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SMARCA4 mutation has emerged as a marker of poor prognosis in lung cancer and has potential predictive value in cancer treatment, but recommendations for which patients require its investigation are lacking. We comprehensively studied SMARCA4 alterations and the clinicopathological significance in a large cohort of immunohistochemically-subtyped non-small cell lung cancer (NSCLC). A total of 1416 patients was studied for the presence of SMARCA4 deficiency by immunohistochemistry (IHC). Thereafter, comprehensive sequencing of tumours was performed for 397 of these patients to study the mutational spectrum of SWI/SNF and SMARCA4 aberrations. IHC evidence of SMARCA4 deficiency was found in 2.9% of NSCLC. Of the sequenced tumours, 38.3% showed aberration in SWI/SNF complex, and 9.3% had SMARCA4 mutations. Strikingly, SMARCA4 aberrations were much more prevalent in large cell carcinoma (LCC) than other histological tumour subtypes. SMARCA4-deficient and SMARCA4-mutated tumours accounted for 40.5% and 51.4% of all LCC, respectively. Multivariable analyses confirmed SMARCA4 mutation was an independent prognostic factor in lung cancer. The immunophenotype of a subset of these tumours frequently showed TTF1 negativity and HepPAR1 positivity. SMARCA4 mutation or its deficiency was associated with positive smoking history and poor prognosis. It also demonstrated mutual exclusion with EGFR mutation. Taken together, the high incidence of SMARCA4 aberrations in LCC may indicate its diagnostic and prognostic value. Our study established the necessity of SMARCA4 IHC in the identification of SMARCA4-aberrant tumours, and this may be of particular importance in LCC and tumours without known driver events., (Copyright © 2024 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

What Is This Summary About?: This summary shows the updated results of an ongoing research study called CROWN that was published in The Lancet Respiratory Medicine in December 2022. In the CROWN study, researchers looked at the effects of two study medicines called lorlatinib and crizotinib. The study included people with advanced non-small-cell lung cancer (NSCLC) that had not been treated previously. All people in the study had cancer cells with changes (known as alterations) in a gene called anaplastic lymphoma kinase , or ALK . This ALK gene is involved in cancer growth. In this updated study, researchers looked at the continued benefit in people who took lorlatinib compared with people who took crizotinib after 3 years., What Did This Study Find?: After 3 years of being observed, people who took lorlatinib were more likely to be alive without their cancer getting worse than people who took crizotinib. At 3 years, 64% of people who took lorlatinib were alive without their cancer getting worse compared with 19% of people who took crizotinib. The cancer was less likely to have spread within or to the brain in people who took lorlatinib than in people who took crizotinib. After 3 years of being observed, 61% of people were still taking lorlatinib and 8% of people were still taking crizotinib. People who took lorlatinib had more severe side effects than people who took crizotinib. However, these side effects were manageable. The most common side effects with lorlatinib were high levels of cholesterol or high levels of triglycerides (a type of fat) in the blood. Life-threatening side effects were seen in 13% of people who took lorlatinib and 8% in crizotinib. Two people who took lorlatinib died because of side effects from lorlatinib., What Do the Results of the Study Mean?: The updated results from the CROWN study showed that a larger percentage of people who took lorlatinib continued to benefit from their treatment after being observed for 3 years compared with those who took crizotinib.

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.

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.

Inflammation in the tumor microenvironment is a complicit and known carcinogenesis driver. Inhibition of IL-1β, one of the most abundant and influential cytokines in the tumor microenvironment, may enhance the efficacy of PD-1. In a post-hoc analysis of phase III cardiovascular CANTOS trial, canakinumab, a monoclonal anti-IL-1β antibody, significantly reduced lung cancer incidence. Immune checkpoint inhibition (ICI) is the standard of care in non-small-cell lung cancer. However, ICI efficacy is heavily impacted by programmed death ligand-1 (PD-L1) status. Most patients with non-small-cell lung cancer have low PD-L1 expression levels. Thus, combinational strategies are needed to improve ICI efficacy and expand its use. Here, we describe the preclinical and clinical evidence to support the combination of IL-1β and PD-1 under investigation in the CANOPY program. The perioperative use of canakinumab with or without PD-1 inhibition in the CANOPY-N trial is described as a potential chemotherapy-free immunotherapy strategy.

Background: Manual evaluation of programmed death ligand 1 (PD-L1) tumour proportion score (TPS) by pathologists is associated with interobserver bias., Objective: This study explored the role of artificial intelligence (AI)-powered TPS analyser in minimisation of interobserver variation and enhancement of therapeutic response prediction., Methods: A prototype model of an AI-powered TPS analyser was developed with a total of 802 non-small cell lung cancer (NSCLC) whole-slide images. Three independent board-certified pathologists labelled PD-L1 TPS in an external cohort of 479 NSCLC slides. For cases of disagreement between each pathologist and the AI model, the pathologists were asked to revise the TPS grade (<1%, 1%-49% and ≥50%) with AI assistance. The concordance rates among the pathologists with or without AI assistance and the effect of the AI-assisted revision on clinical outcome upon immune checkpoint inhibitor (ICI) treatment were evaluated., Results: Without AI assistance, pathologists concordantly classified TPS in 81.4% of the cases. They revised their initial interpretation by using the AI model for the disagreement cases between the pathologist and the AI model (N = 91, 93 and 107 for each pathologist). The overall concordance rate among the pathologists was increased to 90.2% after the AI assistance (P < 0.001). A reduction in hazard ratio for overall survival and progression-free survival upon ICI treatment was identified in the TPS subgroups after the AI-assisted TPS revision., Conclusion: The AI-powered TPS analyser assistance improves the pathologists' consensus of reading and prediction of the therapeutic response, raising a possibility of standardised approach for the accurate interpretation., Competing Interests: Conflict of interest statement S.I.C., S.S., K.P., D.Y., W.J. and C.-Y.O. are employed by Lunit Inc. and has stock/stock options in Lunit Inc., and M.M., S.P., S.P. and B.J.A. are employed by Lunit Inc. No other disclosures were reported. The AI model in the study is a prototype model, and the model has developed for academic interest, not for commercialisation., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Biomarkers on the basis of tumor-infiltrating lymphocytes (TIL) are potentially valuable in predicting the effectiveness of immune checkpoint inhibitors (ICI). However, clinical application remains challenging because of methodologic limitations and laborious process involved in spatial analysis of TIL distribution in whole-slide images (WSI)., Methods: We have developed an artificial intelligence (AI)-powered WSI analyzer of TIL in the tumor microenvironment that can define three immune phenotypes (IPs): inflamed, immune-excluded, and immune-desert. These IPs were correlated with tumor response to ICI and survival in two independent cohorts of patients with advanced non-small-cell lung cancer (NSCLC)., Results: Inflamed IP correlated with enrichment in local immune cytolytic activity, higher response rate, and prolonged progression-free survival compared with patients with immune-excluded or immune-desert phenotypes. At the WSI level, there was significant positive correlation between tumor proportion score (TPS) as determined by the AI model and control TPS analyzed by pathologists ( P < .001). Overall, 44.0% of tumors were inflamed, 37.1% were immune-excluded, and 18.9% were immune-desert. Incidence of inflamed IP in patients with programmed death ligand-1 TPS at < 1%, 1%-49%, and ≥ 50% was 31.7%, 42.5%, and 56.8%, respectively. Median progression-free survival and overall survival were, respectively, 4.1 months and 24.8 months with inflamed IP, 2.2 months and 14.0 months with immune-excluded IP, and 2.4 months and 10.6 months with immune-desert IP., Conclusion: The AI-powered spatial analysis of TIL correlated with tumor response and progression-free survival of ICI in advanced NSCLC. This is potentially a supplementary biomarker to TPS as determined by a pathologist., Competing Interests: Sehhoon ParkStock and Other Ownership Interests: Lunit Chan-Young OckEmployment: LunitLeadership: LunitStock and Other Ownership Interests: Lunit, Medpacto, Y-BiologicsConsulting or Advisory Role: Medpacto, Y-Biologics, Idience Sergio PereiraEmployment: LunitStock and Other Ownership Interests: Lunit Seonwook ParkEmployment: LunitStock and Other Ownership Interests: LunitResearch Funding: Lunit Minuk MaEmployment: LunitStock and Other Ownership Interests: Lunit Seunghwan ShinEmployment: LunitStock and Other Ownership Interests: Lunit Jaehong AumEmployment: LunitStock and Other Ownership Interests: Lunit Kyunghyun PaengEmployment: LunitLeadership: LunitStock and Other Ownership Interests: Lunit Donggeun YooEmployment: LunitLeadership: LunitStock and Other Ownership Interests: LunitPatents, Royalties, Other Intellectual Property: Having several patents about medical AI developments in Lunit Inc Se Hyun KimConsulting or Advisory Role: Ono Pharmaceutical Jin Seok AhnHonoraria: Pfizer, Roche, BC World, Yuhan, Hanmi, Novartis, JW Pharmaceutical, Amgen, Boehringer IngelheimConsulting or Advisory Role: Bixink, Bayer, Yooyoung Pharmaceutical Co Ltd, Pharmbio Korea, Vifor Pharma Myung-Ju AhnHonoraria: AstraZeneca, Lilly, MSD, TakedaConsulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Lilly, MSD, Takeda, Alpha Pharmaceutical Keunchil ParkConsulting or Advisory Role: AstraZeneca, Lilly, Ono Pharmaceutical, Bristol Myers Squibb, MSD, Merck KGaA, AbbVie, Daiichi Sankyo, Boehringer Ingelheim, JNJ, Geinus, IMBdxSpeakers' Bureau: Boehringer IngelheimResearch Funding: AstraZeneca, MSD Oncology Sang Yong SongEmployment: AstraZeneca/MedImmuneLeadership: AstraZeneca/MedImmuneStock and Other Ownership Interests: AstraZeneca/MedImmune Yung-Jue BangConsulting or Advisory Role: BeiGene, Green Cross, Merck Serono, AstraZeneca/MedImmune, Novartis, MSD Oncology, Hanmi, Genentech/Roche, Daiichi Sankyo, Astellas Pharma, Bristol Myers Squibb, Samyang, Alexo TherapeuticsResearch Funding: AstraZeneca/MedImmune (Inst), Novartis (Inst), Genentech/Roche (Inst), MSD (Inst), Merck Serono (Inst), Bayer (Inst), GlaxoSmithKline (Inst), Bristol Myers Squibb (Inst), Pfizer (Inst), Lilly (Inst), Ono Pharmaceutical (Inst), Taiho Pharmaceutical (Inst), Takeda (Inst), BeiGene (Inst), Curis (Inst), GC Pharma (Inst), Daiichi Sankyo (Inst), Astellas Pharma (Inst), Genexine (Inst) Yoon-La ChoiResearch Funding: Bayer Tony S. MokEmployment: The Chinese University of Hong KongLeadership: Sanomics Limited, AstraZeneca, Hutchison China Meditech, Aurora Tele-Oncology Platform, LunitStock and Other Ownership Interests: Sanomics Limited, Hutchison China Meditech, Aurora Tele-Oncology PlatformHonoraria: AstraZeneca, 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 Health Inc, 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, Bristol Myers Squibb, CStone Pharmaceuticals, Curio Science, Daiichi Sankyo/UCB Japan, Eisai, Fishawack Facilitate, Gritstone Oncology, 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) Se-Hoon LeeHonoraria: AstraZeneca/MedImmune, Roche, Bristol Myers Squibb, MerckConsulting or Advisory Role: AstraZeneca, Bristol Myers Squibb, RocheResearch Funding: MerckTravel, Accommodations, Expenses: NovartisNo other potential conflicts of interest were reported.

Background: The efficacy of atezolizumab (A) and/or bevacizumab (B) with carboplatin/paclitaxel (CP) chemotherapy was explored in the phase III, randomized IMpower150 study in patients with non-squamous non-small cell lung cancer (NSCLC) according to KRAS mutations (m KRAS ) and co-occurring STK11 , KEAP1, or TP53 mutations., Methods: Mutation status was determined by circulating tumor DNA next-generation sequencing. Overall survival (OS) and progression-free survival (PFS) were analyzed in a mutation-evaluable intention-to-treat population (MEP; n=920) and SP263 (programmed cell death ligand 1 (PD-L1)) biomarker-evaluable population (n=774)., Results: Within the m KRAS population (24.5% of MEP), ABCP showed numerical improvements vs BCP in median OS (19.8 vs 9.9 months; HR 0.50; 95% CI 0.34 to 0.72) and PFS (8.1 vs 5.8 months; HR 0.42; 95% CI 0.29 to 0.61)-greater than with ACP (OS: 11.7 vs 9.9 months; HR 0.63; 95% CI 0.43 to 0.91; PFS: 4.8 vs 5.8 months; HR 0.80; 95% CI 0.56 to 1.13) vs BCP. Across PD-L1 subgroups in m KRAS patients, OS and PFS were longer with ABCP vs BCP, but OS with ACP was similar to BCP in PD-L1-low and PD-L1-negative subgroups. Conversely, in KRAS -WT patients, OS was longer with ACP than with ABCP or BCP across PD-L1 subgroups. KRAS was frequently comutated with STK11 , KEAP1, and TP53 ; these subgroups conferred different prognostic outcomes. Within the m KRAS population, STK11 and/or KEAP1 mutations were associated with inferior OS and PFS across treatments compared with STK11 -WT and/or KEAP 1-WT. In m KRAS patients with co-occurring m STK11 and/or m KEAP1 (44.9%) or m TP53 (49.3%), survival was longer with ABCP than with ACP or BCP., Conclusions: These analyses support previous findings of mutation of STK11 and/or KEAP1 as poor prognostic indicators. While clinical efficacy favored ABCP and ACP vs BCP in these mutational subgroups, survival benefits were greater in the m KRAS and KEAP1 -WT and STK11 -WT population vs m KRAS and m KEAP1 and m STK11 population, suggesting both prognostic and predictive effects. Overall, these results suggest that atezolizumab combined with bevacizumab and chemotherapy is an efficacious first-line treatment in metastatic NSCLC subgroups with m KRAS and co-occurring STK11 and/or KEAP1 or TP53 mutations and/or high PD-L1 expression., Competing Interests: Competing interests: FC reports nonfinancial support from Roche/Genentech during the conduct of the study and personal fees from Roche/Genentech, AstraZeneca, Takeda, Pfizer, Bristol Myers Squibb, Merck Sharp & Dohme, Lilly, and Bayer, outside the submitted work. RMJ reports nonfinancial support from Roche/Genentech during the conduct of the study and personal fees from Bristol Myers Squibb and Roche/Genentech, outside the submitted work. EK reports stock ownership from Genentech Inc outside the submitted work and employment by Genentech. MM reports other from Roche/Genentech outside the submitted work and employment by Roche/Genentech. TSKM reports personal fees from Abbvie, InMed Medical Communication, MD Health (Brazil), Medscape/WebMD, MoreHealth, PeerVoice, Physicians' Education Resource, P. Permanyer SL, PrIME Oncology, Research to Practice, Touch Medical Media, Curio Science, Inivata, and Berry Oncology. He reports personal fees and other from ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, Blueprint Medicines, CStone Pharmaceuticals, Daiichi Sankyo, Eisai, Fishawack Facilitate, Gritstone Oncology, Guardant Health, Hengrui Therapeutics, Ignyta, IQVIA, Incyte, Janssen, Lilly, Loxo-Oncology, Lunit, Mirati Therapeutics, OrigiMed, Puma Technology, Roche, Sanofi-Aventis R&D, Takeda, and Yuhan. He reports grants from Clovis Oncology, SFJ Pharmaceuticals, and XCovery; grants and personal fees from G1 Therapeutics; and grants, personal fees, and other from AstraZeneca, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, and Pfizer. He reports other from Aurora, Virtus Medical Group, AstraZeneca, Hutchison Chi-Med, Sanomics, and geneDecode, outside the submitted work. SM reports employment by and stock ownership in F. Hoffmann-La Roche. MN reports grants and personal fees from Ono Pharmaceutical, Bristol Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Merck Sharp & Dohme, Novartis, Daiichi Sankyo, and Takeda Pharmaceutical Company; and personal fees from Boehringer-Ingelheim, Merck Biopharma, Teijin Pharma, and AbbVie, outside the submitted work. MR reports personal fees from Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Lilly, Merck, Mirati, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Bioepis, outside the submitted work. DS reports employment by Genentech and stock ownership in F. Hoffmann-La Roche. MDT reports employment by Genentech and stock ownership in F. Hoffmann-La Roche. GS reports previous employment by Genentech. MAS reports nonfinancial support from Roche/Genentech during the conduct of the study; grants and personal fees from Roche/Genentech and AstraZeneca; personal fees from Merck, Guardant, Bristol Myers Squibb, and Bayer; and grants from Novartis, outside the submitted work. HJW reports personal fees from Genentech/Roche, AstraZeneca, Merck, Takeda, and Bristol Myers Squibb, outside the submitted work. WZ reports employment by Genentech., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To compare efficacy and safety of dacomitinib versus gefitinib as first-line therapy for EGFR mutation-positive advanced NSCLC in Asian patients enrolled in the ongoing ARCHER 1050 trial., Materials and Methods: In this ongoing, randomized, open-label, phase 3 trial (NCT01774721), eligible patients with newly diagnosed advanced EGFR mutation-positive NSCLC were randomized (1:1) to receive oral dacomitinib 45 mg/day or oral gefitinib 250 mg/day. Randomization, by a central computer system, was stratified by race and EGFR mutation type (exon 19 deletion mutation/exon 21 L858R substitution mutation). The primary endpoint was PFS by blinded independent review., Results: Of 346 Asian patients, 170 were randomized to dacomitinib and 176 to gefitinib. The hazard ratio (HR) for PFS with dacomitinib versus gefitinib was 0.509 (95 % confidence interval [CI]: 0.391-0.662; 1-sided p < 0.0001; median 16.5 months [95 % CI: 12.9-18.4] vs. 9.3 months [95 % CI: 9.2-11.0]). HR for OS with dacomitinib versus gefitinib was 0.759 (95 % CI: 0.578-0.996; median 37.7 months [95 % CI: 30.2-44.7] vs. 29.1 months [95 % CI: 25.6-36.0]). The OS benefit was still maintained in those patients who had a stepwise dose reduction of dacomitinib (to 30 and 15 mg/day). The most common adverse events (AEs) were diarrhea (154 [90.6 %] patients), paronychia (110 [64.7 %]), dermatitis acneiform (96 [56.5 %]), and stomatitis (87 [51.2 %]) with dacomitinib, and diarrhea (100 [56.8 %]), alanine aminotransferase increased (81 [46.0 %]), and aspartate aminotransferase increased (75 [42.6 %]) with gefitinib. Treatment-related serious AEs were reported in 16 (9.4 %) and 8 (4.5 %) patients treated with dacomitinib and gefitinib, respectively., Conclusion: First-line dacomitinib was associated with significant prolongation of PFS and improved OS compared with gefitinib in Asian patients with EGFR mutation-positive advanced NSCLC. The AE profiles of dacomitinib and gefitinib in Asian patients were consistent with the overall ARCHER 1050 population., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Canakinumab is a human IgGκ monoclonal antibody, with high affinity and specificity for IL-1β. The Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS) trial, evaluating canakinumab for cardiovascular disease, provided the first signal of the potential of IL-1β inhibition on lung cancer incidence reduction. Here, we describe the rationale and design for CANOPY-N, a randomized Phase II trial evaluating IL-1β inhibition with or without immune checkpoint inhibition as neoadjuvant treatment in patients with non-small-cell lung cancer. Patients with stage IB to IIIA non-small-cell lung cancer eligible for complete resection will receive canakinumab or pembrolizumab as monotherapy, or in combination. The primary end point is major pathological response by central review; secondary end points include overall response rate, major pathological response (local review), surgical feasibility rate and pharmacokinetics. Clinical trial registration: NCT03968419 (ClinicalTrials.gov).

Aim: Patient-reported symptoms, functioning and overall quality of life (QoL) were compared between dacomitinib and gefitinib in ARCHER 1050. Patients & methods: Patients (n = 448) with advanced EGFR mutation-positive non-small-cell lung cancer completed the EORTC-QLQ-C30 questionnaire and its lung-specific module, LC-13. Mean scores over time were analyzed using a mixed model for repeated measures. Results: Both treatments showed early improvement in disease-related symptoms that was maintained during treatment. Treatment-related diarrhea and sore mouth decreased following dose reduction with dacomitinib. There were no clinically meaningful changes in functioning and overall QoL in either treatment group. Conclusion: Longer treatment duration, enabled by dose reduction, allowed patients on dacomitinib to improve treatment-related symptoms and maintain functioning and overall QoL for longer than gefitinib.

Background: ARCHER 1050, an ongoing, randomized, open-label, phase III trial of dacomitinib versus gefitinib in newly diagnosed patients with advanced non-small-cell lung cancer (NSCLC) and an EGFR-activating mutation, reported significant improvement in overall survival (OS) with dacomitinib., Objective: This paper reports an updated OS analysis of ARCHER 1050 after an extended follow-up., Patients and Methods: In this multinational, multicenter trial, adults (aged ≥ 18 years or ≥ 20 years in Japan and Korea) with newly diagnosed NSCLC and EGFR mutation (exon 19 deletion or exon 21 L858R substitution), and no history of central nervous system metastases, were randomized 1:1 to receive dacomitinib 45 mg/day (n = 227) or gefitinib 250 mg/day (n = 225). Randomization was stratified by race and EGFR mutation type. An ad hoc updated analysis of OS was conducted at the protocol-defined cut-off of 48 months from first dosing of the last enrolled patient (13 May 2019)., Results: After a median follow-up of 47.9 months, 133 (58.6%) patients had died in the dacomitinib arm and 152 (67.6%) in the gefitinib arm. The hazard ratio (HR) for OS was 0.748 (95% CI 0.591-0.947; two-sided P = 0.0155); median OS was 34.1 months with dacomitinib versus 27.0 months with gefitinib. The HR for OS in patients with dose reduction(s) in the dacomitinib arm (n = 154) compared with all patients in the gefitinib arm was 0.554 (95% CI 0.420-0.730); median OS was 42.5 months for patients with dose reduction(s) in the dacomitinib arm. The most common adverse events were diarrhea (87.7%), paronychia (61.7%), dermatitis acneiform (49.3%), and stomatitis (43.6%) with dacomitinib, and diarrhea (55.8%) and alanine aminotransferase increased (40.2%) with gefitinib., Conclusions: The OS benefit from first-line treatment with dacomitinib versus gefitinib was maintained after extended follow-up in patients with advanced NSCLC with EGFR-activating mutations. CLINICALTRIALS.GOV: NCT01774721 (registered 24 January 2013).

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.)

Aim: We evaluated reasons for dacomitinib dose reduction (DR) and examined adverse event (AE) incidence, key efficacy end points (progression-free survival [PFS]/overall survival [OS]), and pharmacokinetics in dose-reducing patients in the ARCHER 1050 trial. Patients & methods: Newly diagnosed patients with EGFR mutation-positive, advanced non-small-cell lung cancer received oral dacomitinib (45 mg once-daily [QD]), with stepwise toxicity-managing DR (30 and 15 mg QD) permitted. Results: Skin toxicities (62.7%) were the most common DR-leading AEs. The AE incidence and severity decreased following DRs. Initial plasma dacomitinib exposure (45 mg QD) was generally lower in patients remaining at 45 mg QD compared with dose-reducing patients. Median PFS and OS were similar in all dacomitinib-treated patients and dose-reducing patients. Conclusion: Tolerability-guided dose modifications enabled patients to continue with dacomitinib and benefit from PFS/OS improvement. Trial registration number: NCT01774721.

Aim: This pooled safety analysis was conducted to analyze incidence and management of key dacomitinib-associated adverse drug reactions (ADRs). Patients & methods: Patients with EGFR mutation-positive advanced non-small-cell lung cancer who received first-line dacomitinib at the 45 mg/day recommended starting dose were included. ADRs were identified based on reasonable association with EGFR tyrosine kinase inhibitors. Results: Overall, 251/255 patients (98%) experienced ADRs. The most common were diarrhea, rash, stomatitis, nail disorder and dry skin. Dose interruptions and dose reductions were reported in 47 and 52% of patients, respectively. Fewer grade 3 key ADRs were observed following dose reductions. Conclusion: Dacomitinib was generally tolerable. Most reported ADRs were known to be associated with EGFR tyrosine kinase inhibitors and were managed with standard medical management and dose modifications.

Introduction: The phase III randomized PROFILE 1014 study demonstrated superiority of crizotinib to first-line chemotherapy in prolonging progression-free survival (PFS) in previously untreated patients with ALK receptor tyrosine kinase gene (ALK)-positive advanced nonsquamous NSCLC. This result was consistent with that in the smaller subset of East Asian patients in PROFILE 1014. The subsequent study reported here prospectively evaluated crizotinib in a larger East Asian patient population., Methods: In this open-label phase III study (PROFILE 1029), patients were randomized 1:1 to receive orally administered crizotinib 250 mg twice daily continuously (3-week cycles) or intravenously administered chemotherapy (pemetrexed 500 mg/m 2 , plus cisplatin 75 mg/m 2 , or carboplatin [at a dose to produce area under the concentration-time curve of 5-6 mg·min/mL]) every 3 weeks for a maximum of six cycles. PFS confirmed by independent radiology review was the primary end point., Results: Crizotinib significantly prolonged PFS (hazard ratio, 0.402; 95% confidence interval [CI]: 0.286-0.565; p < 0.001). The median PFS was 11.1 months with crizotinib and 6.8 months with chemotherapy. The objective response rate was 87.5% (95% CI: 79.6-93.2%) with crizotinib versus 45.6% (95% CI: 35.8-55.7%) with chemotherapy (p < 0.001). The most common adverse events were increased transaminase levels, diarrhea, and vision disorders with crizotinib and leukopenia, neutropenia, and anemia with chemotherapy. Significantly greater improvements from baseline in patient-reported outcomes were seen in crizotinib-treated versus chemotherapy-treated patients., Conclusions: First-line crizotinib significantly improved PFS, objective response rate, and patient-reported outcomes compared with standard platinum-based chemotherapy in East Asian patients with ALK-positive advanced NSCLC, which is similar to the results from PROFILE 1014. The safety profiles of crizotinib and chemotherapy were consistent with those previously published., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Opinion Statement: Non-small cell lung cancer (NSCLC) harboring epidermal growth receptor (EGFR) mutation has distinct genomic characteristics. Introduction of systemic treatments that specifically targeted actionable EGFR mutations has changed the therapeutic paradigm in this group of patients. Moreover, newer generations of EGFR tyrosine-kinase inhibitors (EGFR-TKIs) with superior pharmacokinetics and pharmacodynamics properties such as dacomitinib and osimertinib, when used in the front-line setting, have shown more favorable treatment outcomes than first-generation EGFR-TKIs. In addition, evolving molecular technologies such as droplet digital polymerase chain reaction (ddPCR) and next-generation sequencing (NGS) has enhanced our understanding towards the genetics and epigenetics in pathogenesis, drug-resistant mechanisms as well as improved diagnostic accuracy and efficacy. On the other hand, the recent development in immunotherapies has pushed anti-cancer treatment to new frontiers in many cancers including lung cancer. While ongoing research are focusing on how benefits of immunotherapy can be potentiated, the combinational use of EGFR-TKIs and checkpoint inhibitors have been shown repeatedly in prior trials to cause significant toxicities. This approach cannot be recommended outside of a clinical trial at this time. Overall, remarkable progresses have opened new therapeutic strategies with which patient survival is further improved. In this review, we shall discuss the latest treatment strategies in EGFR mutation positive NSCLC with a focus on latest evidence, and how advances in molecular diagnostics can play an important role patient management.

The isolation and analysis of circulating cell-free tumor DNA in plasma is a powerful tool with considerable potential to improve clinical outcomes across multiple cancer types, including NSCLC. Assays of this nature that use blood as opposed to tumor samples are frequently referred to as liquid biopsies. An increasing number of innovative platforms have been recently developed that improve not only the fidelity of the molecular analysis but also the number of tests performed on a single specimen. Circulating tumor DNA assays for detection of both EGFR sensitizing and resistance mutations have already entered clinical practice and many other molecular tests - such as detection of resistance mutations for Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase rearrangements - are likely to do so in the near future. Due to an abundance of new evidence, an appraisal was warranted to review strengths and weaknesses, to describe what is already in clinical practice and what has yet to be implemented, and to highlight areas in need of further investigation. A multidisciplinary panel of experts in the field of thoracic oncology with interest and expertise in liquid biopsy and molecular pathology was convened by the International Association for the Study of Lung Cancer to evaluate current available evidence with the aim of producing a set of recommendations for the use of liquid biopsy for molecular analysis in guiding the clinical management of advanced NSCLC patients as well as identifying unmet needs. In summary, the panel concluded that liquid biopsy approaches have significant potential to improve patient care, and immediate implementation in the clinic is justified in a number of therapeutic settings relevant to NSCLC., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: In clinical trials of patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) treated with crizotinib, evaluation of the relationship between the percentage of ALK-positive cells by fluorescence in situ hybridization (FISH)-particularly near the cut-off defining positive status-and clinical outcomes have been limited by small sample sizes., Patients and Methods: Data were pooled from three large prospective trials (one single-arm and two randomized versus chemotherapy) of crizotinib in patients with ALK-positive NSCLC determined by Vysis ALK Break Apart FISH using a cut-off of ≥15% ALK-positive cells. Logistic regression and proportional hazards regression analyses were used to explore the association of percent ALK-positive cells with objective response and progression-free survival (PFS), respectively., Results: Of 11 081 screened patients, 1958 (18%) were ALK positive, 7512 (68%) were ALK negative, and 1540 (14%) were uninformative. Median percentage of ALK-positive cells was 58% in ALK-positive patients and 2% in ALK-negative patients. Of ALK-positive patients, 5% had 15%-19% ALK-positive cells; of ALK-negative patients, 2% had 10%-14% ALK-positive cells. Objective response rate for ALK-positive, crizotinib-treated patients with ≥20% ALK-positive cells was 56% (n = 700/1246), 55% (n = 725/1312) for those with ≥15% ALK-positive cells, and 38% for those with 15%-19% ALK-positive cells (n = 25/66). As a continuous variable, higher percentages of ALK-positive cells were estimated to be associated with larger differences in objective response and PFS between crizotinib and chemotherapy; however, tests for interaction between treatment and percentage of ALK-positive cells were not significant (objective response, P = 0.054; PFS, P = 0.17)., Conclusions: Patients with ALK-positive NSCLC benefit from treatment with crizotinib across the full range of percentage of ALK-positive cells, supporting the clinical utility of the 15% cut-off. The small number of patients with scores near the cut-off warrant additional study given the potential for misclassification of ALK status due to technical or biologic reasons.

Purpose ARCHER 1050, a randomized, open-label, phase III study of dacomitinib versus gefitinib in treatment-naïve patients with advanced non-small-cell lung cancer (NSCLC) and activating mutations in EGFR, reported significant improvement in progression-free survival with dacomitinib. The mature overall survival (OS) analysis for the intention-to-treat population is presented here. Patients and Methods In this multinational, multicenter study, patients age 18 years or older (≥ 20 years in Japan and Korea) who had an Eastern Cooperative Oncology Group performance status of 0 or 1 and newly diagnosed NSCLC with activating mutations in EGFR (exon 19 deletion or exon 21 L858R) were enrolled and randomly assigned in a 1:1 manner to dacomitinib (n = 227) or gefitinib (n = 225). Random assignment was stratified by race (Japanese, Chinese, other East Asian, or non-Asian) and EGFR mutation type. The final OS analysis was conducted with a data cutoff date of February 17, 2017; at that time 220 deaths (48.7%) were observed. Results During a median follow-up time of 31.3 months, 103 (45.4%) and 117 (52.0%) deaths occurred in the dacomitinib and gefitinib arms, respectively. The estimated hazard ratio for OS was 0.760 (95% CI, 0.582 to 0.993; two-sided P = .044). The median OS was 34.1 months with dacomitinib versus 26.8 months with gefitinib. The OS probabilities at 30 months were 56.2% and 46.3% with dacomitinib and gefitinib, respectively. Preliminary subgroup analyses for OS that are based on baseline characteristics were consistent with the primary OS analysis. Conclusion In patients with advanced NSCLC and EGFR activating mutations, dacomitinib is the first second-generation epidermal growth factor receptor tyrosine kinase inhibitor (TKI) to show significant improvement in OS in a phase III randomized study compared with a standard-of-care TKI. Dacomitinib should be considered one of the standard treatment options for these patients.

Purpose The phase III PROFILE 1014 trial compared crizotinib with chemotherapy as first-line treatment in patients with anaplastic lymphoma kinase (ALK) -positive advanced nonsquamous non-small-cell lung cancer. Here, we report the final overall survival (OS) results. Patients and Methods Patients were randomly assigned to receive oral crizotinib 250 mg twice daily (n = 172) or intravenous pemetrexed 500 mg/m 2 plus cisplatin 75 mg/m 2 or carboplatin (area under the concentration-time curve of 5 to 6 mg·mL/min) every 3 weeks for a maximum of six cycles (n = 171). Crossover to crizotinib was permitted after disease progression. OS was analyzed using a stratified log-rank test and a prespecified rank-preserving structural failure time model to account for crossover. Results Median follow-up duration for OS was approximately 46 months for both arms. In the chemotherapy arm, 144 patients (84.2%) received crizotinib in subsequent lines. Hazard ratio for OS was 0.760 (95% CI, 0.548 to 1.053; two-sided P = .0978). Median OS was not reached (NR) with crizotinib (95% CI, 45.8 months to NR) and 47.5 months with chemotherapy (95% CI, 32.2 months to NR). Survival probability at 4 years was 56.6% (95% CI, 48.3% to 64.1%) with crizotinib and 49.1% (95% CI, 40.5% to 57.1%) with chemotherapy. After crossover adjustment, there was an improvement in OS that favored crizotinib (hazard ratio, 0.346; 95% bootstrap CI, 0.081 to 0.718). The longest OS was observed in crizotinib-treated patients who received a subsequent ALK tyrosine kinase inhibitor. No new safety signals were identified. Conclusion The final analysis of the PROFILE 1014 study provides a new benchmark for OS in patients with ALK-rearranged non-small-cell lung cancer and highlights the benefit of crizotinib for prolonging survival in this patient population.

Epidermal growth factor receptor (EGFR)-mutation-positive non-smallcell lung cancer (NSCLC) is incurable, despite high rates of response to EGFR tyrosine kinase inhibitors (TKIs). We investigated receptor tyrosine kinases (RTKs), Src family kinases and focal adhesion kinase (FAK) as genetic modifiers of innate resistance in EGFR-mutation-positive NSCLC. We performed gene expression analysis in two cohorts (Cohort 1 and Cohort 2) of EGFR-mutation-positive NSCLC patients treated with EGFR TKI. We evaluated the efficacy of gefitinib or osimertinib with the Src/FAK/Janus kinase 2 (JAK2) inhibitor, TPX0005 in vitro and in vivo. In Cohort 1, CUB domain-containing protein-1 (CDCP1) was an independent negative prognostic factor for progression-free survival (hazard ratio of 1.79, p=0.0407) and overall survival (hazard ratio of 2.23, p=0.0192). A two-gene model based on AXL and CDCP1 expression was strongly associated with the clinical outcome to EGFR TKIs, in both cohorts of patients. Our preclinical experiments revealed that several RTKs and non-RTKs, were up-regulated at baseline or after treatment with gefitinib or osimertinib. TPX-0005 plus EGFR TKI suppressed expression and activation of RTKs and downstream signaling intermediates. Co-expression of CDCP1 and AXL is often observed in EGFR-mutation-positive tumors, limiting the efficacy of EGFR TKIs. Co-treatment with EGFR TKI and TPX-0005 warrants testing., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Front-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) therapy is the standard of care for lung cancer patients with sensitising EGFR mutations (exon 19 deletion or L858R mutation). Several phase III studies have demonstrated the superiority of gefitinib, erlotinib (first generation of TKIs) or afatinib (second generation) to chemotherapy in progression-free survival and response rates. Drug-related toxicities, such as diarrhoea, acneiform skin rash, mucositis, and paronychia, are frequently encountered in patients who receive EGFR TKIs. Other rare side-effects, such as hepatic impairment and interstitial lung disease, should be identified early and managed carefully. Patients with uncommon EGFR mutations, such as G719X, S768I, and L861Q, may require special selection of EGFR TKIs. The combination of erlotinib plus bevacizumab has been accepted in certain parts of the world as an alternative front-line treatment. This review article summarizes the studies leading to the establishment of EGFR TKIs in EGFR-mutant lung cancer patients. The side-effect profiles of the current EGFR TKIs in these large trials are listed, and the management of uncommon EGFR mutations is discussed. Finally, the potential role of combination front-line treatment is discussed.

Background: Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor. We compared its efficacy and safety with that of the reversible EGFR tyrosine kinase inhibitor gefitinib in the first-line treatment of patients with advanced EGFR-mutation-positive non-small-cell lung cancer (NSCLC)., Methods: In this international, multicentre, randomised, open-label, phase 3 study (ARCHER 1050), we enrolled adults (aged ≥18 years or ≥20 years in Japan and South Korea) with newly diagnosed advanced NSCLC and one EGFR mutation (exon 19 deletion or Leu858Arg) at 71 academic medical centres and university hospitals in seven countries or special administrative regions. We randomly assigned participants (1:1) to receive oral dacomitinib 45 mg/day (in 28-day cycles) or oral gefitinib 250 mg/day (in 28-day cycles) until disease progression or another discontinuation criterion was met. Randomisation, stratified by race and EGFR mutation type, was done with a computer-generated random code assigned by a central interactive web response system. The primary endpoint was progression-free survival assessed by masked independent review in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT01774721, and is ongoing but no longer recruiting patients., Findings: Between May 9, 2013, and March 20, 2015, 452 eligible patients were randomly assigned to receive dacomitinib (n=227) or gefitinib (n=225). Median duration of follow-up for progression-free survival was 22·1 months (95% CI 20·3-23·9). Median progression-free survival according to masked independent review was 14·7 months (95% CI 11·1-16·6) in the dacomitinib group and 9·2 months (9·1-11·0) in the gefitinib group (hazard ratio 0·59, 95% CI 0·47-0·74; p<0·0001). The most common grade 3-4 adverse events were dermatitis acneiform (31 [14%] of 227 patients given dacomitinib vs none of 224 patients given gefitinib), diarrhoea (19 [8%] vs two [1%]), and raised alanine aminotransferase levels (two [1%] vs 19 [8%]). Treatment-related serious adverse events were reported in 21 (9%) patients given dacomitinib and in ten (4%) patients given gefitinib. Two treatment-related deaths occurred in the dacomitinib group (one related to untreated diarrhoea and one to untreated cholelithases/liver disease) and one in the gefitinib group (related to sigmoid colon diverticulitis/rupture complicated by pneumonia)., Interpretation: Dacomitinib significantly improved progression-free survival over gefitinib in first-line treatment of patients with EGFR-mutation-positive NSCLC and should be considered as a new treatment option for this population., Funding: SFJ Pharmaceuticals Group and Pfizer., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: The extent to which intratumoral heterogeneity of programmed death ligand 1 (PD-L1) expression causes discordance of PD-L1 expression between paired samples remains unclear. Here, PD-L1 status was compared between whole sections from NSCLCs and the corresponding tissue microarrays (TMAs) serving as surrogate biopsy specimens., Methods: PD-L1 expression was evaluated by 22C3 immunohistochemistry assay on 190 archival surgical specimens and matched to the TMA results. PD-L1 expression was determined by the tumor proportion score (TPS) and classified as TPS lower than 1%, TPS of 1% to 49%, and TPS of 50% or higher. Agreement statistics were used., Results: The percentage of PD-L1 expression on tumor cells differed greatly between individual TMAs and matched surgical specimens. When PD-L1 TPS was adopted, a total of 36 of 190 discordance cases (18.9%) were observed, with a κ-value of 0.630 between paired samples. The TMAs underestimated or overestimated PD-L1 status in 19 of 36 (52.8%) and 17 of 36 (47.2%) of the matched surgical specimens, respectively (p = 0.118). The discordance rate was much lower in cases with a PD-L1 TPS lower than 1% compared with in cases with a TPS of 1% to 49% and TPS of 50% or higher (18.4% versus 56.7% and 43.3%, p < 0.001). When a TPS of 50% or higher was used as the cutoff, the discordance rate of PD-L1 TPS less than 50% was further reduced to 7.5%. Such discrepancies were due mainly to intratumoral heterogeneity of PD-L1 expression and nonsignificant association with clinicopathological features., Conclusions: PD-L1 expression in TMAs correlates moderately well with that in the corresponding surgical specimens, indicating that evaluating PD-L1 expression in diagnostic biopsy specimens could be misleading in defining sensitivity to pembrolizumab treatment yet may be reliable as a way to exclude patients with a PD-L1 TPS less than 50% from first-line pembrolizumab treatment., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown., Methods: In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during receipt of first-line EGFR-TKI therapy. The primary end point was investigator-assessed progression-free survival., Results: The median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the central nervous system (CNS), the median duration of progression-free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%)., Conclusions: Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced non-small-cell lung cancer (including those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy. (Funded by AstraZeneca; AURA3 ClinicalTrials.gov number, NCT02151981 .).

Objective: The Phase III, randomized, open-label IPASS study (NCT00322452) of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) gefitinib versus carboplatin/paclitaxel for Asian patients with advanced non-small-cell lung cancer (NSCLC) showed that investigator-assessed progression-free survival (PFS) and objective response rate (ORR) were significantly prolonged in patients with EGFR mutation-positive NSCLC who received gefitinib versus patients with EGFR mutation-negative NSCLC. We report post-hoc analyses of IPASS data by blind independent central review (BICR), performed at the request of the US FDA, in a subset of patients with EGFR mutation-positive NSCLC., Patients and Methods: Eligible patients (aged ≥18 years; histologically/cytologically confirmed Stage IIB/IV adenocarcinoma NSCLC; non- or former light-smokers; treatment-naïve) were randomly assigned 1:1 to gefitinib (250mg/day) or carboplatin (dose calculated to produce an area under the curve of 5 or 6 mg/mL/minute)/paclitaxel (200mg/m 2 ). Primary endpoint: PFS. BICR analyses included PFS, ORR, and duration of response (DoR)., Results: Scans from 186 IPASS patients (gefitinib n=88, carboplatin/paclitaxel n=98) with EGFR mutation-positive NSCLC were available for BICR. Consistent with investigator-assessed results, in patients with EGFR mutation-positive NSCLC: PFS (hazard ratio 0.54; 95% confidence interval [CI] 0.38, 0.79; p=0.0012) and ORR (odds ratio 3.00; 95% CI 1.63, 5.54; p=0.0004) were significantly longer with gefitinib versus carboplatin/paclitaxel. The median DoR by BICR was 9.6 months with gefitinib and 5.5 months with carboplatin/paclitaxel., Conclusion: BICR analysis of IPASS data support the original, investigator-assessed results. EGFR mutation-positive status remains a significant predictor of response to first-line TKI therapy., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Intracranial efficacy of first-line crizotinib versus chemotherapy was compared prospectively in the phase III PROFILE 1014 study in ALK-positive non-small-cell lung cancer., Patients and Methods: Patients were randomly assigned to receive crizotinib (250 mg twice daily; n = 172) or chemotherapy (pemetrexed 500 mg/m(2) plus cisplatin 75 mg/m(2) or carboplatin at area under the curve 5 to 6, every 3 weeks for ≤ six cycles; n = 171). Patients with stable treated brain metastases (tBM) were eligible. Intracranial efficacy was assessed at baseline and every 6 or 12 weeks in patients with or without known brain metastases (BM), respectively; intracranial time to tumor progression (IC-TTP; per protocol) and intracranial disease control rate (IC-DCR; post hoc) were measured. The intent-to-treat population was also assessed., Results: Of 343 patients in the intent-to-treat population, 23% had tBM at baseline. A nonsignificant IC-TTP improvement was observed with crizotinib in the intent-to-treat population (hazard ratio [HR], 0.60; P = .069), patients with tBM (HR, 0.45; P = .063), and patients without BM (HR, 0.69; P = .323). Among patients with tBM, IC-DCR was significantly higher with crizotinib versus chemotherapy at 12 weeks (85% v 45%, respectively; P < .001) and 24 weeks (56% v 25%, respectively; P = .006). Progression-free survival was significantly longer with crizotinib versus chemotherapy in both subgroups (tBM present: HR, 0.40; P < .001; median, 9.0 v 4.0 months, respectively; BM absent: HR, 0.51; P < .001; median, 11.1 v 7.2 months, respectively) and in the intent-to-treat population (HR, 0.45; P < .001; median, 10.9 v 7.0 months, respectively)., Conclusion: Compared with chemotherapy, crizotinib demonstrated a significantly higher IC-DCR in patients with tBM. Improvements in IC-TTP were not statistically significant in patients with or without tBM, although sensitivity to detect treatment differences in or between the two subgroups was low., (© 2016 by American Society of Clinical Oncology.)

Mutations in the epidermal growth factor receptor gene (EGFR) represent one of the most frequent "actionable" alterations in non-small cell lung cancer (NSCLC). Typified by high response rates to targeted therapies, EGFR tyrosine kinase inhibitors (TKIs) are now established first-line treatment options and have transformed the treatment paradigm for NSCLC. With the recent breakthrough designation and approval of the third-generation EGFR TKI osimertinib, available systemic and local treatment options have expanded, requiring new clinical algorithms that take into account individual patient molecular and clinical profiles. In this International Association for the Study of Lung Cancer commissioned consensus statement, key pathologic, diagnostic, and therapeutic considerations, such as optimal choice of EGFR TKI and management of brain metastasis, are discussed. In addition, recommendations are made for clinical guidelines and research priorities, such as the role of repeat biopsies and use of circulating free DNA for molecular studies. With the rapid pace of progress in treating EGFR-mutant NSCLC, this statement provides a state-of-the-art review of the contemporary issues in managing this unique subgroup of patients., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Activation of MET oncogene as the result of amplification or activation mutation represents an emerging molecular target for cancer treatment. We comprehensively studied MET alterations and the clinicopathologic correlations in a large cohort of treatment-naïve non-small cell lung carcinoma (NSCLC)., Experimental Design: Six hundred eighty-seven NSCLCs were tested for MET exon 14 splicing site mutation (METΔ14), DNA copy number alterations, and protein expression by Sanger sequencing, FISH, and IHC, respectively., Results: METΔ14 mutation was detected in 2.62% (18/687) of NSCLC. The mutation rates were 2.6% in adenocarcinoma, 4.8% in adenosquamous carcinoma, and 31.8% in sarcomatoid carcinoma. METΔ14 mutation was not detected in squamous cell carcinoma, large cell carcinoma, and lymphoepithelioma-like carcinoma but significantly enriched in sarcomatoid carcinoma (P < 0.001). METΔ14 occurred mutually exclusively with known driver mutations but tended to coexist with MET amplification or copy number gain (P < 0.001). Low-level MET amplification and polysomy might occur in the background of EGFR or KRAS mutation whereas high-level amplification (MET/CEP7 ratio ≥5) was mutually exclusive to the major driver genes except METΔ14. Oncogenic METΔ14 mutation and/or high-level amplification occurred in a total of 3.3% (23/687) of NSCLC and associated with higher MET protein expression. METΔ14 occurred more frequently in older patients whereas amplification was more common in ever-smokers. Both METΔ14 and high-level amplification were independent prognostic factors that predicted poorer survival by multivariable analysis., Conclusions: The high incidence of METΔ14 mutation in sarcomatoid carcinoma suggested that MET inhibition might benefit this specific subgroup of patients. Clin Cancer Res; 22(12); 3048-56. ©2016 AACRSee related commentary by Drilon, p. 2832., (©2016 American Association for Cancer Research.)

Background Video-assisted thoracic surgery (VATS) for major lung resection has undergone major changes from three or four-port approach to the recently possible single-port VATS approach. Outcomes following single-port VATS major lung resection are analyzed to determine safety and efficacy. Methods A prospective database of 150 consecutive patients who underwent single-port VATS major lung resection between March 2012 and January 2014 was reviewed. Patient demographics, perioperative parameters, histopathology, and outcomes up to follow-up of 2 years were analyzed by descriptive and Kaplan-Meier survival statistics. Results Single-port VATS major lung resection was successfully performed in 142 patients (conversion rate 5.3%) for both malignant and benign diseases of the lung. Overall, 130 patients (87%) had nonsmall-cell lung carcinoma (NSCLC), 9 (6%) had other types of primary lung cancer, and the remaining for secondary malignancies and benign diseases. Among the 130 patients with NSCLC, 93 (71.5%) were stage I, 28 were stage II (21.5%), and 9 (7%) were stage III or greater. There was no intraoperative or 30-day mortality. However, one perioperative death occurred on day 49, and another on day 60 postoperatively due to infective causes. The overall 2-year mortality rate for all patients was 3%. The disease-free survival rate for subgroups, stage I NSCLC, and stage II or greater NSCLC were 96 and 83%, respectively. Conclusions Single-port VATS major lung resection for malignant and benign lung diseases is associated with low perioperative morbidity and mortality. Disease-free survival rates for NSCLC are acceptable and comparable with conventional VATS., (Georg Thieme Verlag KG Stuttgart · New York.)

Lung cancer stem cells (LCSCs) play a critical role in lung cancer development, however, it is unknown whether thromboxane synthase (TXS) plays a role in the maintenance of LCSCs stemness. This study aimed to determine the in vivo role of TXS in lung cancer induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a smoking carcinogen. Results showed that ozagrel, a TXS blocker, suppressed NNK-induced lung tumors in mice. The expressions of CD133 and ALDH1A1 were positively associated with TXS. Similar results were observed in human NSCLC tumor samples. NNK significantly stimulated TXS and enhanced the generation of LCSCs, evident by the upregulation of CD133 and ALDH1A1 expression, and the increase in the number and size of tumor spheres. NNK also promoted the expression of LCSC-related molecules including β-catenin and Nanog. All these NNK-mediated effects could be offset by ozagrel. In the colony formation assay, NNK increased whereas ozagrel decreased the number of colonies. Collectively, LCSCs and TXS participate in NNK-induced lung cancer. Our data suggest that TXS is a promising therapeutic target as it is a key molecular in NNK-mediated stemness of LCSCs., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Sorafenib monotherapy has shown benefits in phase II trials as third-/fourth-line treatment in patients with non-small-cell lung cancer (NSCLC)., Methods: The phase III, multinational, double-blind, placebo-controlled Monotherapy admInistration of Sorafenib in patientS wIth nOn-small-cell luNg cancer (MISSION) trial randomized patients with advanced relapsed/refractory NSCLC, following two or three prior treatment regimens, to sorafenib 400 mg twice a day (n = 350) or matching placebo (n = 353) plus best supportive care. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS) and time to progression. Epidermal growth factor receptor and KRAS mutation status was analyzed in archival tumor and/or circulating tumor DNA from blood samples obtained during screening., Results: Median OS was similar in the sorafenib and placebo groups (8.2 versus 8.3 mo; hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.84-1.17; p = 0.47). Median PFS (2.8 versus 1.4 mo; HR, 0.61; 95% CI, 0.51-0.72; p < 0.0001), and time to progression (2.9 versus 1.4 mo; HR, 0.54; 95% CI, 0.45-0.65; p < 0.0001) were significantly greater with sorafenib than with placebo. Among the 89 patients with epidermal growth factor receptor mutations, OS (13.9 versus 6.5 mo; HR, 0.48; 95% CI, 0.30-0.76; p = 0.002) and PFS (2.7 versus 1.4 mo; HR, 0.27; 95% CI, 0.16-0.46; p < 0.001) were significantly higher with sorafenib than placebo. PFS was significantly longer with sorafenib than placebo in patients with either wild-type or mutated KRAS, but OS was similar. Common drug-related adverse events were rash/desquamation, diarrhea, and fatigue, consistent with the safety profile of sorafenib., Conclusions: Third-/fourth-line sorafenib therapy did not significantly increase OS in patients with relapsed/refractory NSCLC, despite significantly increasing PFS., (Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Previous studies have shown that the levels of 15-lipoxygenase 1 (15-LOX-1) and 15-LOX-2 as well as their metabolites 13-S-hydroxyoctadecadienoic acid (13(S)-HODE) and 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) are significantly reduced in smokers with non-small cell lung carcinoma (NSCLC). Furthermore, animal model experiments have indicated that the reduction of these molecules occurs before the establishment of cigarette smoking carcinogen-induced lung tumors, and this suggests roles in lung tumorigenesis. However, the functions of these molecules remain unknown in NSCLC., Methods: NSCLC cells were treated with exogenous 13(S)-HODE and 15(S)-HETE, and then the ways in which they affected cell function were examined. 15-LOX-1 and 15-LOX-2 were also overexpressed in tumor cells to restore these 2 enzymes to generate endogenous 13(S)-HODE and 15(S)-HETE before cell function was assessed., Results: The application of exogenous 13(S)-HODE and 15(S)-HETE significantly enhanced the activity of peroxisome proliferator-activated receptor γ (PPARγ), inhibited cell proliferation, induced apoptosis, and activated caspases 9 and 3. The overexpression of 15-LOX-1 and 15-LOX-2 obviously promoted the endogenous levels of 13(S)-HODE and 15(S)-HETE, which were demonstrated to be more effective in the inhibition of NSCLC., Conclusions: This study has demonstrated that exogenous or endogenous 13(S)-HODE and 15(S)-HETE can functionally inhibit NSCLC, likely by activating PPARγ. The restoration of 15-LOX activity to increase the production of endogenous 15(S)-HETE and 13(S)-HODE may offer a novel research direction for molecular targeting treatment of smoking-related NSCLC. This strategy can potentially avoid side effects associated with the application of synthetic PPARγ ligands., (© 2015 American Cancer Society.)

Background: Optimum management strategies for patients with advanced non-small-cell lung cancer (NSCLC) with acquired resistance to EGFR tyrosine-kinase inhibitors are undefined. We aimed to assess the efficacy and safety of continuing gefitinib combined with chemotherapy versus chemotherapy alone in patients with EGFR-mutation-positive advanced NSCLC with acquired resistance to first-line gefitinib., Methods: The randomised, phase 3, multicentre IMPRESS study was done in 71 centres in 11 countries in Europe and the Asia-Pacific region. Eligible patients were aged at least 18 years with histologically confirmed, chemotherapy-naive, stage IIIB-IV EGFR-mutation-positive advanced NSCLC with previous disease control with first-line gefitinib and recent disease progression (Response Evaluation Criteria in Solid Tumors version 1.1). Participants were randomly assigned (1:1) by central block randomisation to oral gefitinib 250 mg or placebo once daily in tablet form; randomisation did not include stratification factors. All patients also received the platinum-based doublet chemotherapy cisplatin 75 mg/m(2) plus pemetrexed 500 mg/m(2) on the first day of each cycle. After completion of a maximum of six chemotherapy cycles, patients continued their randomly assigned treatment until disease progression or another discontinuation criterion was met. All study investigators and participants were masked to treatment allocation. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The study has completed enrolment, but patients are still in follow-up for overall survival. This trial is registered with ClinicalTrials.gov, number NCT01544179., Findings: Between March 29, 2012, and Dec 20, 2013, 265 patients were randomly assigned: 133 to the gefitinib group and 132 to the placebo group. At the time of data cutoff (May 5, 2014), 98 (74%) patients had disease progression in the gefitinib group compared with 107 (81%) in the placebo group (hazard ratio 0·86, 95% CI 0·65-1·13; p=0·27; median progression-free survival 5·4 months in both groups [95% CI 4·5-5·7 in the gefitinib group and 4·6-5·5 in the placebo group]). The most common adverse events of any grade were nausea (85 [64%] of 132 patients in the gefitinib group and 81 [61%] of 132 patients in the placebo group) and decreased appetite (65 [49%] and 45 [34%]). The most common adverse events of grade 3 or worse were anaemia (11 [8%] of 132 patients in the gefitinib group and five [4%] of 132 patients in the placebo group) and neutropenia (nine [7%] and seven [5%]). 37 (28%) of 132 patients in the gefitinib group and 28 (21%) of 132 patients in the placebo group reported serious adverse events., Interpretation: Continuation of gefitinib after radiological disease progression on first-line gefitinib did not prolong progression-free survival in patients who received platinum-based doublet chemotherapy as subsequent line of treatment. Platinum-based doublet chemotherapy remains the standard of care in this setting., Funding: AstraZeneca., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Most patients with non-small-cell lung cancer tumours that have EGFR mutations have deletion mutations in exon 19 or the Leu858Arg point mutation in exon 21, or both (ie, common mutations). However, a subset of patients (10%) with mutations in EGFR have tumours that harbour uncommon mutations. There is a paucity of data regarding the sensitivity of these tumours to EGFR inhibitors. Here we present data for the activity of afatinib in patients with advanced non-small-cell lung cancer that have tumours harbouring uncommon EGFR mutations., Methods: In this post-hoc analysis, we used prospectively collected data from tyrosine kinase inhibitor-naive patients with EGFR mutation-positive advanced (stage IIIb-IV) lung adenocarcinomas who were given afatinib in a single group phase 2 trial (LUX-Lung 2), and randomised phase 3 trials (LUX-Lung 3 and LUX-Lung 6). Analyses were done in the intention-to-treat population, including all randomly assigned patients with uncommon EGFR mutations. The type of EGFR mutation (exon 19 deletion [del19], Leu858Arg point mutation in exon 21, or other) and ethnic origin (LUX-Lung 3 only; Asian vs non-Asian) were pre-specified stratification factors in the randomised trials. We categorised all uncommon mutations as: point mutations or duplications in exons 18-21 (group 1); de-novo Thr790Met mutations in exon 20 alone or in combination with other mutations (group 2); or exon 20 insertions (group 3). We also assessed outcomes in patients with the most frequent uncommon mutations, Gly719Xaa, Leu861Gln, and Ser768Ile, alone or in combination with other mutations. Response was established by independent radiological review. These trials are registered with ClinicalTrials.gov, numbers NCT00525148, NCT00949650, and NCT01121393., Findings: Of 600 patients given afatinib across the three trials, 75 (12%) patients had uncommon EGFR mutations (38 in group 1, 14 in group 2, 23 in group 3). 27 (71·1%, 95% CI 54·1-84·6) patients in group 1 had objective responses, as did two (14·3%, 1·8-42·8) in group 2 and two (8·7%, 1·1-28·0) in group 3. Median progression-free survival was 10·7 months (95% CI 5·6-14·7) in group 1, 2·9 months (1·2-8·3) in group 2; and 2·7 months (1·8-4·2) in group 3. Median overall survival was 19·4 months (95% CI 16·4-26·9) in group 1, 14·9 months (8·1-24·9) in group 2, and 9·2 months (4·1-14·2) in group 3. For the most frequent uncommon mutations, 14 (77·8%, 95% CI 52·4-93·6) patients with Gly719Xaa had an objective response, as did nine (56·3%, 29·9-80·2) with Leu861Gln, and eight (100·0%, 63·1-100·0) with Ser768Ile., Interpretation: Afatinib was active in non-small-cell lung cancer tumours that harboured certain types of uncommon EGFR mutations, especially Gly719Xaa, Leu861Gln, and Ser768Ile, but less active in other mutations types. Clinical benefit was lower in patients with de-novo Thr790Met and exon 20 insertion mutations. These data could help inform clinical decisions for patients with non-small-cell lung cancer harbouring uncommon EGFR mutations., Funding: Boehringer Ingelheim., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

ABSTRACT  Rearrangement of ALK gene has been identified as exerting a potent transforming effect as driver oncogene in patients with non-small-cell lung cancer (NSCLC). Crizotinib is a small-molecule oral inhibitor of ALK, c-Met/HGF receptor and ROS1 receptor kinases. Its efficacy in ALK-rearranged NSCLC has been established. Crizotinib's effect on ROS1 receptor kinases and c-Met with relevance to NSCLC is also actively being explored. Resistance mechanisms such as secondary gatekeeper mutations in ALK gene and activation of other oncogenes have been identified to confer acquired resistance to crizotinib. This article reviews the pharmacological properties of crizotinib, preclinical and clinical results that led to its approval in ALK-positive NSCLC and current directions of clinical research in overcoming crizotinib resistance.

Background: This phase II, open-label study investigated intercalated combinations of eribulin and erlotinib in unselected patients with advanced non-small-cell lung cancer previously treated with platinum-based chemotherapies., Patients and Methods: Eligible patients were randomized to eribulin mesylate 2.0 mg/m(2) on day 1 with erlotinib 150 mg on days 2-16 (21-day regimen) or eribulin mesylate 1.4 mg/m(2) on days 1 and 8 with erlotinib 150 mg on days 15-28 (28-day regimen). The primary end point was objective response rate (ORR)., Results: One hundred and twenty-three patients received ≥ 1 cycle of therapy (63, 21-day regimen; 60, 28-day regimen). ORRs were 13% [95% confidence interval (CI) 6%-24%] and 17% (95% CI 8%-29%), and disease control rates were 48% (95% CI 35%-61%) and 63% (95% CI 50%-75%) for the 21- and 28-day regimens, respectively. The median progression-free survival and overall survival were similar with both regimens. Both regimens were well tolerated with common grade ≥ 3 toxicities being neutropenia, asthenia/fatigue, and dyspnoea. Sequential administration of erlotinib did not interfere with the pharmacokinetic profile of eribulin., Conclusion: Intercalated combination of eribulin and erlotinib demonstrated modest activity and the addition of erlotinib did not appear to improve treatment outcome in an unselected population. The 28-day regimen is suitable for further investigation. Clinicaltrials.gov identifier: NCT01104155., (© The Author 2014. 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.)

Background: In IPASS (NCT00322452), progression-free survival (PFS, primary endpoint) was significantly longer with first-line gefitinib versus carboplatin/paclitaxel in never/light ex-smokers with advanced pulmonary adenocarcinoma in Asia, both in the overall intent-to-treat (ITT) population and in the EGFR mutation-positive subgroup. To further characterize the clinical relevance of these data, we investigated objective response rate (ORR) and health-related quality of life (HRQoL) in patients treated with gefitinib., Methods: Objective response was assessed (RECIST) 6-weekly (previously reported). Post hoc assessments included median time to response, median duration of response and change in tumor size. The analysis of response population included those patients treated with gefitinib who responded (n = 262 from ITT; n = 94 from EGFR mutation-positive subgroup). The percentage of patients with deterioration in HRQoL (Functional Assessment of Cancer Therapy-Lung [FACT-L], Trial Outcome Index [TOI]) and symptoms (Lung Cancer Subscale [LCS]) at 4 months post-randomization was analyzed according to progression status (EFQ population grouped by progressors/non-progressors in both treatment arms). The ORR (ITT) and incidence of skin rash/acne (evaluable-for-safety) were summarized., Results: In patients whose tumors responded to gefitinib, median time to response was 6.1 weeks in the ITT population (n = 262) and 6.0 weeks in the EGFR mutation-positive subgroup (n = 94); median duration of response was 9.7 and 8.7 months in these groups, respectively. There was significant tumor shrinkage with gefitinib. A greater percentage of patients in the EFQ population whose tumors progressed experienced deterioration in HRQoL and symptoms at 4 months versus patients whose tumors did not progress (FACT-L 33.7% vs 16.3%; TOI 33.7% vs 13.2%; LCS 31.7% vs 15.5%). In the gefitinib arm of the EFS population, incidence of rash was 75.8% and 68.1% in EGFR mutation-positive and -negative subgroups, respectively (with ORR for the gefitinib arm of the ITT 71.2% vs 1.1%, respectively)., Conclusions: Patients whose tumors responded to first-line gefitinib experienced significant tumor shrinkage and a rapid, durable response. Deterioration in HRQoL and lung cancer symptoms at 4 months post-randomization was found to be associated with tumor progression, highlighting the role of patient-reported outcomes in the evaluation of advanced NSCLC disease. Rash was not supported as a predictive marker of response to gefitinib., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Introduction: The echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) fusion gene has been identified as a potent oncogenic driver in non-small-cell lung cancer, in particular adenocarcinoma (ADC). It defines a unique subgroup of lung ADC, which may be responsive to ALK inhibitors. Detection of ALK rearrangement by fluorescence in situ hybridization (FISH) or reverse transcriptase polymerase chain reaction (RT-PCR) is considered to be the standard procedure, but each with its own limitation. We evaluated the practical usefulness of immunohistochemistry (IHC) to detect ALK expression as a reliable detection method of ALK rearrangement in lung ADC., Methods: We tested 373 lung ADCs for ALK rearrangement by IHC and FISH. Multiplex RT-PCR was performed to confirm the fusion variants., Results: Twenty-two of 373 lung ACs (5.9%) were positive for ALK immunoreactivity. ALK-positive tumor cells demonstrated strong and diffused granular staining in the cytoplasm. All the ALK IHC-positive cases were confirmed to harbor ALK rearrangement, either by FISH, or RT-PCR. Two cases with positive ALK protein expression, but negative for breakapart FISH signal were shown to harbor EML4-ALK variant 1 by RT-PCR. None of the ALK IHC-negative cases were FISH-positive. In addition, we identified a novel EML4-ALK fusion variant (E3:ins53A20), and its potent transformation potential has been confirmed by in vivo tumorigenicity assay., Conclusion: IHC can effectively detect ALK rearrangement in lung cancer. It might provide a reliable and cost-effective diagnostic approach in routine pathologic laboratories for the identification of suitable candidates for ALK-targeted therapy.

Non-small cell lung cancer (NSCLC) tumours with certain mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase have been termed 'oncogene addicted' to reflect their dependence on EGFR-mediated pro-survival signalling and their high susceptibility to apoptosis induced by EGFR tyrosine kinase inhibitors (EGFR-TKIs, e.g. gefitinib and erlotinib). The most common mutations (L858R and exon 19 deletions) predict an improved clinical response to first-line oral EGFR-TKIs compared with standard platinum-based chemotherapy in patients with advanced NSCLC. Moreover, these mutations are also prognostic of a relatively indolent course of disease, regardless of treatment, as compared with classical NSCLC. Treatment strategies for oncogene-addicted NSCLC are therefore distinct from those for non-oncogene addicted NSCLC, and will depend on the specific genetic mutation present., (Copyright © 2011. Published by Elsevier Ltd.)

The epidermal growth factor receptor (EGFR) mutation is the first recognized molecular target in non-small cell lung cancer that makes personalized therapy feasible. This molecular alteration has been demonstrated to be more frequent in Asians, non-smokers and patients with adenocarcinoma histology. Several retrospective and subgroup analyses of phase III trials have shown the single agent, erlotinib, to be associated with higher response rates and longer progression-free survival in patients harbouring an EGFR mutation. Two prospective randomized phase III studies from China and Europe have confirmed the role of first-line erlotinib in patients with the mutations. Erlotinib has also been evaluated in combination with chemotherapy in either a concurrent or intercalated regimen. Earlier trials were limited by little information on the EGFR mutational status of the enrolled patients, and an ongoing phase III trial with translational biomarker analysis will provide more comprehensive data on the combination.