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Introduction: The primary analysis (median follow-up 34.9 months across all arms) of the phase 3 POSEIDON study demonstrated a statistically significant overall survival (OS) improvement with first-line tremelimumab plus durvalumab and chemotherapy (T+D+CT) versus CT in patients with EGFR/ALK-wild-type metastatic NSCLC (mNSCLC). D+CT showed a trend for OS improvement versus CT that did not reach statistical significance. This paper reports prespecified OS analyses after longer-term follow-up (median >5 years)., Methods: 1013 patients were randomized (1:1:1) to T+D+CT, D+CT, or CT, stratified by tumor cell (TC) PD-L1 expression (≥50% vs <50%), disease stage (IVA vs IVB), and histology (squamous vs nonsquamous). Serious adverse events were collected during follow-up., Results: After median follow-up of 63.4 months across all arms, T+D+CT showed sustained OS benefit versus CT (hazard ratio [HR] 0.76, 95% CI: 0.64-0.89; 5-year OS: 15.7% vs 6.8%). OS improvement with D+CT versus CT (HR 0.84, 95% CI: 0.72-1.00; 5-year OS: 13.0%) was consistent with the primary analysis. OS benefit with T+D+CT versus CT remained more pronounced in nonsquamous (HR 0.69, 95% CI: 0.56-0.85) versus squamous (HR 0.85, 95% CI: 0.65-1.10) mNSCLC. OS benefit with T+D+CT versus CT was still evident regardless of PD-L1 expression, including patients with PD-L1 TC <1%, and remained evident in STK11-mutant (nonsquamous), KEAP1-mutant, and KRAS-mutant (nonsquamous) mNSCLC. No new safety signals were identified., Conclusions: After median follow-up of >5 years, T+D+CT showed durable long-term OS benefit versus CT, supporting its use as first-line treatment in mNSCLC, including in patient subgroups with harder-to-treat disease., (Copyright © 2024. Published by Elsevier Inc.)

Background: Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC)., Methods: In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR -mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review., Results: Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR -related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib., Conclusions: Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR -mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.)., (Copyright © 2024 Massachusetts Medical Society.)

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

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

In patients with previously treated advanced or metastatic non-small cell lung cancer (NSCLC), atezolizumab therapy improves survival with manageable safety. The open-label, single-arm phase III/IV TAIL study (NCT03285763) evaluated atezolizumab monotherapy in patients with previously treated NSCLC, including those with Eastern Cooperative Oncology Group performance status of 2, severe renal impairment, prior anti-programmed death 1 therapy, autoimmune disease, and age ≥75 years. Patients received atezolizumab intravenously (1200 mg) every 3 weeks. At data cut-off for final analysis, the median follow-up was 36.1 (range 0.0-42.3) months. Treatment-related (TR) serious adverse events (SAEs) and TR immune-related adverse events (irAEs) were the coprimary endpoints. Secondary endpoints included overall survival (OS), progression-free survival (PFS), overall response rate, and duration of response. Safety and efficacy in key patient subgroups were also assessed. TR SAEs and TR irAEs occurred in 8.0% and 9.4% of patients, respectively. No new safety signals were documented. In the overall population, median OS and PFS (95% CI) were 11.2 months (8.9 to 12.7) and 2.7 months (2.3 to 2.8), respectively. TAIL showed that atezolizumab has a similar risk-benefit profile in clinically diverse patients with previously treated NSCLC, which may guide treatment decisions for patients generally excluded from pivotal clinical trials., Competing Interests: Competing interests: AA reports personal honoraria for lectures from BMS, Astra Zeneca, and MSD; advisory board participation for Roche, Astra Zeneca, BMS, Sanofi, and Eli Lilly. BR-V reports honoraria for educational events for Janssen, MSD, and Bristol-Myers Squibb; advisory board participation for MSD and Takeda. DR-A reports personal and/or other fees from BMS, MSD, Roche/Genentech, Novartis, Astra Zeneca, and Boehringer-Ingelheim. JA-A reports advisory board participation for Astra Zeneca, Roche, MSD, BMS, Takeda, and Pfizer; speaker bureau for Roche, MSD, BMS, Takeda, and Pfizer. HJMS reports payment for expert testimony from BMS for immune-oncology educational website advice; advisory board participation for MSD. EH reports employment by Roche and stockholding in Roche. MK reports employment by Genentech and stockholding in Roche. JT reports former employment by Roche and stockholding in Roche. YH reports employment by Roche and stockholding in Roche. HKV reports employment by Roche and stockholding in Roche. TN-D reports personal consulting fees from Takeda, Pfizer, Roche, Amgen, Astra Zeneca, Bayer, BMS, Boehringer-Ingelheim, Chugai, Janssen, Lilly, Merck, MSD, Novartis, and Otsuka; personal honoraria for lectures/presentations from Takeda, Pfizer, Roche, Amgen, Astra Zeneca, Bayer, BMS, Boehringer-Ingelheim, Chugai, Janssen, Lilly, Merck, MSD, Novartis, and Otsuka; support for attending meetings and/or travel from Astra Zeneca, BMS, Boehringer-Ingelheim, MSD, Roche, and Takeda; chair of the independent monitoring committee for Roche and BluePrint Medicines. SA, JY, and KS report no competing interests., (© 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.)

Background: Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19., Methods: In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov, NCT04421027., Findings: Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of -2·7 percentage points (95% CI -7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41-0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47-0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups., Interpretation: Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19., Funding: Eli Lilly and Company., Translations: For the French, Japanese, Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests VCM received research grants from the US Centers for Disease Control and Prevention (CDC), Gilead Sciences, the US National Institutes of Health (NIH), Veterans Affairs, and ViiV; received honoraria from Eli Lilly and Company; served as an advisory board member for Eli Lilly and Company and Novartis; and participated as a study section chair for the NIH. AVR received research grants from Eli Lilly and Company; and served as a speaker or consultant for AbbVie, Eli Lilly and Company, Novartis, Pfizer, Roche, Sobi, and Union Chimique Belge. SB, CEK, VK, RL, MLBP, AC, SC, BC, PR, XZ, and DHA are employees and shareholders of Eli Lilly and Company. JDG received research support from Eli Lilly and Company, Regeneron Pharmaceuticals, and Gilead Sciences; grants from Eurofins Viracor and the Biomedical Advanced Research and Development Authority (administered by Merck); speaker fees from Eli Lilly and Company, Gilead Sciences, and Mylan Pharmaceuticals; and advisory board fees from Gilead Sciences. JAA served as a speaker and scientific advisor for AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly and Company, Foundation Medicine, Novartis, MSD, Roche, and Takeda. VE received a research grant from Eli Lilly and Company. MS received research grants from Eli Lilly and Company, NIAID, and Novartis; and served as a board member for NBOME, Osteopathic Founders Foundation, and COGMED. EWE received research grants from the CDC, NIH, and Veterans Affairs; and served as an unpaid consultant for Eli Lilly and Company. RDP declares no competing interests, (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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

Background: Atezolizumab treatment improves survival, with manageable safety, in patients with previously treated advanced/metastatic non-small cell lung cancer. The global phase III/IV study TAIL (NCT03285763) was conducted to evaluate the safety and efficacy of atezolizumab monotherapy in a clinically diverse population of patients with previously treated non-small cell lung cancer, including those not eligible for pivotal trials., Methods: Patients with stage IIIB/IV non-small cell lung cancer whose disease progressed after 1-2 lines of chemotherapy were eligible for this open-label, single-arm, multicenter study, including those with severe renal impairment, an Eastern Cooperative Oncology Group performance status of 2, prior anti-programmed death 1 (PD-1) therapy, and autoimmune disease. Atezolizumab was administered intravenously (1200 mg every 3 weeks). Coprimary endpoints were treatment-related serious adverse events and immune-related adverse events., Results: 619 patients enrolled and 615 received atezolizumab. At data cutoff, the median follow-up was 12.6 months (95% CI 11.9 to 13.1). Treatment-related serious adverse events occurred in 7.8% and immune-related adverse events in 8.3% of all patients and as follows, respectively, in these subgroups: renal impairment (n=78), 11.5% and 12.8%; Eastern Cooperative Oncology Group performance status of 2 (n=61), 14.8% and 8.2%; prior anti-PD-1 therapy (n=39), 5.1% and 7.7%; and autoimmune disease (n=30), 6.7% and 10.0%. No new safety signals were reported. In the overall population, the median overall survival was 11.1 months (95% CI 8.9 to 12.9), the median progression-free survival was 2.7 months (95% CI 2.1 to 2.8) and the objective response rate was 11%., Conclusions: This study confirmed the benefit-risk profile of atezolizumab monotherapy in a clinically diverse population of patients with previously treated non-small cell lung cancer. These safety and efficacy outcomes may inform treatment decisions for patients generally excluded from checkpoint inhibitor trials., Competing Interests: Competing interests: Support of the parent study and funding of editorial support were provided by F. Hoffmann-La Roche/Genentech. AA is a consultant to Merck Sharpe & Dohme, AstraZeneca, Bristol Myers Squibb, and F. Hoffmann-La Roche and has received research funding from Bristol Myers Squibb, F. Hoffmann-La Roche, and Celgene and honoraria from Eli Lilly and Pfizer. SA is a consultant to and has received research funding, honoraria, and travel expenses from F. Hoffmann-La Roche, Bristol Myers Squibb, and Celgene, is a consultant to Merck Sharpe & Dohme, and has received research funding, travel expenses, and honoraria from Novartis, Eli Lilly, and AstraZeneca. BRV is a consultant to Merck Sharpe & Dohme and Eli Lilly and has received honoraria and travel expenses from F. Hoffmann-La Roche, Eli Lilly, Bristol Myers Squibb and Merck Sharpe & Dohme. DR-A is an advisor to and has received speaker honoraria from Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck Sharpe & Dohme, F. Hoffmann-La Roche, Pfizer, and AstraZeneca. JA-A is a consultant to, on a speaker bureau for, and has received travel expenses from Merck Sharpe & Dohme, AstraZeneca, Pfizer, Boehringer Ingelheim, Eli Lilly, Novartis, F. Hoffmann-La Roche, and Bristol Myers Squibb. HJMS is a consultant to Merck Sharpe & Dohme, AstraZeneca, and Bristol Myers Squibb and is secretary of the oncology section of NVALT (Dutch lung physician’s organization) and president of the Dutch Lung Cancer Audit. JY has nothing to disclose. KS is on a speaker bureau for Merck Sharpe & Dohme, has received research funding from F. Hoffmann-La Roche and Novartis, has received research funding and travel expenses from Bristol Myers Squibb, and has received travel expenses from Genesis. KT, JT, and AC are employees of F. Hoffmann-La Roche. HP and PP-M are employees of Genentech. TN-D is a consultant to Amgen, Bayer, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck Sharpe & Dohme, Novartis, Otsuka, Pfizer, Roche, and Takeda, and is on a speaker bureau for AstraZeneca, Merck Sharpe & Dohme, F. Hoffmann-La Roche, and Takeda., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: IMpower133 (ClinicalTrials.gov identifier: NCT02763579), a randomized, double-blind, phase I/III study, demonstrated that adding atezolizumab (anti-programmed death-ligand 1 [PD-L1]) to carboplatin plus etoposide (CP/ET) for first-line (1L) treatment of extensive-stage small-cell lung cancer (ES-SCLC) resulted in significant improvement in overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET. Updated OS, disease progression patterns, safety, and exploratory biomarkers (PD-L1, blood-based tumor mutational burden [bTMB]) are reported., Patients and Methods: Patients with untreated ES-SCLC were randomly assigned 1:1 to receive four 21-day cycles of CP (area under the curve 5 mg per mL/min intravenously [IV], day 1) plus ET (100 mg/m 2 IV, days 1-3) with atezolizumab (1,200 mg IV, day 1) or placebo, and then maintenance atezolizumab or placebo until unacceptable toxicity, disease progression, or loss of clinical benefit. Tumor specimens were collected; PD-L1 testing was not required for enrollment. The two primary end points, investigator-assessed PFS and OS, were statistically significant at the interim analysis. Updated OS and PFS and exploratory biomarker analyses were conducted., Results: Patients received atezolizumab plus CP/ET (n = 201) or placebo plus CP/ET (n = 202). At the updated analysis, median follow-up for OS was 22.9 months; 302 deaths had occurred. Median OS was 12.3 and 10.3 months with atezolizumab plus CP/ET and placebo plus CP/ET, respectively (hazard ratio, 0.76; 95% CI, 0.60 to 0.95; descriptive P = .0154). At 18 months, 34.0% and 21.0% of patients were alive in atezolizumab plus CP/ET and placebo plus CP/ET arms, respectively. Patients derived benefit from the addition of atezolizumab, regardless of PD-L1 immunohistochemistry or bTMB status., Conclusion: Adding atezolizumab to CP/ET as 1L treatment for ES-SCLC continued to demonstrate improved OS and a tolerable safety profile at the updated analysis, confirming the regimen as a new standard of care. Exploratory analyses demonstrated treatment benefit independent of biomarker status.

Objective: Lung cancer is one the leading causes of mortality worldwide. Symptomatic manifestations of the disease generally occur in the advanced-stage setting, and therefore an important number of patients have advanced or metastatic disease by the time they are diagnosed. This situation contributes to a poor prognosis in the treatment of lung cancer. Evidencebased clinical recommendations are of great value to support decision-making for daily practice, and thus improving health care quality and patient outcomes., Materials and Methods: This document was an initiative of the Mexican Society of Oncology (SMEO) in collaboration with Mexican Center of Clinical Excellence (Cenetec) according to Interna- tional Standards. Such standards included those described by the IOM, NICE, SIGN and GI-N. An interdisciplinary Guideline Development Group (GDG) was put together which included medical oncologists, surgical oncologistsc, radiation therapists, and methodologists with expertise in critical appraisal, sys- tematic reviews and clinical practice guidelines development., Results: 62 clinical questions were agreed among members of the GDG. With the evidence identified from systematic reviews, the GDG developed clinical recommendations using a Modified Delphi Panel technique. Patients' representatives validated them., Conclusions: These Clinical Practice Guideline aims to support the shared decision-making process for patients with different stages of non-small cell lung cancer. Our goal is to improve health-care quality on these patients., Competing Interests: Declaration of conflict of interests. The authors declare that they have no conflict of interests.

Background: High serum carcinoembryonic antigen (CEA) levels are an independent prognostic factor for recurrence and survival in patients with non-small cell lung cancer (NSCLC). Its role as a predictive marker of treatment response has not been widely characterized., Methods: 180 patients with advanced NSCLC (stage IIIB or Stage IV), who had an elevated CEA serum level (>10 ng/ml) at baseline and who had no more than one previous chemotherapy regimen, were included. CEA levels were measured after two treatment cycles of platinum based chemotherapy (93%) or a tyrosine kinase inhibitor (7%). We evaluate the change in serum CEA levels and the association with response measured by RECIST criteria., Results: After two chemotherapy cycles, the patients who achieved an objective response (OR, 28.3%) had a reduction of CEA levels of 55.6% (95%CI [box drawings light horizontal]64.3 to [box drawings light horizontal]46.8) compared to its basal level, with an area under the ROC curve (AURC) of 0.945 (95%CI 0.91-0.99), and a sensitivity and specificity of 90.2 and 89.9%, respectively, for a CEA reduction of ≥14%. Patients that achieved a decrease in CEA levels ≥14% presented an overall response in 78% of cases, stable disease in 20.3% and progression in 1.7%, while patients that did not attain a reduction ≥14% had an overall response of 4.1%, stable disease of 63.6% and progression of 32.2% (p < 0.001). Patients with stable (49.4%) and progressive disease (22.2%) had an increase of CEA levels of 9.4% (95%CI 1.5-17.3) and 87.5% (95%CI 60.9-114) from baseline, respectively (p < 0.001). The AURC for progressive disease was 0.911 (95%CI 0.86-0.961), with sensitivity and specificity of 85 and 15%, respectively, for a CEA increase of ≥18%. PFS was longer in patients with a ≥14% reduction in CEA (8.7 vs. 5.1 months, p < 0.001). Neither reduction of CEA nor OR were predictive of OS., Conclusions: A CEA level reduction is a sensitive and specific marker of OR, as well as a sensitive indicator for progression to chemotherapy in patients with advanced NSCLC who had an elevated CEA at baseline and had received no more than one chemotherapy regimen. A 14% decrease in CEA levels is associated with a better PFS.

Mexican specialists in oncology, oncologic surgery, thoracic surgery, pneumology, pathology, molecular biology, anesthesiology, algology, psychology, nutrition, and rehabilitation (all of them experts in lung cancer treatment) in order to develop the National Consensus on Lung Cancer. The consensus has been developed as an answer to the need of updated Mexican guidelines for the optimal treatment of the disease, as well as to the requirements that such guidelines be established by multidisciplinary panel, depicting the current attention given to cancer lung cases in Mexico. Thus, this paper analyses the epidemiological review, screening, diagnosis, staging, pathology, translational medicine, and the suitable therapies for early, locally advanced, and metastatic disease in the first, second, and third lines of management, as well as rehabilitation and palliative measures.