICAL, Nippon Kayaku, EP-CRSU, Mebix, Janssen Pharmaceutical, AbbVie, Bayer Yakuhin, Eisai, Mochida Pharmaceutical, Covance, Japan Clinical Research Operations, Takeda Pharmaceutical, GlaxoSmithKline, Sanofi, Sysmex, Medical Research Support, Otsuka Pharmaceutical, SRL, Pfizer R&D, and Amgen; and personal fees from Eli Lilly, KYORIN Pharmaceutical, Ono Pharmaceutical, Pfizer, Amgen, Nippon Kayaku, AstraZeneca, Chugai Pharmaceutical, MSD, Boehringer Ingelheim, Taiho Pharmaceutical, Bayer Yakuhin, CMIC ShiftZero, Life Technologies, Neo Communication, Roche Diagnostics, AbbVie, Merck Biopharma, Kyowa Kirin, Takeda Pharmaceutical, 3H Clinical Trial, Care Net, Medical Review, Medical Mobile Communications, YODOSHA, Nikkei Business Publications, Japan Clinical Research Operations, CMIC, Novartis Pharma, TAIYO Pharma, and Bristol-Myers Squibb., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: The combination of an antibody to programmed cell death-1 (PD-1) or to its ligand (PD-L1) with chemotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC). Bevacizumab is expected to enhance the efficacy not only of chemotherapy but also of PD-1/PD-L1 antibodies through blockade of vascular endothelial growth factor-mediated immunosuppression, but further data are needed to support this., Objective: To evaluate the efficacy and safety of bevacizumab administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous NSCLC., Design, Setting, and Participants: An open-label phase 3 randomized clinical trial was conducted at 37 hospitals in Japan. Patients with advanced nonsquamous NSCLC without genetic driver alterations or those with genetic driver alterations who had received treatment with at least 1 approved tyrosine kinase inhibitor were enrolled between January 20, 2019, and August 12, 2020., Interventions: Patients were randomly assigned to receive either atezolizumab plus carboplatin with pemetrexed (APP) or atezolizumab, carboplatin plus pemetrexed, and bevacizumab (APPB). After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab was administered until evidence of disease progression, development of unacceptable toxic effects, or the elapse of 2 years from the initiation of protocol treatment., Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the intention-to-treat (ITT) population., Results: A total of 412 patients were enrolled (273 men [66%]; median age, 67.0 [range, 24-89] years) and randomly assigned, with 205 in the APPB group and 206 in the APP group of the ITT population after exclusion of 1 patient for good clinical practice violation. The median BICR-assessed PFS was 9.6 months with APPB vs 7.7 months with APP (stratified hazard ratio [HR], 0.86; 95% CI, 0.70-1.07; 1-sided stratified log-rank test; P = .92). According to prespecified subgroup analysis of BICR-assessed PFS, an improved PFS with APPB vs APP was apparent specifically in driver oncogene-positive patients (median, 9.7 vs 5.8 months; stratified HR, 0.67; 95% CI, 0.46-0.98). Toxic effects related to bevacizumab were increased in the APPB group., Conclusions and Relevance: The findings of this trial did not show superiority of APPB over APP for patients with nonsquamous NSCLC; however, this regimen showed a similar tolerability and improved survival relative to APP in patients with driver oncogenes., Trial Registration: Japan Registry of Clinical Trials Identifier: jRCT2080224500.

The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Although the primary endpoint of disease-free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer-related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co-mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co-mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co-mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07-28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co-mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR-mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Aim: We investigated association between skin adverse events (AEs) and efficacy with dacomitinib in patients with EGFR -positive non-small-cell lung cancer (NSCLC). Methods: Post hoc analyses from ARCHER 1050 evaluated efficacy in patients who did and did not experience grade ≥2 skin AEs with dacomitinib. Landmark analyses were performed at 3 and 6 months. Results: In patients who had skin AEs (72.2%) vs. those who did not (27.7%), median progression-free survival was 16.0 vs. 9.2 months, median overall survival (OS) was 37.7 vs. 21.6 months, and objective response rate was 80.2 vs. 61.5%; OS was improved at 3 and 6 months landmark analyses. Conclusion: Presence of grade ≥2 skin AEs was associated with numerically improved efficacy and represents a valuable biomarker of treatment outcome with dacomitinib in patients with advanced NSCLC. Clinical Trial Registration: NCT01774721 (ClinicalTrials.gov).

Background: Actionable tumor genomic alterations, primarily EGFR mutations, occur in nearly 70% of Japanese advanced nonsquamous non-small cell lung cancer (NSCLC) patients. Standard assessment of tumor tissue includes rapid testing for EGFR mutations, ALK fusions and ROS1 fusions. We conducted a prospective observational study (WJOG13620L) of follow-on next-generation sequencing of circulating tumor DNA (ctDNA) in patients without driver alterations after EGFR testing., Methods: Patients with untreated advanced (Stage IIIB-IV or relapsed) nonsquamous NSCLC without EGFR mutations according to single-plex testing of tumor tissue, were enrolled into this study. Patients with other known driver mutations or who underwent comprehensive genomic profiling were excluded. Plasma was analyzed by Guardant360, and the primary endpoint was the proportion of patients with pathogenic gene alterations in at least one of nine genes., Results: Among the 72 patients enrolled, ALK and ROS1 fusions were tested in 86.1% and 65.2%, respectively. Alterations in pre-defined genes were detected in 21 patients (29.2%; 95% confidence interval: 19.0-41.1, p < 0.001 [one-sided null hypothesis proportion of 10%]), including RET fusion (n = 1) and mutations in KRAS (n = 11), EGFR (n = 5), ERBB2 (n = 3), and BRAF (n = 1). Median time from sample submission to results was 8 days (range, 5-17 days)., Conclusion: Rapid follow-on comprehensive testing of ctDNA should be considered prior to first-line treatment for patients with advanced nonsquamous NSCLC when no alterations are detected after single-plex tissue testing., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The JIPANG study is an open-label phase III trial evaluating the efficacy of pemetrexed plus cisplatin (PemP) versus vinorelbine plus cisplatin (NP) as adjuvant chemotherapy in patients with stage II-IIIA nonsquamous non-small-cell lung cancer (NSCLC). Here, we report the long follow-up overall survival (OS) data. Eligible patients were randomly assigned to receive either PemP or NP. The primary end point was recurrence-free survival (RFS), and the secondary end point included OS. This analysis was performed using data collected 5 years after the last patient enrollment. Among 804 patients enrolled, 783 patients were eligible (384 for NP and 389 for PemP). The updated median RFS was 37.5 months in the NP arm and 43.4 months in the PemP arm with a hazard ratio of 0.95 (95% CI, 0.79 to 1.14). At a median follow-up of 77.3 months, the OS rates at 3 and 5 years were 84.1% and 75.6% versus 87.0% and 75.0% with a hazard ratio of 1.04 (95% CI, 0.81 to 1.34). This long-term follow-up analysis showed that PemP had similar efficacy to NP in both RFS and OS for this population, with one of the longest OS data compared with the historical data.

Importance: Biomarker testing for driver mutations is essential for selecting appropriate non-small cell lung cancer (NSCLC) treatment but is insufficient., Objective: To investigate the status of biomarker testing and drug therapy for NSCLC in Japan for identifying problems in treatment., Design, Setting, and Participants: The REVEAL cohort study included retrospective data collection and prospective follow-up from 29 institutions across Japan. Of 1500 patients diagnosed with advanced or recurrent NSCLC between January 1 and March 18, 2021, 1479 were eligible. Cases recognized at the wrong clinical stage (n = 12), diagnosed outside the study period (n = 6), not treated according to eligibility criteria before recurrence (n = 2), and with deficient consent acquisition procedure (n = 1) were excluded., Main Outcomes and Measures: The primary end point was the biomarker testing status. Treatment-related factors were examined., Results: Among the 1479 patients included in the analysis, the median age was 72 (range, 30-95) years; 1013 (68.5%) were men; 1161 (78.5%) had an Eastern Cooperative Oncology Group performance status 0 or 1; 1097 (74.2%) were current or past smokers; and 947 (64.0%) had adenocarcinoma. Biomarker status was confirmed in 1273 patients (86.1%). Multigene testing was performed in 705 cases (47.7%); single-gene testing, in 847 (57.3%); and both, in 279 (18.9%). Biomarker testing was performed for EGFR in 1245 cases (84.2%); ALK, in 1165 (78.8%); ROS1, in 1077 (72.8%); BRAF, in 803 (54.3%); and MET, in 805 (54.4%). Positivity rates among 898 adenocarcinoma cases included 305 (34.0%) for EGFR, 29 (3.2%) for ALK, 19 (2.1%) for ROS1, 11 (1.2%) for BRAF, and 14 (1.6%) for MET. Positivity rates among 375 nonadenocarcinoma cases were 14 (3.7%) for EGFR, 6 (1.6%) for ALK, 1 (0.3%) for ROS1, 3 (0.8%) for BRAF, and 8 (2.1%) for MET. Poor physical status, squamous cell carcinoma, and other comorbidities were associated with hampered multigene testing. Targeted therapy was received as first-line treatment by 263 of 278 cases (94.6%) positive for EGFR, 25 of 32 (78.1%) positive for ALK, 15 of 24 (62.5%) positive for ROS1, 9 of 12 (75.0%) positive for BRAF, and 12 of 19 (63.2%) positive for MET. Median overall survival of patients with positive findings for driver gene alteration and who received targeted therapy was 24.3 (95% CI, not reported) months; with positive findings for driver gene alteration and who did not receive targeted therapy, 15.2 (95% CI, 7.7 to not reported) months; and with negative findings for driver gene alteration, 11.0 (95% CI, 10.0-12.5) months. Multigene testing for nonadenocarcinomas and adenocarcinomas accounted for 705 (47.7%) of all NSCLC cases., Conclusions and Relevance: These findings suggest that multigene testing has not been sufficiently implemented in Japan and should be considered prospectively, even in nonadenocarcinomas, to avoid missing rare driver gene alterations.

Small amounts of epidermal growth factor receptor (EGFR) T790M mutation (micro-T790M), which is detected using droplet digital PCR (ddPCR) but not conventional PCR, in formalin-fixed and paraffin-embedded (FFPE) samples have been investigated as a predictive factor for the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). However, the predictive value of micro-T790M remains controversial, possibly owing to the failure to examine artificial T790M in FFPE specimens. Therefore, we examined the predictive value of micro-T790M in first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKI efficacy using a new method to exclude FFPE-derived artificial mutations in our retrospective cohort. The primary objective was time to treatment failure (TTF) of 1G, 2G, and 3G EGFR-TKIs according to micro-T790M status. In total, 315 patients with EGFR-positive non-small cell lung cancer treated with 1G, 2G, and 3G EGFR-TKIs were included in this study. The proportion of patients positive for micro-T790M in the 1G, 2G, and 3G EGFR-TKI groups was 48.2%, 47.1%, and 47.6%, respectively. In the micro-T790M-positive group, the TTF was significantly longer in the 2G and 3G EGFR-TKI groups than in the 1G TKI group. No differences in the micro-T790M-negative group were observed. Micro-T790M status detected using ddPCR, eliminating false positives, may be a valuable predictor of EGFR-TKI efficacy., (© 2023. The Author(s).)

Importance: Administration of durvalumab after concurrent chemoradiotherapy is the standard treatment of unresectable, locally advanced non-small cell lung cancer (NSCLC); however, 20% to 30% of patients do not receive durvalumab because of adverse events (AEs) during concurrent chemoradiotherapy. In addition, radiotherapy and immunotherapy have a synergistic effect., Objective: To investigate the efficacy and safety of durvalumab immunotherapy plus concurrent radiotherapy followed by maintenance with durvalumab therapy for treatment of locally advanced NSCLC without chemotherapy., Design, Setting, and Participants: The multicenter, single-arm DOLPHIN (Phase II Study of Durvalumab [MEDI4736] Plus Concurrent Radiation Therapy in Advanced Localized NSCLC Patients) nonrandomized controlled trial was performed by 12 institutions in Japan from September 13, 2019, to May 31, 2022. Participants in the primary registration phase included 74 patients with programmed cell death ligand 1 (PD-L1)-positive, unresectable, locally advanced NSCLC. The current analyses were conducted from June 1, 2022, to October 31, 2022., Interventions: Patients received radiotherapy (60 Gy) in combination with concurrent and maintenance durvalumab immunotherapy, 10 mg/kg every 2 weeks, for up to 1 year., Main Outcomes and Measures: The primary end point of the rate of 12-month progression-free survival (PFS), as assessed by an independent central review, was estimated using the Kaplan-Meier method and evaluated with 90% CIs calculated using the Greenwood formula. The key secondary end points were PFS, objective response rate, treatment completion rate, and AEs., Results: Data from 35 patients (median [range] age, 72 [44-83] years; 31 [88.6%] men) were included in the full analysis set of the evaluable population. The 12-month PFS rate was 72.1% (90% CI, 59.1%-85.1%), and the median PFS was 25.6 months (95% CI, 13.1 months to not estimable) at a median follow-up of 22.8 months (range, 4.3-31.8 months). Scheduled radiation therapy was completed in 97.1% of patients. The confirmed objective response rate was 90.9% (95% CI, 75.7%-98.1%), and the treatment completion rate was 57.6% (95% CI, 39.2%-74.5%). Among 34 patients evaluated in the safety analysis set, AEs of grade 3 or 4 occurred in 18 patients (52.9%), and of grade 5 in 2 patients (5.9%). Pneumonitis or radiation pneumonitis of any grade occurred in 23 patients (67.6%), and of grades 3 or 4 in 4 patients (11.8%)., Conclusions and Relevance: Findings from this phase 2 nonrandomized controlled trial indicate that durvalumab immunotherapy combined with curative radiotherapy for patients with PD-L1-positive, unresectable, locally advanced NSCLC is a promising treatment with tolerable AEs and is appropriate as a study treatment for phase 3 clinical trials., Trial Registration: Japan Registry of Clinical Trials ID: jRCT2080224763.

Introduction: The PACIFIC regimen of consolidation therapy with the programmed cell death-ligand 1 inhibitor durvalumab after definitive concurrent chemoradiation therapy has become a standard of care for individuals with unresectable stage III NSCLC. Nevertheless, approximately half of the treated patients experience disease progression within 1 year, with the mechanisms of treatment resistance being poorly understood. We here performed a nationwide prospective biomarker study to explore the resistance mechanisms (WJOG11518L:SUBMARINE)., Methods: A total of 135 patients with unresectable stage III NSCLC who received the PACIFIC regimen were included for comprehensive profiling of the tumor microenvironment by immunohistochemistry, transcriptome analysis, and genomic sequencing of pretreatment tumor tissue and flow cytometric analysis of circulating immune cells. Progression-free survival was compared on the basis of these biomarkers., Results: The importance of preexisting effective adaptive immunity in tumors was revealed for treatment benefit regardless of genomic features. We also identified CD73 expression by cancer cells as a mechanism of resistance to the PACIFIC regimen. Multivariable analysis of immunohistochemistry data with key clinical factors as covariables indicated that low CD8 + tumor-infiltrating lymphocyte density and the high CD73 + cancer cells were independently associated with poor durvalumab outcome (hazard ratios = 4.05 [95% confidence interval: 1.17-14.04] for CD8 + tumor-infiltrating lymphocytes; 4.79 [95% confidence interval: 1.12-20.58] for CD73). In addition, whole-exome sequencing of paired tumor samples suggested that cancer cells eventually escaped immune pressure as a result of neoantigen plasticity., Conclusions: Our study emphasizes the importance of functional adaptive immunity in stage III NSCLC and implicates CD73 as a promising treatment target, thus providing insight forming a basis for development of a new treatment approach in NSCLC., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: The ALTA-1L study compared brigatinib with crizotinib in untreated ALK-rearranged non-small cell lung cancer (NSCLC) patients, demonstrating the efficacy of brigatinib. Although the median progression-free survival (PFS) of brigatinib group was 24.0 months, the one-year PFS rate was 70%. In the NEJ009 study, patients with EGFR mutations showed improved outcomes with gefitinib plus chemotherapy compared with gefitinib monotherapy. To evaluate the efficacy of the combination of brigatinib with chemotherapy for patients with ALK-rearranged NSCLC, we designed B-DASH study (WJOG 14720L)., Methods: B-DASH study is a multicenter, two-arm, phase II study. Eligible patients have untreated stage IIIB, stage IIIC, stage IV, or postoperative relapse ALK-rearranged nonsquamous NSCLC. Patients will be randomized in a 1:1 ratio to receive brigatinib (180 mg once daily with a 7-day lead-in period at 90 mg) monotherapy or carboplatin (area under the curve = 5 on day 1) plus pemetrexed (500 mg/m 2 on day 1) and brigatinib in a 3-week cycle for up to four cycles, followed by pemetrexed and brigatinib as maintenance therapy. The target hazard ratio of 0.62 is set based on the NEJ009 study. With one-sided alpha = 0.20 and power = 0.8, the sample size for the B-DASH study was calculated to be 110, considering the possibility of patients dropping out. The primary endpoint is PFS. The key secondary endpoints are the overall response rate and overall survival. We will evaluate tumor-derived DNA from plasma specimens before treatment, 42 days after administering the study drug, and on the day of progressive disease. Recruitment began in November 2021 and is ongoing., Discussion: The efficacy of combination therapy with tyrosine kinase inhibitors and cytotoxic chemotherapy was demonstrated in patients with EGFR mutations but remains unclear in patients with ALK-rearranged NSCLC. The B-DASH study is the only trial of brigatinib combined with chemotherapy in patients with untreated ALK-rearranged NSCLC., Trial Registration: jRCT identifier: jRCTs041210103., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has limited treatment options for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Although osimertinib or afatinib alone induced drug-resistant clones with EGFR secondary mutation in a preclinical model, its combination prevented the appearance of these mutations. We investigated alternating-dose therapy of osimertinib and afatinib in patients with EGFR-mutant NSCLC in a single-arm Phase II trial., Methods: Treatment-naïve patients with stage IV NSCLC harboring an activating EGFR mutation were enrolled. Alternating cycles of osimertinib (80 mg/day) followed by afatinib (20 mg/day) were administered every 8 weeks. Genomic analysis was performed using circulating tumor DNA obtained before and after the treatment., Results: Among the 46 enrolled patients, the median progression-free survival was 20.2 months. The overall response rate was 69.6%. The median overall survival was not reached. Among the 26 plasma samples obtained after the acquisition of resistance, 3 showed an increased MET gene copy number, and 1 showed BRAF mutation. Meanwhile, no EGFR secondary mutation was detected., Conclusion: The efficacy of our treatment was not significantly different from osimertinib alone, as reported previously in untreated advanced NSCLC patients with EGFR mutations. Although the sample size was limited, this treatment may prevent the emergence of EGFR secondary mutations that trigger drug resistance. Further studies are warranted to establish the significance of this treatment., Clinical Trial Registration: jRCTs051180009., Competing Interests: Disclosure 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 © 2023 Elsevier Inc. All rights reserved.)

The phase 2, single-arm, multicenter, open-label J-ALTA study evaluated the efficacy and safety of brigatinib in Japanese patients with advanced ALK+ non-small-cell lung cancer (NSCLC). One expansion cohort of J-ALTA enrolled patients previously treated with ALK tyrosine kinase inhibitors (TKIs); the main cohort included patients with prior alectinib ± crizotinib. The second expansion cohort enrolled patients with TKI-naive ALK+ NSCLC. All patients received brigatinib 180 mg once daily (7-day lead-in at 90 mg daily). Among 47 patients in the main cohort, 5 (11%) remained on brigatinib at the study end (median follow-up: 23 months). In this cohort, the independent review committee (IRC)-assessed objective response rate (ORR) was 34% (95% CI, 21%-49%); median duration of response was 14.8 months (95% CI, 5.5-19.4); median IRC-assessed progression-free survival (PFS) was 7.3 months (95% CI, 3.7-12.9). Among 32 patients in the TKI-naive cohort, 25 (78%) remained on brigatinib (median follow-up: 22 months); 2-year IRC-assessed PFS was 73% (90% CI, 55%-85%); IRC-assessed ORR was 97% (95% CI, 84%-100%); the median duration of response was not reached (95% CI, 19.4-not reached); 2-year duration of response was 70%. Grade ≥3 adverse events occurred in 68% and 91% of TKI-pretreated and TKI-naive patients, respectively. Exploratory analyses of baseline circulating tumor DNA in ALK TKI-pretreated NSCLC showed associations between poor PFS and EML4-ALK fusion variant 3 and TP53. Brigatinib is an important treatment option for Japanese patients with ALK+ NSCLC, including patients previously treated with alectinib., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: ONO-4538-52/TASUKI-52 was performed in Japan, Korea, and Taiwan to determine the oncological effectiveness and safety of combining nivolumab or placebo with bevacizumab plus platinum chemotherapy for the initial (first-line) treatment of patients with advanced non-squamous non-small cell lung cancer (nsNSCLC). At the interim analysis (minimum follow-up, 7.4 months), the independent radiology review committee-assessed progression-free survival was significantly longer in the nivolumab arm, but overall survival (OS) data were immature., Methods: Here, we present the updated OS data. Patients with treatment-naïve stage IIIB/IV or recurrent nsNSCLC without driver mutations in ALK, EGFR, or ROS1, were randomized 1:1 to receive either nivolumab or placebo. Patients in both arms received paclitaxel, carboplatin, and bevacizumab, administered 3-weekly for a maximum of 6 cycles. Nivolumab/placebo and bevacizumab were subsequently continued until disease progression or unacceptable toxicity., Results: Overall, 550 patients were randomized. At the time of the analysis (minimum follow-up: 19.4 months), the median OS was longer in the nivolumab arm than in the placebo arm (30.8 vs. 24.7 months; hazard ratio 0.74, 95% confidence interval 0.58-0.94). The 12-month OS rates were 81.3% vs. 76.3% in the nivolumab vs. placebo arms, respectively. The respective 18-month OS rates were 69.0% vs. 61.9%., Conclusion: Nivolumab plus platinum chemotherapy and bevacizumab demonstrated longer OS vs. the placebo combination. We believe this regimen is viable as a standard, first-line treatment for patients with advanced nsNSCLC without driver mutations in ALK, EGFR, or ROS1., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Ramucirumab plus erlotinib (RAM + ERL) demonstrated superior progression-free survival (PFS) over placebo + ERL (PBO + ERL) in the phase III RELAY study of patients with epidermal growth factor receptor (EGFR)-mutated metastatic non-small-cell lung cancer (EGFR+ mNSCLC; NCT02411448). Next-generation sequencing (NGS) was used to identify clinically relevant alterations in circulating tumor DNA (ctDNA) and explore their impact on treatment outcomes., Patients and Methods: Eligible patients with EGFR+ mNSCLC were randomized 1 : 1 to ERL (150 mg/day) plus RAM (10 mg/kg)/PBO every 2 weeks. Liquid biopsies were to be prospectively collected at baseline, cycle 4 (C4), and postdiscontinuation follow-up. EGFR and co-occurring/treatment-emergent (TE) genomic alterations in ctDNA were analyzed using Guardant360 NGS platform., Results: In those with valid baseline samples, detectable activating EGFR alterations in ctDNA (aEGFR+) were associated with shorter PFS [aEGFR+: 12.7 months (n = 255) versus aEGFR-: 22.0 months (n = 131); hazard ratio (HR) = 1.87, 95% confidence interval (CI) 1.42-2.51]. Irrespective of detectable/undetectable baseline aEGFR, RAM + ERL was associated with longer PFS versus PBO + ERL [aEGFR+: median PFS (mPFS) = 15.2 versus 11.1 months, HR = 0.63, 95% CI 0.46-0.85; aEGFR-: mPFS = 22.1 versus 19.2 months, HR = 0.80, 95% CI 0.49-1.30]. Baseline alterations co-occurring with aEGFR were identified in 69 genes, most commonly TP53 (43%), EGFR (other than aEGFR; 25%), and PIK3CA (10%). PFS was longer in RAM + ERL, irrespective of baseline co-occurring alterations. Clearance of baseline aEGFR by C4 was associated with longer PFS (mPFS = 14.1 versus 7.0 months, HR = 0.481, 95% CI 0.33-0.71). RAM + ERL improved PFS outcomes, irrespective of aEGFR mutation clearance. TE gene alterations were most commonly in EGFR [T790M (29%), other (19%)] and TP53 (16%)., Conclusions: Baseline aEGFR alterations in ctDNA were associated with shorter mPFS. RAM + ERL was associated with improved PFS outcomes, irrespective of detectable/undetectable aEGFR, co-occurring baseline alterations, or aEGFR+ clearance by C4. aEGFR+ clearance by C4 was associated with improved PFS outcomes. Monitoring co-occurring alterations and aEGFR+ clearance may provide insights into mechanisms of EGFR tyrosine kinase inhibitor resistance and the patients who may benefit from intensified treatment schedules., Competing Interests: Disclosure EBG declares grants from ABL-Bio, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Dynavax Technologies, EMD Serono, Eli Lilly and Company, Genentech, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon, and Novartis; consulting fees from AbbVie, ABL-Bio, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly and Company, Gilead, GlaxoSmithKline, Ipsen, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, and Xilio; payment for expert testimony from UCLA relating to motif neoepitopes for cancer immunotherapy; leadership/fiduciary role with LUNGevity and Jonsson Comprehensive Cancer Center at UCLA. JVH declares advisory board/committee membership with Genentech, Mirati Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Boehringer-Ingelheim Pharmaceuticals, DAVA Oncology, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Immunocore, and Novartis; research support from AstraZeneca, Boehringer-Ingelheim, Spectrum, and Takeda; royalties and licensing fees from Spectrum. MR declares consulting fees from Amgen, AstraZeneca, Boehringer-Ingelheim, BeiGene, BMS, GSK, Mirati, Merck, MSD, Eli Lilly and Company, Novartis, Pfizer, Roche, Regeneron, and Sanofi; honoraria from Amgen, AstraZeneca, Boehringer-Ingelheim, BeiGene, BMS, GSK, Mirati, Merck, MSD, Eli Lilly and Company, Novartis, Pfizer, Roche, Regeneron, and Sanofi; support for meetings/travel from Amgen, AstraZeneca, Boehringer-Ingelheim, BeiGene, BMS, GSK, Mirati, Merck, MSD, Eli Lilly and Company, Novartis, Pfizer, Roche, Regeneron, and Sanofi; board participation for Daiichi and Sanofi. KN declares 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., Eli Lilly and Company, Hitachi, Sysmex, and Otsuka Pharmaceutical; consulting fees from SymBio Pharmaceuticals, Solasia Pharma, Eli Lilly and Company, and Otsuka Pharmaceutical; honoraria from Chugai, Pfizer, Eli Lilly and Company, MSD, Novartis Pharma, AstraZeneca, Amgen, Merck Biopharma, Roche Diagnostics, Yakult Honsha, Guardant Health, Takeda Pharmaceuticals, Boehringer-Ingelheim Japan, FUJIREBIO, Bristol-Myers Squibb, Merck Biopharma, Janssen Pharmaceutical Daiichi-Sankyo, and Ono Pharmaceutical. MN declares honoraria from Ono Pharmaceuticals, Chugai Pharmaceutical, Taiho Pharmaceutical, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly and Company, AstraZeneca, MSD, AbbVie, Takeda, Pfizer, Boehringer-Ingelheim, Novartis, Nippon Kayaku, Merck, and Janssen. SN declares grants from Eli Lilly and Company; consulting fees from BMS, Eli Lilly and Company, Takeda, Roche, Pfizer, AstraZeneca, BI, MSD, AbbVie, PharmaMar, and BeiGene; support for meetings and/or travel from Eli Lilly and Company, Thermo Fisher, and Takeda; participation on advisory boards for Guardant Health, GSK, Novocure, Amgen, AstraZeneca, Janssen, and Eli Lilly and Company; and declares leadership/fiduciary roles as President of WALCE (Women against Lung Cancer in Europe) Onlus. LPA declares grants from MSD, AstraZeneca, Pfizer, and BMS; consulting fees from Eli Lilly and Company, MSD, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, Takeda, and Daiichi-Sankyo; honoraria from AstraZeneca, Janssen, Merck, and Mirati; member of the board of directors of Altum Sequencing and Genomica; principal investigator for studies sponsored by Alkermes, Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, IO Biotech, Janssen-Cilag, Eli Lilly and Company, MSD, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Takeda, and Tesaro. SP declares consulting fees from Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, Guardant Health, Incyte, Janssen, Eli Lilly and Company, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and EQRx; honoraria from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche, Takeda, and Pfizer; payment for expert testimony from Roche and Merck Serono; support for attending meetings and/or travel from Janssen and Roche; unpaid leadership/fiduciary roles in British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, and ETOP-IBCSG Partners Foundation Board. SPA declares no conflicts of interest. HG was an employee and stockholder of Eli Lilly and Company during the time of study analysis and manuscript preparation; contributions to the manuscript were made as part of the roles at Eli Lilly and Company. BDB and CVG are full-time employees and minor shareholders of Eli Lilly and Company. KN declares grants to institution from AstraZeneca, MSD, Ono Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis, Pfizer Japan Inc., Bristol-Myers Squibb, Eli Lilly and Company, Chugai Pharmaceutical, Daiichi-Sankyo, Merck, Paraxel International Corp., PRA Health Sciences, EPS Corporation, Kissei Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., PPD-SNBL K.K., SymBio Pharmaceuticals Limited, IQVIA Services Japan K.K., Syneos Health Clinical K.K., Nippon Kayaku Co. Ltd., EP-CRSU Co. Ltd., Mebix, Janssen Pharmaceutical K.K., AbbVie Inc., Bayer Yakuhin Ltd., Eisai, Mochida Pharmaceutical Co. Ltd. Covance Japan Inc., Japan Clinical Research Operations, Takeda Pharmaceutical Co. Ltd., GlaxoSmithKline, Sanofi, Sysmex Corporation, Medical Research Support, Otsuka Pharmaceutical Co. Ltd., SRL Inc., Pfizer R&D Japan G.K., and Amgen Inc.; consulting fees from Eli Lilly and Company, KYORIN Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., and Pfizer Japan Inc.; honoraria from Ono Pharmaceutical Co. Ltd., Amgen Inc. Nippon Kayaku Co. Ltd., AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly and Company, MSD, Pfizer Japan Inc., Nippon Boehringer-Ingelheim Co. Ltd., Taiho Pharmaceutical Co. Ltd., Bayer Yakuhin, CMIC ShiftZero K.K., Life Technologies Japan Ltd., Neo Communication, Roche Diagnostics K.K., AbbVie Inc, Merck Biopharma Co. Ltd., Kyowa Kirin Co. Ltd., Takeda Pharmaceutical Co. Ltd., 3H Clinical Trial Inc., Care Net Inc., Medical Review Co. Ltd., Medical Mobile Communications Co. Ltd., Yodosha Co. Ltd., Nikkei Business Publications Inc., Japan Clinical Research Operations, CMIC Co. Ltd., Novartis, TAIYO Pharma Co. Ltd., KYORIN Pharmaceutical Co. Ltd., and Bristol-Myers Squibb K.K.; patents planned, issued, or pending with Daiichi-Sankyo. Data sharing Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the United States and European Union and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Ramucirumab plus erlotinib (RAM+ERL) demonstrated superior progression-free survival (PFS) in RELAY, a randomised Phase III trial in patients with untreated, metastatic, EGFR-mutated, non-small-cell lung cancer (EGFR+ NSCLC). Here, we present the relationship between TP53 status and outcomes in RELAY., Materials and Methods: Patients received oral ERL plus intravenous RAM (10 mg/kg IV) or placebo (PBO+ERL) every 2 weeks. Plasma was assessed by Guardant 360 next-generation sequencing and patients with any gene alteration detected at baseline were included in this exploratory analysis. Endpoints included PFS, overall response rate (ORR), disease control rate (DCR), DoR, overall survival (OS), safety, and biomarker analysis. The association between TP53 status and outcomes was evaluated., Results: Mutated TP53 was detected in 165 (42.7%; 74 RAM+ERL, 91 PBO+ERL) patients, wild-type TP53 in 221 (57.3%; 118 RAM+ERL, 103 PBO+ERL) patients. Patient and disease characteristics and concurrent gene alterations were comparable between those with mutant and wildtype TP53. Independent of treatment, TP53 mutations, most notably on exon 8, were associated with worse clinical outcomes. In all patients, RAM+ERL improved PFS. While ORR and DCR were comparable across all patients, DoR was superior with RAM+ERL. There were no clinically meaningful differences in the safety profiles between those with baseline TP53 mutation and wild-type., Conclusion: This analysis indicates that while TP53 mutations are a negative prognostic marker in EGFR+ NSCLC, the addition of a VEGF inhibitor improves outcomes in those with mutant TP53. RAM+ERL is an efficacious first-line treatment option for patients with EGFR+ NSCLC, independent of TP53 status., Competing Interests: Disclosure This work was supported by Eli Lilly and Company. M. Ceccarelli and C. Visseren-Grul are full-time employees of Eli Lilly and Company. H. Graham was a full-time employee of Eli Lilly and Company at the time of this work. M. Ceccarelli and H. Graham are minor stockholders of Eli Lilly and Company. M. Nishio has received honoraria from Ono Pharmaceuticals, Chugai Pharmaceutical, Taiho Pharmaceutical, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly and Company, AstraZeneca, MSD, AbbVie, Takeda, Pfizer, Boehringer Ingelheim, Novartis, Nippon Kayaku, Merck, and Janssen. L. Paz-Ares has received grants from MSD, AstraZeneca, Pfizer, and Bristol Myers Squibb, consulting fees from Eli Lilly and Company, MSD, Roche, Pharmamar, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, bayer, BMS, Mirati, GSK, Janssen, Takeda, and Merck, honoraria from Roche/Genentech, Eli Lilly and Company, Pfizer, Bristol-Myers Squibb, MSD, BMS, AstraZeneca, Merck Serono, PharmaMar, Novartis, Celgene, Amgen, Mirati, and Abbvie, travel expenses from Roche, AstraZeneca, MSD, Bristol-Myers Squibb, Eli Lilly and Company, and Pfizer, and is an advisory board member for Altum Sequencing and Genomica. M. Reck has received consulting fees, honoraria, and travel expenses from Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Beigene, Eli Lilly and Company, GSK, Daiichi-Sankyo, Merck, MSD, Mirati, Novartis, Pfizer, Sanofi, Roche, and Samsung Bioepis, and is an advisory board member for Daiichi-Sankyo and Sanofi. K. Nakagawa has received grants from AstraZeneca K.K., MSD K.K., Ono Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma K.K., Pfizer Japan Inc., Bristol Myers Squibb, Eli Lilly Japan K.K., Chugai Pharmaceutical, Daiichi Sankyo, Merck Biopharma, PAREXEL International Corp., Pra Healthsciences, EPS Corporation, Kissei Pharmaceutical, EPS International, Taiho Pharmaceutical, PPD-SNBL K.K, SymBio Pharmaceuticals, IQVIA Services JAPAN K.K., Syneos Health Clinical K.K., Nippon Kayaku, EP-CRSU, Mebix, Janssen, AbbVie, Bayer Yakuhin, Eisai, Mochida Pharmaceutical, Covance Japan Inc., Japan Clinical Research Operations, Takeda, GlaxoSmithKline K.K., Sanofi K.K., Sysmex Corporation, Medical Research Support, Otsuka Pharmaceutical, SRL Inc., Pfizer R&D Japan G.K., and Amgen, consulting feed from Eli Lilly Japan K.K., KYORIN Pharmaceutical, Ono Pharmaceutical, Pfizer Japan, honoraria from Ono Pharmaceutical, Amgen, Nippon Kayaku, AstraZeneca K.K., Chugai Pharmaceutical, Eli Lilly Japan K.K., MSD K.K., Pfizer Japan, Nippon Boehringer Ingelheim, Taiho Pharmaceutical, Bayer Yakuhin, CMIC ShiftZero K.K., Life Technologies Japan, Neo Communication, Roche Diagnostics K.K., AbbVie, Merck Biopharma, Kyowa Kirin, Takeda, 3H Clinical Trial, Care Net, Medical Review, Medical Mobile Communications, Yodosha, Nikkei Business Publications, Japan Clinical Research Operations, CMIC, Novartis Pharma K.K., Taiyo Pharma, Kyorin Pharmaceutical, and Bristol-Myers Squibb K.K., and has patents planned with Daiichi Sankyo. E. Garon has received funding from Eli Lilly and Company, grants from ABL-Bio; AstraZeneca, Bristol Myers Squibb, Dynavax Technologies, EMD Serono, Genentech, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon, and Novartis, consulting fees from ABL-Bio, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly and Company, Gilead, GlaxoSmithKline, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, and Xilio, and has a leadership role on the scientific advisory board for Lungevity. S. Popat has received consulting fees from Amgen, AstraZeneca, Bayer, Beigene, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, Guardant Health, Incyte, Janssen, Eli Lilly and Company, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and EQRx, honoraria from AstraZeneca, BAey, Guardant Health, Janssen, Merck Serono, Roche, Takeda, and Pfizer, payment for expert testimony from Roche and Merck Serono, travel expenses from Janssen and Roche, and has a leadership role on a board for British Thoracic Oncology Group, ALK Positive UK, Lung Caner Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, and ETO-IBCSG Partners Foundation. S. Novello has received consulting fees from Sanofi and Novartis, honoraria from AstraZeneca, Amgen, MSD, Takeda, Roche, Pfizer, Thermofisher, Novartis, and Sanofi, and is an advisory board member for AstraZeneca, Roche, Pfizer and MSD., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although segmentectomy is a widely used surgical procedure, lobectomy is the standard procedure for resectable non-small-cell lung cancer (NSCLC). This study aimed to evaluate the efficacy and safety of segmentectomy for NSCLC up to 3 cm in size, including ground-glass opacity (GGO) and predominant GGO., Methods: A multicentre, single-arm, confirmatory phase 3 trial was conducted across 42 institutions (hospitals, university hospitals, and cancer centres) in Japan. Segmentectomy with hilar, interlobar, and intrapulmonary lymph node dissection was performed as protocol surgery for patients with a tumour diameter of up to 3 cm, including GGO and dominant GGO. Eligible patients were those aged 20-79 years with an Eastern Cooperative Oncology Group performance score of 0 or 1 and clinical stage IA tumour confirmed by thin-sliced CT. The primary endpoint was 5-year relapse-free survival (RFS). This study is registered with the University Hospital Medical Information Network Clinical Trials (UMIN000011819), and is ongoing., Findings: A total of 396 patients were registered from Sept 20, 2013, to Nov 13, 2015, of whom 357 underwent segmentectomy. At a median follow-up of 5·4 years (IQR 5·0-6·0), the 5-year RFS was 98·0% (95% CI 95·9-99·1). This finding exceeded the 87% of the pre-set threshold 5-year RFS and the primary endpoint was met. Grade 3 or 4 early postoperative complications occurred in seven patients (2%), but no grade 5 treatment-related deaths occurred., Interpretation: Segmentectomy should be considered as part of standard treatment for patients with predominantly GGO NSCLC with a tumour size of 3 cm or less in diameter, including GGO even if it exceeds 2 cm., Funding: National Cancer Centre Research and Development Fund and Japan Agency for Medical Research and Development., Competing Interests: Declaration of interests KA, AH, HI, TK, HK, TMiy, RN, YO, MO, JO, YT, and SW report research funding from the National Cancer Center Research and Development Fund by the National Cancer Center and Practical Research for Innovative Cancer Control Fund by Japan Agency for Medical Research and Development. HF reports lecture fees from Chugai Pharmaceuticals, outside of the submitted work. MW reports honoraria from Nihon Medi-Physics outside of the submitted work. MTs reports research funding from Boehringer-Ingelheim Japan and commissioned research for clinical trials from MSD, Astrazeneca, Ono Pharmaceutical, Bristol-Myers Squibb, Eli Lilly Japan, Novartis, and BMG; lecture fees from Johnson & Johnson Japan, AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, MSD, Bristol-Myers Squibb, Teijin Pharma, Taiho Pharma, Medtronic Japan, ONO Pharmaceutical, Daiichi-Sankyo, and Novartis, outside of the submitted work; is on the advisory board of AstraZeneca, Chugai Pharmaceutical, MSD, Novartis, and Eli Lilly, outside of the submitted work; and also is on the committee of Japan Lung Cancer Society and Japanese Association of Chest Surgery, Cancer Net Japan, Japanese Organization for Research, and Treatment of Cancer, outside of the submitted work. TMim reports research funding from the Japan Society for the Promotion of Science KAKENHI (grant number 20K09177) by the Japan Society for Promotion of Science, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: With recent improvements in surgical techniques for segmentectomy, we hypothesized that segmentectomy is feasible and more effective than wedge resection for non-small-cell lung cancer (NSCLC). We compared perioperative and oncological outcomes for segmentectomy and wedge resection., Methods: We performed a retrospective analysis of 720 patients who underwent sublobar resection (segmentectomy, 479; wedge resection, 241) for clinical stage 0 or I NSCLC from January 2017 to June 2020. An adequate surgical margin was defined as a surgical margin distance of ≥2 cm or ≥ the total tumour size. Recurrence-free survival (RFS) was estimated using the Kaplan-Meier method for clinical stage IA., Results: There was no significant difference in the rate of major (grade ≥III) complications between segmentectomy (1.7%) and wedge resection (1.2%) (P = 0.76). The probability of obtaining adequate surgical margins was significantly higher with segmentectomy (71.4%) versus wedge resection (59.5%) (P = 0.002), and the difference was especially prominent for clinical stage IA2 (75.3% vs 56.9%; P = 0.012). Among patients with clinical stage IA, segmentectomy significantly improved the RFS compared with wedge resection (hazard ratio 2.7; 95% confidence interval 1.60-4.61; log-rank P < 0.001). Subgroup analysis based on the tumour status revealed that segmentectomy had a better RFS in clinical stage IA2 (P < 0.001) and in pure-solid tumours (P = 0.022) than wedge resection., Conclusions: We demonstrate that segmentectomy is a feasible procedure with comparable safety outcomes and better surgical margins and cancer control than wedge resection, particularly for clinical stage IA2 NSCLC., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is an established standard treatment option for chemotherapy-naive patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). However, of such patients who have received prior treatment with a first- or second-generation EGFR TKI, only approximately half are eligible for osimertinib therapy because its indication as second-line treatment and beyond is limited to metastatic NSCLC that is positive for the T790M resistance mutation of the EGFR gene. This study was initiated at the request of a dedicated network for patients with lung cancer in Japan., Methods: We conducted a phase II study to assess the efficacy of osimertinib in patients with EGFR mutation-positive NSCLC in whom systemic disease (T790M-negative) progressed after treatment with first- or second-generation EGFR TKIs and platinum-based chemotherapy. The primary end point was response rate (assessed by a central imaging reviewer)., Results: From August 2020 to February 2021, 55 patients from 15 institutions were enrolled in the study. The overall response for primary analysis was achieved in 16 patients (29.1 %; 95 % CI, 17.6-42.9), which exceeded the threshold response rate necessary for analysis. Stable disease was found in 16 patients (29.1 %), and progressive disease, in 18 (32.7 %). The median length of progression-free survival (PFS) was 4.07 months (95 % CI 2.10-4.30), and the rate of 12-month PFS was 17.3 %., Conclusions: Osimertinib demonstrated modest antitumor activity against progressive EGFR T790M-negative disease., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Takeda reports personal fees from Chugai Pharmaceutical Co., LTD., AstraZeneca K.K., Bristol-Myers Squibb Company, Novartis Pharma K.K., and Ono Pharmaceutical Co.,LTD. Dr Shimokawa has no conflicts of interest. Dr. Nakamura reports personal fees from MSD, AstraZeneca, Chugai Pharma, Kyowa Hakko Kirin, Nippon Boehringer Ingelheim, and Taiho Pharmaceutical. Dr. Nosaki reports personal fees from AstraZeneca K.K. Dr Watanabe has no conflicts of interest. Dr. Kato reports grants from Abbvie, Amgen, AstraZeneca, Blueprint, Chugai, Eli Lilly, Haihe, Merck Biopharma, MSD, Novartis, Pfizer, Regeneron, and Takeda, and personal fees Abbvie, Amgen, AstraZeneca, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Glaxo, Merck Biopharma, MSD, Nippon Kayaku, Novartis, Ono, Pfizer, Roche, Taiho, and Takeda. Dr. Hayakawa has no conflicts of interest. Dr. Tanaka reports grants and personal fees from Astra Zeneca, Chugai Pharmaceutical, MSD, Ono Pharmaceutical, Bristol-Myers Squibb, Daiichi Sankyo Pharmaceutical, Eli Lilly, Takeda Pharmaceutical, Taiho Pharmaceutical, Merck, and Boehringer Ingelheim; grants from Amgen and Abbvie; and personal fees from Sun Pharmaceutical, Eisai, and Novartis. Dr. Takahashi reports grants from AstraZeneca KK, Chugai Pharmaceutical Co., LTD., Eli Lilly Japan K.K., Ono Pharmaceutical Co., LTD., MSD K.K., Pfizer Japan Inc., Amgen Inc., Boehringer Ingelheim Japan, and Merck Biopharma Co., LTD, and personal fees from AstraZeneca KK, Chugai Pharmaceutical Co., LTD., Eli Lilly Japan K.K., Ono Pharmaceutical Co., LTD., MSD K.K., Pfizer Japan Inc., Boehringer Ingelheim Japan, INC, Roche Diagnostics K.K., Takeda Pharmaceutical Co LTD., and Yakult Honsha CO. LTD. Dr. Oki reports research grants from MSD K.K., PAREXEL International Corp, Sanofi K.K., AstraZeneca K.K., and Janssen Pharmaceutical K.K. Dr. Tachihara reports grants and personal fees from AstraZeneca and personal fees from Taiho Pharmaceutical, MSD, Eli Lilly Japan K.K, Nippon Boehringer Ingelheim, Chugai Pharmaceutical, and Ono Pharmaceutical. Dr. Fujimoto reports personal fees from AstraZeneca KK, Ono Pharmaceutical Co Ltd, Bristol-Myers Squibb Co Ltd, Taiho Pharmaceutical Co Ltd, Chugai Pharmaceutical Co Ltd, MSD KK, Boehringer Ingelheim Japan Inc, Eli Lilly Japan KK, and Novartis Pharma K.K. Dr. Hayashi reports grants from AstraZeneca K.K., Astellas Pharma Inc., MSD K.K., Ono Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., grants, Pfizer Japan Inc., Bristol-Myers Squibb Company, Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Merck Serono Co., Ltd./ Merck Biopharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Limited., AbbVie Inc, inVentiv Health Japan, ICON Japan K.K., GRITSONE ONCOLOGY.INC, PAREXEL International Corp., Kissei Pharmaceutical Co., Ltd., EPS Corporation., Syneos Health., Pfizer R&D Japan G.K., A2 Healthcare Corp., Quintiles Inc./IQVIA Services JAPAN K.K., EP-CRSU CO., LTD., Linical Co., Ltd., Eisai Co., Ltd., CMIC Shift Zero K.K., and Kyowa Hakko Kirin Co., Ltd, and personal fees from Bayer Yakuhin, Ltd, EPS International Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Amgen K.K, AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K., Guardant healthcare, Kyorin Pharmaceutical Co. Ltd., Merck Biopharma Co. Ltd., MSD K.K., Novartis Pharmaceuticals K.K., Ono Pharmaceutical Co. Ltd., Shanghai Haihe Biopharm, Taiho Pharmaceutical Co. Ltd., Pfizer, and Takeda Pharmaceutical Co. Ltd. Dr. Yamaguchi has no conflicts of interest. Dr. S. Yamamoto have no conflicts of interest. Dr. Iwama reports personal fees from AstraZeneca. Dr. Azuma reports personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, Ono Pharmaceutical, MSD Oncology, Bristol-Myers Squibb, Chugai Pharma. Dr. N. Yamamoto reports grants and personal fees from MSD, personal fees from AstraZeneca, grants and personal fees from Ono Pharmaceutical Co., Ltd., personal fees from Thermo Fisher Scientific, grants and personal fees from Daiichi Sankyo, grants and personal fees from Taiho Pharmaceutical Co., Ltd., grants and personal fees from Takeda Pharmaceutical Co., Ltd., grants and personal fees from Chugai Pharmaceutical Co., Ltd., grants and personal fees from Eli Lilly Japan K.K., grants and personal fees from Boehringer Ingelheim, personal fees from Novartis, grants and personal fees from Pfizer, personal fees from Bristol-Myers Squibb, personal fees from Life Technologies Japan Ltd., personal fees from Nippon Kayaku, grants from Astellas Pharma Inc., grants from Shionogi, grants from Abbvie, grants from MEDICAL RESEARCH, grants from Kyorin Pharmaceutical Co., Ltd., grants from Eisai Co., Ltd., grants from TERUMO CORPORATION, grants from TOPPAN PRINTING Co., Ltd., and grants from TOSOH CORPORATION. Dr. Nakagawa reports grants and personal fees from AstraZeneca K.K.; grants and personal fees from Astellas Pharma Inc.; grants and personal fees from MSD K.K.; grants, personal fees, and other financial assistance from Ono Pharmaceutical Co., Ltd.; grants and personal fees from Nippon Boehringer Ingelheim Co., Ltd.; grants and personal fees from Novartis Pharma K.K.; grants, personal fees, and other financial assistance from Pfizer Japan Inc.; grants and personal fees from Bristol-Myers Squibb Company; grants, personal fees, and other financial assistance from Eli Lilly Japan K.K.; grants and personal fees from Chugai Pharmaceutical Co., Ltd.; grants and personal fees from Daiichi Sankyo Co., Ltd.; grants and personal fees from Merck Serono Co., Ltd./Merck Biopharma Co., Ltd., during the study; personal fees from Clinical Trial Co., Ltd.; personal fees from MEDICUS SHUPPAN, Publishers Co., Ltd.; personal fees from Care Net, Inc.; personal fees from Reno Medical K.K.; personal fees and other financial assistance from Kyorin Pharmaceutical Co., Ltd.; personal fees from Medical Review Co., Ltd.; personal fees from Roche Diagnostics K.K.; personal fees from Bayer Yakuhin, Ltd.; personal fees from Medical Mobile Communications Co., Ltd.; personal fees from 3H Clinical Trial Inc.; personal fees from Nichi-Iko Pharmaceutical Co., Ltd.; grants, personal fees, and other financial assistance from Takeda Pharmaceutical Co., Ltd.; grants and personal fees from Taiho Pharmaceutical Co., Ltd.; grants and personal fees from SymBio Pharmaceuticals Limited; personal fees from NANZANDO Co., Ltd.; personal fees from YODOSHA CO., LTD.; personal fees from Nikkei Business Publications, Inc.; personal fees from Thermo Fisher Scientific K.K.; personal fees from YOMIURI TELECASTING CORPORATION; personal fees from Nippon Kayaku Co., Ltd.; grants and personal fees from AbbVie Inc.; grants from inVentiv Health Japan; grants from ICON Japan K.K.; grants from GRITSONE ONCOLOGY INC.; grants from PAREXEL International Corp.; grants from Kissei Pharmaceutical Co., Ltd.; grants from EPS Corporation; grants from Syneos Health; grants from Pfizer R&D Japan G.K.; grants from A2 Healthcare Corp.; grants from Quintiles Inc./IQVIA Services JAPAN K.K.; grants from EP-CRSU CO., LTD.; grants from Linical Co., Ltd.; grants from Eisai Co., Ltd.; grants from CMIC Shift Zero K.K.; grants from Kyowa Hakko Kirin Co., Ltd; grants from Bayer Yakuhin, Ltd; grants from EPS International Co., Ltd.; and grants from Otsuka Pharmaceutical Co., Ltd., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Since the overall survival (OS) of patients enrolled in the first clinical phase III trial (WJOG5108L) was not recorded owing to time constraints, the present study (WJOG5108LFS) with a longer follow-up (66.6 months) aimed to compare OS of those treated with erlotinib (ER) and gefitinib (GE) for lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation., Methods: Among 536 enrolled patients, 362 (67.5%) were EGFR mutation-positive, including 182 in the ER arm and 180 in the GE arm. Median survival time (MST) and progression-free survival (PFS) were calculated using Kaplan-Meier survival curves. OS and PFS were determined for patients with EGFR mutation., Results: MSTs of ER (n = 182) and GE arms (n = 180) were 31.97 and 27.98 months, respectively (P = 0.3573, hazard ratio = 1.116). MSTs of exon 19 mutation patients in ER (n = 99) and GE arms (n = 89) were 37.49 and 28.91 months, respectively (P = 0.3791). MSTs of L858 mutation patients in ER (n = 82) and GE arms (n = 89) were 22.98 and 27.79 months, respectively (P = 0.7836). In patients with brain metastasis harboring mutation, response rates were 32.8% and 22.2% (P = 0.160), MSTs were 23.46 and 23.89 months (P = 0.7410), and PFS were 9.49 and 6.98 months (P = 0.1481) in the ER (n = 67) and GE arms (n = 72), respectively., Conclusions: No significant differences in OS were observed between the ER and GE arms in all patients with EGFR mutation and those with brain metastasis harboring EGFR mutation., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

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.)

Objective: Immune checkpoint inhibitors (ICIs) have become a key therapeutic modality for advanced non-small cell lung cancer (NSCLC), but most patients experience primary or acquired resistance to these drugs. We here explored the mechanisms underlying both types of ICI resistance by analysis of the tumor immune microenvironment (TME)., Materials and Methods: Four patients who experienced a long-term response to ICI treatment (progression-free survival [PFS] of ≥12 months) followed by disease progression, after which a rebiopsy was immediately performed (cohort-A), as well as four patients who experienced early tumor progression during ICI treatment (PFS of <9 weeks, cohort-B) were enrolled in this retrospective study. The pretreatment TME was evaluated by 16- or 17-color multiplex immunohistochemistry (mIHC)-based spatial profiling at the single-cell level for both cohorts. In cohort-A, changes in the TME after disease progression during ICI treatment were also investigated by mIHC analysis and transcriptomic analysis., Results: Pretreatment tumor tissue from cohort-B manifested poor infiltration of tumor-reactive CD8 + T cells characterized by CD39 and CD103 expression or by programmed cell death-1 expression, implicating insufficient recognition of tumor cells by CD8 + T cells as a mechanism of primary ICI resistance. Analysis of the paired tumor specimens from cohort-A revealed various changes in the TME associated with acquired ICI resistance, including substantial infiltration of myeloid-derived suppressor cells and M2-type tumor-associated macrophages without a marked decline in the number of tumor-reactive CD8 + T cells; a decrease in the number of tumor-reactive CD8 + T cells; and an apparent decrease in neoantigen presentation by tumor cells., Conclusion: The presence of intratumoral tumor-reactive CD8 + T cells may be a prerequisite for a long-term response to ICI treatment in advanced NSCLC, but it is not sufficient for cancer cell eradication. Various TME profiles are associated with acquired ICI resistance, suggesting that patient-specific strategies to overcome such resistance may be necessary., Competing Interests: Declaration of Competing Interest KH reports research funding regarding the submitted work from KANAE Foundation for the Promotion of Medical Science, SGH Foundation, and YOKOYAMA Foundation for Clinical Pharmacology; other research funding from AstraZeneca K.K. and MSD K.K.; honoraria from AS ONE Corporation, Bristol-Myers Squibb Company, MSD K.K., and Ono Pharmaceutical Co., Ltd., outside the submitted work; TT reports research funding from Ono Pharmaceutical Co., Ltd.; honoraria from Ono Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Merck Sharp & Dohme Corp, and Bristol Myers Squibb Co., Ltd., outside the submitted work; HK reports grants from Eisai Co., Ltd., Kobayashi Pharmaceutical. Co., Ltd., and Taiho Pharmaceutical Co., Ltd.; consulting fees from Daiichi-Sankyo Co., Ltd.; honoraria from Bristol-Myers Squibb Company, Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd, Otsuka Pharmaceutical Co., Ltd., Bayer Yakuhin Ltd., MSD K.K., Chugai Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Yakult Pharmaceutical Industry, and Taiho Pharmaceutical Co., Ltd., outside the submitted work; MT has received honoraria from Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., Bristol-Myers Squibb Company, Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan Inc., and Takeda Pharmaceutical Co., Ltd., outside the submitted work; KY reports research funding from Daiichi Sankyo Co., Ltd.; honoraria from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Takeda Pharmaceutical Co., Ltd., Merck Sharp & Dohme K.K., and Nippon Kayaku; patents US20200115467 and US20200061031 pending, outside the submitted work; KT has received honoraria from AstraZeneca K.K., Eisai Co., Ltd., Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Bristol-Myers Squibb Company, MSD K.K., Takeda Pharmaceutical Co., Ltd., and Kyowa Hakko Kirin Co., Ltd., outside the submitted work; HH reports grants from AstraZeneca K.K., Astellas Pharma Inc., MSD K.K., Ono Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Pfizer Japan Inc., Bristol Myers Squibb Co., Ltd., Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Merck Serono Co., Ltd. / Merck Biopharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Limited., AbbVie Inc, inVentiv Health Japan, ICON Japan K.K., GRITSONE ONCOLOGY.INC, PAREXEL International Corp., Kissei Pharmaceutical Co., Ltd., EPS Corporation., Syneos Health., Pfizer R&D Japan G.K., A2 Healthcare Corp., Quintiles Inc. / IQVIA Services JAPAN K.K., EP-CRSU CO., LTD., Linical Co., Ltd., Eisai Co., Ltd., CMIC Shift Zero K.K., Kyowa Hakko Kirin Co., Ltd, Bayer Yakuhin, Ltd, EPS International Co., Ltd., and Otsuka Pharmaceutical Co., Ltd.; honoraria from Amgen K.K., AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eli Lilly Japan K.K., Guardant healthcare, Kyorin Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., MSD K.K., Novartis Pharmaceuticals K.K., Ono Pharmaceutical Co., Ltd., Shanghai Haihe Biopharm, Taiho Pharmaceutical Co., Ltd., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., outside the submitted work; KN reports grants from Boehringer Ingelheim Japan Inc., 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 K.K.; consulting fees from SymBio Pharmaceuticals Ltd., Solasia Pharma, Eli Lilly Japan K.K., and Otsuka Pharmaceutical Co., Ltd.; honoraria from Boehringer Ingelheim Japan Inc., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Novartis Pharma K.K., Eisai Co., Ltd., MSD K.K., Bristol-Myers Squibb Company, Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi K.K., Guardant Health, Inc., Eli Lilly Japan K.K., Amgen K.K., Merck Biopharma Co., Ltd., Roche Diagnostics K.K., Yakult Honsha Co., Ltd., Takeda Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., FUJIREBIO Inc., outside the submitted work; KN reports grants from MSD K.K., ICON Japan K.K., Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Bristol-Myers Squibb Company, Taiho Pharmaceutical Co., Ltd., PAREXEL International Corp., Ono Pharmaceutical Co., Ltd., Sysmex Corporation, A2 Healthcare Corp., AbbVie Inc., Chugai Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan Inc., SymBio Pharmaceuticals Limited., AstraZeneca K.K., EPS International Co., Ltd., CMIC Shift Zero K.K., Eisai Co., Ltd., Mochida Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., Kyowa Hakko Kirin Co., Ltd., EPS Corporation Co., Ltd., Daiichi Sankyo Co., Ltd., Quintiles Inc. / IQVIA Services JAPAN K.K., Pfizer Japan Inc., Bayer Yakuhin Ltd., Otsuka Pharmaceutical Co., Ltd., PRA HEALTHSCIENCES, Merck Biopharma Co., Ltd., Covance Japan Inc., Medical Research Support, Sanofi K.K., Syneos Health., Pfizer R&D Japan G.K., PPD-SNBL K.K., and Japan Clinical Research Operations; consulting fees from Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., KYORIN Pharmaceutical Co., Ltd., and Ono Pharmaceutical Co., Ltd.; honoraria from Astellas Pharma Inc., AstraZeneca K.K., MSD K.K., Ono Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Bristol Myers Squibb Co., Ltd., Medical Review Co., Ltd., Thermo Fisher Scientific K.K., KYORIN Pharmaceutical Co., Ltd., Nikkei Business Publications, Inc., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Merck Biopharma Co., Ltd., Novartis Pharma K.K., Pfizer Japan Inc., CareNet, Inc, YODOSHA CO., LTD., Hisamitsu Pharmaceutical Co., Inc., MEDICUS SHUPPAN Publishers Co., Ltd., YOMIURI TELECASTING CORPORATION., NANZANDO Co., Ltd., Roche Diagnostics K.K., Nippon Kayaku Co., Ltd., Bayer Yakuhin, Co., Ltd., Kyowa Hakko Kirin Co., Ltd., AbbVie Inc., Amgen K.K., 3H Clinical Trial Inc., Nichi-Iko Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., and Medical Mobile Communications Co., Ltd., outside the submitted work. The remaining 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 Elsevier B.V. All rights reserved.)

Aim: This study aims to evaluate Japanese patients' preferences in first-line therapy choice for advanced non-small cell lung cancer(NSCLC)with epidermal growth factor receptor(EGFR)mutations., Methods: A cross-sectional discrete-choice experiment was conducted on advanced NSCLC patients in Japan. Participants completed the online questionnaire that included different levels of 5 treatment attributes: time to disease progression, chance of rash, next therapy option, frequency of health care visits and administration route. The primary analysis estimated the relative attribute importance. The preferences of EGFR mutation-positive patients were compared with those of EGFR mutation-negative/unknown patients to observe whether preference differs by mutation status., Results: A total of 158 participants completed the survey. The analysis on the overall study population revealed next therapy option(mean relative attribute importance[SD]: 39.30 [17.07])as the most important attribute, followed by time to disease progression(25.52[10.51]), chance of rash(21.58 [11.74]), with administration route(7.63[6.99])and frequency of health care visits(5.96[3.40])the least preferred. The results in the subgroups by EGFR mutation status were similar., Conclusion: Next therapy option is the major influencing factor for treatment choice of molecular targeting therapy among advanced NSCLC patients in Japan, emphasizing the importance of communicating the next treatment options to patients at the time of their first treatment.

Background: We evaluated the safety and efficacy of the anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) brigatinib in Japanese patients with TKI-naive ALK-positive non-small cell lung cancer (NSCLC) from the phase 2, open-label, single-arm, multicenter J-ALTA study., Methods: In the TKI-naive cohort of J-ALTA, the primary end point was independent review committee (IRC)-assessed 12-month progression-free survival (PFS). Secondary end points included objective response rate (ORR), intracranial response, overall survival (OS), and safety., Results: The data were cut approximately 12 months after last patient enrollment. Thirty-two patients with ALK TKI-naive ALK-positive NSCLC were enrolled (median age [range], 60.5 [29-85] years; median duration of follow-up, 14.2 [3.2-19.3] months; median treatment duration, 13.8 [0.4-19.3] months). IRC-assessed 12-month PFS was 93.0% (90% confidence interval (CI) 79.2-97.8%); ORR, 96.9% (95% CI 83.8-99.9%), 12-month OS, 96.9% (95% CI 79.8-99.6%), and median OS was not reached. Of five patients with measurable baseline CNS metastases, two had partial intracranial response. The most common treatment-emergent adverse events were increased blood creatine phosphokinase (81%), hypertension (59%), and diarrhea (47%). Grade ≥ 3 adverse events occurred in 91% of patients; pneumonitis was reported in 3 (9%) patients., Conclusions: In the J-ALTA TKI-naive cohort, brigatinib demonstrated clinically meaningful efficacy consistent with the international phase 3 study. The safety profile in Japanese patients was consistent with previous studies. Brigatinib is an important first-line option for Japanese patients with ALK-positive NSCLC., Clinical Registration: NCT03410108., (© 2022. The Author(s).)

Background: Salvage surgery is performed for selected patients with relapses of locally advanced lung cancer after definitive chemoradiation therapy (CRT), and it seems to be effective. To assess the feasibility of salvage surgery after definitive CRT, this study compared clinical outcomes of surgery after definitive CRT with those of surgery after induction CRT., Methods: Medical records of patients who underwent surgery from January 2000 to January 2018 were reviewed. The study compared patients with salvage anatomic pulmonary resection after definitive CRT with patients with surgery after induction CRT in terms of perioperative and long-term outcomes., Results: A total of 23 patients underwent salvage surgery after definitive CRT for locally advanced lung cancer (salvage group), and 36 underwent surgery after induction CRT for cN2 stage III non-small cell lung cancer (induction CRT group). The surgical procedures in the salvage group were 2 segmentectomies, 13 lobectomies, 1 bilobectomy, and 7 pneumonectomies, and those in the induction CRT group were 34 lobectomies and 2 bilobectomies. There was no 30-day or 90-day mortality in either group. The 5-year overall survival was 44.7% for the salvage group and 58.6% for the induction CRT group. The 5-year progression-free interval was 42.2% for the salvage group and 47.7% for the induction CRT group., Conclusions: Salvage anatomic pulmonary resection after definitive CRT for locally advanced lung cancer is feasible, with acceptable morbidity and prognosis in highly selected patients., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Pembrolizumab is a standard-of-care for advanced non-small-cell lung cancer (NSCLC). We assessed pembrolizumab as adjuvant therapy for completely resected stage IB-IIIA NSCLC., Methods: In this randomised, triple-blind, phase 3 trial (PEARLS/KEYNOTE-091), patients were recruited from 196 medical centres in 29 countries. Eligible patients were aged 18 years or older, with completely resected, pathologically confirmed stage IB (tumours of ≥4 cm in diameter), II, or IIIA NSCLC per the American Joint Committee on Cancer staging system (7th edition) of any histology or PD-L1 expression level, and an Eastern Cooperative Oncology Group performance status of 0 or 1; adjuvant chemotherapy was to be considered for stage IB disease and was strongly recommended for stage II and IIIA disease, according to national and local guidelines. Using a central interactive voice-response system, eligible participants were randomly assigned (1:1), using a minimisation technique and stratified by disease stage, previous adjuvant chemotherapy, PD-L1 expression, and geographical region, to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks for up to 18 cycles. Participants, investigators, and analysts were masked to treatment assignment. Dual primary endpoints were disease-free survival in the overall population and in the population with PD-L1 tumour proportion score (TPS) of 50% or greater. Efficacy was assessed in the intention-to-treat (ITT) population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants randomly assigned to treatment who received at least one dose of study treatment. Here we report results of the second interim analysis, prespecified to occur when approximately 118 disease-free survival events had occurred in the PD-L1 TPS of 50% or greater population. This study is registered with ClinicalTrials.gov, NCT02504372, and is active but not recruiting., Findings: Between Jan 20, 2016, and May 6, 2020, 1177 (60%) of 1955 screened participants were randomly assigned to pembrolizumab (n=590, including n=168 with PD-L1 TPS of ≥50%) or placebo (n=587; including n=165 with PD-L1 TPS of ≥50%) and included in the ITT population. Median follow-up as of data cutoff (Sept 20, 2021) for this interim analysis was 35·6 months (IQR 27·1-45·5). In the overall population, median disease-free survival was 53·6 months (95% CI 39·2 to not reached) in the pembrolizumab group versus 42·0 months (31·3 to not reached) in the placebo group (HR 0·76 [95% CI 0·63-0·91], p=0·0014). In the PD-L1 TPS of 50% or greater population, median disease-free survival was not reached in either the pembrolizumab group (95% CI 44·3 to not reached) or the placebo group (95% CI 35·8 to not reached; HR 0·82 [95% CI 0·57-1·18]; p=0·14). Grade 3 or worse adverse events occurred in 198 (34%) of 580 participants who received pembrolizumab and 150 (26%) of 581 participants who received placebo. Grade 3 or worse events that occurred in at least ten participants in either treatment group were hypertension (35 [6%]) and pneumonia (12 [2%]) with pembrolizumab and hypertension (32 [6%]) with placebo. Serious adverse events occurred in 142 (24%) participants in the pembrolizumab group and 90 (15%) in the placebo group; serious adverse events that occurred in more than 1% of participants were pneumonia (13 [2%]), pneumonitis (12 [2%]), and diarrhoea (seven [1%]) with pembrolizumab and pneumonia (nine [2%]) with placebo. Treatment-related adverse events led to death in four (1%) participants treated with pembrolizumab (one due to both cardiogenic shock and myocarditis, one due to both septic shock and myocarditis, one due to pneumonia, and one due to sudden death) and in no participants treated with placebo., Interpretation: Pembrolizumab significantly improved disease-free survival compared with placebo and was not associated with new safety signals in completely resected, PD-L1-unselected, stage IB-IIIA NSCLC. Pembrolizumab is potentially a new treatment option for stage IB-IIIA NSCLC after complete resection and, when recommended, adjuvant chemotherapy, regardless of PD-L1 expression., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co., Competing Interests: Declaration of interests MO, LP-A, SM, UD, KO, LH, EE, DI, AM-M, MF, MT, J-SL, KN, MM, NJ, RS, BB, and SP report funding to their institutions from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co (Rahway, NJ, USA; MSD) to support conduct of this study. All authors received medical writing support for the preparation of this manuscript from MSD. MO additionally reports consulting fees for serving on advisory boards for MSD, Merck, Pierre Fabre, Amgen, Puma, Iteos, and PharmaMar; honoraria from Roche and Lilly in China; travel support from MSD; payment for serving as a member of an independent data monitoring committee for PharmaMar; and payment from ALPI (Sweden) for an academic review. LP-A additionally reports institutional grants or contracts from MSD, AstraZeneca, Pfizer, and Bristol Myers Squibb (BMS); consulting fees from Lilly, MSD, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, and Takeda; honoraria from AstraZeneca, Janssen, Merck, and Mirati; participation on a data safety monitoring board for Altum Sequencing and Genomica; and serving as a principal investigator on trials for Alkermes, Amgen, AstraZeneca, BMS, Daiichi Sankyo, IO Biotech, Janssen-Cilag, Lilly, MSD, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Takeda, and Tesaro. UD additionally reports consulting fees from Roche. KO additionally reports institutional grants or contracts from Pfizer and Takeda; consulting fees from Amgen, Takeda, MSD, Janssen, Roche, and AstraZeneca; and travel support from MSD. DI additionally reports consulting fees from MSD, Roche, AstraZeneca, Amgen, Pfizer, Sanofi, Bayer, BMS, GSK, Janssen, and Takeda; honoraria from MSD, Roche, AstraZeneca, Amgen, Pfizer, Sanofi, Bayer, BMS, and Takeda; and travel support from AstraZeneca. AM-M additionally reports consulting fees for advisory board membership from AstraZeneca/MedImmune, BMS, F Hoffmann-La Roche AG, MSD, and Pfizer; honoraria from AstraZeneca/MedImmune, BMS, F Hoffmann-La Roche AG, MSD, and Pfizer; serving as a steering committee member for AstraZeneca/MedImmune; and travel support from AstraZeneca/MedImmune, BMS, F Hoffmann-La Roche AG, MSD, Pfizer, and Lilly. MF additionally reports honoraria from Roche and Sanofi; travel support from AstraZeneca; and serving as an advisory board member for MSD, Roche, and AstraZeneca. MT additionally reports institutional grants or contracts from Boehringer-Ingelheim Japan, MSD, AstraZeneca KK, Ono Pharmaceutical, and Novartis; consulting fees from AstraZeneca KK, Chugai Pharmaceutical, and MSD KK; honoraria from Johnson & Johnson Japan, AstraZeneca KK, Eli Lilly Japan, Chugai Pharmaceutical, Taiho Pharma, Medtronic Japan, Ono Pharmaceutical, MSD KK, BMS KK, Daiichi Sankyo KK, and Teijin Pharma; serving as a data safety monitoring committee member for Chugai Pharmaceutical; and serving as an advisory board member for AstraZeneca KK, MSD, Novartis, and Eli Lilly. KN additionally reports institutional grants or contracts from AstraZeneca KK, MSD KK, Ono Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma KK, Pfizer Japan, BMS, Eli Lilly Japan KK, Chugai Pharmaceutical, Daiichi Sankyo, Merck Biopharma, Parexel International, PRA Health Sciences, EPS Corporation, Kissei Pharmaceutical, Taiho Pharmaceutical, PPD-SNBL KK, SymBio Pharmaceutical, IQVIA Services Japan KK, Syneos Health Clinical KK, Nippon Kayaku, EP-CRSU, Mebix, Janssen Pharmaceutical KK, AbbVie, Bayer Yakuhin, Eiasi, Mochida Pharmaceutical, Covance Japan, Japan Clinical Research Operations, Takeda Pharmaceutical, GSK KK, Sanofi KK, Sysmex Corporation, Medical Research Support, Otsuka Pharmaceutical, SRL, Pfizer R&D Japan GK, and Amgen; consulting fees from Eli Lilly Japan KK, Kyorin Pharmaceutical, Ono Pharmaceutical, and Pfizer Japan; honoraria from Ono Pharmaceutical, Amgen, Nippon Kayaku, AstraZeneca KK, Chugai Pharmaceutical, Eli Lilly Japan KK, MSD KK, Pfizer Japan, Nippon Boehringer Ingelheim, Taiho Pharmaceutical, Bayer Yakuhin, CMIC ShiftZero KK, Life Technologies Japan, Neo Communication, Roche Diagnostics KK, AbbVie, Merck Biopharma, Kyowa Kirin, Takeda Pharmaceutical, 3H Clinical Trial, CareNet, Medical Review, Yodosha, Nikkei Business Publications, Japan Clinical Research Operations, CMIC, Novartis Pharma KK, Taiyo Pharma, Kyorin Pharmaceutical, BMS KK; and patents with Daiichi Sankyo. RS additionally reports institutional grants or contracts from AstraZeneca, BMS, Daiichi Sankyo, Celgene, Ipsen, Janssen, Mirati, MSD, Novartis, Pfizer, Pierre Fabre, and Roche; consulting fees from AstraZeneca, BMS, Boehringer Ingelheim, GSK, Janssen, MSD, Pfizer, Roche, Sandoz, Seagen, and Takeda; honoraria from Amgen, AstraZeneca, Blueprint Medicines, BMS, Boehringer Ingelheim, GSK, MSD, Novartis, and Roche; data safety monitoring or advisory board participation with Roche and Takeda; and a leadership role with the European Thoracic Oncology Platform International Breast Cancer Study Group (ETOP IBCSG) Partners Foundation. BB additionally reports institutional grants or contracts from 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Chugai Pharmaceutical, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, Eisai, Genzyme Corporation, GSK, Inivata, Ipsen, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals, and Turning Point Therapeutics. SP additionally reports institutional grants or contracts from Amgen, AstraZeneca, BeiGene, BMS, GSK, MSD, and Roche/Genentech; consulting fees paid to their institution from AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Imedex, IQVIA, Incyte, iTeos, Janssen, Medscape, MSD, Merck Serono, Merrimack, Novartis, Novocure, Oncology Education, PharmaMar, PeerView, PER, Phosplatin Therapeutics, Pfizer, Prime, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seagen, Takeda, and Vaccibody; honoraria paid to their institution from AiCME, AstraZeneca, Boehringer Ingelheim, BMS, ecancer, Eli Lilly, Foundation Medicine, Illumina, Imedex, Medscape, MSD, Mirati, Novartis, PeerView, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, and Takeda; travel support from AstraZeneca, BMS, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pfizer, Roche/Genentech, and Takeda; and participation on a data safety monitoring or advisory board, with all fees paid to their institution, from AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Incyte, iTeos, Janssen, MSD, Merck Serono, Merrimack, Novartis, Novocure, PharmaMar, Phosplatin Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seagen, Takeda, and Vaccibody. JY, AS, and SMK report salary for full-time employment from MSD; AS and SMK also own stock in Merck & Co, Rahway, NJ, USA., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Pemetrexed is common cytotoxic chemotherapy among non-squamous non-small cell lung cancer (non-Sq-NSCLC) patients; however, among epidermal growth factor receptor (EGFR)-positive lung cancer, there is no clear evidence to support the efficacy of sequential treatment with pemetrexed., Material and Methods: We performed a post-hoc analysis of subsequent chemotherapies among 144 patients who received the post-protocol treatment in the phase III trial WJTOG 3405 comparing gefitinib to cisplatin plus docetaxel, and analyzed the effect of pemetrexed on overall survival (OS)., Results: Patients with treatment including pemetrexed exhibited significantly longer OS in comparison to those without pemetrexed; the median OS in the pemetrexed + and pemetrexed- patients were 40.7 months and 28.0 months, respectively (0.55 of HR [95% CI: 0.38-0.80, p = 0.0020]). On the other hand, other treatments, including docetaxel, TS-1 and paclitaxel showed no significant impact on OS. The multivariate analysis with a time-dependent Cox proportional hazards model showed that treatment including pemetrexed, as well as PS 0 and post-operative recurrence, were independent predictors of a good prognosis. Moreover, among patients who received at least four lines of prior treatment, pemetrexed + treatment also significantly prolonged OS in comparison to pemetrexed- treatment (median OS pemetrexed + vs. pemetrexed-: 44.4 months vs. 32.6 months; HR: 0.55 [95% CI: 0.31-0.94, p = 0.0290])., Conclusions: Sequential treatment including pemetrexed against EGFR-mutated NSCLC might be associated with a better outcome. It was considered that pemetrexed should be administered without fail as a sequential treatment to improve the prognosis of EGFR-mutated NSCLC as well as like EGFR-tyrosine kinase inhibitors., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Introduction: To evaluate the efficacy and safety of osimertinib plus bevacizumab for previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations., Methods: We conducted a randomized, open-label, phase 2 study at 21 institutions in Japan. Previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations received either osimertinib (80 mg, daily) plus bevacizumab (15 mg/kg, every 3 wk) or osimertinib monotherapy, and were stratified according to sex, stage, and EGFR mutation status. The primary end point was progression-free survival (PFS) in the intention-to-treat population, assessed by means of blinded, independent central radiologic review., Results: Between January 2018 and September 2018, a total of 122 patients were enrolled (osimertinib + bevacizumab arm, 61 patients; osimertinib monotherapy arm, 61 patients). At a median follow-up duration of 19.8 months, the median PFS was 22.1 months for osimertinib plus bevacizumab and 20.2 months for osimertinib monotherapy, with a hazard ratio of 0.862 (60% confidence interval: 0.700-1.060, 95% confidence interval: 0.531-1.397, one-sided stratified log-rank p = 0.213). Adverse events of grade 3 or worse were observed in 34 patients (56%) in the osimertinib plus bevacizumab arm and 29 (48%) in the osimertinib monotherapy arm. In addition, two (3%) and 11 patients (18%) experienced any grade pneumonitis, respectively, and grade 3 pneumonitis was observed in one patient (2%) in each arm., Conclusions: This study failed to exhibit the efficacy of osimertinib plus bevacizumab for improving the PFS among patients with nonsquamous NSCLC harboring EGFR mutations as first-line treatment., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

The patient was a 67-year-old male undergoing maintenance hemodialysis due to chronic renal failure caused by diabetic nephropathy. A left upper lobe resection was carried out for non-small cell lung cancer of the left upper lobe. It was histologically confirmed as pleomorphic carcinoma pT3N0M0, Stage ⅡB. He suffered a relapse with multiple metastases occurring in both lungs 3 months following surgery. The PD-L1 tumor proportion score(TPS)was 90%, indicating a high level of expression; 200mg of pembrolizumab was administered every 3 weeks on non-dialysis days. Two courses of administration achieved a partial response. A total of 17 courses were administered until discontinuation due to drug-induced lung injury.

Purpose: In RELAY, ramucirumab plus erlotinib (RAM + ERL) improved progression-free survival (PFS) in patients with untreated, metastatic, EGFR-mutated, non-small cell lung cancer (NSCLC). Here, we present the exposure-response relationship of RAM from RELAY., Methods: Patients received ERL (150 mg/day) with either RAM (10 mg/kg) or placebo (PBO + ERL) every 2 weeks (Q2W). A population pharmacokinetic model predicted RAM minimum concentration after first dose (C min,1 ), and at steady state (C min,ss ), which were used to evaluate correlation between RAM exposure and efficacy and safety. The Kaplan-Meier method and Cox regression analyses were utilized to evaluate exposure-efficacy by C min,1 quartile. Exposure-safety was evaluated by assessing incidence rates for safety parameters by C min,ss quartile, with ordered categorical analysis used for ALT/AST only., Results: Analyses included 216 patients treated with RAM + ERL and 225 patients treated with PBO + ERL. Adjusting for significant baseline covariates, no exposure-efficacy relationship was identified in RELAY: PFS hazard ratio (mean, 95% confidence intervals) for the C min,1 quartiles were 0.67 (0.45-0.99), 0.77 (0.53-1.12), 0.57 (0.38-0.84), and 0.50 (0.33-0.76). No apparent exposure-safety relationship was observed for selected safety endpoints, including Grade ≥ 3 hypertension, diarrhea, and dermatitis acneiform, and any grade hypertension, any grade and Grade ≥ 3 proteinuria, and any grade ALT/AST increased within liver failure/liver injury., Conclusions: No association was observed between RAM exposure and response, suggesting that the RELAY regimen of RAM 10 mg/kg Q2W with ERL is an optimized, efficacious, and safe first-line treatment for patients with untreated, metastatic, EGFR-mutated NSCLC., Trial Registration: ClinicalTrials.gov, NCT02411448., (© 2022. The Author(s).)

Introduction: Alternation of osimertinib and afatinib is a potential approach to overcome osimertinib resistance and to allow complementation of drug efficacy without compromising safety in patients with epidermal growth factor receptor gene (EGFR)-mutated non-small cell lung cancer (NSCLC)., Methods: Treatment-naive patients with stage IV NSCLC harboring an activating EGFR mutation (L858R or exon-19 deletion) were enrolled. Alternating cycles of osimertinib at 80 mg/day for 8 weeks followed by afatinib at 20 mg/day for 8 weeks were administered. The primary end point was 12-month progression-free survival (PFS) probability., Results: Forty-six patients were enrolled and treated with study therapy. The 12-month PFS probability was 70.2% (60% confidence interval [CI], 63.9-75.6%; 95% CI, 54.2-81.5%), which did not meet the primary end point. After a median follow-up time of 25.7 months, the median PFS was 21.3 months (95% CI, 16.3 months-not reached). The overall response rate was 69.6% (95% CI, 54.2-82.3%). The most common treatment-related adverse events (any grade or grade ≥ 3, respectively) were diarrhea (73.9%, 4.3%), rash acneiform (63.0%, 2.2%), and paronychia (52.2%, 0%). Five cases of pneumonitis, two of grade 2 and thres of grade 3, were apparent, all of which developed during osimertinib treatment. Exploratory evaluation of circulating tumor DNA suggested that coexisting TP53 mutations did not influence PFS for the alternating therapy., Conclusions: Alternating therapy with osimertinib and afatinib for treatment-naive patients with EGFR- mutated advanced NSCLC did not meet its primary end point, despite the encouraging efficacy and safety profile of this treatment strategy., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: This open-label Phase III trial (NCT02264990) evaluated the PARP inhibitor, veliparib, combined with carboplatin/paclitaxel versus chemotherapy alone for first-line treatment of patients with advanced non-squamous non-small cell lung cancers (NSCLC). A 52-gene expression classifier (LP52) previously shown to identify patients more likely to respond to veliparib was evaluated as a planned correlative analysis., Materials and Methods: Adult current or former smokers with advanced non-squamous NSCLC were randomized 1:1 to veliparib (120 mg daily for 7 days/cycle) with carboplatin and paclitaxel or to investigators' choice of platinum doublet chemotherapy (up to 6, 21-day cycles), with optional pemetrexed maintenance. Prospective analysis of the LP52 signature was conducted using a clinical Qiagen/HTG assay. The primary endpoint was overall survival (OS) in LP52+ patients., Results: Overall, 595 patients received veliparib + carboplatin/paclitaxel (n = 298) or chemotherapy alone (n = 297); 13% (n = 40) in each arm were LP52+. The primary endpoint was not met; median OS was 11.2 months with veliparib + carboplatin/paclitaxel versus 9.2 months with chemotherapy alone in the LP52+ subgroup (hazard ratio [HR] 0.644, 95% confidence interval [CI]: 0.396-1.048; P = .113). In the overall population, median OS was 12.1 months in both arms (HR 0.986, 95% CI: 0.827-1.176; P = .846). No new safety signals were observed., Conclusion: In patients with non-squamous NSCLC, there was no significant improvement in OS with veliparib + carboplatin/paclitaxel versus chemotherapy alone, although a trend toward improved OS in the LP52+ population suggests this subgroup may benefit from veliparib. Statistical power was limited due to the small sample size., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: This retrospective study examined whether adding the maximum standardized uptake value of a primary tumor to the consolidation-to-tumor ratio from a high-resolution computed tomography scan can improve the predictive accuracy for pathological noninvasive lung cancer and lead to better patient selection for sublobar resection., Methods: We included 926 patients with clinical stage IA non-small cell lung cancer. Pathological noninvasive cancer (n = 515) was defined as any case without lymphatic invasion, vascular invasion, or lymph node metastasis. The prediction accuracies of maximum standardized uptake value and consolidation-to-tumor ratio were evaluated using receiver operating characteristic curves and area under the curve., Results: For consolidation-to-tumor ratio or maximum standardized uptake value alone, the area under the curves were 0.733 (95% confidence interval, 0.708-0.758) and 0.842 (95% confidence interval, 0.816-0.866), respectively. When the consolidation-to-tumor ratio and maximum standardized uptake value were combined, the area under the curve was 0.854 (95% confidence interval, 0.829-0.876). However, to obtain a predictive specificity of 97%, sensitivity needed to be 42.5% for the consolidation-to-tumor ratio, 38.3% for the maximum standardized uptake value, and 45.0% for these 2 in combination., Conclusions: Our results suggest that despite the high area under the curve for maximum standardized uptake value, caution is needed when using maximum standardized uptake value to select candidates for sublobar resection. We found that a low maximum standardized uptake value did not mean the tumor was a pathological noninvasive lung cancer. Therefore, using consolidation-to-tumor ratios from high-resolution computed tomography to decide whether sublobar resection is appropriate for patients with clinical stage IA non-small cell lung cancer is better than using maximum standardized uptake value when setting specificity to a conservative 97% for predicting pathological noninvasive lung cancer., (Copyright © 2021 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Introduction: Osimertinib is a standard first-line treatment for non-small cell lung cancer (NSCLC) harboring mutations of the epidermal growth factor receptor gene (EGFR). However, tumors with the L858R mutation appear to be less sensitive to EGFR-tyrosine kinase inhibitors (TKIs) than those with exon-19 deletions, and subgroup analysis of the FLAURA study revealed that osimertinib did not significantly prolong overall survival (OS) compared with gefitinib or erlotinib in patients with the L858R. The RELAY study revealed a similar high efficacy of combination therapy with erlotinib plus ramucirumab (E+RAM) in patients with L858R and in those with exon-19 deletions. Patients who acquire the TKI resistance-associated T790M mutation during E+RAM treatment can also expect to receive benefit from second-line osimertinib. We have therefore planned a phase III study to evaluate the clinical efficacy of E+RAM compared with osimertinib monotherapy for untreated patients with advanced NSCLC harboring L858R., Patients and Methods: A total of 230 patients will be enrolled. The primary end point is time to failure of strategy (TFS), which is defined for this study as the time from randomization of treatment until disease progression or death on osimertinib, or the time from randomization until first disease progression or death of the primary treatment when osimertinib is not administered in the E+RAM group. Secondary end points include OS and progression-free survival., Conclusion: This is the first phase III clinical trial to target only NSCLC patients with the L858R mutation. Its results may establish an optimal treatment for such individuals., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: Although the efficacy of programmed cell death-1 (PD-1) blockade is generally poor for non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR) gene, EGFR tyrosine kinase inhibitors (TKIs) may improve the tumor immune microenvironment. We performed a randomized study to assess whether nivolumab improves outcome compared with chemotherapy in such patients previously treated with EGFR-TKIs., Patients and Methods: Patients with EGFR-mutated NSCLC who acquired EGFR-TKI resistance not due to a secondary T790M mutation of EGFR were randomized 1:1 to nivolumab (n = 52) or carboplatin-pemetrexed (n = 50). The primary endpoint was progression-free survival (PFS)., Results: Median PFS and 1-year PFS probability were 1.7 months and 9.6% for nivolumab versus 5.6 months and 14.0% for carboplatin-pemetrexed [log-rank P < 001; hazard ratio (HR) of 1.92, with a 60% confidence interval (CI) of 1.61-2.29]. Overall survival was 20.7 and 19.9 months [HR, 0.88 (95% CI, 0.53-1.47)], and response rate was 9.6% and 36.0% for nivolumab and carboplatin-pemetrexed, respectively. No subgroup including patients with a high tumor mutation burden showed a substantially longer PFS with nivolumab than with carboplatin-pemetrexed. The T-cell-inflamed gene expression profile score (0.11 vs. -0.17, P = 0.036) and expression of genes related to cytotoxic T lymphocytes or their recruitment were higher in tumors that showed a benefit from nivolumab., Conclusions: Nivolumab did not confer a longer PFS compared with carboplatin-pemetrexed in the study patients. Gene expression profiling identified some cases with a favorable tumor immune microenvironment that was associated with nivolumab efficacy., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: PD-L1 expression on tumor cells is a marker of PD-1/PD-L1 antibody treatment efficacy for advanced non-small cell lung cancer (NSCLC). PD-L1 antibody (atezolizumab) prolongs overall survival (OS) compared with platinum doublet as first-line treatment for NSCLC with high PD-L1 expression. Bevacizumab enhanced cytotoxic agent and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor efficacy in non-squamous (NS)-NSCLC, and PD-1/PD-L1 antibodies in preclinical models., Methods: This single-arm phase II study investigated clinical benefits of adding bevacizumab 15 mg/kg to atezolizumab 1200 mg fixed dose in a first-line setting for advanced NS-NSCLC patients with PD-L1 expression ≥50% without EGFR / ALK / ROS1 alterations. Primary endpoint was objective response rate (ORR) assessed by central review committee. Secondary endpoints were progression-free survival (PFS), duration of response (DOR), OS, and safety., Results: Of 39 enrolled patients, 33 (84.6%) had stage IV NSCLC and 36 (92.3%) had smoking history. As of March 31, 2020, no patient had a complete response and 25 patients had a partial response (ORR=64.1%, 95% CI 47.18 to 78.80). Twelve-month PFS and OS rates were 54.9% (35.65 to 70.60) and 70.6% (50.53 to 83.74), respectively. The median DOR in 25 responders was 10.4 months (4.63-not reached). The median treatment cycle was 12 (1 to 27). Nineteen patients discontinued study treatment because of disease progression (N=17) or immune-related adverse events (AEs) (N=2) (sclerosing cholangitis or encephalopathy). There were 23 serious AEs in 12 patients, but no grade 4/5 toxicity., Conclusions: Atezolizumab with bevacizumab is a potential treatment for NS-NSCLC with high PD-L1 expression., Trial Registration Number: JapicCTI-184038., Competing Interests: Competing interests: TS reports grants and honoraria from Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, MSD, Novartis, Pfizer Japan, and Takeda Pharmaceutical; grants from Abbvie, Kissei Pharmaceutical, Loxo Oncology, and Merck Biopharma; honoraria from AstraZeneca, Bristol-Myers Squibb, Covidien Japan, Kyowa Kirin, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, and Thermo Fischer Scientific; and salary from Precision Medicine Asia outside the submitted work. KNosaki reports personal fees from Chugai Pharmaceutical outside the submitted work. RToyozawa reports honoraria from Bristol-Myers Squibb, Chugai Pharmaceutical, Kyowa Kirin, MSD, Nippon Boehringer Ingelheim, Nippon Kayaku, and Taiho Pharmaceutical; grants from Abbvie, Amgen, Daiichi Sankyo, Pfizer Japan, and Takeda Pharmaceutical; and grants and honoraria from Eli Lilly Japan, and Novartis outside the submitted work. SS reports lecture fees from Chugai Pharmaceutical, AstraZeneca, MSD, Bristol-Myers Squibb, Ono Pharmaceutical, Nippon Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Eli Lilly, Novartis, Kyowa Kirin, and Yakult Honsha outside the submitted work. HH reports grants and personal fees from Chugai Pharmaceutical during the conduct of the study; grants and personal fees from AstraZeneca, Nippon Boehringer Ingelheim, and Ono Pharmaceutical; personal fees from Bristol-Myers Squibb, Eli Lilly Japan, Kyorin Pharmaceutical, Merck Biopharma, MSD, Novartis, Pfizer Japan, Shanghai Haihe Biopharma, Taiho Pharmaceutical, and Takeda Pharmaceutical; and grants from Chugai Pharmaceutical outside the submitted work. HM reports grants and personal fees from AstraZeneca, Chugai Pharmaceutical, Takeda Pharmaceutical, and Daiichi Sankyo; grants from Abbvie and IQVIA; and personal fees from Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Pfizer, Novartis, Eli Lilly Japan, and Taiho Pharmaceutical outside the submitted work. TK reports grants and fees for speaking/advisory board/supported research from Abbvie, Amgen, AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Merck Biopharma, MSD, and Novartis; grants, speaker fees, and supported research from Bristol-Myers Squibb; grants and fees for speaking/scientific advice/supported research from Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical; speaker fees from Boehringer Ingelheim; fees for speaking/advisory boards from Daiichi Sankyo; fees for advisory board from Nippon Kayaku; fees for scientific advice from Takeda Pharmaceutical; and grants from Regeneron Pharmaceuticals outside the submitted work. SN reports grants and personal fees from Chugai Pharmaceutical during the conduct of the study; and grants and personal fees from AstraZeneca, Pfizer, Taiho Pharmaceutical, Boehringer Ingelheim, MSD, Ono Pharmaceutical, Kyorin Pharmaceutical, and Eli Lilly Japan; personal fees from Janssen Pharmaceutical and Novartis; and grants from Merck Serono, Sanofi, Shionogi, Takeda Pharmaceutical, and Teijin Pharma outside the submitted work. HY reports honoraria for lecture fees from Chugai Pharmaceutical during the conduct of the study; and honoraria for lecture fees from AstraZeneca, Nippon Boehringer Ingelheim, Bristol-Myers Squibb, Taiho Pharmaceutical, Eli Lilly Japan, Ono Pharmaceutical, Kyowa Kirin, MSD, Delta-Fly Pharma, Pfizer, Novartis, and Nippon Kayaku outside the submitted work. IO reports grants from Taiho Pharmaceutical during the conduct of the study; and grants and personal fees from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD Oncology, Eli Lilly, Bristol-Myers Squibb, and Chugai Pharmaceutical; grants from Astellas Pharma, Novartis, and Abbvie; and personal fees from Pfizer outside the submitted work.HD reports personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, Pfizer, and Ono Pharmaceutical outside the submitted work. KA reports personal fees from Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, MSD Oncology, and Bristol-Myers Squibb outside the submitted work. HT reports grants from Chugai Pharmaceutical during the conduct of the study; grants and personal fees from Bristol-Myers Squibb, Eli Lilly, MSD, Taiho Pharmaceutical, Pfizer, Novartis, Chugai Pharmaceutical, AstraZeneca, Boehringer Ingelheim, Merck, and Ono Pharmaceutical outside the submitted work. KNishino reports grants and personal fees from Nippon Boehringer Ingelheim and personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, Roche Diagnostics, Novartis, Pfizer, Ono Pharmaceutical, and Merck outside the submitted work. RTohnai reports research expenses from Chugai Pharmaceutical during the conduct of the study. NY reports grants and personal fees from Chugai Pharmaceutical during the conduct of the study; and grants and personal fees from MSD, AstraZeneca, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Takeda Pharmaceutical, Eli Lilly Japan, Boehringer Ingelheim, Novartis, and Pfizer; personal fees from Thermo Fisher Scientific, Bristol-Myers Squibb, Life Technologies Japan, Nippon Kayaku, and Merck Biopharma; and grants from Astellas Pharma, Tsumura, Shionogi, Abbvie, Amgen, Kyorin Pharmaceutical, Eisai, Terumo Corporation, Toppan Printing, and Tosoh Corporation outside the submitted work. KNakagawa reports grants and personal fees from AstraZeneca, MSD, Nippon Boehringer Ingelheim, Novartis, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, and Merck Serono/Merck Biopharma, and grants, personal fees and other consulting and advisory role fees from Astellas Pharma, Ono Pharmaceutical, Pfizer, and Eli Lilly Japan during the conduct of the study; personal fees from Medicus Shuppan Publishers, CareNet, Medical Review, Roche Diagnostics, Medical Mobile Communications, 3H Clinical Trial, Nichi-Iko Pharmaceutical, Yodosha, Nikkei Business Publications, Thermo Fisher Scientific, Yomiuri Telecasting Corporation, Nippon Kayaku, Hisamitsu Pharmaceutical, Nanzando, and Amgen; personal fees and others from Kyorin Pharmaceutical; grant, personal fees and other consulting/advisor role fees from Takeda Pharmaceutical; grants and personal fees from Taiho Pharmaceutical, Abbvie, Kyowa Kirin, and Bayer Yakuhin; and grants from SymBio Pharmaceuticals, Icon Japan, PAREXEL International, Kissei Pharmaceutical, EPS Corporation, Syneos Health, Pfizer R&D Japan, A2 Healthcare, IQVIA, Eisai, CMIC Shift Zero, EPS International, Otsuka Pharmaceutical, PRA Health Sciences, Covance Japan, Medical Research Support, Sanofi, PPD-SNBL, Japan Clinical Research Operations, Sysmex Corporation, Mochida Pharmaceutical, and GlaxoSmithKline outside the submitted work. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have not been approved for patients with non-small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody-drug conjugate, in patients with HER2 -mutant NSCLC have not been investigated extensively., Methods: We conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic HER2 -mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed., Results: A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification., Conclusions: Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2 -mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number, NCT03505710.)., (Copyright © 2021 Massachusetts Medical Society.)

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.

Purpose: EGFR-tyrosine kinase inhibitor (TKI) is a standard first-line therapy for activated EGFR -mutated non-small cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance. Clinical trials of the HER3-targeting antibody-drug conjugate patritumab deruxtecan (HER3-DXd) demonstrated its anticancer activity in EGFR -mutated NSCLC; however, the mechanisms that regulate HER3 expression are unknown. This study was conducted with the aim to clarify the mechanisms underlying HER3 regulation in EGFR -mutated NSCLC tumors and explored the strategy for enhancing the anticancer activity of HER3-DXd in EGFR -mutated NSCLC., Experimental Design: Paired tumor samples were obtained from 48 patients with EGFR -mutated NSCLC treated with EGFR-TKI(s). HER3 expression was immunohistochemically quantified with H-score, and genomic alteration and transcriptomic signature were tested in tumors from pretreatment to post-EGFR-TKI resistance acquisition. The anticancer efficacy of HER3-DXd and osimertinib was evaluated in EGFR -mutated NSCLC cells., Results: We showed augmented HER3 expression in EGFR -mutated tumors with acquired EGFR-TKI resistance compared with paired pretreatment samples. RNA sequencing revealed that repressed PI3K/AKT/mTOR signaling was associated with HER3 augmentation, especially in tumors from patients who received continuous EGFR-TKI therapy. An in vitro study also showed that EGFR-TKI increased HER3 expression, repressed AKT phosphorylation in multiple EGFR -mutated cancers, and enhanced the anticancer activity of HER3-DXd., Conclusions: Our findings help clarify the mechanisms of HER3 regulation in EGFR -mutated NSCLC tumors and highlight a rationale for combination therapy with HER3-DXd and EGFR-TKI in EGFR -mutated NSCLC., (©2021 American Association for Cancer Research.)

Introduction: RELAY was a global, double-blind, placebo-controlled phase III study that demonstrated superior progression-free survival (PFS) for ramucirumab plus erlotinib (RAM + ERL) versus placebo plus erlotinib (PBO + ERL) in the first-line treatment of patients with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) mutation-positive, metastatic non-small-cell lung cancer (NSCLC)., Objective: This article provides an in-depth analysis of the safety profile of RAM + ERL versus PBO + ERL observed in RELAY., Methods: Eligible patients met these criteria: stage IV NSCLC; EGFR exon 19 deletion or exon 21 substitution (L858R) mutation; Eastern Cooperative Oncology Group performance status 0 or 1; and no central nervous system metastases. Patients were randomized (1:1) to receive erlotinib 150 mg/day orally plus either ramucirumab 10 mg/kg intravenously or matching placebo once every 2 weeks, until disease progression or unacceptable toxicity. The primary endpoint was PFS. Safety was evaluated based on reported treatment-emergent adverse events (AEs) and clinical laboratory assessments., Results: The safety population comprised 446 patients (221 in RAM+ERL arm; 225 in PBO + ERL arm) who received at least one dose of study drug between January 2016 and February 2018. The overall incidence of grade ≥ 3 AEs was higher with RAM + ERL than with PBO + ERL, primarily driven by grade 3 hypertension. Grade ≥ 3 dermatitis acneiform and diarrhea were also reported more frequently in the RAM + ERL arm. The increased incidence of AEs with RAM + ERL was easily detected through routine monitoring and managed through dose adjustments and appropriate supportive care., Conclusion: This in-depth safety analysis from RELAY supports that RAM + ERL, irrespective of the increased incidence of AEs, does not affect a patient's ability to benefit from treatment., Clinical Trial Registration Number: NCT02411448., (© 2021. The Author(s).)

Considering the increasing number of identified driver oncogene alterations, additional genetic tests are required to determine the treatment for advanced non-small-cell lung cancer (NSCLC). Next-generation sequencing can detect multiple driver oncogenes simultaneously, enabling the analysis of limited amounts of biopsied tissue samples. In this retrospective, multicenter study (UMIN ID000039523), we evaluated real-world clinical data using the Oncomine Dx Target Test Multi-CDx System (Oncomine DxTT) as a companion diagnostic system. Patients with NSCLC who were tested for a panel of 46 genes using the Oncomine DxTT between June 2019 and January 2020 were eligible for enrollment. Patients from 19 institutions affiliated to the West Japan Oncology Group were recruited. The primary endpoint of the study was the success rate of genetic alteration testing in four driver genes (EGFR, ALK, ROS1, and BRAF) using the Oncomine DxTT. In total, 533 patients were enrolled in the study. The success rate of genetic alteration testing for all four genes was 80.1% (95% CI 76.5%-83.4%). Surgical resection was associated with the highest success rate (88.0%), which was significantly higher than that for bronchoscopic biopsy (76.8%, P = .005). Multivariate analysis revealed a significant difference for surgical resection alone (P = .006, 95% CI 1.36-6.18, odds ratio 2.90). Although the success rate of genetic alteration testing immediately after Oncomine DxTT induction was not sufficient in this study, optimizing specimen quantity and quality may improve the use of driver gene testing in clinical settings., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Tumour burden (TB) is implicated in resistance to programmed cell death-1/PD-L1 inhibitor (immune checkpoint inhibitor [ICI]) therapy. However, whether TB contributes to such resistance in non-small-cell lung cancer (NSCLC) has remained unknown., Methods: A total of 260 treatment-naïve patients with advanced NSCLC who started ICI monotherapy (ICI cohort), platinum-doublet therapy (Chemo cohort) or ICI and platinum-doublet therapy (ICI+Chemo cohort) as first-line treatment were consecutively included. TB was estimated on the basis of the sum of the diameters of measurable target lesions as per Response Evaluation Criteria in Solid Tumours. Progression-free survival (PFS) in the ICI cohort was evaluated as per TB as a preplanned primary objective, with the analysis based on propensity score-weighted survival curves and estimation of restricted mean survival time (RMST). The Chemo cohort served as a control to determine whether TB is predictive of ICI treatment outcomes. The ICI+Chemo cohort was exploratory. The relation of TB to tumour immune status was assessed by immune-related gene expression profiling (irGEP) of pretreatment tumour tissue., Results: In the ICI cohort, patients with a low TB showed a significantly longer PFS than did those with a high TB (median, 17.9 vs 4.3 months; weighted hazard ratio, 0.32 [95% confidence interval, 0.19-0.53]). No such difference was apparent in the other cohorts. A significant difference in overall survival was also observed only in the ICI cohort. RMST-based analysis confirmed these results. The irGEP analysis implicated M2-type macrophages, angiogenesis and transforming growth factor-β as well as protumourigenic signalling pathways in ICI resistance conferred by a high TB., Conclusion: A high TB was associated with a poor outcome of ICI therapy for advanced NSCLC as a result of immunosuppressive phenotypes. Development of combination or novel treatment strategies for such disease is thus warranted., Competing Interests: Conflict of interest statement Haratani received honoraria from AS ONE Corp., AstraZeneca K.K., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD K.K. and Ono Pharmaceutical Co. Ltd. as well as research funding from AstraZeneca K.K. and MSD K.K. Hayashi received honoraria from AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Kyorin Pharmaceutical Co. Ltd., Merck Biopharma Co. Ltd., MSD K.K., Novartis Pharmaceuticals K.K., Ono Pharmaceutical Co. Ltd., Shanghai Haihe Biopharma, Taiho Pharmaceutical Co. Ltd. and Takeda Pharmaceutical Co. Ltd.; consulting fees from AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Merck Biopharma Co. Ltd., Pfizer Japan Inc., Shanghai Haihe Biopharma, and Takeda Pharmaceutical Co. Ltd.; and research funding from AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Chugai Pharmaceutical Co. Ltd. and Ono Pharmaceutical Co. Ltd. Tanizaki received honoraria from AstraZeneca K.K., Boehringer-Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K. and Taiho Pharmaceutical Co. Ltd. Kato received honoraria from Bristol-Myers Squibb Co. Ltd. and Eli Lilly Japan K.K. Mitani received honoraria from Ono Pharmaceutical Co. Ltd. and Taiho Pharmaceutical Co. Ltd.; research funding from Taiho Pharmaceutical Co. Ltd. Tanaka received honoraria from AstraZeneca K.K., Bristol-Myers Squibb Co. Ltd., Eisai Co. Ltd., Kyowa Kirin Co. Ltd., Merck Biopharma Co. Ltd., MSD K.K. and Ono Pharmaceutical Co. Ltd. Nishio received honoraria from Amgen Inc., AstraZeneca K.K., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Eli Lilly Japan K.K., F. Hoffmann-La Roche Ltd., Guardant Health Inc., Ignyta Inc., Korea Otsuka Pharmaceutical Co. Ltd., Life Technologies Japan Ltd., Merck Biopharma Co. Ltd., MSD K.K., Nippon Boehringer Ingelheim Co. Ltd., North East Japan Study Group, Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Pfizer Japan Inc., Sanofi K.K., Solasia Pharma K.K., SymBio Pharmaceuticals Ltd., Thoracic Oncology Research Group and Yakult Honsha Co. Ltd. Nakagawa received honoraria from AbbVie Inc., Amgen Inc., Astellas Pharma Inc., AstraZeneca K.K., Bayer Yakuhin Ltd., Bristol Myers Squibb Co. Ltd., Care Net Inc., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K., Hisamitsu Pharmaceutical Co. Inc., Kyorin Pharmaceutical Co. Ltd., Kyowa Kirin Co. Ltd., Medical Mobile Communications Co. Ltd, Medical Review Co. Ltd., Medicus Shuppan Publishers Co. Ltd., Merck Biopharma Co. Ltd., Merck Serono Co. Ltd., MSD K.K., Nanzando Co. Ltd., Nichi-Iko Pharmaceutical Co. Ltd., Nikkei Business Publications Inc., Nippon Boehringer Ingelheim Co. Ltd., Nippon Kayaku Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Pfizer Japan Inc., Roche Diagnostics K.K., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Thermo Fisher Scientific K.K., Yodosha Co. Ltd., Yomiuri Telecasting Corp., 3H Clinical Trial Inc.; consulting fees from Eli Lilly Japan K.K., Kyorin Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., Pfizer Japan Inc. and Takeda Pharmaceutical Co. Ltd.; and research funding from AbbVie Inc., Astellas Pharma Inc., AstraZeneca K.K., A2 Healthcare Corp., Bayer Yakuhin Ltd., Bristol Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., CMIC Shift Zero K.K., Covance Japan Inc., Daiichi Sankyo Co. Ltd., Eisai Co. Ltd., Eli Lilly Japan K.K., EPS Corp., EPS International Co. Ltd., GlaxoSmithKline K.K., ICON Japan K.K., IQVIA Services Japan K.K., Japan Clinical Research Operations, Kissei Pharmaceutical Co. Ltd., Kyowa Kirin Co. Ltd., MSD K.K., Medical Research Support, Merck Serono Co. Ltd., Merck Biopharma Co. Ltd., Mochida Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Parexel International Corp., Pfizer Japan Inc., Pfizer R&D Japan G.K., PPD-SNBL K.K, PRA Health Sciences, Sanofi K.K., SymBio Pharmaceuticals Ltd., Syneos Health, Sysmex Corp., Taiho Pharmaceutical Co. Ltd., and Takeda Pharmaceutical Co. Ltd. All remaining authors have declared no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)