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Although comprehensive biomarker testing is recommended for all patients with advanced/metastatic non-small cell lung cancer (NSCLC) before initiation of first-line treatment, tissue availability can limit testing. Genomic testing in liquid biopsies can be utilized to overcome the inherent limitations of tissue sampling and identify the most appropriate biomarker-informed treatment option for patients. The Blood First Assay Screening Trial is a global, open-label, multicohort trial that evaluates the efficacy and safety of multiple therapies in patients with advanced/metastatic NSCLC and targetable alterations identified by liquid biopsy. We present data from Cohort D (ROS1-positive). Patients ≥18 years of age with stage IIIB/IV, ROS1-positive NSCLC detected by liquid biopsies received entrectinib 600 mg daily. At data cutoff (November 2021), 55 patients were enrolled and 54 had measurable disease. Cohort D met its primary endpoint: the confirmed objective response rate (ORR) by investigator was 81.5%, which was consistent with the ORR from the integrated analysis of entrectinib (investigator-assessed ORR, 73.4%; data cutoff May 2019, ≥12 months of follow-up). The safety profile of entrectinib was consistent with previous reports. These results demonstrate consistency with those from the integrated analysis of entrectinib in patients with ROS1-positive NSCLC identified by tissue-based testing, and support the clinical value of liquid biopsies to inform clinical decision-making. The integration of liquid biopsies into clinical practice provides patients with a less invasive diagnostic method than tissue-based testing and has faster turnaround times that may expedite the reaching of clinical decisions in the advanced/metastatic NSCLC setting. ClinicalTrials.gov registration: NCT03178552 ., (© 2024. The Author(s).)

After disease progression on EGFR tyrosine kinase inhibitor (TKI) therapy, patients with EGFR -mutated NSCLC who are then treated with platinum-based chemotherapy (PBC) obtain only limited clinical benefit with transient responses. Therapies with greater efficacy and tolerable safety profiles are needed in this setting. The receptor tyrosine kinase HER3 is widely expressed in NSCLC, and increased expression is associated with poor treatment outcomes. In the U31402-A-U102 phase I trial, HER3-DXd showed promising antitumor activity with manageable safety in heavily pre-treated patients with EGFR -mutated NSCLC across a range of tumor HER3 expression levels and EGFR TKI resistance mechanisms. HERTHENA-Lung02 is the first phase III trial to evaluate the safety and efficacy of HER3-DXd versus PBC in patients with progression on a third-generation EGFR TKI. Clinical Trial Registration: NCT05338970 (clinicaltrials.gov); 2021-005879-40 (EudraCT Number).

Lorlatinib is a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). In clinical trials, lorlatinib has shown durable efficacy and a manageable safety profile in treatment-naive patients and in those who have experienced progression while receiving first- and/or second-generation ALK TKIs. Lorlatinib has a distinct safety profile from other ALK TKIs, including hyperlipidemia and central nervous system effects. Clinical trial data showed that most adverse events (AEs) can be managed effectively or reversed with dose modifications (such as dose interruptions or reductions) or with concomitant medications without compromising clinical efficacy or quality of life for patients. A pragmatic approach to managing AEs related to lorlatinib is required. We present patient-focused recommendations for the evaluation and management of select AEs associated with lorlatinib developed by clinicians and nurses with extensive lorlatinib expertise in routine clinical practice. The recommendations follow the general framework of "prepare, monitor, manage, reassess" to streamline AE management and assist in practical, actionable, and personalized patient care., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Geoffrey Liu reports grant support from AstraZeneca, Boehringer Ingelheim, Pfizer, Amgen, EMD Serono and Takeda; and participation on an advisory board for AstraZeneca, EMD Serono, Jazz Pharmaceuticals, MSD, Novartis, Pfizer, Roche, BMS, Bayer, Novartis, Amgen, and Takeda. Julien Mazieres reports institutional grant support from AstraZeneca, Pierre Fabre, and Roche; and advisory board fees from AstraZeneca, BMS, Daiichi Sankyo, Merck, MSD, Novartis, Pfizer, and Roche. Jan Stratmann reports personal fees from Roche, Boehringer Ingelheim, AstraZeneca, BMS, Oncopeptides, Amgen, LEO Pharma, Novartis, Takeda, Lilly, MSD/Merck, Sanofi, Pfizer, outside of the submitted work and institutional grants from AstraZeneca outside of the submitted work. Sai-Hong Ignatius Ou reports institutional grant for clinical research from Mirati, J&J/Janssen, Pfizer, Revolution Medicine, Nuvalent, Merck, and BMS; speaker honorarium from Pfizer and J&J/Janssen; advisory honorarium from Pfizer, J&J/Janssen, AnHeart Therapeutics, Lilly, BeiGene, and DAVA Oncology; stock ownership in Turning Point Therapeutics and Elevation Oncology; and ownership (<5%) in MBrace Therapeutics and BlossomHill Therapeutics. Tony Mok reports institutional grants from AstraZeneca, BMS, G1 Therapeutics, Merck, MSD, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, Takeda, and Xcovery; consulting fees from AbbVie, ACEA Pharma, Adagene, Alpha Biopharma, Amgen, Amoy Diagnostics, Bayer, BeiGene, Berry Oncology, Boehringer Ingelheim, Blueprint, BMS, Bridge Biotherapeutics, Covidien, C4 Therapeutics, Cirina, CStone Pharmaceuticals, Curio Science, D3 Bio, Da Volterra, Daiichi Sankyo, Eisai, Elevation Oncology, G1 Therapeutics, geneDecode, Gilead Sciences, Gritstone Oncology, Guardant Health, Hengrui Therapeutics, HutchMed, Ignyta, Incyte, Inivata, IQVIA, Janssen, Lilly, Lunit USA, Loxo Oncology, Lucence Health, Medscape/WebMD, Merck, MSD, Mirati, MiRXES, MoreHealth, Novartis, Omega Therapeutics, OrigiMed, OSE Immunotherapeutics, PeerVoice, Pfizer, prIME Oncology, Puma Biotechnology, Qiming Development, Roche/Genentech, Sanofi, SFJ Pharmaceuticals, Simcere of America, Synergy Research, Takeda, Tigermed, Vertex, Virtus, and Yuhan; honoraria from ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, BeiGene, Boehringer Ingelheim, BMS, Daiichi Sankyo, Daz Group, Fishawack Facilitate, InMed, Janssen, Jiahui Holdings, LiangYiHui Healthcare, Lilly, Lucence Health, MD Health Brazil, Medscape, Merck Pharmaceuticals HK, MSD, MiRXES, Novartis, OrigiMed, Permanyer, PeerVoice, Physicians’ Education Resource, Pfizer, prIME Oncology, Research to Practice, Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting, Taiho, Takeda, and Touch Independent Medical Education; travel support from AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, MiRXES, MSD, Novartis, Pfizer, and Roche; institutional travel support from BMS, Boehringer Ingelheim, MSD, Novartis, Pfizer, and Roche; participation on advisory boards for AbbVie, ACEA Pharma, Amgen, AstraZeneca, Berry Oncology, Blueprint, Boehringer Ingelheim, Bowtie Life Insurance, BMS, C4 Therapeutics, Covidien, CStone Pharmaceuticals, Curio Science, D3 Bio, Daiichi Sankyo, Eisai, Fishawack Facilitate, G1 Therapeutics, geneDecode, Gilead Sciences, Gritstone Oncology, Guardant Health, Hengrui Therapeutics, HutchMed, Ignyta, Incyte, Inivata, IQVIA, Janssen, Lakeshore Biotech, Lilly, Loxo Oncology, Lunit, Merck, MSD, Mirati, MiRXES, Novartis, OrigiMed, Pfizer, Puma Biotechnology, Roche/Genentech, Sanofi-Aventis, SFJ Pharmaceuticals, Simcere of America, Takeda, Vertex, Virtus, and Yuhan; leadership or fiduciary role at AstraZeneca, HutchMed, Lunit, ACT Genomics-Sanomics Group, and Aurora Tele-Oncology; and stock ownership in AstraZeneca, Aurora Tele-Oncology, Biolidics, HutchMed, and ACT Genomics-Sanomics Group. Mary Grizzard reports no conflicts of interest. Yasushi Goto reports grant support for the clinical trial group from AstraZeneca and Pfizer; institutional grant support from AbbVie, BMS, Daiichi Sankyo, Eli Lilly, Kyorin Pharmaceutical, Novartis, Ono Pharmaceutical, Pfizer, and Preferred Networks; honoraria from BMS, Boehringer Ingelheim, Chugai Pharmaceutical, Eli Lilly, Merck, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho, and Thermo Fisher; participation on advisory boards for AstraZeneca, BMS, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Guardant Health, Illumina, MSD, Novartis, Ono Pharmaceutical, Pfizer, and Taiho; and leadership or fiduciary role at Cancer Net Japan and Japanese Association of Medical Technologists. Enriqueta Felip reports institutional funding from Merck and Fundación Merck Salud; consulting fees from Amgen, AstraZeneca, Bayer, BMS, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Merck, MSD, Novartis, Peptomyc, Pfizer, Roche, Sanofi, and Takeda; honoraria from Amgen, AstraZeneca, BMS, Eli Lilly, Janssen, Medical Trends, Medscape, Merck, MSD, PeerVoice, Pfizer, Roche, Sanofi, Takeda, and Touch Oncology; and independent board membership for Grifols. Benjamin J. Solomon reports royalties for contribution to a section from UpToDate; consulting fees for participation on advisory boards from Amgen, AstraZeneca, BMS, Janssen, MSD, Novartis, Pfizer, Sanofi, Takeda, and Roche/Genentech; honoraria from Amgen, AstraZeneca, BMS, Pfizer, Takeda, and Roche/Genentech; and leadership or fiduciary role as a board member of Thoracic Oncology Group of Australia and Cancer Council of Victoria. Todd M. Bauer reports consulting fees from Bayer, Pfizer, and Lilly; honoraria from Bayer, BMS, Guardant Health, Pfizer, and Lilly; travel support from Pfizer; participation on advisory boards for AstraZeneca, Bayer, Illumina, and Pfizer; and institutional support for participation on an advisory board for Blueprint., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

Background: The combination of platinum-based chemotherapy with immune-checkpoint inhibitors (ICIs) is a standard of care option in the front-line treatment of advanced non-small cell lung cancer (NSCLC). Positive efficacy and safety results have been demonstrated with different chemo-ICI combinations in the corresponding clinical trials, however no randomized prospective comparison is available and there is no evidence on how to choose among the available regimens., Methods: A virtual International Expert Panel took place in July 2023 to review data on chemo-ICI regimens available in the first-line setting in patients with NSCLC, and reach common considerations both in clinical practice and in research setting., Results: Overall, all panelists agreed that safety of the chemo-immunotherapy combination regimens is supported by reviewed data, showing no additional toxicity concerns over those of the individual components of each regimen and highlighting differences in toxicity profile based on ICI component (single anti-PD-1 versus double anti-PD-1 and anti-CTLA-4). Among disease characteristics, PD-L1 value (<1%) but not histology was considered a potential selection factor in favor of the combination with dual ICI. With regards to clinical features, the panelists agreed that chemotherapy, whichever the ICI combination regimen, remains the backbone to counteract disease-related symptoms included those conditioning worse performance status. The panelists defined high, medium, and low priorities in clinical research. High priority was attributed to prospectively evaluating the impact of the addition of anti-CTLA-4 on brain metastasis, biomarker subgroups, and the optimal duration and schedule of combination regimens., Conclusions: Based on the available evidence, the panelists reached common considerations on strengths and differences between chemotherapy plus single agent ICI and chemotherapy plus double agent ICIs in patients with advanced NSCLC. In the absence of direct comparison, different toxicity profile and subgroup analysis by PD-L1 are considered as the main potential features to select among the two regimens, however to be confirmed by recommended prospective randomized clinical research., Competing Interests: Declaration of competing interest C. Gridelli received honoraria as speaker bureau or advisory board member or as consultant from MSD, BMS, Roche, Astra Zeneca, Novartis, Pfizer, Menarini, Boehringer, Karyopharm, Eli Lilly, Amgen, Sanofi, GSK, Boehringer Ingelheim. S. Peters received education grants, provided consultation, attended advisory boards and/or provided lectures for the following organizations: AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, Beigene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Imedex, IQVIA, Incyte, iTeos, Janssen, Medscape, Medtoday, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Novocure, OncologyEducation, Pharma Mar, Phosplatin Therapeutics, PER, Peerview, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, Vaccibody. T. Mok received education grants, honoraria, provided consultation, attended advisory boards and/or provided lectures for the following organizations: AstraZeneca, Aurora Tele-Oncology Platform, Lunit, ACT Genomics-Sanomics Group, HUTCHMED, Alpha Biopharma, ACEA Pharmaceutical Research, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo/UCB Japan, Fishawack Facilitate, InMed, Lilly, Merck Sharp & Dohme, Novartis, Origimed, Pfizer, Prime Oncology, Roche, Sanofi Aventis GmbH, Taiho Pharmaceutical, Takeda, Lucence, Medscape, Permanyer Publications, PeerVoice, Physicans' Education Resource, Research to Practice, Shanghai BeBirds Translation & Consulting, Liangyihui Network Technology Co, Ltd, AbbVie, Berry Oncology, Blueprint Medicines, C4 Therapeutics, CStone Pharmaceuticals, Curio Science, D3, Eisai, Gilead Sciences, Gritstone Bio, Guardant Health, touchIME, Hengrui Therapeutics, Ignyta, Incyte, Inivata, IQvia, Lilly, Loxo, Lunit, Merck Serono, Mirati Therapeutics, Puma Biotechnology, SFJ Pharmaceuticals Group, Vertex, Yuhan, Qiming Development (HK) Ltd, G1 Therapeutics, Janssen, geneDecode. Stock and Other Ownership Interests: Aurora Tele-Oncology Platform, HUTCHMED, ACT Genomics-Sanomics Group. MC Garassino received education grants, honoraria, provided consultation, attended advisory boards and/or provided lectures for the following organizations: MSD Oncology, AstraZeneca/MedImmune, GlaxoSmithKline, Takeda, Roche, Bristol Myers Squibb, Novartis, Tiziana Life Sciences, Sanofi, Celgene, Daiiki Sankyo, Inivata, Incyte, Pfizer, Seattle Genetics, Lilly, GlaxoSmithKline, Bayer, Blueprint Medicines, Janssen, Regeneron, Otsuka, AstraZeneca, Roche/Genentech, Spectrum Pharmaceuticals, Ipsen, Exelixis, Amgen. Luis Paz-Ares reports institutional research support from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharpe & Dohme, and Laboratorios Pfizer Ltda.; personal fees (self/family) from Altum Secuency, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly and Company, Genomica, Ipsen Biopharmaceuticals Inc., Janssen Biotech, Merck Sharpe & Dohme, Mirati, Novartis, Laboratorios Pfizer Ltda., PharmaMar, Roche, Servier Pharmaceuticals, and Takeda Oncology; and serves as a board member at Genómica and Altum all outside the submitted work. F. de Marinis received honoraria or consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Novartis, Takeda, Xcovery, and Roche. Dr. Attili reports no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: In the phase 3 POSEIDON study, first-line tremelimumab plus durvalumab and chemotherapy significantly improved overall survival and progression-free survival versus chemotherapy in metastatic non-small-cell lung cancer (NSCLC). We present patient-reported outcomes (PROs)., Patients and Methods: Treatment-naïve patients were randomized 1:1:1 to tremelimumab plus durvalumab and chemotherapy, durvalumab plus chemotherapy, or chemotherapy. PROs (prespecified secondary endpoints) were assessed using the European Organisation for Research and Treatment of Cancer 30-item core quality of life questionnaire version 3 (QLQ-C30) and its 13-item lung cancer module (QLQ-LC13). We analyzed time to deterioration (TTD) of symptoms, functioning, and global health status/quality of life (QoL) from randomization by log-rank test and improvement rates by logistic regression., Results: 972/1013 (96 %) patients randomized completed baseline QLQ-C30 and QLQ-LC13 questionnaires, with scores comparable between treatment arms. Patients receiving tremelimumab plus durvalumab and chemotherapy versus chemotherapy had longer median TTD for all PRO items. Hazard ratios for TTD favored tremelimumab plus durvalumab and chemotherapy for all items except diarrhea; 95 % confidence intervals did not cross 1.0 for global health status/QoL, physical functioning, cognitive functioning, pain, nausea/vomiting, insomnia, constipation, hemoptysis, dyspnea, and pain in other parts. For durvalumab plus chemotherapy, median TTD was longer versus chemotherapy for all items except nausea/vomiting and diarrhea. Hazard ratios favored durvalumab plus chemotherapy for all items except appetite loss; 95 % confidence intervals did not cross 1.0 for global health status/QoL, physical functioning, role functioning, dyspnea, and pain in other parts. For both immunotherapy plus chemotherapy arms, improvement rates in all PRO items were numerically higher versus chemotherapy, with odds ratios > 1., Conclusions: Tremelimumab plus durvalumab and chemotherapy delayed deterioration in symptoms, functioning, and global health status/QoL compared with chemotherapy. Together with significant improvements in survival, these results support tremelimumab plus durvalumab and chemotherapy as a first-line treatment option in metastatic NSCLC., Competing Interests: Declaration of Competing Interest Edward B. Garon reports grants or contracts from ABL Bio, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Dynavax Technologies, Eli Lilly, EMD Serono, Genentech, Gilead, 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, Gilead, GlaxoSmithKline, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, Xilio, and Zymeworks; and travel support from A2 Bio and Novartis. Byoung Chul Cho reports consulting fees from Abion, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Bridgebio Therapeutics, Bristol-Myers Squibb, CJ, CureLogen, Cyrus Therapeutics, Eli Lilly, GI-Cell, Hanmi, HK Inno-N, Imnewrun Biosciences, Janssen, KANAPH Therapeutic, Medpacto, MSD, Novartis, Ono Pharmaceutical, Onegene Biotechnology, Oscotec, Pfizer, RandBio, Roche, Takeda, and Yuhan; advisory board participation for Bridgebio Therapeutics, Cyrus Therapeutics, Guardant Health, Kanaph Therapeutics, and Oscotec; honoraria from ASCO, AstraZeneca, ESMO, Guardant Health, IASLC, Korean Cancer Association, Korean Cancer Study Group, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, MSD, Novartis, Pfizer, Roche, and The Chinese Thoracic Oncology Society; research funding from AbbVie, Abion, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bridgebio Therapeutics, CHA Bundang Medical Center, Champions Oncology, CJ Bioscience, CJ Blossom Park, Cyrus Therapeutics, Dizal Pharma, Dong-A ST, Eli Lilly, Genexine, GI-Cell, GIInnovation, Hanmi, Illumina, ImmuneOncia, Interpark Bio, Janssen, J Ints Bio, Kanaph Therapeutics, LG Chem, Medpacto, MOGAM Institute, MSD, Novartis, Nuvalent, Oncternal, Ono Pharmaceutical, Oscotec, Regeneron, Therapex, and Yuhan; royalties from Champions Oncology, Crown Bioscience, and Imagen; board membership for Interpark Bio and J Ints Bio; stock ownership in Bridgebio Therapeutics, Cyrus Therapeutics, Gencurix, Interpark Bio, Kanaph Therapeutics, J Ints Bio, and TheraCanVac; and other relationships for DAAN Biotherapeutics (Founder) and Korean University Health System (Employment). Alexander Luft has nothing to disclose. Jorge Alatorre-Alexander reports advisory board participation for Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, and Roche; travel support from AstraZeneca, MSD, and Roche; and honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, and Roche. Sarayut Lucien Geater reports research funding (to institution) from AstraZeneca, Boehringer Ingelheim, MSD, Novartis and Roche; honoraria from AstraZeneca, and Boehringer Ingelheim; and advisory board participation for Pfizer. Sang-We Kim reports research funding (to institution) from Yuhan; and travel support from AstraZeneca. Grygorii Ursol has nothing to disclose. Maen Hussein reports consulting fees from AbbVie, Aptitude Health, AstraZeneca, Athenex, Biopharma, Bristol-Myers Squibb, Coherus Biosciences, CTI BioPharma, Exelixis, GIntrinsiQ, IntegraConnect, Integra PrecisionQ, IntrinsiQ, Karyopharm Therapeutics, Mirati Therapeutics, National Community Oncology Dispensing Association, and Oncocyte. Farah Louise Lim has nothing to disclose. Cheng-Ta Yang has nothing to disclose. Luiz Henrique Araujo reports consulting fees from AstraZeneca, Bristol-Myers Squibb, Illumina, Lilly, MSD, Roche, and Sanofi; honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, Merck, MSD, Pfizer, and Roche; travel support from AstraZeneca, Bristol-Myers Squibb, and Daiichi-Sankyo; and grants or contracts from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, Merck, MSD, Novartis, Pfizer, and Roche. Haruhiro Saito reports honoraria from AstraZeneca and ONO Pharmaceutical; and grants or contracts from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, and ONO Pharmaceutical. Niels Reinmuth reports honoraria from AstraZeneca, Bristol-Myers Squibb, Lilly, MSD, and Roche; and consulting fees from AstraZeneca, Bristol-Myers Squibb, MSD, and Roche. Nenad Medic, Helen Mann and Xiaojin Shi are full time employees of and own stock in AstraZeneca. Solange Peters reports honoraria (to institution) from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, ecancer, Eli Lilly, Fishawack, Imedex, IQVIA, Medscape, MSD, Novartis, Oncology Education, PER, Pfizer, Prime Oncology, RMEI Medical Education, Research to Practice, Roche/Genentech, and Takeda; advisory board participation for AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Biocartis, Bioinvent, Bristol-Myers Squibb, Clovis Oncology, Daiichi-Sankyo, Debiopharm Group, Eli Lilly, Foundation Medicine, Illumina, Incyte, Janssen, Merck Serono, MSD, Merrimack, Novartis, Pfizer, PharmaMar, Phosplatin Therapeutics, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, and Takeda; and research funding (to institution) from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Illumina, Iovance Biotherapeutics, Lilly, Merck Serono, MSD, Novartis, Pharma Mar, Pfizer, Phosplatin Therapeutics, Takeda, Sanofi, Seattle Genetics, and Roche/Genentech. Tony Mok reports honoraria from ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca (before 1/1/19), BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Daz, Fishawack Facilitate, InMed Medical Communication, Janssen, Jiahui Holdings, LiangYiHui Healthcare, Lilly, Lucence Health, MD Health Brazil, Medscape, Merck, MiRXES, MSD, Novartis, OrigiMed, P. Permanyer SL, PeerVoice, PER, Pfizer, Prime Oncology, Research to Practice, Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting, Taiho Pharmaceutical, Takeda, and Touch Independent Medical Education; consulting fees from for AbbVie, ACEA Pharma, Adagene, Alpha Biopharma, Amgen, Amoy Diagnostics, Bayer, BeiGene, Berry Oncology, Boehringer Ingelheim, Blueprint Medicines, Bristol-Myers Squibb, Covidien, C4 Therapeutics, Cirina, CStone Pharmaceuticals, Curio Science, D3 Bio, Da Volterra, Daiichi-Sankyo, Eisai, Elevation Oncology, G1 Therapeutics, geneDecode, Gilead, Gritstone Oncology, Guardant Health, Hengrui Therapeutics, HutchMed, Ignyta, Inivata, IQVIA, Janssen, Lilly, Lunit USA, Loxo Oncology, Lucence Health, Medscape/WebMD, Merck Serono, MSD, Mirati Therapeutics, MiRXES, MoreHealth, Novartis, Omega Therapeutics, OrigiMed, OSE Immunotherapeutics, PeerVoice, Pfizer, Prime Oncology, Puma Biotechnology, Qiming Development, Roche/Genetech, Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, SFJ Pharmaceutical, Simcere of America, Synergy Research, Takeda, Tigermed, Vertex Pharmaceuticals, Virtus Medical Group, and Yuhan; advisory board participation for AbbVie, ACEA Pharma, Amgen, AstraZeneca, Berry Oncology, Blueprint Medicines, Boehringer Ingelheim, Bowtie Life Insurance, Bristol-Myers Squibb, C4 Therapeutics, Covidien, CStone Pharmaceuticals, Curio Science, D3 Bio, Daiichi-Sankyo, Eisai, Fishawack Facilitate, G1 Therapeutics, Gilead, Gritstone Oncology, Guardant Health, geneDecode (uncompensated), Hengrui Therapeutics, HutchMed, Ignyta, Incyte, Inivata, IQVIA, Janssen, Lakeshore Biotech, Lilly, Loxo Oncology, Lunit, Merck Serono, Mirati Therapeutics, MiRXES, MSD, Novartis, OrigiMed, Pfizer, Puma Biotechnology, Roche/Genentech, Sanofi-Aventis, SFJ Pharmaceutical, Simcere of America, Takeda, Vertex Pharmaceuticals, Virtus Medical Group, Yuhan; leadership roles for ACT Genomics-Sanomics, AstraZeneca, Aurora Tele-Oncology, HutchMed, and Lunit USA; stock/stock options in Act Genomics-Sanomics, AstraZeneca, Aurora Tele-Oncology, Biolidics, and HutchMed; research funding (to institution) from AstraZeneca, Bristol-Myers Squibb, G1 Therapeutics, MSD, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, and XCovery; and travel support (some to institution) from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, MiRXES, MSD, Novartis, Pfizer, Roche. Melissa Johnson reports research funding (paid to institution) from AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Carisma Therapeutics, Checkpoint Therapeutics, City of Hope National Medical Center, Corvus Pharmaceuticals, Curis, CytomX, Daiichi-Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, Erasca, EQRx, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunitas Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Kartos Therapeutics, Loxo Oncology, Lycera, Memorial-Sloan Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, StemCentRx, Syndax Pharmaceuticals, Takeda, Tarveda, TCR2 Therapeutics, Tempest, Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL, and Y-mAbs Therapeutics; and consulting fees (paid to institution) from AbbVie, Arcus Biosciences, Amgen, Arrivent, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Calithera, Daiichi-Sankyo, EcoR1, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Ideaya Biosciences, Immunocore, iTeos, Janssen, Jazz Pharmaceuticals, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Oncorus, Pyramid Biosciences, Regeneron Pharmaceuticals, Revolution Medicines, SeaGen, Sanofi-Aventis, Takeda, Turning Point Therapeutics, Synethekine, and VBL Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Biomarker tests in lung cancer have been traditionally ordered by the treating oncologist upon confirmation of an appropriate pathological diagnosis. The delay this introduces prolongs yet further what is already a complex, multi-stage, pre-treatment pathway and delays the start of first-line systemic treatment, which is crucially informed by the results of such analysis. Reflex testing, in which the responsibility for testing for an agreed range of biomarkers lies with the pathologist, has been shown to standardise and expedite the process. Twelve experts discussed the rationale and considerations for implementing reflex testing as standard clinical practice., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Disclosure LEH reports personal fees as an invited speaker from Benecke, Medtalks and VJOncology; personal fees for participation in mentorship programme funded by AstraZeneca; personal fees for travel support from Roche; personal fees as member of the committee that revised the Dutch guidelines on NSCLC, brain metastases and leptomeningeal metastases; fees paid to her institution for an educational webinar from Janssen; fees paid to her institution for advisory board membership from Amgen, Bristol Myers Squibb (BMS), Boehringer Ingelheim, Janssen, Lilly, Merck, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Roche and Takeda; fees paid to her institution as an invited speaker from AstraZeneca, Bayer, high5oncology, Lilly and MSD; fees paid to her institution for interview sessions from Roche; fees paid to her institution for podcast appearance from Takeda; institutional research grants from AstraZeneca, Boehringer Ingelheim, Roche, Takeda, Pfizer and Merck; institutional funding as a local principal investigator (PI) from AbbVie, AstraZeneca, Blueprint Medicines, Gilead, GlaxoSmithKline (GSK), Merck Serono, Mirati, MSD, Novartis, Roche and Takeda; non-remunerated roles as chair for metastatic NSCLC of the lung cancer group for European Organisation for Research and Treatment of Cancer (EORTC) and as the secretary of the studies foundation for NVALT (Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose). KMK reports personal fees as an invited speaker from Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Medscape, Merck Serono, MSD, Novartis, Pfizer, Prime Oncology, Roche and Roche Diagnostics/Ventana; personal fees for consultancy and advisory board membership from AbbVie, Amgen, AstraZeneca, Bayer, Debiopharm, Diaceutics, Janssen, Merck Serono, MSD, Novartis, Pfizer, Regeneron, Roche and Roche Diagnostics/Ventana; non-remunerated roles as the past Pathology Committee Chair for IASLC (International Association for the Study of Lung Cancer) and member of the UK Lung Cancer Consortium. JM reports fees paid to her institution as an invited speaker from AstraZeneca, Boehringer Ingelheim, BMS, MSD and Roche; fees paid to her institution for expert testimony from AstraZeneca, Boehringer Ingelheim and MSD; fees paid to her institution for travel expenses from Ipsen. TSM reports personal fees as an invited speaker from AbbVie, ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, BMS, Daiichi Sankyo, Daz Group, Eli Lilly, Fishawack Facilitate, InMed Medical Communication, Janssen, Jiahui Holdings Co., LiangYiHui Healthcare, Lucene Health Inc., Lunit USA, Inc., MD Health, Medscape/WebMD, Merck Serono, MSD, MiRXES, Novartis, OrigiMed, PeerVoice, PER, Permanyer SL, Pfizer, Prime Oncology, Research to Practice, Roche, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting Co., Taiho Pharmaceutical Co., Takeda and Touch Medical Media; personal fees for advisory board membership from AbbVie, ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Berry Oncology, Blueprint Medicines, Boehringer Ingelheim, BMS, C4 Therapeutics, Cirina Ltd., Covidien LP, CStone Pharma, Curio Science, D3 Bio Ltd., Da Volterra, Daiichi Sankyo, Eisai, Eli Lilly, Fishawack Facilitate, G1 Therapeutics, Gilead Sciences, Gritstone Oncology, Guardant Health, Hengrui, Ignyta, Incyte, Inivata, IQVIA, Janssen, Lakeshore Biotech, Loxo Oncology, Lucene Health Inc., Lunit USA, Inc., Medscape/WebMD, Merck Serono, Mirati Therapeutics, MiRXES, MoreHealth, MSD, Novartis, OrigiMed, OSE Immunotherapeutics, Pfizer, Puma Tech, Qiming Development, Roche, Roche/Genentech, Sanofi-Aventis, SFJ Pharmaceutical Ltd., Synergy Research, Takeda, Tigermed, Vertex Pharmaceuticals, Virtus Medical and Yuhan; personal fees as the Chairman for ACT Genomics-Sanomics Group; personal fees as a member of the board of directors from AstraZeneca and HutchMed; holds stocks/shares from AstraZeneca, Aurora Tele-Oncology, Biolidics Ltd., HutchMed and Sanomics Ltd.; institutional funding from AstraZeneca, BMS, Clovis Oncology, G1 Therapeutics, Merck Serono, MSD, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, Takeda and XCovery; non-remunerated roles as an invited speaker with AstraZeneca, Aurora Tele-Oncology, Lunit USA, Inc. and Sanomics Ltd. and for an advisory role with geneDecode; non-remunerated leadership roles with ASCO (American Society of Clinical Oncology), ATORG (Asian Thoracic Oncology Research Group), CLCRF (Chinese Lung Cancer Research Foundation Limited), CSCO (Chinese Society of Clinical Oncology), HKCF (Hong Kong Cancer Fund), HKCTS (Hong Kong Cancer Therapy Society), IASLC and St. Stephen’s College & Prep School (Hong Kong). UN reports fees paid to her institution as an invited speaker from MSD; fees paid to her institution for advisory board membership and a writing engagement from AstraZeneca; institutional funding as a coordinating PI for Bayer; non-remunerated roles as a PI for clinical trials funded by Deutsche Krebshilfe and as a member of the board of directors and vice-chair of ‘Strahlenschutzkommission’ from the German Commission on Radiological Protection. AP reports personal fees as an invited speaker from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Mundipharma and Takeda; personal fees for advisory board membership from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Janssen, MSD, Pfizer and Roche; non-remunerated activities with AIOM (Italian Association of Medical Oncology) as member of the Scientific Committee for lung cancer guidelines. SP reports personal fees for an editorial role as an Associate Editor for Annals of Oncology; fees paid to her institution as an invited speaker from AstraZeneca, BMS, Boehringer Ingelheim, e-cancer, Eli Lilly, Fishawack, Illumina, Imedex, Medscape, Mirati, MSD, Novartis, OncologyEducation, PER, Pfizer, PRIME, RMEI, Roche/Genentech, RTP, Sanofi and Takeda; fees paid to her institution for advisory board membership from AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Bio Invent, Biocartis, Blueprint Medicines, BMS, Boehringer Ingelheim, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Incyte, IQVIA, iTeos, Janssen, Merck Serono, Mirati, MSD, Novartis, Novocure, Pfizer, PharmaMar, Phosplatin Therapeutics, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda and Vaccibody; institutional funding as a steering committee member from AstraZeneca, BeiGene, BMS, iTeos, Mirati, MSD, PharmaMar, Phosplatin Therapeutics and Roche/Genentech; institutional funding as a coordinating PI from AstraZeneca; institutional funding as a trial chair from GSK and Roche/Genentech; non-remunerated role as President and Council Member for the Ballet Béjart Lausanne Foundation; non-remunerated leadership roles as President of ESMO (2020-2022), Vice-President of SAMO (Swiss Academy of Multidisciplinary Oncology), Vice-President of Lung Group for SAKK (Swiss Group for Clinical Cancer Research); non-remunerated role as PI involved in academic trials for ETOP (European Thoracic Oncology Platform)/EORTC/SAKK; non-remunerated role as Council Member and Scientific Committee Chair for ETOP/IBCSG Partners (International Breast Cancer Study Group); member of AACR (American Association for Cancer Research), ASCO, ASMAC/VSAO (Association of Swiss Interns and Residents), FMH (Association of Swiss Physicians) and IASLC. DP reports personal fees as an invited speaker from AbbVie, AstraZeneca, Janssen, Novartis, Peer CME, Pfizer, priME Oncology and Samsung; personal fees for advisory board membership from AbbVie, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Janssen, Merck, Novartis, Pfizer, Roche and Samsung; institutional funding as a PI from AbbVie, AstraZeneca, BMS, Daiichi Sankyo, Janssen, Merck, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi and Sanofi-Aventis. EFS reports personal fees as an invited speaker from Boehringer Ingelheim and Daiichi Sankyo; personal fees for advisory board membership from Merck Serono; fees paid to his institution for advisory board membership from AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen, MSD, Roche, Sanofi and Takeda; institutional funding as a local PI from AstraZeneca, Genmab, Gilead and Pfizer. BJS reports personal fees as an invited speaker from AstraZeneca, Pfizer and Roche/Genentech; personal fees for advisory board membership from Amgen and Roche/Genentech; fees paid to his institution for advisory board membership from AstraZeneca, BMS, Merck and Novartis; fees paid to his institution for steering committee membership from Novartis, Pfizer and Roche/Genentech; personal fees as a member of the board of directors from Cancer Council Victoria and Thoracic Oncology Group of Australasia; personal fees as a consultant from Peter MacCallum Cancer Centre; royalties from UpToDate. GV reports personal fees as an invited speaker and for advisory board membership from Roche; personal fees as a consultant from Ab Medica; institutional funding as a PI from AIRC (Fondazione AIRC per la ricerca sul cancro ETS) and the Italian Ministry of Health. MR reports personal fees as an invited speaker from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Lilly, Merck, MSD, Novartis, Roche and Sanofi; personal fees for advisory board membership from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Mirati, MSD, Pfizer, Roche and Sanofi.

Introduction: Most published guidelines for genomic biomarker testing in NSCLC reflect the disease epidemiology and treatments readily available in Europe and North America. Nevertheless, 60% of annual global NSCLC cases occur in Asia, where patient characteristics, tumor molecular profiles, and treatments vary greatly from the Western world. For example, mutations in the EGFR occur at a higher prevalence in Asia than in other world regions. Although medical associations such as the International Association for the Study of Lung Cancer, European Society for Medical Oncology, and American Society of Clinical Oncology have described principles for tumor genomic biomarker testing in NSCLC, there is a need for recommendations specific for Asia., Methods: This report provides consensus recommendations for NSCLC biomarker testing from Asian lung cancer experts for clinicians working in Asia to improve patient care. Biomarker testing approaches for actionable genetic alterations in EGFR, ALK, ROS1, and others are discussed., Results: These recommendations are divided into nonmetastatic and metastatic forms of adenocarcinoma and squamous cell carcinoma. Owing to the higher prevalence of EGFR mutations in Asia, the experts emphasized the need for EGFR testing to include not just common mutations (exon 19 deletions and L858R substitutions) but also other uncommon EGFR mutations. In addition to the assessment of biomarkers in the tumor tissue, the role of assessing tumor biomarkers by liquid biopsy is discussed., Conclusion: This consensus provides practical recommendations for biomarker testing in nonmetastatic and metastatic Asian NSCLC patients., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Disclosure LEH reports personal fees as an invited speaker from Benecke, Medtalks and VJOncology; personal fees for participation in mentorship programme funded by AstraZeneca; personal fees for travel support from Roche; personal fees as member of the committee that revised the Dutch guidelines on NSCLC, brain metastases and leptomeningeal metastases; fees paid to her institution for an educational webinar from Janssen; fees paid to her institution for advisory board membership from Amgen, Bristol-Myers Squibb (BMS), Boehringer Ingelheim, Janssen, Lilly, Merck, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Roche and Takeda; fees paid to her institution as an invited speaker from AstraZeneca, Bayer, high5oncology, Lilly and MSD; fees paid to her institution for interview sessions from Roche; fees paid to her institution for podcast appearance from Takeda; institutional research grants from AstraZeneca, Boehringer Ingelheim, Roche, Takeda, Pfizer and Merck; institutional funding as a local principal investigator (PI) from AbbVie, AstraZeneca, Blueprint Medicines, Gilead, GlaxoSmithKline (GSK), Merck Serono, Mirati, MSD, Novartis, Roche and Takeda; non-remunerated roles as chair for metastatic NSCLC of the lung cancer group for European Organisation for Research and Treatment of Cancer (EORTC) and as the secretary of the studies foundation for Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose (NVALT). KK reports personal fees as an invited speaker from Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Medscape, Merck Serono, MSD, Novartis, Pfizer, Prime Oncology, Roche and Roche Diagnostics/Ventana; personal fees for consultancy and advisory board membership from AbbVie, Amgen, AstraZeneca, Bayer, Debiopharm, Diaceutics, Janssen, Merck Serono, MSD, Novartis, Pfizer, Regeneron, Roche and Roche Diagnostics/Ventana; non-remunerated roles as the past Pathology Committee Chair for International Association for the Study of Lung Cancer (IASLC) and member of the UK Lung Cancer Consortium. JM reports fees paid to her institution as an invited speaker from AstraZeneca, Boehringer Ingelheim, BMS, MSD and Roche; fees paid to her institution for expert testimony from AstraZeneca, Boehringer Ingelheim and MSD; fees paid to her institution for travel expenses from Ipsen. TSM reports personal fees as an invited speaker from AbbVie, ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, BMS, Daiichi Sankyo, Daz Group, Eli Lilly, Fishawack Facilitate, InMed Medical Communication, Janssen, Jiahui Holdings Co., LiangYiHui Healthcare, Lucene Health Inc., Lunit USA, Inc., MD Health, Medscape/WebMD, Merck Serono, MIRXES, MSD, Novartis, OrigiMed, PeerVoice, PER, Permanyer SL, Pfizer, Prime Oncology, Research to Practice, Roche, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting Co., Taiho Pharmaceutical Co., Takeda and Touch Medical Media; personal fees for advisory board membership from AbbVie, ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Berry Oncology, Blueprint Medicines, Boehringer Ingelheim, BMS, C4 Therapeutics, Cirina Ltd, Covidien LP, CStone Pharma, Curio Science, D3 Bio Ltd, Da Volterra, Daiichi Sankyo, Eisai, Eli Lilly, Fishawack Facilitate, G1 Therapeutics, Gilead Sciences, Gritstone Oncology, Guardant Health, Hengrui, Ignyta, Incyte, Inivata, IQVIA, Janssen, Lakeshore Biotech, Loxo Oncology, Lucene Health Inc., Lunit USA, Inc., Medscape/WebMD, Merck Serono, Mirati Therapeutics, MiRXES, MoreHealth, MSD, Novartis, OrigiMed, OSE Immunotherapeutics, Pfizer, Puma Tech, Qiming Development, Roche, Roche/Genentech, Sanofi-Aventis, SFJ Pharmaceutical Ltd, Synergy Research, Takeda, Tigermed, Vertex Pharmaceuticals, Virtus Medical and Yuhan; personal fees as the Chairman for ACT Genomics-Sanomics Group; personal fees as a member of the board of directors from AstraZeneca and HutchMed; holds stocks/shares from AstraZeneca, Aurora Tele-Oncology, Biolidics Ltd, HutchMed and Sanomics Ltd.; institutional funding from AstraZeneca, BMS, Clovis Oncology, G1 Therapeutics, Merck Serono, MSD, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, Takeda and XCovery; non-remunerated roles as an invited speaker with AstraZeneca, Aurora Tele-Oncology, Lunit USA, Inc. and Sanomics Ltd and for an advisory role with geneDecode; non-remunerated leadership roles with American Society of Clinical Oncology (ASCO), Asian Thoracic Oncology Research Group (ATORG), Chinese Lung Cancer Research Foundation Limited (CLCRF), Chinese Society of Clinical Oncology (CSCO), Hong Kong Cancer Fund (HKCF), Hong Kong Cancer Therapy Society (HKCTS), IASLC and St. Stephen’s College & Prep School (Hong Kong). UN reports fees paid to her institution as an invited speaker from MSD; fees paid to her institution for advisory board membership and a writing engagement from AstraZeneca; institutional funding as a coordinating PI for Bayer; non-remunerated roles as a PI for clinical trials funded by Deutsche Krebshilfe and as a member of the board of directors and vice-chair of ‘Strahlenschutzkommission’ from the German Commission on Radiological Protection. AP reports personal fees as an invited speaker from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Mundipharma and Takeda; personal fees for advisory board membership from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Janssen, MSD, Pfizer and Roche; non-remunerated activities with Italian Association of Medical Oncology (AIOM) as member of the Scientific Committee for lung cancer guidelines. SP reports personal fees for an editorial role as an Associate Editor for Annals of Oncology; fees paid to her institution as an invited speaker from AstraZeneca, BMS, Boehringer Ingelheim, ecancer, Eli Lilly, Fishawack, Illumina, Imedex, Medscape, Mirati, MSD, Novartis, OncologyEducation, Physician’s Education Resource (PER), Pfizer, Partnerships in International Medical Education (PRIME), RMEI Medical Education, LLC (RMEI), Roche/Genentech, Research To Practice (RTP), Sanofi and Takeda; fees paid to her institution for advisory board membership from AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Bio Invent, Biocartis, Blueprint Medicines, BMS, Boehringer Ingelheim, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Incyte, IQVIA, iTeos, Janssen, Merck Serono, Mirati, MSD, Novartis, Novocure, Pfizer, PharmaMar, Phosplatin Therapeutics, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda and Vaccibody; institutional funding as a steering committee member from AstraZeneca, BeiGene, BMS, iTeos, Mirati, MSD, PharmaMar, Phosplatin Therapeutics and Roche/Genentech; institutional funding as a coordinating PI from AstraZeneca; institutional funding as a trial chair from GSK and Roche/Genentech; non-remunerated role as President and Council Member for the Ballet Béjart Lausanne Foundation; non-remunerated leadership roles as President of ESMO (2020-2022), Vice- President of Swiss Academy of Multidisciplinary Oncology (SAMO), Vice-President of Lung Group for Swiss Group for Clinical Cancer Research (SAKK); non-remunerated role as PI involved in academic trials for European Thoracic Oncology Platform (ETOP)/EORTC/SAKK; non-remunerated role as Council Member and Scientific Committee Chair for ETOP/International Breast Cancer Study Group (IBCSG) Partners member of American Association of Cancer Research (AACR), ASCO, Association Suisse des médecines-assistant(e)s et chef(fe)s de Clinique (ASMAC)/Verband Schweizerischer Assistenz- und Oberärztinnen und- ärzte (VSAO), Fédération des médecins suisses (FMH) and IASLC. DP reports personal fees as an invited speaker from AbbVie, AstraZeneca, Janssen, Novartis, Peer CME, Pfizer, priME Oncology and Samsung; personal fees for advisory board membership from AbbVie, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Janssen, Merck, Novartis, Pfizer, Roche and Samsung; institutional funding as a PI from AbbVie, AstraZeneca, BMS, Daiichi Sankyo, Janssen, Merck, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi and Sanofi-Aventis. ES reports personal fees as an invited speaker from Boehringer Ingelheim and Daiichi Sankyo; personal fees for advisory board membership from Merck Serono; fees paid to his institution for advisory board membership from AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen, MSD, Roche, Sanofi and Takeda; institutional funding as a local PI from AstraZeneca, Genmab, Gilead and Pfizer. BJS reports personal fees as an invited speaker from AstraZeneca, Pfizer and Roche/Genentech; personal fees for advisory board membership from Amgen and Roche/Genentech; fees paid to his institution for advisory board membership from AstraZeneca, BMS, Merck and Novartis; fees paid to his institution for steering committee membership from Novartis, Pfizer and Roche/Genentech; personal fees as a member of the board of directors from Cancer Council Victoria and Thoracic Oncology Group of Australasia; personal fees as a consultant from Peter MacCallum Cancer Centre; royalties from UpToDate. GV reports personal fees as an invited speaker and for advisory board membership from Roche; personal fees as a consultant from Ab Medica; institutional funding as a PI from Fondazione AIRC per la ricerca sul cancro ETS (AIRC) and the Italian Ministry of Health. MR reports personal fees as an invited speaker from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Lilly, Merck, MSD, Novartis, Roche and Sanofi; personal fees for advisory board membership from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Mirati, MSD, Pfizer, Roche and Sanofi.

Background: We evaluated whether tissue tumor mutational burden (tTMB) and STK11, KEAP1, and KRAS mutations have clinical utility as biomarkers for pembrolizumab monotherapy versus platinum-based chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the phase III KEYNOTE-042 trial., Patients and Methods: This retrospective exploratory analysis assessed prevalence of tTMB and STK11, KEAP1, and KRAS mutations determined by whole-exome sequencing of tumor tissue and matched normal DNA and their associations with outcomes in KEYNOTE-042. Clinical utility of tTMB was assessed using a prespecified cut point of 175 mutations/exome., Results: Of 793 patients, 345 (43.5%) had tTMB ≥175 mutations/exome and 448 (56.5%) had tTMB <175 mutations/exome. No association was observed between PD-L1 expression and tTMB. Continuous tTMB score was associated with improved overall survival (OS) and progression-free survival among patients receiving pembrolizumab (Wald test, one-sided P < 0.001) but not those receiving chemotherapy (Wald test, two-sided P > 0.05). tTMB ≥175 mutations/exome was associated with improved outcomes for pembrolizumab versus chemotherapy, whereas tTMB <175 mutations/exome was not {OS: hazard ratio, 0.62 [95% confidence interval (CI) 0.48-0.80] and 1.09 (95% CI 0.88-1.36); progression-free survival: 0.75 (0.59-0.95) and 1.27 (1.04-1.55), respectively}. Improved OS [hazard ratio (95% CI)] for pembrolizumab versus chemotherapy was observed regardless of STK11 [STK11 mutant (n = 33): 0.37 (0.16-0.86), STK11 wild-type (n = 396): 0.83 (0.65-1.05)]; KEAP1 [KEAP1 mutant (n = 64): 0.75 (0.42-1.35), KEAP1 wild-type (n = 365): 0.78 (0.61-0.99)], or KRAS [KRAS mutant (n = 69): 0.42 (0.22-0.81); KRAS wild-type (n = 232): 0.86 (0.63-1.18)] mutation status., Conclusion: tTMB with a cut point of ≥175 mutations/exome is a potential predictive biomarker for pembrolizumab monotherapy for advanced/metastatic PD-L1 tumor proportion score ≥1% NSCLC. Pembrolizumab is a standard first-line treatment in this setting regardless of STK11, KEAP1, or KRAS mutation status., (Copyright © 2023 Merck Sharp & Dohme LLC., a subsidiary Merck & Co., Inc., The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: The phase 3 NEPTUNE study (NCT02542293) evaluated first-line durvalumab plus tremelimumab (DT) versus chemotherapy for metastatic NSCLC. Prespecified exploratory analyses were conducted in an extended cohort enrolled in China., Materials and Methods: Patients were randomized (1:1) to DT or standard chemotherapy, stratified by PD-L1 tumor cell (TC) expression (≥25 % vs < 25 %), histology, and smoking history. The primary analysis for this cohort was overall survival (OS) in patients with PD-L1 TC < 1 %. Secondary analyses included OS and progression-free survival (PFS) in the ITT population and PD-L1 subgroups, and safety. No alpha was allocated to these cohort analyses (data cut-off, 21-September-2020)., Results: 78 and 82 patients were randomized to DT and chemotherapy, respectively; 26 and 29 had PD-L1 TC < 1 % (median follow-up, 31.2 and 29.7 months [censored patients]). Among patients with PD-L1 TC < 1 %, OS favored DT versus chemotherapy (HR 0.60; 95 % CI, 0.32-1.11), with medians of 15.0 months (95 % CI, 10.5-27.4) and 11.7 months (95 % CI, 8.6-20.5), respectively; 24-month rates were 36.0 % (95 % CI, 18.2-54.2) and 17.9 % (95 % CI, 6.5-33.7). In the ITT population, OS was prolonged with DT versus chemotherapy (HR 0.70; 95 % CI, 0.48-1.02); medians were 20.0 and 14.1 months and 24-month rates were 44.2 % and 30.4 %. PFS was similar in the PD-L1 TC < 1 % (HR 1.13; 95 % CI, 0.59-2.14) and ITT (HR 0.95; 95 % CI, 0.66-1.36) populations; 12-month rates were 15.6 % versus 11.3 % and 23.9 % versus 16.6 %. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 31.2 % with DT and 52.6 % with chemotherapy; 3.9 % versus 10.3 % discontinued due to TRAEs., Conclusions: In exploratory analyses, first-line DT showed a trend towards improved OS versus chemotherapy among Chinese patients in the PD-L1 TC < 1 % population and ITT population, with 24-month OS and 12-month PFS rates indicating benefit in survival curve tails. DT was well tolerated with no new safety signals., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Zhou reports receiving personal fees from AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Pfizer, Roche, and Sanofi. Ms. Mann and Dr. Shire are full-time employees of AstraZeneca. Ms. Mann owns stock in AstraZeneca. Dr. Naicker was a full-time employee of AstraZeneca with stock ownership at the time of the study and when the reported analyses were conducted. Dr. Mok became a nonexecutive director on the AstraZeneca Board in January 2019 and stepped down as the principal investigator on the NEPTUNE study, is an independent nonexecutive director of and shareholder in HutchMed, is Board Chairman of and shareholder in the Act Genomics-Sanomics Group, serves on the Board of Directors of and is a shareholder in Aurora, and serves on the Board of Directors (NEID) of and has stock options in Lunit USA Inc., and has stock options in Biolidics Ltd. In addition, he reports receiving personal fees from AbbVie, ACEA Pharma, Adagene, Alpha Biopharma, Amgen, Amoy Diagnostics, Bayer Healthcare Pharmaceuticals Ltd, BeiGene, Berry Oncology, Blueprint Medicines Corporation, Boehringer Ingelheim, Bowtie Life Insurance Co Ltd, C4 Therapeutics Inc., Covidien LP, CStone Pharmaceuticals, Curio Science, D3 Bio Ltd, Da Volterra, Daiichi Sankyo Inc., Daz Group, Eisai, Elevation Oncology, F. Hoffmann-La Roche Ltd/Genentech, Fishawack Facilitate Ltd, Gilead Sciences Inc., Gritstone Oncology Inc., Guardant Health, Hengrui Therapeutics Inc., Ignyta Inc., Incyte Corporation, Inivata, InMed Medical Communication, IQVIA, Janssen, Jiahui Holdings Co. Ltd, Lakeshore Biotech, Liangyihui Healthcare, Lilly, Loxo-Oncology Inc., Lucence Health Inc., MD Health Brazil, Medscape/WebMD, Merck Pharmaceuticals HK Ltd, Mirati Therapeutics Inc., MiRXES Group, MoreHealth, Omega Therapeutics Inc., OrigiMed Co. Ltd, OSE Immunotherapeutics, PeerVoice, Physicians' Education Resource, P. Permanyer SL, PrIME Oncology, Puma Biotechnology Inc., Qiming Development (HK), Research to Practice, Sanofi Aventis R&D, Shanghai BeBirds Translation & Consulting Co. Ltd, Simcere of America Inc., Synergy Research, Taiho Pharmaceutical Co. Ltd, Takeda Pharmaceuticals HK Ltd, Tigermed, Touch Independent Medical Education Ltd, Vertex Pharmaceuticals, Virtus Medical Group, and Yuhan Corporation; grants and personal fees from AstraZeneca, Bristol-Myers Squibb, G1 Therapeutics, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, Takeda, and XCovery; and has undertaken consultancy (uncompensated) for geneDecode Co. Ltd. Dr. de Castro Jr reports receiving personal fees from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Libbs, Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Sanofi. The remaining authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. This analysis evaluates acquired resistance mechanisms to second-line osimertinib (n = 78) in patients with EGFR T790M advanced non-small cell lung cancer (NSCLC) from AURA3 (NCT02151981), a randomized phase 3 study comparing osimertinib with chemotherapy. Plasma samples collected at baseline and disease progression/treatment discontinuation are analyzed using next-generation sequencing. Half (50%) of patients have undetectable plasma EGFR T790M at disease progression and/or treatment discontinuation. Fifteen patients (19%) have >1 resistance-related genomic alteration; MET amplification (14/78, 18%) and EGFR C797X mutation (14/78, 18%)., (© 2023. The Author(s).)

Purpose: The open-label, phase III POSEIDON study evaluated tremelimumab plus durvalumab and chemotherapy (T + D + CT) and durvalumab plus chemotherapy (D + CT) versus chemotherapy alone (CT) in first-line metastatic non-small-cell lung cancer (mNSCLC)., Methods: Patients (n = 1,013) with EGFR / ALK wild-type mNSCLC were randomly assigned (1:1:1) to tremelimumab 75 mg plus durvalumab 1,500 mg and platinum-based chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression and one additional tremelimumab dose; durvalumab plus chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression; or chemotherapy for up to six 21-day cycles (with or without maintenance pemetrexed; all arms). Primary end points were progression-free survival (PFS) and overall survival (OS) for D + CT versus CT. Key alpha-controlled secondary end points were PFS and OS for T + D + CT versus CT., Results: PFS was significantly improved with D + CT versus CT (hazard ratio [HR], 0.74; 95% CI, 0.62 to 0.89; P = .0009; median, 5.5 v 4.8 months); a trend for improved OS did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.02; P = .0758; median, 13.3 v 11.7 months; 24-month OS, 29.6% v 22.1%). PFS (HR, 0.72; 95% CI, 0.60 to 0.86; P = .0003; median, 6.2 v 4.8 months) and OS (HR, 0.77; 95% CI, 0.65 to 0.92; P = .0030; median, 14.0 v 11.7 months; 24-month OS, 32.9% v 22.1%) were significantly improved with T + D + CT versus CT. Treatment-related adverse events were maximum grade 3/4 in 51.8%, 44.6%, and 44.4% of patients receiving T + D + CT, D + CT, and CT, respectively; 15.5%, 14.1%, and 9.9%, respectively, discontinued treatment because of treatment-related adverse events., Conclusion: D + CT significantly improved PFS versus CT. A limited course of tremelimumab added to durvalumab and chemotherapy significantly improved OS and PFS versus CT, without meaningful additional tolerability burden, representing a potential new option in first-line mNSCLC.

Introduction: NEPTUNE, a phase 3, open-label study, evaluated first-line durvalumab plus tremelimumab versus chemotherapy in metastatic NSCLC (mNSCLC)., Methods: Eligible patients with EGFR and ALK wild-type mNSCLC were randomized (1:1) to first-line durvalumab (20 mg/kg every 4 weeks until progression) plus tremelimumab (1 mg/kg every 4 weeks for up to four doses) or standard chemotherapy. Randomization was stratified by tumor programmed death-ligand 1 expression (≥25% versus <25%), tumor histologic type, and smoking history. The amended primary end point was overall survival (OS) in patients with blood tumor mutational burden (bTMB) greater than or equal to 20 mutations per megabase (mut/Mb). Secondary end points included progression-free survival (PFS) in patients with bTMB greater than or equal to 20 mut/Mb and safety and tolerability in all treated patients., Results: As of June 24, 2019, 823 patients were randomized (intention-to-treat [ITT]); 512 (62%) were bTMB-evaluable, with 129 of 512 (25%) having bTMB greater than or equal to 20 mut/Mb (durvalumab plus tremelimumab [n = 69]; chemotherapy [n = 60]). Baseline characteristics were balanced in the intention-to-treat. Among patients with bTMB greater than or equal to 20 mut/Mb, OS improvement with durvalumab plus tremelimumab versus chemotherapy did not reach statistical significance (hazard ratio 0.71 [95% confidence interval: 0.49-1.05; p = 0.081]; median OS, 11.7 versus 9.1 months); the hazard ratio for PFS was 0.77 (95% confidence interval, 0.51-1.15; median PFS, 4.2 versus 5.1 months). In the overall safety population, incidence of grade 3 or 4 treatment-related adverse events was 20.7% (durvalumab plus tremelimumab) and 33.6% (chemotherapy)., Conclusions: NEPTUNE did not meet its primary end point of improved OS with durvalumab plus tremelimumab versus chemotherapy in patients with mNSCLC and bTMB greater than or equal to 20 mut/Mb. Despite the amended study design, with a resultant small primary analysis population, therapeutic activity was aligned with expectations based on mechanistic biology and previous studies., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Brigatinib is a potent next-generation ALK tyrosine kinase inhibitor approved for treatment-naive and crizotinib-refractory advanced ALK-positive (ALK+) NSCLC. We evaluated brigatinib after other next-generation ALK tyrosine kinase inhibitors., Methods: In this single-arm, phase 2, ALK in Lung Cancer Trial of brigAtinib-2 (NCT03535740), patients with advanced ALK+ NSCLC whose disease progressed on alectinib or ceritinib received brigatinib 180 mg once daily (after 7-d 90-mg lead-in). Primary end point was independent review committee (IRC)-assessed overall response rate (ORR). Circulating tumor DNA (ctDNA) was analyzed., Results: Among 103 patients (data cutoff: September 30, 2020; median follow-up [range]: 10.8 [0.5-17.7] mo), confirmed IRC-ORR was 26.2% (95% confidence interval [CI]: 18.0-35.8), median duration of response, 6.3 months (95% CI: 5.6-not reached), and median progression-free survival (mPFS), 3.8 months (95% CI: 3.5-5.8). mPFS was 1.9 months (95% CI: 1.8-3.7) in patients with ctDNA-detectable baseline ALK fusion (n = 64). Among 86 patients who progressed on alectinib, IRC-ORR was 29.1% (95% CI: 19.8-39.9); mPFS was 3.8 months (95% CI: 1.9-5.4). Resistance mutations were present in 33.3% (26 of 78) of baseline ctDNA; 54% (14 of 26) of mutations were G1202R; 52% (33 of 64) of patients with detectable ALK fusion had EML4-ALK variant 3. Most common all-grade treatment-related adverse events were increased creatine phosphokinase (32%) and diarrhea (27%). The mean dose intensity of brigatinib (180 mg once daily) was 85.9%., Conclusions: In ALK in Lung Cancer Trial of brigAtinib-2, brigatinib was found to have a limited activity in patients with ALK+ NSCLC post-ceritinib or post-alectinib therapy. mPFS was longer with brigatinib in patients without baseline detectable plasma ALK fusion., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: Quality of life (QoL) for patients with non-small cell lung cancer (NSCLC) is negatively impacted by their disease and treatment side effects. We present detailed patient-reported outcome (PRO) data from the phase 3 CROWN study, which compared lorlatinib with crizotinib in patients with previously untreated ALK-positive advanced NSCLC., Materials and Methods: PROs were assessed using the European Organisation for Research and Treatment of Cancer QoL Questionnaire with Lung Cancer module. A longitudinal, random-intercept, random-slope, mixed-effect model assessed score changes from baseline up to (not including) end of treatment. Mean changes of absolute scores from baseline at each cycle were calculated and presented up to cycle 18 (≥ 10-point change considered clinically meaningful)., Results: In both lorlatinib (n = 148) and crizotinib (n = 140) arms, there were longitudinal improvements across multiple functioning and symptom scores during treatment compared with pre-treatment. Numerical improvements for most longitudinal functioning scores (physical, role, emotional, social) favored lorlatinib; cognitive functioning favored crizotinib. Numerical improvements favored lorlatinib for several symptoms (fatigue, nausea and vomiting, insomnia, appetite loss, constipation, diarrhea [clinically meaningful improvement], and cough); peripheral neuropathy favored crizotinib. Subgroup analyses showed PROs did not differ by presence/absence of baseline brain metastases., Conclusions: Patients receiving first-line lorlatinib or crizotinib showed improvements and delayed deterioration in QoL, functioning, and several symptoms. Alongside the previously reported significantly longer progression-free survival and higher intracranial response rates for lorlatinib versus crizotinib, these data further support the use of lorlatinib over crizotinib in patients with advanced ALK-positive NSCLC with/without baseline brain metastases and provide evidence of several QoL improvements with lorlatinib when used in the first-line setting., Competing Interests: Declaration of Competing Interest ICMJE form COIs Dr Mazieres reports receiving personal consulting fees or honorarium from Pfizer, and personal consultancy fees from F. Hoffman La-Roche Ltd, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Hengrui Therapeutics, and Amgen. Dr Iadeluca, Ms Reisman, Dr Thurm, Ms Polli are employees of Pfizer and hold Pfizer stock/stock options. Dr Shaw reports receiving personal honoraria, advisory board or consultancy fees, and institutional research support from Pfizer, and is currently an employee of Novartis and holds Novartis stock/stock options. Dr Solomon reports receiving personal honoraria or advisory board fees from Pfizer, Novartis, F. Hoffman La-Roche Ltd, Amgen, AstraZeneca, Merck Sharp & Dohme, Bristol Myers Squibb, BeiGene, Takeda, Janssen, and Lilly. Dr Bauer reports receiving personal consultancy and speakers’ bureau fees from AstraZeneca, Lilly, Bayer; personal consultancy fees from Bristol Myers Squibb, Foundation Medicine, Pfizer, Loxo Oncology, Guardant Health, Exelixis, Blueprint Medicines; payment/reimbursement of exact expenses from Lilly, Bristol Myers Squibb, Foundation Medicine, Ignyta, Moderna Therapeutics, Loxo Oncology, Bayer, Guardant Health; institutional consultancy fees from Leap Therapeutics, Ignyta, Moderna Therapeutics, Pfizer; and institutional grant support from Pfizer, Daiichi Sankyo, Medpacto, Incyte, Mirati Therapeutics, MedImmune, AbbVie, AstraZeneca, MabVax, Stemline Therapeutics, Merck, Lilly, GlaxoSmithKline, Novartis, Genentech, Deciphera, Merrimack, Immunogen, Millennium, Phosplatin Therapeutics, Calithera Biosciences, Kolltan Pharmaceuticals, Principia Biopharma, Peleton, Immunocore, F. Hoffman La-Roche Ltd, Aileron Therapeutics, Bristol Myers Squibb, Amgen, Onyx, Sanofi, Boehringer Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio, Top Alliance BioScience, Janssen, Clovis Oncology, Takeda, Karyopharm Therapeutics, Foundation Medicine, ARMO BioSciences, Leap Therapeutics, Ignyta, Moderna Therapeutics, Pfizer, Loxo Oncology, and Bayer. Dr de Marinis reports receiving personal advisory fees from AstraZeneca, Bristol Myers Squibb, Novartis, F. Hoffman La-Roche Ltd, and Merck Sharp & Dohme. Dr Felip reports receiving personal speakers’ bureau fees from Medscape, Peervoice, Springer, Touch Independent Medical Education, prIME Oncology, CME Outfitters; personal advisory board fees from AbbVie, Amgen, Bayer, Blueprint Medicines, Lilly, GlaxoSmithKline, Janssen, Merck, Puma Biotechnology, F. Hoffman La-Roche Ltd, Sanofi Genzyme, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Takeda, Daichii Sankyo; personal advisory or board member fees from Grifols; grant support from Fundación Merck Salud. Dr Goto reports receiving grant support or contracts from Pfizer, AZK; institutional grant support or contracts from AbbVie, Lilly, Pfizer, Bristol Myers Squibb, ONO Pharmaceutical, Novartis, Kyorin Pharmaceutical, Daiichi Sankyo, Preferred Networks Inc.; personal honoraria for lectures, presentations, speakers’ bureau, manuscript writing or educational events from Lilly, Chugai Pharmaceutical, Taiho Pharmaceutical, Boehringer Ingelheim, ONO Pharmaceutical, Bristol Myers Squibb, Pfizer, Merck Sharp & Dohme, Novartis, Merck, and Thermo Fisher; personal advisory board or data safety monitoring board fees from AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim, Lilly, Taiho Pharmaceutical, Pfizer, Novartis, Guardant Health, Illumina, Daiichi Sankyo, ONO Pharmaceutical, Bristol Myers Squibb, and Merck Sharp & Dohme; and reports a leadership, fiduciary or board role with Cancer Net Japan, and JAMT. Dr Kim reports receiving medical writing support from Pfizer; institutional grant support from Pfizer, Alpha Biopharma, Amgen, AstraZeneca, Boehringer Ingelheim, Bridge BioTherapeutics, Chong Keun Dang, Daiichi Sankyo, GlaxoSmithKline, Hanmi, Janssen, Merck, Merus, Mirati Therapeutics, Merck Sharp & Dohme, Novartis, ONO Pharmaceutical, F. Hoffman La-Roche Ltd, Takeda, TP Therapeutics, Xcovery, and Yuhan; and travel support from Amgen, and Daiichi Sankyo. Dr Mok reports receiving grant support from AstraZeneca, Bristol-Myers Squibb, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Takeda, Clovis Oncology, SFJ Pharmaceuticals, XCovery, G1 Therapeutics Inc.; personal consultancy, advisory or lecture fees from Abbvie, ACEA Pharmaceuticals, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Blueprint Medicines Corporation, CStone Pharmaceuticals, Daiichi Sankyo, Eisai, Fishawack Facilitate Ltd., geneDecode (uncompensated), Gritstone Oncology Inc., Guardant Health, Hengrui Therapeutics, Ignyta Inc., IQVIA, Incyte Corporation, InMed Medical Communication, Janssen, Lilly, Loxo-Oncology, Lunit USA, Inc., MD Health (Brazil), Medscape/WebMD, Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc., MoreHealth, Novartis, OrigiMed, PeerVoice, Physicians' Education Resource, P. Permanyer SL, Pfizer, Inc, PrIME Oncology, Puma Biotechnology Inc, Research to Practice, Roche, Sanofi-Aventis R&D, Takeda, Touch Medical Media, Virtus Medical Group (stock option), Yuhan Corporation, HutchMed (shareholder), SFJ Pharmaceuticals, Curio Science, Inivata, Berry Oncology, G1 Therapeutics Inc., Aurora (shareholder), Qiming Development (HK) Ltd., Daz Group, Lucence Health Inc., Merck Pharmaceuticals HK Ltd, Shanghai BeBirds Translation & Consulting Co., Ltd, Liangyihui Network Technology Co., Ltd, Taiho, Gilead Sciences, Inc, Vertex Pharmaceuticals, Covidien LP, Elevation Oncology, C4 Therapeutics, Inc, D3 Bio Ltd.; shareholder or stock options from Loxo-Oncology, Lunit USA, Inc., Act Genomics-Sanomics Group; Board of Director at AstraZeneca PLC (Jan 2019 onwards), HutchMed (Oct 2018 onwards), Act Genomics-Sanomics Group (Board Chairman 2015 onwards), Lunit USA, Inc. (Mar 2021 onwards), Aurora (Sep 2020 onwards). Dr Liu reports receiving grants or contracts from institutions - NCI (US), CIHR (Canada), CCSRI (Canada), AstraZeneca, Takeda, Boehringer Ingelheim; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (personal) from AstraZeneca, Pfizer, EMD Serono, Takeda, Jazz; Participation on a Data Safety Monitoring Board or Advisory Board (personal) from AstraZeneca, Pfizer, EMD Serono, Merck, Abbvie, Jazz, Takeda, Roche, BMS, Novartis., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Lorlatinib significantly improved progression-free survival (PFS) versus crizotinib and showed robust intracranial activity in patients with previously untreated advanced ALK -positive non-small-cell lung cancer (NSCLC) in the phase III CROWN trial. Here, we report post hoc efficacy outcomes in patients with and without brain metastases at baseline, and present data on the incidence and management of CNS adverse events (AEs) in CROWN., Methods: Eligible patients were randomly assigned 1:1 to first-line lorlatinib (100 mg once daily) or crizotinib (250 mg twice a day); no crossover between treatment arms was permitted. Tumor assessments, including CNS magnetic resonance imaging, were performed at screening and then at 8-week intervals. Regular assessments of patient-reported outcomes were conducted., Results: PFS by blinded independent central review was improved with lorlatinib versus crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78% v 22% and 78% v 45%, respectively). Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression versus crizotinib in patients with (7% v 72%) and without (1% v 18%) brain metastases at baseline. In total, 35% of patients had CNS AEs with lorlatinib, most of grade 1 severity. Occurrence of CNS AEs did not result in a clinically meaningful difference in patient-reported quality of life. At analysis, 56% of CNS AEs had resolved (33% without intervention; 17% with lorlatinib dose modification), and 38% were unresolved; most required no intervention. Lorlatinib dose modification did not notably influence PFS., Conclusion: First-line lorlatinib improved PFS outcomes and reduced CNS progression versus crizotinib in patients with advanced ALK -positive non-small-cell lung cancer with or without brain metastases at baseline. Half of all CNS AEs resolved without intervention or with lorlatinib dose modification.

Tumor mutational burden (TMB) is being explored as a predictive biomarker for cancer immunotherapy outcomes in non-small cell lung cancer. BFAST (NCT03178552)-an open-label, global, multicohort trial-evaluated the safety and efficacy of first-line targeted therapies or immunotherapy in patients with unresectable Stage IIIB or IV advanced or metastatic non-small cell lung cancer who were selected for biomarker status using blood-based targeted next-generation sequencing. In the Phase 3 cohort C evaluating blood-based (b)TMB as a biomarker of atezolizumab efficacy, patients with bTMB of ≥10 (N = 471) were randomized 1:1 to receive atezolizumab or platinum-based chemotherapy per local standard of care. Cohort C did not meet its primary endpoint of investigator-assessed progression-free survival in the population with bTMB of ≥16 (hazard ratio, 0.77; 95% confidence interval: 0.59, 1.00; P = 0.053). Adverse events leading to treatment withdrawal occurred in 10% of patients in the atezolizumab arm and 20% in the chemotherapy arm. Adverse events of special interest occurred in 42% of patients in the atezolizumab arm and 26% in the chemotherapy arm. A prespecified exploratory analysis compared the bTMB clinical trial assay with the FoundationOne Liquid Companion Diagnostic assay and showed high concordance between assays. Additional exploration of bTMB to identify optimal cutoffs, confounding factors, assay improvements or cooperative biomarkers is warranted., (© 2022. The Author(s).)

Tyrosine kinase inhibitors (TKIs) are the standard of care for patients with non-small cell lung cancer (NSCLC) that harbor mutations of the epidermal growth factor receptor (EGFR) gene. First-line therapy for these patients is often osimertinib, a third-generation EGFR TKI. Erlotinib, gefitinib, afatinib, and dacomitinib are first- and second-generation TKIs that are also available. However, almost all patients eventually develop disease progression due to TKI-acquired resistance. The mechanisms of resistance after TKI exposure often involve EGFR or its downstream pathways. While a frequently utilized strategy for combating acquired resistance to EGFR TKIs remains standard platinum-based chemotherapy, clinical investigation of promising novel agents targeting common resistance mechanisms such as MET, HER2, and HER3 is of increased interest. In this review, we discuss the mechanisms of resistance to TKIs in EGFR-mutant NSCLC, examine current treatment standards, and discuss novel developing therapies. Both EGFR-dependent (involving secondary mutations in EGFR) and EGFR-independent (mutations that bypass EGFR signaling and histologic transformation) resistance mechanisms are considered. Several novel treatment strategies are emerging to overcome these resistance mechanisms, as the understanding and identification of specific EGFR-TKI resistance mechanisms continues to improve. The treatments in development aim to target or bypass the mechanisms of resistance, including MET-, HER2-, and HER3-directed therapies. In patients with acquired TKI resistance, molecular profiling at the time of initial progression may help identify relevant mechanisms of resistance. Clinical trial participation is vital to continued investigation for EGFR-mutant NSCLC., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Stage I non-small cell lung cancer (NSCLC) presents diverse outcomes. To identify molecular features leading to tumor recurrence in early-stage NSCLC, we perform multiregional whole-exome sequencing (WES), RNA sequencing, and plasma-targeted circulating tumor DNA (ctDNA) detection analysis between recurrent and recurrent-free stage I NSCLC patients (CHN-P cohort) who had undergone R0 resection with a median 5-year follow-up time. Integrated analysis indicates that the multidimensional clinical and genomic model can stratify the prognosis of stage I NSCLC in both CHN-P and EUR-T cohorts and correlates with positive pre-surgical deep next generation sequencing (NGS) ctDNA detection. Increased genomic instability related to DNA interstrand crosslinks and double-strand break repair processes is significantly associated with early tumor relapse. This study reveals important molecular insights into stage I NSCLC and may inform clinical postoperative treatment and follow-up strategies., Competing Interests: Declaration of interests M.J.-H. is a Cancer Research UK Fellow and has received funding from CRUK, National Institute for Health Research, Rosetrees Trust, UKI NETs, and NIHR University College London Hospitals Biomedical Research Center. M.J.-H. is a member of the Scientific Advisory Board and Steering Committee for Achilles Therapeutics. A.Y., K.L., R.W., J.B., L.W., H.L., Y.S., and S.W. are employees of Berry Oncology Corporation., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: We retrospectively assessed prognostic value of circulating cell-free DNA (cfDNA) using data from the phase III ALEX study in treatment-naïve, advanced ALK+ non-small cell lung cancer (NSCLC)., Patients and Methods: Patients were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151). cfDNA was quantified from baseline plasma samples, with patients stratified into ≤median and >median cfDNA biomarker-evaluable populations (BEP). Effect of cfDNA concentration on outcomes was analyzed using a Cox regression model with treatment group as covariate, and in multivariate analyses., Results: Median cfDNA concentration in the BEP was 11.53 ng/mL (n = 276). A positive correlation was found between cfDNA concentration and number of lesions, organ lesion sites, and tumor size (sum of longest diameter; all P < 0.0001). In both treatment arms, patients in the >median BEP were more likely to experience disease progression than the ≤median BEP [alectinib adjusted HR = 2.04; 95% confidence interval (CI), 1.07-3.89; P = 0.0305 and crizotinib adjusted HR = 1.83; 95% CI, 1.11-3.00, P = 0.0169]. Median progression-free survival was longer with alectinib than crizotinib in both ≤median and >median BEPs (P < 0.0001). Overall survival data remain immature; survival probability was lower in the >median versus ≤median BEP in both treatment arms (alectinib HR = 2.52; 95% CI, 1.08-5.88; P = 0.0333 and crizotinib HR = 2.63; 95% CI, 1.27-5.47; P = 0.0096)., Conclusions: These data suggest that plasma cfDNA concentration may have prognostic value in advanced ALK+ NSCLC. Prospectively designed studies are warranted to investigate this finding., (©2022 The Authors; Published by the American Association for Cancer Research.)

The European Society for Medical Oncology (ESMO) held a virtual consensus-building process on epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer in 2021. The consensus included a multidisciplinary panel of 34 leading experts in the management of lung cancer. The aim of the consensus was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where the available evidence is either limited or conflicting. The main topics identified for discussion were: (i) tissue and biomarkers analyses; (ii) early and locally advanced disease; (iii) metastatic disease and (iv) clinical trial design, patient's perspective and miscellaneous. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the recommendations developed, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation., Competing Interests: Disclosure AP received education grants, provided consultation, attended advisory board meetings and/or provided lectures for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Daiichi Sankyo, eCancer, Eli Lilly, Janssen, Medscape, Merck Sharp & Dohme (MSD), Merck KGaA, Novartis, Pfizer, Roche/Genentech, Takeda, outside the submitted work. NL reports unrelated institutional research funding received from Amgen, Array, AstraZeneca, Bayer, BMS, Lilly, EMD Serono, Guardant Health, MSD, Pfizer, Roche, Takeda and unrelated personal fees (CME lectures, consulting) received from Bayer, Boehringer Ingelheim, BMS, Canadian Agency for Drugs and Technologies in Health, EMD Serono, MSD, Novartis, Sanofi Genzyme. SPo reports personal fees from Amgen, AstraZeneca, Bayer, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Daiichi Sankyo, Guardant Health, Janssen, Lilly, Merck KGaA, Novartis, Roche, Takeda, Seattle Genetics, Turning Point Therapeutics, GlaxoSmithKline, outside the submitted work. KK reports personal fees from AstraZeneca, Roche, during the conduct of the study. MJA reports personal fees from AstraZeneca, Takeda, Roche, Alpha Pharmaceutical, Amgen, Lilly, ONO, MSD, Merck, outside the submitted work. MEA reports personal fees from Biocartis, Invivoscribe, Janssen Global Services, BMS, AstraZeneca, Roche, Merck, RMEI Medical Education, Clinical Care Options, PeerView Institute for medical education, outside the submitted work. OA reports personal fees from Pfizer, grants and personal fees from AstraZeneca, Boehringer Ingelheim, personal fees from Lilly, Merck, BMS, grants and personal fees from Roche, outside the submitted work. DP reports personal fees from AstraZeneca, BMS, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, Samsung, AbbVie, Janssen, outside the submitted work; and clinical trials research (as principal investigator or co-investigator): AstraZeneca, AbbVie, BMS, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, MedImmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, Janssen. FdM reports grants and personal fees from AstraZeneca, grants from Boehringer, personal fees from Roche, BMS, Novartis, MSD, Pfizer, Takeda, outside the submitted work. AMD reports personal fees from Roche, Eli Lilly, Pfizer, Pharmamar, Takeda, Boehringer Ingelheim, grants and personal fees from AstraZeneca, personal fees from Jansen, Chiesi, grants and personal fees from Amgen, personal fees from Bayer, Sanofi, outside the submitted work. RD reports personal fees from Pfizer, personal fees and non-financial support from Roche, non-financial support from AstraZeneca, personal fees from Novartis, Boehringer Ingelheim, Foundation Medicine, Karyopharm, outside the submitted work. CFF reports grants and other from AstraZeneca, other from MSD, grants and other from Elekta, during the conduct of the study. JF reports personal fees from Blueprint Medicines, Novartis, Janssen, AstraZeneca, outside the submitted work. EF reports personal fees from AbbVie, Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BMS, Eli Lilly, GlaxoSmithKline, Janssen, Medscape, Merck KGaA, MSD, Novartis, PeerVoice, Pfizer, prIME Oncology, Puma Biotechnology, Roche, Sanofi Genzyme, Springer, Takeda, Touch Medical, grants from Grant for Oncology Innovation (GOI), grants from Fundación Merck Salud, personal fees from CME Outfitters, BeiGene, Medical Trends, Peptomyc, Regeneron, from Syneos Health, outside the submitted work; and Grifols: independent member of the board. GC reports consultation fees from Pfizer, Roche, AstraZeneca, BMS, Daichii Sankyo, Seagen, Gilead, Novartis, Lilly, Ellipsis, Merck. RH reports consultation fees from AbbVie Pharmaceuticals, ARMO Biosciences, AstraZeneca, Bayer HealthCare Pharmaceuticals Inc., Bolt Biotherapeutics, BMS, Candel Therapeutics, Inc., Checkpoint Therapeutics, Cybrexa Therapeutics, DynamiCure Biotechnology, LLC, eFFECTOR Therapeutics, Inc., Eli Lilly and Company, EMD Serono, Foundation Medicine, Inc., Genentech/Roche, Genmab, Gilead, Halozyme Therapeutics, Heat Biologics, HiberCell, Inc., I-Mab Biopharma, Immune-Onc Therapeutics, Immunocore, Infinity Pharmaceuticals, Johnson & Johnson, Loxo Oncology, Merck and Company, Mirati Therapeutics, Nektar, Neon Therapeutics, NextCure, Novartis, Ocean Biomedical, Inc., Oncocyte Corp., Oncternal Therapeutics, Pfizer, Refactor Health, Inc., Ribbon Therapeutics, Sanofi, Seattle Genetics, Shire PLC, Spectrum Pharmaceuticals, STCube Pharmaceuticals, Inc., Symphogen, Takeda, Tesaro, Tocagen, Ventana Medical Systems, Inc., WindMIL Therapeutics, Xencor, Inc., research support from AstraZeneca, Eli Lilly and Company, Genentech/Roche, Merck and Company, and participation on board of Immunocore Holdings Limited, Junshi Pharmaceuticals. PAJ reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, personal fees from Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Loxo Oncology, grants and personal fees from Eli Lilly, personal fees from SFJ Pharmaceuticals, Voronoi, grants and personal fees from Daiichi Sankyo, personal fees from Biocartis, Novartis, Sanofi, grants and personal fees from Takeda Oncology, personal fees from Mirati Therapeutics, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, AbbVie, grants from Revolution Medicines, grants from PUMA, grants from Astellas, outside the submitted work. In addition, PAJ is a co-inventor on a DFCI patent on EGFR mutations and receives postmarketing royalties from Lab Corp. TJ reports personal fees from Pfizer, AstraZeneca, BMS, Merck, MSD, Takeda, Boehringer Ingelheim, Roche, Ignyta, Novartis, Bayer, Amgen, Gilead, Puma Pharmaceuticals, outside the submitted work. TM reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chugai, personal fees from Pfizer, during the conduct of the study; personal fees from BMS, grants and personal fees from Ono, MSD, personal fees from Novartis, grants and personal fees from Taiho, personal fees from Takeda, Amgen, Invitae, Merck Biopharma, Thermo Fisher, grants from Bridge Biotherapeutics, grants and personal fees from Ethicon, outside the submitted work. TM reports personal fees and other from AbbVie, Inc., ACEA Pharma, Alpha Biopharma Co. Ltd, Amgen, Amoy Diagnostics Co. Ltd, grants, personal fees and other from AstraZeneca, personal fees and other from BeiGene, Boehringer Ingelheim, grants, personal fees and other from BMS, personal fees and other from Blueprint Medicines Corporation, CStone Pharmaceuticals, Daiichi Sankyo, Eisai, Fishawack Facilitate Ltd, other from geneDecode, personal fees and other from Gritstone Oncology Inc., Guardant Health, Hengrui Therapeutics, Ignyta Inc., Incyte Corporation, personal fees from InMed Medical Communication, personal fees and other from Janssen, Lilly, Loxo Oncology, Lunit USA, Inc., personal fees from MD Health (Brazil), Medscape/WebMD, grants, personal fees and other from Merck Serono, MSD, personal fees and other from Mirati Therapeutics Inc., personal fees from MoreHealth, grants, personal fees and other from Novartis, personal fees and other from OrigiMed, personal fees from PeerVoice, Physicians' Education Resource, P. Permanyer SL, grants, personal fees and other from Pfizer, Inc., personal fees from PrIME Oncology, personal fees and other from Puma Biotechnology Inc., personal fees from Research to Practice, grants, personal fees and other from Roche, personal fees and other from Sanofi-Aventis R&D, grants, personal fees and other from Takeda, personal fees from Touch Medical Media, other from Virtus Medical Group, personal fees and other from Yuhan Corporation, other from AstraZeneca PLC, Hutchison Chi-Med, Sanomics Ltd, grants from Clovis Oncology, grants, personal fees and other from SFJ Pharmaceuticals, grants from Xcovery, personal fees and other from Curio Science, personal fees from Inivata, Berry Oncology, grants and personal fees from G1 Therapeutics Inc., other from Aurora, personal fees from Qiming Development (HK) Ltd, Daz Group, Lucence Health Inc., Merck Pharmaceuticals HK Ltd, Shanghai BeBirds Translation & Consulting Co., Ltd, Liangyihui Network Technology Co., Ltd, Taiho, personal fees and other from Gilead Sciences, Inc, Vertex Pharmaceuticals, personal fees from Covidien LP, outside the submitted work. NN reports personal fees from MSD, grants and personal fees from Qiagen, Biocartis, Incyte, Roche, BMS, Merck, Thermo Fisher, AstraZeneca, personal fees from Sanofi, Eli Lilly, Bayer, ArcherDx, grants and personal fees from Illumina, personal fees from Amgen, outside the submitted work. LPA reports grants from MSD, AstraZeneca, Pfizer, BMS, personal fees from Lilly, MSD, Roche, Pharmamar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Ipsen, Sanofi, Bayer, Blueprint, BMS, Mirati, Janssen, other from Genomica, Altum sequencing, outside the submitted work. SR reports personal fees from AstraZeneca, BMS, Amgen, GlaxoSmithKline, Merck, Takeda, Eisai, Lilly, outside the submitted work. LS reports grants and personal fees from AstraZeneca, grants from Novartis, personal fees from Janssen, grants and personal fees from Genentech, personal fees from Takeda, Pfizer, grants from Boehringer Ingelheim, outside the submitted work. JV reports honoraria for invited speaker from AstraZeneca, BMS, MSD, and Novartis; participation on advisory board of AstraZeneca, BMS, Boehringer Ingelheim, Daichi Sankyo, MSD, Pfizer, and Roche; grant from MSD. IIW reports grants and personal fees from Genentech/Roche, Bayer, BMS, AstraZeneca, Pfizer, HTG Molecular, personal fees from Asuragen, grants and personal fees from Merck, GlaxoSmithKline, Guardant Health, personal fees from Flame, grants and personal fees from Novartis, Sanofi, personal fees from Daiichi Sankyo, grants and personal fees from Amgen, personal fees from Oncocyte, MSD, Platform Health, grants from Adaptive, Adaptimmune, EMD Serono, Takeda, Karus, Johnson & Johnson, 4D, Iovance, Akoya, outside the submitted work. JW reports personal fees from Amgen, AstraZeneca, Bayer, Blueprint, grants and personal fees from BMS, personal fees from Boehringer Ingelheim, Chugai, Daiichi Sankyo, Ignyta, grants and personal fees from Janssen, personal fees from Lilly, Loxo, MSD, grants and personal fees from Novartis, Pfizer, personal fees from Roche, Seattle Genetics, Takeda, outside the submitted work. YLW reports personal fees from AstraZeneca, BeiGene, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, Sanofi, Novartis, Takeda; grants from AstraZeneca, Boehringer Ingelheim, BMS, Hengrui and Roche, outside the submitted work. JCHY reports personal fees and other from Amgen, grants, personal fees and other from AstraZeneca, personal fees and other from Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, other from Eli Lilly, personal fees and other from Merck KGaA, Darmstadt, Germany, MSD, Novartis, personal fees from Ono Pharmaceuticals, Pfizer, personal fees and other from Roche/Genentech, Takeda Oncology, Yuhan Pharmaceuticals, other from Johnson & Johnson, Glaxo, Puma Technology, outside the submitted work. YY reports and contracted studies with ArcherDx, Chugai Pharma and Thermo Fisher Science; honoraria for lectures from MSD, Chugai Pharma, AstraZeneca, Pfizer, Roche/Ventana, Agilent/Dako, Thermo Fisher Science, ArcherDx, Novartis, Eli Lilly, Amgen and Sysmex; participation on advisory board of MSD, Chugai Pharma, AstraZeneca, Novartis, Amgen, Takeda and Daiichi-Sankyo. GP reports grants from Amgen, grants, personal fees and non-financial support from Merck, grants and non-financial support from AstraZeneca, grants and personal fees from Roche, BMS, grants from Lilly, grants and personal fees from MSD, Novartis, outside the submitted work. SPe received education grants, provided consultation, attended advisory board meetings and/or provided lectures for AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, BioInvent, Blueprint Medicines Corporation, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, MSD, Merck Serono, Merrimack, Novartis, PharmaMar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda and Vaccibody, from whom she received honoraria (all fees to institution). All other authors have declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

A proportion of patients with lung cancer experience long-term clinical benefit with immune checkpoint inhibitors (ICIs). However, most patients develop disease progression during treatment or after treatment discontinuation. Definitions of immune resistance are heterogeneous according to different clinical and biologic features. Primary resistance and acquired resistance, related to tumor-intrinsic and tumor-extrinsic mechanisms, are identified according to previous response patterns and timing of occurrence. The clinical resistance patterns determine differential clinical approaches. To date, several combination therapies are under development to delay or prevent the occurrence of resistance to ICIs, including the blockade of immune coinhibitory signals, the activation of those with costimulatory functions, the modulation of the tumor microenvironment, and the targeting T-cell priming. Tailoring the specific treatments with distinctive biologic resistance mechanisms would be ideal to improve the design and results of clinical trial. In this review, we reviewed the available evidence on immune resistance mechanisms, clinical definitions, and management of resistance to ICIs in lung cancer. We also reviewed data on novel strategies under investigation in this setting., Competing Interests: Antonio PassaroConsulting or Advisory Role: Roche/Genentech, Bristol Myers Squibb, AstraZeneca, MSD Oncology, Pfizer, Boehringer Ingelheim, Johnson & Johnson/Janssen, Novartis, LillySpeakers' Bureau: AstraZeneca, Johnson & Johnson/Janssen, Boehringer Ingelheim Julie BrahmerHonoraria: JanssenConsulting or Advisory Role: Bristol Myers Squibb, Lilly, Merck, Amgen, Genentech, GlaxoSmithKline, AstraZeneca, Regeneron, Sanofi, Eisai¸ Turning Point TherapeuticsResearch Funding: Bristol Myers Squibb (Inst), AstraZeneca (Inst), Spectrum Pharmaceuticals (Inst), Revolution (Inst), RAPT Therapeutics (Inst), Genentech/Roche (Inst)Other Relationship: Bristol Myers Squibb Scott AntoniaConsulting or Advisory Role: Bristol-Myers Squibb, Merck, Memgen¸ Achilles Therapeutics, Amgen, Celsius Therapeutics, EMD Serono, G1 Therapeutics, GlaxoSmithKline, Glympse Bio, RAPT Therapeutics, Samyang, Venn Therapeutics, Tarus Therapeutics¸Patents, Royalties, Other Intellectual Property: Oncolytic virusTravel, Accommodations, Expenses: RAPT Therapeutics, Amgen¸ Achilles Therapeutics Tony MokEmployment: The Chinese University of Hong KongLeadership: Sanomics Limited, Hutchison China Meditech, Aurora Tele-Oncology PlatformStock and Other Ownership Interests: Sanomics Limited, Hutchison China Meditech, Aurora Tele-Oncology Platform,Honoraria: AstraZeneca, Alpha Biopharma, ACEA Pharmaceutical Research, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo/UCB Japan, Fishawack Facilitate, InMed, Lilly, Origimed, Pfizer, Prime Oncology, Roche, Sanofi Aventis GmbH, Taiho Pharmaceutical, Takeda, Medscape, P. Permanyer SL, PeerVoice, Physicans' Education Resource, Research to Practice, Shanghai BeBirds Translation & Consulting Co, Liangyihui Network Technology Co, LtdConsulting or Advisory Role: AbbVie, ACEA Pharmaceutical Research, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, BeiGene, Berry Oncology, Boehringer Ingelheim, Blueprint Medicines¸ CStone Pharmaceuticals, Bristol Myers Squibb, Curio Science, Daiichi Sankyo/UCB Japan, Gritstone Oncology, Fishawack Facilitate, Guardant Health, Hengrui Therapeutics, Ignyta, Incyte, Inivata, IQVIA, Lilly, Loxo, Lunit, Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics¸ Novartis, Pfizer, Puma Biotechnology, Roche, SFJ Pharmaceuticals Group, Takeda, Vertex, Yuhan, Qiming Development (HK) LtdResearch Funding: AstraZeneca (Inst), Boehringer Ingelheim (Inst), Pfizer (Inst), Novartis (Inst), SFJ Pharmaceuticals Group (Inst), Roche (Inst), Merck Sharp & Dohme (Inst), Bristol Myers Squibb (Inst), Xcovery (Inst), G1 Therapeutics (Inst), Merck Serono (Inst), Takeda (Inst) Solange PetersHonoraria: Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), MSD (Inst), AstraZeneca (Inst), Takeda (Inst), Illumina (Inst), Medscape (Inst)Consulting or Advisory Role: Roche/Genentech (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Pfizer (Inst), MSD (Inst), Amgen (Inst), AstraZeneca (Inst), Janssen (Inst), Regeneron (Inst), Merck Serono (Inst), Boehringer Ingelheim (Inst), Takeda (Inst), Lilly (Inst), AbbVie (Inst), Bayer (Inst), Biocartis (Inst), Debiopharm Group (Inst), Illumina (Inst), PharmaMar¸ Sanofi (Inst), Seattle Genetics (Inst), Blueprint Medicines (Inst), Daiichi Sankyo (Inst), Incyte (Inst), Bioinvent (Inst), Clovis Oncology (Inst), Vaccibody (Inst), Phosplatin Therapeutics (Inst)Research Funding: BMS (Inst), MSD (Inst), Amgen (Inst), Lilly (Inst), AstraZeneca (Inst), Pfizer¸ Illumina (Inst), Merck Serono (Inst), Novartis (Inst), Biodesix (Inst), Boehringer Ingelheim (Inst), Phosplatin Therapeutics (Inst)Travel, Accommodations, Expenses: Roche, Bristol Myers Squibb, MSD, Sanofi, Incyte, ESMOUncompensated Relationships: European Thoracic Oncology Platform (ETOP), Annals of OncologyNo other potential conflicts of interest were reported.

Background: Immunotherapy represents the standard of care in the first-line treatment of advanced non-small-cell lung cancer (NSCLC), either as monotherapy in high programmed death-ligand 1 (PD-L1)-positive tumors (≥50%) or in combination with platinum-based chemotherapy regardless of PD-L1 status. However, most pivotal clinical trials of immune checkpoint inhibitors (ICIs) did not include patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2. Hence, a consensus is lacking on the safety and efficacy of ICIs in this specific subgroup of patients., Materials and Methods: A virtual International Expert Panel took place in July 2021 with the aim of reviewing the available evidence on the use of ICIs in NSCLC patients with ECOG PS 2, both in clinical practice and in a research setting., Results: All panelists expressed concern about the applicability of currently available PS scales to evaluate patients for ICI treatment. The panelists agreed that, though limited, the available data support the safety of single-agent immunotherapy in PS 2 NSCLC patients, whereas concern was raised on the safety of ICI combinations, mainly related to chemotherapy and/or anti-cytotoxic T-lymphocyte-associated antigen 4 toxicity. On the basis of reviewed data, ICI efficacy may be speculated in PS 2 NSCLC patients; however, PS 2 remains a negative prognostic category as compared to PS 0-1 in patients treated with ICI, as it is for chemotherapy. The panelists defined high, medium and low priorities in clinical research. High priority was attributed to the inclusion of PS 2 patients in prospective clinical trials and the specific evaluation of combined ICI treatments with attenuated chemotherapy doses., Conclusions: Based on the current evidence, the panelists outlined the major limitations affecting PS 2 patients with NSCLC and reached common considerations on the feasibility, safety and effectiveness of ICI monotherapy and ICI combinations in the first-line setting., Competing Interests: Disclosure CG received honoraria as speaker bureau or advisory board member or as consultant from MSD, BMS, Roche, AstraZeneca, Novartis, Pfizer, Menarini, Boehringer, Karyopharm and Eli Lilly. SP reports personal fees for speaking or attending advisory boards, and has participated in investigation in trials for Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Clovis, F. Hoffmann-La Roche, Illumina, Merck Sharp & Dohme, Merck Serono, Novartis and Pfizer; and personal fees for speaking or attending advisory boards for AbbVie, Bayer, Biocartis, Bioinvent, Daiichi Sankyo, Debiopharm, ecancer, Foundation Medicine, Janssen, Lilly, Medscape, Merrimack, Pharma Mar, Regeneron, Sanofi, Seattle Genetics and Takeda (all fees to institution). TM reported receiving personal fees, grants or other fees from AbbVie, ACEA Pharma, Alpha Biopharma Co Ltd, Amgen, Amoy Diagnostics Co Ltd, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Blueprint Medicines Corporation, CStone Pharmaceuticals, Daiichi Sankyo, Eisai, Fishawack Facilitate Ltd, geneDecode, Gritstone Oncology Inc, Guardant Health, Hengrui Therapeutics, Ignyta Inc, IQVIA, Incyte Corporation, InMed Medical Communication, Janssen, Lilly, Loxo-Oncology, Lunit Inc, MD Health (Brazil), Medscape/WebMD, Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc, MORE Health, Novartis, OrigiMed, PeerVoice, Physicians' Education Resource, Permanyer SL, Pfizer Inc, PrIME Oncology, Puma Technology Inc, Research to Practice, Roche, Sanofi-Aventis R&D, Takeda, Touch Medical Media, Virtus Medical Group, Yuhan Corporation, AstraZeneca PLC, Hutchison Chi-Med, Sanomics Ltd, Clovis Oncology, SFJ Pharmaceuticals, Xcovery, Curio Science, Inivata, Berry Oncology, G1 Therapeutics Inc and Aurora. PMF received honoraria or consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, Novartis, Janssen, Iteos, Flame, Sanofi, Genentech, F-Star, G1 therapeutics and Surface Oncology; and research funding from AstraZeneca, BMS, Kyowa, Corvus and Novartis. MR reports honoraria for consultancy and lecture roles from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Merck, Mirati, Merck Sharp & Dohme, Novartis and Pfizer. FdM received honoraria or consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Novartis, Takeda, Xcovery and Roche. IA has declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Acquired resistance (AR) to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] blockade is frequent in non-small-cell lung cancer (NSCLC), occurring in a majority of initial responders. Patients with AR may have unique properties of persistent antitumor immunity that could be re-harnessed by investigational immunotherapies. The absence of a consistent clinical definition of AR to PD-(L)1 blockade and lack of uniform criteria for ensuing enrollment in clinical trials remains a major barrier to progress; such clinical definitions have advanced biologic and therapeutic discovery. We examine the considerations and potential controversies in developing a patient-level definition of AR in NSCLC treated with PD-(L)1 blockade. Taking into account the specifics of NSCLC biology and corresponding treatment strategies, we propose a practical, clinical definition of AR to PD-(L)1 blockade for use in clinical reports and prospective clinical trials. Patients should meet the following criteria: received treatment that includes PD-(L)1 blockade; experienced objective response on PD-(L)1 blockade (inclusion of a subset of stable disease will require future investigation); have progressive disease occurring within 6 months of last anti-PD-(L)1 antibody treatment or rechallenge with anti-PD-(L)1 antibody in patients not exposed to anti-PD-(L)1 in 6 months., Competing Interests: Disclosure AJS reports consulting/advising role to J&J and Perceptive Advisors. SJA reports consulting/advising role from Bristol-Myers Squibb, Merck, CBMG, AstraZeneca, Memgen, RAPT, and Venn, Achilles Therapeutics, Celsius, Samyang Biopharma, Glaxo Smith Klein, Amgen, other from Bristol-Myers Squibb, Merck, Rapt, Achilles Therapeutics, Celsius, GlaxoSmithKline, Amgen, grants from Novartis; expenses from Bristol-Myers Squibb, Merck, CBMG, AstraZeneca, Memgen, RAPT, and Venn, Achilles Therapeutics, Celsius, Samyang Biopharma, Glaxo Smith Klein, Amgen, other from Bristol-Myers Squibb, Merck, Rapt, Achilles Therapeutics, Celsius, GlaxoSmithKline, Amgen, grants from Novartis. MMA reports grants and personal fees from Genentech, grants and personal fees from Bristol-Myers Squibb, personal fees from Merck, grants and personal fees from AstraZeneca, grants from Lilly, personal fees from Maverick, personal fees from Blueprint Medicine, personal fees from Syndax, personal fees from Ariad, personal fees from Nektar, personal fees from Gritstone, personal fees from ArcherDx, personal fees from Mirati, personal fees from NextCure, personal fees from EMD Serono. EF reports personal fees from AbbVie, personal fees from Amgen, personal fees from AstraZeneca, personal fees from Bayer, personal fees from Blue Print Medicines, personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers Squibb, personal fees from Eli Lilly, personal fees from GSK, personal fees from Janssen, personal fees from Medscape, personal fees from Merck KGaA, personal fees from Merck Sharp & Dohme, personal fees from Novartis, personal fees from Roche, personal fees from PeerVoice, personal fees from Pfizer, personal fees from prIME Oncology, personal fees from Puma Biotechnology, personal fees from Roche, personal fees from Sanofi Genzyme, personal fees from Springer, personal fees from Takeda, personal fees from TouchIME, grants from Grant for Oncology Innovation (GOI), grants from Fundación Merck Salud, outside the submitted work; and Grífols: Independent Member of the Board. JG reports grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Genentech/Roche, personal fees from Takeda, grants and personal fees from Blueprint, grants and personal fees from Loxo, personal fees from Oncorus, personal fees from Regeneron, personal fees from Pfizer, personal fees from Incyte, grants and personal fees from Novartis, grants and personal fees from Merck, personal fees from Agios, personal fees from Amgen, grants from Array, grants from Tesaro, grants from Moderna, grants from Adaptimmune, grants from Alexo, personal fees from Ironwood Pharmaceuticals, personal fees from Gilead, personal fees from EMD Serono, personal fees from AstraZeneca, personal fees from Mirati. SNG reports personal fees and other from Bristol Myers Squibb, personal fees from Nektar, other from Genentech, other from Ariad/Takeda, other from Iovance Biotherapeutics, during the conduct of the study. FSH reports grants, personal fees and other from Bristol-Myers Squibb, personal fees from Merck, personal fees from EMD Serono, grants, personal fees and other from Novartis, personal fees from Surface, personal fees from Compass Therapeutics, personal fees from Apricity, personal fees from Aduro, personal fees from Sanofi, personal fees from Pionyr, personal fees from 7 Hills Pharma, personal fees from Verastem, personal fees from Torque, personal fees from Rheos, personal fees from Kairos, personal fees from Bicara, from Psioxus Therapeutics, other from Pieris Pharmaceutical, from Zumutor, from Corner Therapeutics, personal fees from Eisai, personal fees from Checkpoint Therapeutics, outside the submitted work; In addition, FSH has a patent Methods for Treating MICA-Related Disorders (#20100111973) with royalties paid, a patent Tumor antigens and uses thereof (#7250291) issued, a patent Angiopoiten-2 Biomarkers Predictive of Anti-immune checkpoint response (#20170248603) pending, a patent Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms (#20160340407) pending, a patent Therapeutic peptides (#20160046716) pending, a patent Therapeutic Peptides (#20140004112) pending, a patent Therapeutic Peptides (#20170022275) pending, a patent Therapeutic Peptides (#20170008962) pending, a patent Therapeutic Peptides Patent number: 9402905 issued, a patent Methods of using pembrolizumab and trebananib pending, a patent Vaccine compositions and methods for restoring NKG2D pathway function against cancers Patent number: 10279021 issued, a patent Antibodies that bind to MHC class I polypeptide-related sequence A Patent number: 10106611 issued, and a patent Anti- galectin antibody biomarkers predictive of anti-immune checkpoint and anti-angiogenesis responses. 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MDH reports personal fees from Merck, personal fees from Genentech/Roche, grants, personal fees and non-financial support from BMS, personal fees and non-financial support from AstraZeneca, personal fees from Mirati, personal fees from Syndax, personal fees and other from Shattuck Labs, personal fees from Nektar, personal fees and other from Immunai, personal fees and other from Arcus, from Eli Lilly, during the conduct of the study; In addition, Dr. Hellmann has a patent A patent filed by Memorial Sloan Kettering related to the use of tumor mutational burden to predict response to immunotherapy (PCT/US2015/062208) licensed to PGDx., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

This is a summary of a research study (known as a clinical trial) called CROWN. The study tested two medicines called lorlatinib and crizotinib in participants with untreated non-small cell lung cancer that had spread to other parts of their body. All those who took part had changes in a gene called ALK, which is involved in cell growth. In total, 296 participants from 23 countries took part. Half the participants took lorlatinib and half took crizotinib. After participants started taking lorlatinib or crizotinib, they were checked regularly to see if their tumors had grown or spread to other parts of their body (known as tumor progression) and to monitor any side effects. After 1 year of treatment, the participants who took lorlatinib were twice as likely to be alive with no tumor growth as the participants who took crizotinib. More participants who took lorlatinib had cancer that shrank (76%) compared with the participants who took crizotinib (58%). This was also true of the participants whose cancer had spread to their brain. The most common side effects in participants who took lorlatinib were increases in the amount of cholesterol and triglycerides (a type of fat) in their blood, swelling, weight gain, nerve damage, unclear thoughts, and diarrhea. Among the participants who took crizotinib, the most common side effects were diarrhea, feeling like you want to throw up, sight problems, swelling, vomiting, changes in liver function, and feeling tired. Overall, the CROWN study showed that fewer participants with advanced ALK+ non-small cell lung cancer died or had tumor growth with lorlatinib compared with crizotinib treatment. ClinicalTrials.gov NCT number: NCT03052608.

Introduction: The Blood First Assay Screening Trial is an ongoing open-label, multicohort study, prospectively evaluating the relationship between blood-based next-generation sequencing (NGS) detection of actionable genetic alterations and activity of targeted therapies or immunotherapy in treatment-naive advanced or metastatic NSCLC. We present data from the ALK-positive cohort., Methods: Patients aged more than or equal to 18 years with stage IIIB or IV NSCLC and ALK rearrangements detected by blood-based NGS using hybrid capture technology (FoundationACT) received alectinib 600 mg twice daily. Asymptomatic or treated central nervous system (CNS) metastases were permitted. Primary end point was investigator-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors version 1.1). Secondary end points were independent review facility-assessed ORR, duration of response, progression-free survival (PFS), overall survival, and safety. Exploratory end points were investigator-assessed ORR in patients with baseline CNS metastases and relationship between circulating biomarkers and response., Results: In total, 2219 patients were screened and blood-based NGS yielded results in 98.6% of the cases. Of these, 119 patients (5.4%) had ALK-positive disease; 87 were enrolled and received alectinib. Median follow-up was 12.6 months (range: 2.6-18.7). Confirmed ORR was 87.4% (95% confidence interval [CI]: 78.5-93.5) by investigator and 92.0% (95% CI: 84.1-96.7) by independent review facility. Investigator-confirmed 12-month duration of response was 75.9% (95% CI: 63.6-88.2). In 35 patients (40%) with baseline CNS disease, investigator-assessed ORR was 91.4% (95% CI: 76.9-98.2). Median PFS was not reached; 12-month investigator-assessed PFS was 78.4% (95% CI: 69.1-87.7). Safety data were consistent with the known tolerability profile of alectinib., Conclusions: These results reveal the clinical application of blood-based NGS as a method to inform clinical decision-making in ALK-positive NSCLC., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Importance: Ensartinib, an oral tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system efficacy for patients with ALK-positive non-small cell lung cancer (NSCLC)., Objective: To compare ensartinib with crizotinib among patients with advanced ALK-positive NSCLC who had not received prior treatment with an ALK inhibitor., Design, Setting, and Participants: This open-label, multicenter, randomized, phase 3 trial conducted in 120 centers in 21 countries enrolled 290 patients between July 25, 2016, and November 12, 2018. Eligible patients were 18 years of age or older and had advanced, recurrent, or metastatic ALK-positive NSCLC., Interventions: Patients were randomized (1:1) to ensartinib, 225 mg once daily, or crizotinib, 250 mg twice daily., Main Outcomes and Measures: The primary end point was blinded independent review committee-assessed progression-free survival (PFS). Secondary end points included systemic and intracranial response, time to central nervous system progression, and overall survival. Efficacy was evaluated in the intent-to-treat (ITT) population as well as a prespecified modified ITT (mITT) population consisting of patients with central laboratory-confirmed ALK-positive NSCLC., Results: A total of 290 patients (149 men [51.4%]; median age, 54 years [range, 25-90 years]) were randomized. In the ITT population, the median PFS was significantly longer with ensartinib than with crizotinib (25.8 [range, 0.03-44.0 months] vs 12.7 months [range, 0.03-38.6 months]; hazard ratio, 0.51 [95% CI, 0.35-0.72]; log-rank P < .001), with a median follow-up of 23.8 months (range, 0-44 months) for the ensartinib group and 20.2 months (range, 0-38 months) for the crizotinib group. In the mITT population, the median PFS in the ensartinib group was not reached, and the median PFS in the crizotinib group was 12.7 months (95% CI, 8.9-16.6 months; hazard ratio, 0.45; 95% CI, 0.30-0.66; log-rank P < .001). The intracranial response rate confirmed by a blinded independent review committee was 63.6% (7 of 11) with ensartinib vs 21.1% (4 of 19) with crizotinib for patients with target brain metastases at baseline. Progression-free survival for patients without brain metastases was not reached with ensartinib vs 16.6 months with crizotinib as a result of a lower central nervous system progression rate (at 12 months: 4.2% with ensartinib vs 23.9% with crizotinib; cause-specific hazard ratio, 0.32; 95% CI, 0.16-0.63; P = .001). Frequencies of treatment-related serious adverse events (ensartinib: 11 [7.7%] vs crizotinib: 9 [6.1%]), dose reductions (ensartinib: 34 of 143 [23.8%] vs crizotinib: 29 of 146 [19.9%]), or drug discontinuations (ensartinib: 13 of 143 [9.1%] vs crizotinib: 10 of 146 [6.8%]) were similar, without any new safety signals., Conclusions and Relevance: In this randomized clinical trial, ensartinib showed superior efficacy to crizotinib in both systemic and intracranial disease. Ensartinib represents a new first-line option for patients with ALK-positive NSCLC., Trial Registration: ClinicalTrials.gov Identifier: NCT02767804.

Although precision medicine has had a mixed impact on the clinical management of patients with advanced-stage cancer overall, for NSCLC, and more specifically for lung adenocarcinoma, the advances have been dramatic, largely owing to the genomic complexity and growing number of druggable oncogene drivers. Furthermore, although tumor tissue is historically the "accepted standard" biospecimen for these molecular analyses, there are considerable innate limitations. Thus, liquid biopsy represents a practical alternative source for investigating tumor-derived somatic alterations. Although data are most robust in NSCLC, patients with other cancer types may also benefit from this minimally invasive approach to facilitate selection of targeted therapies. The liquid biopsy approach includes a variety of methodologies for circulating analytes. From a clinical point of view, plasma circulating tumor DNA is the most extensively studied and widely adopted alternative to tissue tumor genotyping in solid tumors, including NSCLC, first entering clinical practice for detection of EGFR mutations in NSCLC. Since the publication of the first International Association for the Study of Lung Cancer (IASLC) liquid biopsy statement in 2018, several additional advances have been made in this field, leading to changes in the therapeutic decision-making algorithm for advanced NSCLC and prompting this 2021 update. In view of the novel and impressive technological advances made in the past few years, the growing clinical application of plasma-based, next-generation sequencing, and the recent Food and Drug and Administration approval in the United States of two different assays for circulating tumor DNA analysis, IASLC revisited the role of liquid biopsy in therapeutic decision-making in a recent workshop in October 2020 and the question of "plasma first" versus "tissue first" approach toward molecular testing for advanced NSCLC. Moreover, evidence-based recommendations from IASLC provide an international perspective on when to order which test and how to interpret the results. Here, we present updates and additional considerations to the previous statement article as a consensus from a multidisciplinary and international team of experts selected by IASLC., (Copyright © 2021. Published by Elsevier Inc.)

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have improved outcomes in ALK -rearranged (ALK+) non-small-cell lung cancer (NSCLC). However, almost all patients eventually develop progressive disease on first-line ALK TKIs (e.g., crizotinib, alectinib and ceritinib). Brigatinib, a second-generation ALK TKI, may show efficacy in alectinib- and ceritinib-refractory ALK+ NSCLC. We describe the rationale and design of ALTA-2, a Phase II study of brigatinib in patients with locally advanced/metastatic ALK+ NSCLC and documented progressive disease on alectinib or ceritinib. The primary end point is confirmed objective response rate per independent review committee using response evaluation criteria in solid tumors version 1.1. Secondary end points include duration of response, progression-free survival, overall survival, safety and health-related quality of life.

In the global KEYNOTE-042 study (Clinicaltrials.gov, NCT02220894), pembrolizumab significantly improved overall survival (OS) vs chemotherapy in patients with previously untreated programmed death ligand 1 (PD-L1)-positive locally advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations. We present results from patients in KEYNOTE-042 enrolled from China in the global or extension study (NCT03850444; protocol identical to global study). Patients were randomized 1:1 (stratified by ECOG performance status 0 vs 1, squamous vs nonsquamous histology and PD-L1 tumor proportion score [TPS] ≥50% vs 1%-49%) to 35 cycles of pembrolizumab 200 mg every 3 weeks (Q3W) or investigator's choice of 4 to 6 cycles of carboplatin plus paclitaxel or pemetrexed Q3W with optional pemetrexed maintenance for nonsquamous tumors. Primary endpoints were OS in patients with PD-L1 TPS ≥50%, ≥20% or ≥1%. Two hundred sixty-two patients (pembrolizumab, n = 128; chemotherapy, n = 134) were enrolled from China. At data cutoff (February 21, 2020; median follow-up, 33.0 [range, 25.6-41.9] months), pembrolizumab was shown to improve OS vs chemotherapy in patients with PD-L1 TPS ≥50% (hazard ratio [95% CI], 0.63 [0.43-0.94]), TPS ≥20% (0.66 [0.47-0.92]) and TPS ≥1% (0.67 [0.50-0.89]). Grade 3 to 5 treatment-related adverse events occurred less frequently with pembrolizumab vs chemotherapy (19.5% vs 68.8%). In 22 patients who completed 35 cycles of pembrolizumab, objective response rate was 77.3% and median duration of response was 27.6 months. Consistent with the global KEYNOTE-042 study, pembrolizumab improved OS vs chemotherapy in this study of Chinese patients with locally advanced/metastatic NSCLC and PD-L1 TPS ≥1%, supporting first-line pembrolizumab monotherapy for PD-L1-positive advanced/metastatic NSCLC in China., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Tyrosine kinase inhibitors (TKIs) have dramatically changed the clinical prospects of patients with non-small cell lung cancer harboring epidermal growth factor receptor (EGFR)-activating mutations. Despite prolonged disease control and high tumor response rates, all patients eventually progress on EGFR TKI treatment. Here, we review the mechanisms of acquired EGFR TKI resistance, the methods for monitoring its appearance, as well as current and future efforts to define treatment strategies to overcome resistance., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: In the phase 3 CheckMate 078 study, nivolumab showed significant overall survival (OS) benefit and superior tolerability versus docetaxel in a predominantly Chinese patient population with non-small cell lung cancer (NSCLC). However, data on long-term outcomes with immunotherapy in Asian patients are limited. We report 2-year efficacy and safety data., Methods: Patients with advanced/metastatic NSCLC and disease progression after platinum-doublet chemotherapy were randomized 2:1 to nivolumab (3 mg/kg every 2 weeks; n = 338) or docetaxel (75 mg/m 2 every 3 weeks; n = 166) until progression, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was OS; secondary endpoints included progression-free survival, objective response rate, and safety., Results: After 25.9 months minimum follow-up, 21 patients (6 %) remained on nivolumab versus 0 on docetaxel. Median OS was 11.9 months with nivolumab versus 9.5 months with docetaxel (HR: 0.75; 95 % CI: 0.61-0.93); 2-year OS rates were 28 % versus 18 %, respectively. Survival benefits were observed across a variety of predefined subgroups. At 2 years, 39 % and 0 % of responders had ongoing responses with nivolumab and docetaxel, respectively. Grade 3-4 treatment-related adverse events occurred in 12 % of patients with nivolumab versus 47 % with docetaxel, leading to discontinuation in 4 % and 5 % of patients, respectively. No new treatment-related deaths occurred., Conclusion: At 2 years, nivolumab maintained a favorable safety profile and continued to demonstrate superior OS versus docetaxel in this predominantly Chinese patient population with previously treated NSCLC. These data are consistent with long-term outcomes from the global CheckMate 017/057 studies., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Lorlatinib, a third-generation inhibitor of anaplastic lymphoma kinase (ALK), has antitumor activity in previously treated patients with ALK -positive non-small-cell lung cancer (NSCLC). The efficacy of lorlatinib, as compared with that of crizotinib, as first-line treatment for advanced ALK -positive NSCLC is unclear., Methods: We conducted a global, randomized, phase 3 trial comparing lorlatinib with crizotinib in 296 patients with advanced ALK -positive NSCLC who had received no previous systemic treatment for metastatic disease. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included independently assessed objective response and intracranial response. An interim analysis of efficacy was planned after approximately 133 of 177 (75%) expected events of disease progression or death had occurred., Results: The percentage of patients who were alive without disease progression at 12 months was 78% (95% confidence interval [CI], 70 to 84) in the lorlatinib group and 39% (95% CI, 30 to 48) in the crizotinib group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.19 to 0.41; P<0.001). An objective response occurred in 76% (95% CI, 68 to 83) of the patients in the lorlatinib group and 58% (95% CI, 49 to 66) of those in the crizotinib group; among those with measurable brain metastases, 82% (95% CI, 57 to 96) and 23% (95% CI, 5 to 54), respectively, had an intracranial response, and 71% of the patients who received lorlatinib had an intracranial complete response. The most common adverse events with lorlatinib were hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects. Lorlatinib was associated with more grade 3 or 4 adverse events (mainly altered lipid levels) than crizotinib (in 72% vs. 56%). Discontinuation of treatment because of adverse events occurred in 7% and 9% of the patients, respectively., Conclusions: In an interim analysis of results among patients with previously untreated advanced ALK -positive NSCLC, those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib. The incidence of grade 3 or 4 adverse events was higher with lorlatinib than with crizotinib because of the frequent occurrence of altered lipid levels. (Funded by Pfizer; CROWN ClinicalTrials.gov number, NCT03052608.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis., Patients and Methods: Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum-pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points., Results: A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum-pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum-pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67-1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5-31.5) versus 22.5 months (95% CI 20.2-28.8) for osimertinib and platinum-pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18-1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16-0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum-pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum-pemetrexed arm., Conclusions: In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum-pemetrexed, which possibly reflects the high crossover rate of patients from platinum-pemetrexed to osimertinib., Clinical Trials Number: ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981., Competing Interests: Disclosures VAP has declared honorarium from F Hoffman-La Roche; advisory or consultancy fees from Nektar Therapeutics, Astra Zeneca Pharmaceuticals, Arrys Therapeutics, Merck & Co, LOXO Oncology, Araxes Pharma, F. Hoffman–LaRoche Ltd, Janssen Research Foundation, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly & Co, Novartis Pharmaceuticals Corp., Takeda Pharmaceuticals, AbbVie, TRM Oncology, Tesaro, Exelixis, Gritstone, Leeds Biolabs, IDEAYA, Bolt Therapeutics, and G2 Innovation; and research funding from Eli Lilly & Co, Novartis, Merck, Astra Zeneca Pharmaceuticals, F Hoffman-La Roche, Nektar Therapeutics, Janssen, Bristol-Myers Squibb, Checkmate, and Incyte. TSM has declared honoraria from ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, Bayer, Boehringer Ingelheim, Blueprint Medicines Corporation, Bristol-Myers Squibb, Celgene, CStone Pharmaceuticals, Eli Lilly, Fishawack Facilitate, Hengrui Therapeutics, Ignyta, Incyte Corporation, InMed Medical Communication, IQVIA, Janssen, Loxo Oncology, Merck Serono, MSD, MORE Health, Novartis, OncoGenex Pharmaceuticals, OrigiMed, PeerVoice, Pfizer, PrIME Oncology, Roche/Genentech, Sanofi-Aventis R&D, SFJ Pharmaceutical, Takeda Pharmaceuticals HK, Vertex Pharmaceuticals, and Yuhan Corporation; advisory or consultancy fees from ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, Bayer, Boehringer Ingelheim, Blueprint Medicines Corporation, Bristol-Myers Squibb, Celgene, Cirina, CStone Pharmaceuticals, Eli Lilly, Fishawack Facilitate, GeneDecode, Hengrui Therapeutics, Ignyta, Incyte Corporation, InMed Medical Communication, IQVIA, Janssen, Loxo-Oncology, Merck Serono, MSD, MORE Health, Novartis, OncoGenex Pharmaceuticals, OrigiMed, PeerVoice, Pfizer, PrIME Oncology, Roche/Genentech, Sanofi-Aventis R&D, SFJ Pharmaceutical, Takeda Pharmaceuticals HK, Vertex Pharmaceuticals, and Yuhan Corporation; leadership roles for AstraZeneca and Hutchison Chi-Med; research funding from AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, MSD, Novartis, Pfizer, Roche, SFJ, and Xcovery; shareholdings in Hutchison Chi-Med, and Sanomics; stock options in Clearbridge BioMedics (now Biolidics), Loxo-Oncology, OrigiMed, and Virtus Medical Group; and officer or director for AstraZeneca, Hutchison Chi-Med (remunerated), American Society of Clinical Oncology (ASCO), Asian Thoracic Oncology Research Group (ATORG), Chinese Lung Cancer Research Foundation Limited (CLCRF), Chinese Society of Clinical Oncology (CSCO), Hong Kong Cancer Fund (HKCF), Hong Kong Cancer Therapy Society (HKCTS), and International Association for the Study of Lung Cancer (IASLC; term ended on 30/4/19 [non-remunerated]). J-YH has declared honoraria from Roche, AstraZeneca, Bristol-Myers Squibb, MSD, and Takeda; advisory or consultancy fees from AstraZeneca, Bristol-Myers Squibb, MSD, Takeda, Pfizer, Novartis, and Lilly; research funding from Roche, Pfizer, Ono Pharmaceutical, and Takeda. M-JA has declared advisory or consultancy fees from AstraZeneca, MSD, Ono Pharmaceutical, and Lilly; and speaker fees from AstraZeneca, MSD, Ono Pharmaceutical, Lilly, Roche, Alpha Pharmaceutical, and Takeda. SSR has declared honoraria from AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Roche/Genentech, Loxo, Nektar, and Tesaro; advisory or consultancy fees from AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Roche/Genentech, Loxo, Nektar, and Tesaro; and research funding from AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Tesaro, Advaxis, and Takeda. SWK has declared advisory or consultancy fees from AstraZeneca; and research funding from AstraZeneca. FAS has declared advisory or consultancy fees from AstraZeneca; research funding from AstraZeneca; and shareholdings in AstraZeneca. JL has declared honoraria from Roche, AstraZeneca, and Pfizer; and research funding from Roche, Boehringer Ingelheim, Pfizer, and AstraZeneca. HA has declared honoraria from AstraZeneca, Chugai, Pfizer, and Boehringer Ingelheim; and advisory or consultancy fees from AstraZeneca and Pfizer. W-CS has declared travel, accommodation, or expenses from Bristol-Myers Squibb and Boehringer Ingelheim. TJ has declared advisory or consultancy fees from Roche, Bristol-Myers Squibb, Merck, Ignyta, AstraZeneca, Takeda, Boehringer Ingelheim, and Pfizer. MS has declared honoraria from AstraZeneca, Pfizer, Roche, Boehringer Ingelheim, Novartis, Celgene, Takeda, Lilly, Bristol-Myers Squibb, and MSD; advisory or consultancy fees from AstraZeneca, Pfizer, Roche, Boehringer Ingelheim, Novartis, Celgene, Takeda, Lilly, Bristol-Myers Squibb, and MSD; and speaker fees from AstraZeneca, Pfizer, Roche, Boehringer Ingelheim, Novartis, Celgene, Takeda, Lilly, Bristol-Myers Squibb, and MSD. Y-LW has declared honoraria from AstraZeneca, Roche, Eli Lilly, Pfizer, MSD, Bristol-Myers Squibb, and Boehringer Ingelheim; advisory or consultancy fees from AstraZeneca and Roche; and research funding from AstraZeneca and Roche. HM, MM, GL, and YR are employees of and have shareholdings in AstraZeneca. AD, YH, and WSMET have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019)., Patients and Methods: Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety., Results: Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32-0.58; median PFS 34.8 versus 10.9 months crizotinib]. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR 0.67, 95% CI 0.46-0.98). The 5-year OS rate was 62.5% (95% CI 54.3-70.8) with alectinib and 45.5% (95% CI 33.6-57.4) with crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline [HR 0.58 (95% CI 0.34-1.00)] and those without [HR 0.76 (95% CI 0.45-1.26)]. Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed., Conclusions: Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALK-positive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC., Clinical Trials Number: NCT02075840., Competing Interests: Disclosure TM declares a leadership role with Sanonics Ltd, Hutchinson ChiMed and AstraZeneca; honoraria/consulting fees from ACEA Biosciences, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb (BMS), Celgene, Chimed, Cirina, Fishawack Facilitate, Ignyta, Janssen, Lilly, Merck Serono, Merck Sharp & Dohme (MSD), Novartis, OncoGenex, Pfizer, Roche/Genentech, SFJ Pharmaceutical, Takeda and Vertex; and research funding from AstraZeneca, BMS, Clovis Oncology, MSD, Novartis, Pfizer, Roche, SFJ Pharmaceutical and XCovery. DRC declares honoraria/consulting fees from Abbvie, Ariad, Array, Celgene, Clovis Oncology, Eli Lilly, Genoptix, G1 Therapeutics, Novartis, Orion and Roche/Genentech. SMG declares honoraria/consulting fees from Ariad, AstraZeneca, BMS, Pfizer and Roche/Genentech. RR has nothing to disclose. RD declares honoraria/consulting fees from Roche, Pfizer, Novartis, Boehringer-Ingelheim, AstraZeneca, Takeda, Yuhan, XCovery, SeattleGenetics and Celon Pharma. DWK declares non-financial support from Roche for travel to meetings for the study, and provision of writing assistance, medicines, equipment or administrative support; and non-financial support from Amgen and Daiichi-Sankyo for travel to advisory meetings. His institution has received funding from Alpha Biopharma, AstraZeneca/Medimmune, Boehringer-Ingelheim, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, XCovery and Yuhan. MP declares honoraria/consulting fees from Roche/Genentech, Pfizer, Eli Lilly, Boehringer-Ingelheim, Clovis Oncology, MSD, Chugai, BMS, Amgen, Novartis, Pierre Fabre, AstraZeneca and Takeda; and institutional grants for clinical/translational research from Roche, AstraZeneca, Chugai and Takeda. SHIO declares honoraria/consultancy fees from ARIAD, AstraZeneca, Pfizer, Roche/Genentech and TP Therapeutics; speakers' bureau participation for ARIAD, AstraZeneca and Roche/Genentech; research funding from ARIAD, AstraZeneca, Daiichi Sankyo, Pfizer and Roche/Genentech; and stock ownership in TP Therapeutics. JSA declares honoraria from Pfizer, AstraZeneca, Menarini, Roche, Eisai, Boehringer-Ingelheim, BMS-Ono, MSD, Janssen, Samsung Bioepis, Takeda and Amgen. ATS is currently an employee of Novartis and has received honoraria or consulting fees from F. Hoffmann La-Roche Ltd, Genentech, Pfizer, Novartis, Ariad, Ignyta, Daiichi-Sankyo, Taiho, Blueprint medicines, LOXO, EMD Serono and Foundation medicine. WB, VS, MH, JN and TR are employees of F. Hoffmann-La Roche Ltd. SP declares educational grants or honoraria for advisory board attendance and/or lectures from Abbvie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer-Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Roche, Foundation Medicine, Illumina, Janssen, MSD, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics and Takeda., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 editing of immune checkpoint genes could improve the efficacy of T cell therapy, but the first necessary undertaking is to understand the safety and feasibility. Here, we report results from a first-in-human phase I clinical trial of CRISPR-Cas9 PD-1-edited T cells in patients with advanced non-small-cell lung cancer (ClinicalTrials.gov NCT02793856). Primary endpoints were safety and feasibility, and the secondary endpoint was efficacy. The exploratory objectives included tracking of edited T cells. All prespecified endpoints were met. PD-1-edited T cells were manufactured ex vivo by cotransfection using electroporation of Cas9 and single guide RNA plasmids. A total of 22 patients were enrolled; 17 had sufficient edited T cells for infusion, and 12 were able to receive treatment. All treatment-related adverse events were grade 1/2. Edited T cells were detectable in peripheral blood after infusion. The median progression-free survival was 7.7 weeks (95% confidence interval, 6.9 to 8.5 weeks) and median overall survival was 42.6 weeks (95% confidence interval, 10.3-74.9 weeks). The median mutation frequency of off-target events was 0.05% (range, 0-0.25%) at 18 candidate sites by next generation sequencing. We conclude that clinical application of CRISPR-Cas9 gene-edited T cells is generally safe and feasible. Future trials should use superior gene editing approaches to improve therapeutic efficacy.

Background: This study assesses different technologies for detecting epidermal growth factor receptor (EGFR) mutations from circulating tumor DNA in patients with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC) from the AURA3 study (NCT02151981), and it evaluates clinical responses to osimertinib and platinum-pemetrexed according to the plasma T790M status., Methods: Tumor tissue biopsy samples were tested for T790M during screening with the cobas EGFR Mutation Test (cobas tissue). Plasma samples were collected at screening and at the baseline and were retrospectively analyzed for EGFR mutations with the cobas EGFR Mutation Test v2 (cobas plasma), droplet digital polymerase chain reaction (ddPCR; Biodesix), and next-generation sequencing (NGS; Guardant360, Guardant Health)., Results: With cobas tissue test results as a reference, the plasma T790M positive percent agreement (PPA) was 51% (110 of 215 samples) by cobas plasma, 58% (110 of 189) by ddPCR, and 66% (136 of 207) by NGS. Plasma T790M detection was associated with a larger median baseline tumor size (56 mm for T790M-positive vs 39 mm for T790M-negative; P < .0001) and the presence of extrathoracic disease (58% for M1b-positive vs 39% for M0-1a-positive; P = .002). Progression-free survival (PFS) was prolonged in randomized patients (tissue T790M-positive) with a T790M-negative cobas plasma result in comparison with those with a T790M-positive plasma result in both osimertinib (median, 12.5 vs 8.3 months) and platinum-pemetrexed groups (median, 5.6 vs 4.2 months)., Conclusions: PPA was similar between ddPCR and NGS assays; both were more sensitive than cobas plasma. All 3 test platforms are suitable for routine clinical practice. In patients with tissue T790M-positive NSCLC, an absence of detectable plasma T790M at the baseline is associated with longer PFS, which may be attributed to a lower disease burden., (© 2019 American Cancer Society.)

Lung cancer is a common cancer associated with high mortality rates worldwide. Unfortunately, it usually presents at a late stage, precluding the chance of curative therapy. The discovery of oncogenic driver mutations in patients with non-small cell lung cancer over the past 20 years has led to new molecular targeted therapies that have dramatically improved treatment efficacy and quality of life. New generations of therapy that target the drug-resistant mutations have also quickly evolved, benefiting patients who are refractory or intolerant to first-line targeted therapy. Eastern patients, from Southeast Asia, Japan and China, are known to have a higher incidence of epidermal growth factor receptor mutation. Therefore, compared with the West, more patients would benefit from these recent advances. In contrast, survival of patients without driver mutations has benefited from advances in novel therapeutics, including the immune checkpoint inhibitors. The current review aims to highlight the recent developments in the management of advanced-stage non-small cell lung cancer and to compare the differences in clinical practice between Eastern and Western countries., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Introduction: At the prior data cutoff (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectinib versus crizotinib in untreated, anaplastic lymphoma kinase (ALK)-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34-0.65, p < 0.001). The median PFS in the alectinib arm was not reached versus 11.1 months with crizotinib. Retrospective analyses suggest that the echinoderm microtubule-associated protein-like 4 gene-ALK variant (EML4-ALK) may influence ALK-inhibitor treatment benefit. We present updated analyses, including exploratory subgroup analysis by EML4-ALK variant, after an additional 10 months' follow-up (cutoff December 1, 2017)., Methods: Patients were randomized to receive twice-daily alectinib, 600 mg, or crizotinib, 250 mg, until disease progression, toxicity, death, or withdrawal. PFS was determined by the investigators. Baseline plasma and tissue biomarker samples were analyzed by using hybrid-capture, next-generation sequencing to determine EML4-ALK variant., Results: Baseline characteristics were balanced. Investigator-assessed PFS was prolonged with alectinib (stratified hazard ratio = 0.43, 95% confidence interval: 0.32-0.58). The median PFS times were 34.8 months with alectinib and 10.9 months with crizotinib. EML4-ALK fusions were detectable in 129 patient plasma samples and 124 tissue samples; variants 1, 2, and 3/ab did not affect PFS, objective response rate, or duration of response. Investigator-assessed PFS was longer for alectinib than for crizotinib across EML4-ALK variants 1, 2, and 3a/b in plasma and tissue. Despite longer treatment duration (27.0 months in the case of alectinib versus 10.8 months in the case of crizotinib), the safety of alectinib compared favorably with that of crizotinib., Conclusion: Alectinib continues to demonstrate superior investigator-assessed PFS versus crizotinib in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

We investigate if PD-L1 expression and other clinical characteristics predict chemoimmunotherapy (CIT) benefits versus chemotherapy in advanced non-small-cell lung cancer. We performed a meta-analysis of randomized controlled trials of CIT versus chemotherapy identified through electronic searches. In seven randomized controlled trials (n = 4170), CIT prolonged progression-free survival over chemotherapy (hazard ratio [HR]: 0.62; 95% CI: 0.58-0.67; p < 0.00001). The treatment benefits differed between PD-L1-high (HR: 0.41; 95% CI: 0.34-0.49) and PD-L1 low (HR: 0.63; 95% CI: 0.55-0.72; interaction-p = 0.00002) and PD-L1-high and PD-L1-negative (HR: 0.72; 95% CI: 0.65-0.80; interaction-p < 0.00001). Similar benefits were observed regardless of gender, EGFR/ALK status and histological subtype. PD-L1 status is predictive of CIT benefit and may assist patient selection and design of future trials.

Objectives: Although dramatic responses to MET inhibitors have been reported in patients with MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC), the impact of these treatments on overall survival in this population is unknown., Methods: We conducted a multicenter retrospective analysis of patients with METex14 NSCLC to determine if treatment with MET inhibitors impacts median overall survival (mOS). Event-time distributions were estimated using the Kaplan-Meier method and compared with the log-rank test. Multivariable Cox models were fitted to estimate hazard ratios., Results: We identified 148 patients with METex14 NSCLC; the median age was 72; 57% were women and 39% were never smokers. Of the 34 metastatic patients who never received a MET inhibitor, the mOS was 8.1 months; those in this group with concurrent MET amplification had a trend toward worse survival compared to cancers without MET amplification (5.2 months vs 10.5 months, P =  0.06). Of the 27 metastatic patients who received at least one MET inhibitor the mOS was 24.6 months. A model adjusting for receipt of a MET inhibitor as first- or second-line therapy as a time-dependent covariate demonstrated that treatment with a MET inhibitor was associated with a significant prolongation in survival (HR 0.11, 95% CI 0.01-0.92, P =  0.04) compared to patients who did not receive any MET inhibitor. Among 22 patients treated with crizotinib, the median progression-free survival was 7.4 months., Discussion: For patients with METex14 NSCLC, treatment with a MET inhibitor is associated with an improvement in overall survival., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: In the randomized phase IIb LUX-Lung 7 trial, afatinib significantly improved progression-free survival (PFS) and time-to-treatment failure vs gefitinib in patients with treatment-naïve epidermal growth factor receptor mutation-positive non-small cell lung cancer. We report post hoc analyses of tolerability-guided dose adjustment for afatinib and summarize the clinical characteristics of patients who continued afatinib/gefitinib beyond initial radiological progression in LUX-Lung 7., Methods: Patients received afatinib 40 mg/day or gefitinib 250 mg/day until investigator-assessed progression or beyond if beneficial. In case of selected treatment-related adverse events (TRAEs), the afatinib dose could be reduced by 10-mg decrements to minimum 20 mg (only dose interruptions were permitted with gefitinib)., Results: All randomized patients were treated (afatinib, n = 160; gefitinib, n = 159). Sixty-three patients had afatinib dose reduction (< 40 mg/day; 47 within first 6 months). Dose reduction decreased TRAE incidence/severity (before vs after; all grade/grade 3: 100.0%/63.5% vs 90.5%/23.8%). There was no evidence of significant difference in PFS for patients who received < 40 mg/day vs ≥ 40 mg/day for the first 6 months [median: 12.8 vs 11.0 months; hazard ratio 1.34 (95% confidence interval 0.90-2.00)]. Twenty-four and 26 patients continued afatinib and gefitinib, respectively, beyond progression in target lesions; median time from nadir of target lesion diameters to initial progression was 6.7 months and 5.6 months. Of these patients, ~ 70% had objective response or non-complete response/non-progressive disease in non-target lesions at initial progression., Conclusions: Protocol-defined dose adjustment of afatinib may allow patients to remain on treatment longer, maximizing clinical benefit even in the presence of radiological progression.

Objectives: With the availability of several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), sequential therapy could potentially render EGFR mutation-positive non-small cell lung cancer a chronic disease in some patients. In this retrospective analysis of EGFR mutation-positive (Del19/L858R) patients receiving first-line afatinib in LUX-Lung 3, 6, and 7, we assessed uptake of, and outcomes following, subsequent therapies including the third-generation EGFR TKI, osimertinib., Methods: Post-progression therapy data were prospectively collected during follow-up. Molecular testing of tumours at progression/discontinuation of afatinib was not mandatory. Duration of subsequent therapies, and survival following osimertinib, were calculated with Kaplan-Meier estimates., Results: Among 553 patients who discontinued first-line afatinib, second-, third- and fourth-line therapy was administered in 394 (71%), 265 (48%), and 156 (28%) patients. The most common post-progression therapy was platinum-based chemotherapy (46%). Thirty-seven patients received subsequent osimertinib, 10 as second-line treatment. Median progression-free survival on afatinib in these 37 patients was 21.9 months. Median duration of osimertinib therapy was 20.2 months; median overall survival was not reached after a median follow-up of 4.7 years., Conclusions: Most patients treated with first-line afatinib received subsequent therapy. Although limited by sample size, enrichment, and a retrospective nature, data from patients who received sequential afatinib and osimertinib are encouraging, warranting further investigation., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Antibodies that target programmed death 1 (PD-1) or its ligand [programmed death ligand 1 (PD-L1)] have become a mainstay of first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC) without targetable genetic alterations. In this review, we summarize results from recent clinical trials that have evaluated the anti-PD-1 antibodies pembrolizumab and nivolumab and the anti-PD-L1 antibodies atezolizumab and durvalumab as first-line treatment as monotherapy and in combination with chemotherapy, other immunotherapies, and antiangiogenesis agents. We discuss factors that may influence treatment selection, including patient baseline clinical and demographic characteristics, tumor histology, and biomarkers such as PD-L1 expression and tumor mutation burden. While immunotherapy has become a central component of first-line treatment of most patients with advanced NSCLC, important questions remain about how treatment should be managed for individual patients., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Data on immuno-oncology agents in Chinese patients are limited despite a need for new therapies. We evaluated the efficacy and safety of nivolumab in a predominantly Chinese patient population with previously treated NSCLC., Methods: CheckMate 078 was a randomized, open-label, phase III clinical trial in patients from China, Russia, and Singapore with squamous or nonsquamous NSCLC that had progressed during/after platinum-based doublet chemotherapy (ClinicalTrials.gov: NCT02613507). Patients with EGFR/ALK alterations were excluded. Patients (N = 504) were randomized 2:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m 2 every 3 weeks), stratified by performance status, tumor histology, and tumor programmed death ligand 1 expression. The primary endpoint was overall survival (OS); secondary endpoints included objective response rate, progression-free survival, and safety., Results: OS was significantly improved with nivolumab (n = 338) versus docetaxel (n = 166); median OS (95% confidence interval): 12.0 (10.4-14.0) versus 9.6 (7.6-11.2) months, respectively; hazard ratio (97.7% confidence interval): 0.68 (0.52-0.90); p = 0.0006. Objective response rate was 17% with nivolumab versus 4% with docetaxel; median duration of response was not reached versus 5.3 months. Minimum follow-up was 8.8 months. The frequency of grade 3 or greater treatment-related adverse events was 10% with nivolumab and 48% with docetaxel., Conclusions: This is the first phase III study in a predominantly Chinese population reporting results with a programmed death 1 inhibitor. In this population with previously treated advanced NSCLC, nivolumab improved OS versus docetaxel. Results were consistent with global CheckMate 017 and 057 studies., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objective: Patients with advanced non-small-cell lung cancer (NSCLC) with an adenocarcinoma component are recommended to undergo epidermal growth factor receptor (EGFR) mutation testing when being considered for EGFR targeted therapy. We conducted an exploratory analysis to inform the clinical utility of EGFR mutation testing in blood cell-free DNA using the cobas ® EGFR Mutation Test v2., Materials and Methods: Two EGFR mutation tests, a tissue-based assay (cobas ® v1) and a tissue- and blood-based assay (cobas ® v2) were used to analyze matched biopsy and blood samples (897 paired samples) from three Asian studies of first-line erlotinib with similar intent-to-treat populations. ENSURE was a phase III comparison of erlotinib and gemcitabine/platinum, FASTACT-2 was a phase III study of gemcitabine/platinum plus erlotinib or placebo, and ASPIRATION was a single-arm phase II study of erlotinib. Agreement statistics were evaluated, based on sensitivity and specificity between the two assays in subgroups of patients with increasing tumor burden., Results: Patients with discordant EGFR (tissue+/plasma-) mutation status achieved longer progression-free and overall survival than those with concordant (tissue+/plasma+) mutation status. Tumor burden was significantly greater in patients with concordant versus discordant mutations. Pooled analyses of data from the three studies showed a sensitivity of 72.1% (95% confidence interval [CI] 67.8-76.1) and a specificity of 97.9% (95% CI 96.0-99.0) for blood-based testing; sensitivity was greatest in patients with larger baseline tumors., Conclusions: Blood-based EGFR mutation testing demonstrated high specificity and good sensitivity, and offers a convenient and easily accessible diagnostic method to complement tissue-based tests. Patients with a discordant mutation status in plasma and tissue, had improved survival outcomes compared with those with a concordant mutation status, which may be due to their lower tumor burden. These data help to inform the clinical utility of this blood-based assay for the detection of EGFR mutations., (Copyright © 2018 Elsevier B.V. All rights reserved.)