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Development of medicines in rare oncologic patient populations are growing, but well-powered randomized controlled trials are typically extremely challenging or unethical to conduct in such settings. External control arms using real-world data are increasingly used to supplement clinical trial evidence where no or little control arm data exists. The construction of an external control arm should always aim to match the population, treatment settings and outcome measurements of the corresponding treatment arm. Yet, external real-world data is typically fraught with limitations including missing data, measurement error and the potential for unmeasured confounding given a nonrandomized comparison. Quantitative bias analysis (QBA) comprises a collection of approaches for modelling the magnitude of systematic errors in data which cannot be addressed with conventional statistical adjustment. Their applications can range from simple deterministic equations to complex hierarchical models. QBA applied to external control arm represent an opportunity for evaluating the validity of the corresponding comparative efficacy estimates. We provide a brief overview of available QBA approaches and explore their application in practice. Using a motivating example of a comparison between pralsetinib single-arm trial data versus pembrolizumab alone or combined with chemotherapy real-world data for RET fusion-positive advanced non-small cell lung cancer (aNSCLC) patients (1-2% among all NSCLC), we illustrate how QBA can be applied to external control arms. We illustrate how QBA is used to ascertain robustness of results despite a large proportion of missing data on baseline ECOG performance status and suspicion of unknown confounding. The robustness of findings is illustrated by showing that no meaningful change to the comparative effect was observed across several 'tipping-point' scenario analyses, and by showing that suspicion of unknown confounding was ruled out by use of E-values. Full R code is also provided.

Background: The early-generation ROS1 tyrosine kinase inhibitors (TKIs) that are approved for the treatment of ROS1 fusion-positive non-small-cell lung cancer (NSCLC) have antitumor activity, but resistance develops in tumors, and intracranial activity is suboptimal. Repotrectinib is a next-generation ROS1 TKI with preclinical activity against ROS1 fusion-positive cancers, including those with resistance mutations such as ROS1 G2032R., Methods: In this registrational phase 1-2 trial, we assessed the efficacy and safety of repotrectinib in patients with advanced solid tumors, including ROS1 fusion-positive NSCLC. The primary efficacy end point in the phase 2 trial was confirmed objective response; efficacy analyses included patients from phase 1 and phase 2. Duration of response, progression-free survival, and safety were secondary end points in phase 2., Results: On the basis of results from the phase 1 trial, the recommended phase 2 dose of repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily. Response occurred in 56 of the 71 patients (79%; 95% confidence interval [CI], 68 to 88) with ROS1 fusion-positive NSCLC who had not previously received a ROS1 TKI; the median duration of response was 34.1 months (95% CI, 25.6 to could not be estimated), and median progression-free survival was 35.7 months (95% CI, 27.4 to could not be estimated). Response occurred in 21 of the 56 patients (38%; 95% CI, 25 to 52) with ROS1 fusion-positive NSCLC who had previously received one ROS1 TKI and had never received chemotherapy; the median duration of response was 14.8 months (95% CI, 7.6 to could not be estimated), and median progression-free survival was 9.0 months (95% CI, 6.8 to 19.6). Ten of the 17 patients (59%; 95% CI, 33 to 82) with the ROS1 G2032R mutation had a response. A total of 426 patients received the phase 2 dose; the most common treatment-related adverse events were dizziness (in 58% of the patients), dysgeusia (in 50%), and paresthesia (in 30%), and 3% discontinued repotrectinib owing to treatment-related adverse events., Conclusions: Repotrectinib had durable clinical activity in patients with ROS1 fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Checkpoint inhibitor (CPI) therapy revolutionized treatment for advanced non-small-cell lung cancer (NSCLC); however, most patients progress due to primary or acquired resistance. Sitravatinib is a receptor tyrosine kinase inhibitor that can shift the immunosuppressive tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with nivolumab (sitra + nivo) may potentially overcome initial CPI resistance., Patients and Methods: In the phase III SAPPHIRE study, patients with advanced non-oncogenic driven, nonsquamous NSCLC who initially benefited from (≥4 months on CPI without progression) and subsequently experienced disease progression on or after CPI combined with or following platinum-based chemotherapy were randomized 1 : 1 to sitra (100 mg once daily administered orally) + nivo (240 mg every 2 weeks or 480 mg every 4 weeks administered intravenously) or docetaxel (75 mg/m 2 every 3 weeks administered intravenously). The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR; all assessed by blinded independent central review), and safety., Results: A total of 577 patients included randomized: sitra + nivo, n = 284; docetaxel, n = 293 (median follow-up, 17.1 months). Sitra + nivo did not significantly improve OS versus docetaxel [median, 12.2 versus 10.6 months; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.70-1.05; P = 0.144]. The median PFS was 4.4 versus 5.4 months, respectively (HR 1.08, 95% CI 0.89-1.32; P = 0.452). The ORR was 15.6% for sitra + nivo and 17.2% for docetaxel (P = 0.597); CBR was 75.5% and 64.5%, respectively (P = 0.004); median DOR was 7.4 versus 7.1 months, respectively (P = 0.924). Grade ≥3 treatment-related adverse events were observed in 53.0% versus 66.7% of patients receiving sitra + nivo versus docetaxel, respectively., Conclusions: Although median OS was numerically longer with sitra + nivo, the primary endpoint was not met in patients with previously treated advanced nonsquamous NSCLC. The safety profiles demonstrated were consistent with previous reports., Competing Interests: Disclosure HB reports honoraria for lectures for Amgen, Pfizer, Daiichi, and Regeneron; writing engagements (nonfinancial) with Amgen, BMS, and AstraZeneca; advisory board participation with BMS, Lilly, Genentech, Inc., Pfizer, Merck, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, Genmab, Regeneron, BioNTech, Amgen, Axiom, PharmaMar, Takeda, Mirati Therapeutics, Inc., Daiichi, Guardant, Natera, Oncocyte, BeiGene, iTEO, Jazz Pharmaceuticals, Janssen, Da Volterra, Puma, and BerGenBio; full or part-time employment at Fox Chase Cancer Center; stock options from Sonnet Bio, Inspirna (formerly Rgenix) and Nucleai; research grants from BMS and Lilly; principal investigator (nonfinancial) for AstraZeneca, Mirati Therapeutics, Inc., and BMS; data and safety monitoring board for the University of Pennsylvania: CAR T Program, Takeda, Incyte, Novartis, and Springworks; and travel support from Amgen, BMS, Merck, Lilly, EMD-Serono, Genentech, Inc., and Regeneron. FdM reports speaker’s bureau and advisory board participation with AstraZeneca, F. Hoffmann-La Roche Ltd, BMS, and Novartis. DD reports institutional funding from BMS; principal investigator (nonfinancial) for BMS, F. Hoffmann-La Roche Ltd, Mirati Therapeutics, Inc., and MSD; and an advisory role (nonfinancial) for Amgen, BMS, and MSD. CR reports advisory board fees from AstraZeneca; and stocks from Gilead. WSMET reports research grants from MSD, AstraZeneca, and Sanofi/Regeneron; principal investigator (non-financial) for Roche, Mirati Therapeutics, BeiGene, and Genmab. MLJ reports research funding (institutional) from AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, BMS, 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, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech, Inc./F. Hoffmann-La Roche Ltd, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, 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, Inc., Mythic Therapeutics, NeoImmuneTech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, 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 Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL Therapeutics, and Y-mAbs Therapeutic; consulting/advisory role feed (institutional) from AbbVie, Amgen, Arcus Biosciences, ArriVent, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Calithera Biosciences, Daiichi Sankyo, EcoR1, Genentech, Inc./F. Hoffmann-La Roche Ltd, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, IDEAYA Biosciences, Immunocore, iTeos, Janssen, Jazz Pharmaceuticals, Merck, Mirati Therapeutics, Inc., Molecular Axiom, Novartis, Oncorus, Pyramid Biosciences, Regeneron Pharmaceuticals, Revolution Medicines, Sanofi-Aventis, Seagen, Synthekine, Takeda Pharmaceuticals, Turning Point Therapeutics, and VBL Therapeutics. EBG reports research grants from ABL-Bio, AstraZeneca, BMS, Dynavax, Technologies, Eli Lilly, EMD Serono, Genentech, Inc., Iovance Biotherapeutics, Merck, Mirati Therapeutics, Inc., Neon, and Novartis; an advisory role for AbbVie, ABL-Bio, AstraZeneca, Boehringer Ingelheim, BMS, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly, Gilead, GSK, Ipsen, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, and XILO. KH reports financial interests (personal) and advisory board participation with Mirati Therapeutics, Inc., Perthera, BMS, BeiGene, Iovance Biotherapeutics, Lyell, BioNTech, and AstraZeneca; and an institutional research grant or contract with OncoC4. DP reports to be an invited speaker for AstraZeneca, Novartis, priME Oncology, Peer CME, Samsung, AbbVie, Janssen, GSK, Pfizer; advisory board fees from AstraZeneca, BMS, Merck, Novartis, Pfizer, F. Hoffmann-La Roche Ltd, Samsung, Celgene, AbbVie, Daiichi Sankyo, Janssen, Sanofi-Aventis, GSK, Seagen, Pierre Fabre, and Gilead; principal investigator for AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, F. Hoffmann-La Roche Ltd, Medimmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, Janssen, AbbVie, and GSK. MR reports to be an invited speaker for Amgen, AstraZeneca, BMS, Boehringer Ingelheim, GSK, Lilly, Mirati Therapeutics, Inc., MSD, Merck, Novartis, Regeneron, Sanofi, and F. Hoffmann-La Roche Ltd; speaker’s bureau fees from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, GSK, Lilly, Mirati Therapeutics, Inc., MSD, Merck, Novartis, Regeneron, Sanofi, and F. Hoffmann-La Roche Ltd; advisory board fees from Amgen, AstraZeneca, BMS, BioNTech, Boehringer Ingelheim, Daiichi Sankyo, Gilead, GSK, MSD, Mirati Therapeutics, Inc., Pfizer, Regeneron, Sanofi, and F. Hoffmann-La Roche Ltd; and is a member of the data and safety monitoring board for Daiichi Sankyo and Sanofi. SPo reports consulting fees (personal) from Amgen, AstraZeneca, Bayer, Blueprint Medicines, BMS, Boehringer Ingelheim, Daiichi Sankyo, GSK, Guardant Health, Incyte, Janssen, Lilly, Merck Serono, MSD, Novartis, F. Hoffmann-La Roche Ltd, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and EQRx; honoraria for lectures, presentations or speakers bureaus (personal) from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, F. Hoffmann-La Roche Ltd, and Takeda; payment for expert testimony (personal) from F. Hoffmann-La Roche Ltd and Merck Serono; support for attending meetings and/or travel from Janssen and F. Hoffmann-La Roche Ltd; and leadership or fiduciary role in other board, society, committee, or advocacy group (nonfinancial) for the British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, and ETOP-IBCSG Partners Foundation Board. RSH reports consulting fees from DynamiCure Biotechnology, eFFECTOR Therapeutics, Eli Lilly, Genentech, Inc., Gilead, HiberCell, Janssen, Johnson and Johnson, Loxo Oncology, Merck, Mirati Therapeutics, Inc., NextCure, Novartis, Oncocyte Corp, Oncternal Therapeutics, Pfizer, Regeneron Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, Seattle Genetics, and AbbVie; advisory board fees from AstraZeneca, Bolt Therapeutics, BMS, Candel Therapeutics, Cybrexa Therapeutics, EMD Serono, I-Mab Biopharma, Immune-Onc Therapeutics, Normunity, Ocean Biomedical, Revelar Biotherapeutics, Ribbon Therapeutics, Xencor; stock options from Normunity, Immunocore, and Checkpoint Therapeutics; member of the board of directors for Junshi Pharmaceuticals, American Association for Cancer Research, Immunocore, International Association for the Study of Lung Cancer, Society for Immunotherapy of Cancer, and Southwest Oncology Group; full-time employment at Yale Cancer Center; and research support from AstraZeneca, Eli Lilly, Genentech, Inc./F. Hoffmann-La Roche Ltd, and Merck. TAL reports consulting fees from Catalyst, Eisai, Jazz, Janssen, and F. Hoffmann-La Roche Ltd; and advisory board participation with GI Therapeutics, Pfizer, Regeneron, Amgen, AstraZeneca, Novocure, Takeda, Merck, and Jazz Pharmaceuticals. RLS reports full- or part-time employment with Mirati Therapeutics, Inc.; and stocks/shares from Mirati Therapeutics, Inc. XY reports full or part-time employment with Mirati Therapeutics, Inc.; and stocks/shares from Mirati Therapeutics, Inc. RH reports full- or part-time employment with Mirati Therapeutics, Inc.; and stocks/shares from Mirati Therapeutics, Inc. SPe reports honoraria (institutional) from AiCME, AstraZeneca, Boehringer Ingelheim, BMS, ecancer, Eli Lilly, Foundation Medicine, GSK, Illumina, Imedex, Ipsen, Medscape, Merck Sharp, and Dohme, Mirati Therapeutics, Inc., Novartis, PER, PeerView, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., RTP, Sanofi, Takeda, and Galencia; financial support (institutional) from Amgen, Arcus, AstraZeneca, BeiGene, BMS, GSK, iTeos, Merck Sharp and Dohme, Mirati Therapeutics, Inc., Pharma Mar, Promontory Therapeutics, F. Hoffmann-La Roche Ltd/Genentech, Inc., and Seattle Genetics; and is a member of ESMO, ASCO, AACR, IASLC, SSOM, SAKK, and ETOP; Other: Vice President of Swiss Cancer League, past President of ESMO, Strategic Advisory board SPCC (Paris-Saclay) Chair, and ETOP scientific chair. All other authors have declared no conflicts of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial., Patients and Methods: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion., Results: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy., Conclusions: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen., Competing Interests: Disclosure AP: consulting or advisory role for AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Lilly, GSK, Janssen, Merck Sharp & Dohme, Mundipharma, Novartis, and Roche; speakers bureaus for AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, eCancer, Janssen, Merck Sharp & Dohme, Medscape, PeerVoice, and touchONCOLOGY; steering committee member for Janssen and ArriVent Biopharma. SHL: received honoraria from AstraZeneca/MedImmune, Roche, Merck, Lilly, and Amgen; consulting or advisory role for AstraZeneca, Roche, Merck, Pfizer, and Lilly; received research funding from Merck. BM: received speaking honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, Janssen, Jazz Pharmaceuticals, Merck, Novartis, Pfizer, Roche, Sanofi, and Takeda; received support for attending meetings from Janssen, Pfizer, and Sanofi. JYS: participated in advisory boards for AstraZeneca, Roche, Boehringer Ingelheim, Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Chugai Pharmaceutical Co, Ono Pharmaceutical, Takeda, CStone Pharmaceuticals, Janssen, and Bristol Myers Squibb; received speaking honoraria from AstraZeneca, Roche, Boehringer Ingelheim, Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Chugai Pharmaceutical Co, Ono Pharmaceutical, and Bristol Myers Squibb; received grant from Roche. KA: received lecture fees for AstraZeneca K.K., MSD K.K., Ono Pharmaceutical Co. Ltd., Bristol Myers Squibb, and Chugai Pharmaceutical Co. OJV: honoraria or advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, AstraZeneca, Pfizer, Lilly, Takeda, and Janssen; received travel, accommodations, and expenses from Takeda, AstraZeneca, Merck Sharp & Dohme, Pfizer, and Roche/Genentech. EF: consulting or advisory role for Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Lilly, GSK, Janssen, Merck Serono, Novartis, Pfizer, Sanofi, Takeda, Peptomyc, Daiichi Sankyo Europe GmbH, F. Hoffman La-Roche, Merck Sharp & Dohme, BerGenBio, and Turning Point Therapeutics; speakers bureaus for AstraZeneca, Bristol Myers Squibb, Lilly, Medscape, Merck Sharp & Dohme, PeerVoice, Pfizer, Takeda, Amgen, F. Hoffman La-Roche, Janssen, Medical Trends, Merck Serono, Sanofi, and touchONCOLOGY; other relationships with GRIFOLS; received research funding from Merck and Merck KgaA. NG: invited speaker for Amgen, AstraZeneca, Bristol Myers Squibb, Mirati Therapeutics, MSD, Novartis, Pfizer, Roche, and Sanofi; advisory roles for AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Grünenthal, Janssen, Lilly, MSD, Novartis, Owkin, Pfizer, Roche, Sanofi, and Takeda; received research funding for institution from Bristol Myers Squibb, Janssen, Roche, and Sivan; leadership role at ITMIG; family employment at AstraZeneca. ABC: invited speaker for Pfizer, Amgen, Takeda, Novartis, Roche, AstraZeneca, MSD, Janssen, Bristol Myers Squibb, and Sanofi; advisory roles for Novartis, AbbVie, Roche, Exeliom Biosciences, Pfizer, Janssen, Amgen, Takeda, AstraZeneca, and MSD; research funding of institution from Exeliom Biosciences; support for attending meetings from Roche, MSD, Novartis, Pfizer, AstraZeneca, Amgen, and Bristol Myers Squibb; participation on data monitoring safety board for InhaTarget Therapeutics and Merck. RC: invited speaker for Amgen, AstraZeneca, Lilly, GSK, Janssen, MSD, Pfizer, Roche, and Takeda; participated in advisory boards for Amgen, AstraZeneca, Bayer, Lilly, GSK, Janssen, MSD, Novartis, Pfizer, PharmaMar, Roche, Sanofi, and Takeda; speaker in educational activities for Medscape, PeerVoice, and TouchIME; holds stocks or shares in Supportive Care UK; has ownership interest in Christie Private Care; principal investigator for AbbVie, AstraZeneca, Bristol Myers Squibb, Clovis, Lilly, GSK, Janssen, MSD, Novartis, Pfizer, PharmaMar, Roche, and Takeda. FC: received consulting fees from Roche, AstraZeneca, Bristol Myers Squibb, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, PharmaMar, Novocure, Mirati Therapeutics, Galecto, OSE Immunotherapeutics, and MSD; received honoraria for advisory role from Roche, AstraZeneca, Bristol Myers Squibb, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, PharmaMar, Novocure, Mirati Therapeutics, Galecto, OSE Immunotherapeutics, and MSD; received support for attending meetings from OSE Immunotherapeutics; participated in advisory boards for Roche, AstraZeneca, Bristol Myers Squibb, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, PharmaMar, Novocure, Mirati Therapeutics, Galecto, OSE Immunotherapeutics, and MSD. SO: received advisory board consulting fees from Janssen, Bristol Myers Squibb, Novocure, and Roche. SP: participated in advisory boards for Amgen, AstraZeneca, Bayer, BeiGene, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, EQRx, GSK, Guardant Health, Janssen, Lilly, Medscape, MSD, Novartis, Pfizer, Sanofi, and Takeda; consulting fees from Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GSK, Guardant Health, Incyte, Janssen, Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and EQRx; expert testimony for Merck Serono and Roche; invited speaker for VJOncology; received payment or honoraria from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche, and Takeda; principal investigator for ARIAD Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Janssen, Lilly, Roche, Takeda, Trizel, and Turning Point Therapeutics; received support for attending meetings from Janssen and Roche; research grant from Guardant Health; other financial relationships with Amgen, Blueprint Medicines, Elsevier, and MSD. JLT: invited speaker for AstraZeneca, Lilly, MSD, Boehringer Ingelheim, Pfizer, and Takeda; participated in advisory boards for Amgen and AstraZeneca; received support for attending meetings from MSD. PT: received grants and nonfinancial support from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Roche, and Takeda. RDG: received grants from Alliance Foundation, Amgen, AstraZeneca, Big Ten Cancer Research Consortium, Bristol Myers Squibb, Chugai Pharmaceutical Co, Daiichi Sankyo, ECOG-ACRIN, Helsinn, Hoosier Cancer Research Network, Janssen, Jounce Therapeutics, Merck, National Cancer Institute, Pfizer, and Takeda; received payment or honoraria from Clinical Care Options, OncLive, Society for Immunotherapy of Cancer, and Targeted Oncology; received support for attending meetings from the International Association for the Study of Lung Cancer; participated in advisory boards for AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Gilead, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, Oncocyte, Sanofi, and Takeda; leadership or other role in ASCO Scientific Review Committee and Meeting Abstracts, Hoosier Cancer Research Network, Journal of Clinical Oncology, National Cancer Institute Investigational Drug Steering Committee, and the Thoracic Clinical Trial Working Group. WNWJr: participated in advisory boards for AstraZeneca, Bayer, Merck, Novartis, Sanofi, and Takeda; invited speaker for Amgen, Bristol Myers Squibb, Lilly, Genentech/Roche, Janssen, Pfizer, and United Medical; expert testimony for Boehringer Ingelheim. KR: consultant for Amgen, AstraZeneca, Blueprint Medicines, Daiichi Sankyo, EMD Serono, Genentech, GSK, Janssen, Lilly, Merck KGA, Mirati Therapeutics, Seattle Genetics, and Takeda; writing assistance from Blueprint Medicines, Genentech, Janssen, Merck, Mirati Therapeutics, Seattle Genetics, and Takeda; research funding of institution from Genentech, Blueprint Medicines, Calithera, Daiichi Sankyo, Elevation Oncology, and Janssen. TT: received honoraria from AstraZeneca K.K., Pfizer Japan Inc, Eli Lilly Japan, Chugai Pharmaceutical Co, MSD K.K., Pfizer Japan Inc, Takeda, Bristol Myers Squibb Japan, Amgen K.K., and Novartis; research funding of institution from Janssen Pharmaceutical K.K., AstraZeneca K.K., Pfizer Japan Inc, Eli Lilly Japan, Chugai Pharmaceutical Co, MSD K.K., Amgen K.K., Merck Biopharma Co., Ltd., and AnHeart Therapeutics Inc. SG: principal investigator for AstraZeneca, Novartis, and Janssen (fees to institution). DMK: participated in advisory boards for MSD, Merck, Roche, Bristol Myers Squibb, Takeda, Boehringer Ingelheim, Pfizer, Johnson & Johnson, Amgen, Sanofi-Aventis, and Novartis. AB: received consulting fees from Pfizer and Roche; honoraria from Novartis and Eli Lilly; participated in advisory boards for Pfizer, Roche, and Regeneron. MM: received consulting fees from Boehringer Ingelheim, Roche, Takeda, and AstraZeneca. PB, ABB, AG, JG, DM, MW, JX, TS, SS, BD, REK, JMB: employee of Janssen and may hold stock in Johnson & Johnson. RGC: invited speaker for AstraZeneca, Bristol Myers Squibb, Janssen, Lilly, Novartis, Pfizer, Roche, and Takeda; advisory roles for AstraZeneca, Bristol Myers Squibb, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, and Takeda; steering committee member for AstraZeneca and Janssen. BCC: consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Roche, Bristol Myers Squibb, Pfizer, Yuhan Corporation, Janssen, Takeda, Merck Sharp & Dohme, Ono Pharmaceutical, Lilly, MedPacto, Blueprint Medicines, Cyrus Therapeutics, Guardant Health, Novartis, CJ, ABION, BeiGene, CureLogen, Onegene Biotechnology, GI-Cell, HK inno.N, IMNEWRUN, Hanmi Pharmaceutical, Kanaph Therapeutics, BridgeBio, and Oscotec; leadership roles for Interpark Bio and J INTS BIO; patents, royalties, or other intellectual property for Champions Oncology, Crown Bioscience, and Imagen; other relationships with DAAN Biotherapeutics; owns stock or has other ownership interests with Theravance Biopharma, Gencurix, BridgeBio, Kanaph Therapeutics, Cyrus Therapeutics, Interpark Bio, and J INTS BIO; received research funding from Novartis, Bayer, AstraZeneca, MOGAM Biotechnology Research Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan Corporation, Ono Pharmaceutical, Dizal Pharma, Merck Sharp & Dohme, AbbVie, GI Innovation, Lilly, Blueprint Medicines, Interpark Bio, LG Chem, Oscotec, GI-Cell, ABION, Boehringer Ingelheim, CJ Bioscience, CJ Blossom Park, Cyrus Therapeutics, Genexine, Nuvalent Inc, Oncternal Therapeutics, Regeneron, BridgeBio, ImmuneOncia, Illumina, Kanaph Therapeutics, Therapex, J INTS Bio, Hanmi Pharmaceutical, and CHA Bundang Medical Center. All other authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Osimertinib is a central nervous system (CNS)-active, third generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations, with demonstrated efficacy in EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). We present the rationale and design for TARGET (NCT05526755), which will evaluate the efficacy and safety of 5 years of adjuvant osimertinib in patients with completely resected EGFRm stage II to IIIB NSCLC., Materials and Methods: TARGET is a phase II, multinational, open-label, single-arm study. Adults aged ≥18 years (Taiwan ≥20 years), with resected stage II to IIIB NSCLC are eligible; prior adjuvant chemotherapy is allowed. Eligible patients must have locally confirmed common (exon 19 deletion or L858R) or uncommon (G719X, L861Q, and/or S768I) EGFR-TKI sensitizing mutations, alone or in combination. Patients will receive osimertinib 80 mg once daily for 5 years or until disease recurrence, discontinuation or death. The primary endpoint is investigator-assessed disease-free survival (DFS) at 5 years (common EGFR mutations cohort). Secondary endpoints include: investigator-assessed DFS at 3 and 4 years; overall survival at 3, 4, and 5 years (common EGFR mutations cohort); DFS at 3, 4, and 5 years (uncommon EGFR mutations cohort); safety and tolerability, type of recurrence and CNS metastases (both cohorts). Exploratory endpoints include: tissue/plasma concordance; analysis of circulating molecules in plasma samples using different profiling approaches to detect minimal residual disease; incidence and change over time of incidental pulmonary nodules., Results: TARGET is currently recruiting, and completion is expected in 2029., Competing Interests: Disclosure RAS reports research funding from AstraZeneca and Boehringer Ingelheim, and advisory board fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, J INTS BIO, Janssen, Lilly, Merck, Merck Serono, Novartis, Pfizer, Puma, Roche, Taiho, Takeda, Thermo Fisher, Yuhan. FDM reports consultation fees from AstraZeneca, Merck Sharp, & Dohme Oncology, Bristol Myers Squibb, Roche/Genentech, Pfizer, Novartis, and Takeda. JYH reports receiving honoraria from Novartis, Pfizer, Merck, Roche, Janssen, AstraZeneca, and Yuhan, consultation fees from ABION, Janssen, Merck, Novartis, Takeda, Amgen, AstraZeneca, reports grants from Roche, Takeda, ONO, and an advisory board fee from AstraZeneca. JCMH reports speakers’ bureau fees from AstraZeneca, Takeda, Merck Sharp & Dohme, Janssen, Amgen, and Novartis, and advisory board fees from AstraZeneca, Daiichi-Sankyo, Takeda, Merck, Merck Sharp & Dohme, Janssen, Amgen, and Novartis. EM reports employment for AstraZeneca and PHASTAR. LS and MS report employment and stock ownership with AstraZeneca. SP reports paid expert testimony for Merck Serono and Roche, consultation fees from Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, EQRx, GlaxoSmithKline, Guardant Health, Janssen, Lilly, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, Seattle Genetics, Takeda, and Turning Point Therapeutics, research funding (to institution) from Amgen, AstraZeneca, Blueprint, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Guardant Health, Janssen, Lilly, Merck Sharp & Dohme, Roche, Takeda, Seattle Genetics, Trizel, Turning Point Therapeutics and member of the board of directors for Mesothelioma Applied Research Foundation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: This open-label, phase 3 trial (ALTA-3; NCT03596866) compared efficacy and safety of brigatinib versus alectinib for ALK+ NSCLC after disease progression on crizotinib., Methods: Patients with advanced ALK+ NSCLC that progressed on crizotinib were randomized 1:1 to brigatinib 180 mg once daily (7-d lead-in, 90 mg) or alectinib 600 mg twice daily, aiming to test superiority. The primary end point was blinded independent review committee-assessed progression-free survival (PFS). Interim analysis for efficacy and futility was planned at approximately 70% of 164 expected PFS events., Results: The population (N = 248; brigatinib, n = 125; alectinib, n = 123) was notable for long median duration of prior crizotinib (16.0-16.8 mo) and low rate of ALK fusion in baseline circulating tumor DNA (ctDNA; 78 of 232 [34%]). Median blinded independent review committee-assessed PFS was 19.3 months with brigatinib and 19.2 months with alectinib (hazard ratio = 0.97 [95% confidence interval: 0.66-1.42], p = 0.8672]). The study met futility criterion. Overall survival was immature (41 events [17%]). Exploratory analyses pooled across the treatment groups revealed median PFS of 11.1 versus 22.5 months in patients with versus without ctDNA-detectable ALK fusion at baseline (hazard ratio: 0.48 [95% confidence interval: 0.32-0.71]). Treatment-related adverse events in more than 30% of patients (brigatinib, alectinib) were elevated levels of blood creatine phosphokinase (70%, 29%), aspartate aminotransferase (53%, 38%), and alanine aminotransferase (40%, 36%)., Conclusions: Brigatinib was not superior to alectinib for PFS in crizotinib-pretreated ALK+ NSCLC. Safety was consistent with the well-established and unique profiles of each drug. The low proportion of patients with ctDNA-detectable ALK fusion may account for prolonged PFS with both drugs in ALTA-3., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Horizon scanning (HS) is the systematic identification of emerging therapies to inform policy and decision-makers. We developed an agile and tailored HS methodology that combined multi-criteria decision analysis weighting and Delphi rounds. As secondary objectives, we aimed to identify new medicines in melanoma, non-small cell lung cancer and colorectal cancer most likely to impact the Australian government's pharmaceutical budget by 2025 and to compare clinician and consumer priorities in cancer medicine reimbursement., Method: Three cancer-specific clinician panels (total n = 27) and a consumer panel (n = 7) were formed. Six prioritisation criteria were developed with consumer input. Criteria weightings were elicited using the Analytic Hierarchy Process (AHP). Candidate medicines were identified and filtered from a primary database and validated against secondary and tertiary sources. Clinician panels participated in a three-round Delphi survey to identify and score the top five medicines in each cancer type., Results: The AHP and Delphi process was completed in eight weeks. Prioritisation criteria focused on toxicity, quality of life (QoL), cost savings, strength of evidence, survival, and unmet need. In both curative and non-curative settings, consumers prioritised toxicity and QoL over survival gains, whereas clinicians prioritised survival. HS results project the ongoing prevalence of high-cost medicines. Since completion in October 2021, the HS has identified 70 % of relevant medicines submitted for Pharmaceutical Benefit Advisory Committee assessment and 60% of the medicines that received a positive recommendation., Conclusion: Tested in the Australian context, our method appears to be an efficient and flexible approach to HS that can be tailored to address specific disease types by using elicited weights to prioritise according to incremental value from both a consumer and clinical perspective., Policy Summary: Since HS is of global interest, our example provides a reproducible blueprint for adaptation to other healthcare settings that integrates consumer input and priorities., Competing Interests: Declaration of Competing Interest MA has received financial support to attend conferences and meetings by AstraZeneca and serves on the advisory board for Pfizer and Bristol Myers Squibb. PAA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Canofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune. He has received research funding grants from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. He has received travel support from Pfizer. SA has served uncompensated on the boards of Health Issues Centre, Australia, Victorian Agency for Health Information, and Safer Care Victoria. MPB has received honoraria from BNS Australia, USD Oncology, and Novartis. He holds an advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Cartherics for which his institution receives reimbursements. His institution has also received reimbursement for research support from Bristol Myers Squibb, Merck Sharp & Dohme, Pharmaust, Zucero Therapeutics, and CStone Pharmaceuticals. MB has received compensation and research support as an advisor and consultant to Pierre Fabre, MSD, GSK, Servier, and AstraZeneca. MI is on the advisory boards of Pfizer, Roche, Takeda, BeiGene, Amgen, Merck, and MSD and has received honoraria from Pfizer, Roche, Takeda, Novartis, as well as research funding from Pfizer. TJ reports consulting fees from AstraZeneca and MSD, and advisory boards and committees for AstraZeneca, Amgen, Bristol Myers Squibb, Merck & Co., MSD, Gilead, Puma, Pfizer Inc., Roche AG, Specialised Therapeutics, and Takeda Pharmaceutical, outside the submitted work. SK reports honoraria to institution from Astra Zeneca, Roche, Pfizer, Bristol Myers Squibb, MSD and Takeda; consulting fees from AstraZeneca, Pfizer, MSD, Novartis, Roche, Takeda, Amgen; and research funding to institution from Astra Zeneca. MK reports institutional grants from Nordic Farma, Merck-Serono, Pierre Fabre, Servier, Bayer, Bristol Myers Squibb, Merck, and Roche; and consulting fees and honoraria paid to institution from Pierre Fabre and Servier. BTL has served as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly. He has received research grants to his institution from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Hengrui USA, and Lilly. He has received academic travel support from Amgen, Jiangsu Hengrui Medicine and MORE Health. He is an inventor on two institutional patents at MSK (US62/685,057, US62/514,661) and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. BTL is supported by the Memorial Sloan Kettering Cancer Centre Support Grant P30 CA008748 and Research Project Grant R01CA249666 from the National Institutes of Health. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron. JML receives research support from Ipsen Pharmaceuticals, Novartis and Amgen, and reports consulting fees and/or honoraria from Amgen, Ipsen, Taiho, Novartis, SAGA Diagnostics and Natera. BM is on the advisory boards of Amgen, MSD, Bristol Myers Squibb, Beigene and AstraZeneca. GAM has received research support from Bristol Myers Squibb and as Principal Investigator his institution has received reimbursement of trial costs from Roche-Genentech. TMM reports consulting fees and participation on advisory boards for Bristol Myers Squibb, MSD, Merck, AstraZeneca, Novartis, GSK, Eisai, and honoraria from AstraZeneca. TMM has received support to attend meetings from Bristol Myers Squibb and AstraZeneca. LN has received institutional consulting fees from Bristol Myers Squibb, Pfizer, and Merck Sharp & Dohme, and reports support to attend a research meeting from AstraZeneca. NP has served on advisory boards or received personal honoraria from Boehringer Ingelheim, MSD, Merck, Bristol-Myers Squib, Astra Zeneca, Takeda, Pfizer, Roche, Novartis, Ipsen and Bayer and has received research funding to his institution from Bayer, Pfizer and Roche. TMP has received research support from Roche and Pfizer, and holds a consulting or advisory role for Merck, Bristol Myers Squibb, Novartis, Sanofi/Regeneron, and Pfizer. SP is compensated consultant to Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, EQRx, GSK, Guardant Health, Incyte, Janssen, Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, declares expert testimony to Roche and Merck Serono, and travel support from Janssen and Roche.BJS is on the Advisory Boards/Honoraria for Pfizer, Novartis, Roche, AstraZeneca, Merck, Bristol Myers Squibb, Eli Lilly, Amgen, BeiGene, Janssen, Takeda. JAS has received support for conference attendance from MSD (virtual registration ASCO). JT has received consulting fees or honoraria from Haystack Oncology, Servier, Pierre Fabre, MSD, Merck Serono, Amgen, Novartis, Seres and AstraZeneca. JT is on the advisory boards of Beigene, Daiichi Sankyo, Gilead, Illumina, Novartis, BMS, and MSD. WX has received research support from Merck, honoraria from MSD, Merck and AstraZeneca, and support for attending meetings from MSD (virtual registration ASCO) and Eli Lilly (virtual registration SABCS). WX is on the advisory boards of MSD, Merck and Novartis, and holds unpaid positions as Chair of the Melanoma and Skin Cancer trials group and Australasian Merkel Cell Carcinoma interest group.DY has received institutional payments for his role on advisory boards for AstraZeneca, Servier, Specialised Therapeutics, MSD and BayerJZ serves in an advisory/consultancy role for Merck Sharp & Dohme, Specialised Therapeutics, CEND, Deciphera, Revolution Medicine, FivePHusion, Genorbio, 1Global, Novotech, Alloplex Biotherapeutics, NOUS Consulting, and Oncology Republic; owns stock in Biomarin, Ophthea, Amarin, Concert Pharmaceuticals, Frequency Therapeutics, Gilead, Madrigal Pharmaceuticals, UniQure, Zogenix, Orphazyme, Moderna Therapeutics, TWST, Novavax, and Teladoc; has received honoraria from Gilead Sciences, MSD Oncology, and Viatris; and his institution has received research funding from Bristol-Myers Squibb, AstraZeneca, Pfizer, IQvia, Mylan, Ipsen, Eisai, Medtronic, MSD Oncology and Servier; and has received travel, accommodations, expenses from ICON Group, MSD Oncology, and PRAXIS., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Amivantamab has been approved for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor ( EGFR ) exon 20 insertions who have had disease progression during or after platinum-based chemotherapy. Phase 1 data showed the safety and antitumor activity of amivantamab plus carboplatin-pemetrexed (chemotherapy). Additional data on this combination therapy are needed., Methods: In this phase 3, international, randomized trial, we assigned in a 1:1 ratio patients with advanced NSCLC with EGFR exon 20 insertions who had not received previous systemic therapy to receive intravenous amivantamab plus chemotherapy (amivantamab-chemotherapy) or chemotherapy alone. The primary outcome was progression-free survival according to blinded independent central review. Patients in the chemotherapy group who had disease progression were allowed to cross over to receive amivantamab monotherapy., Results: A total of 308 patients underwent randomization (153 to receive amivantamab-chemotherapy and 155 to receive chemotherapy alone). Progression-free survival was significantly longer in the amivantamab-chemotherapy group than in the chemotherapy group (median, 11.4 months and 6.7 months, respectively; hazard ratio for disease progression or death, 0.40; 95% confidence interval [CI], 0.30 to 0.53; P<0.001). At 18 months, progression-free survival was reported in 31% of the patients in the amivantamab-chemotherapy group and in 3% in the chemotherapy group; a complete or partial response at data cutoff was reported in 73% and 47%, respectively (rate ratio, 1.50; 95% CI, 1.32 to 1.68; P<0.001). In the interim overall survival analysis (33% maturity), the hazard ratio for death for amivantamab-chemotherapy as compared with chemotherapy was 0.67 (95% CI, 0.42 to 1.09; P = 0.11). The predominant adverse events associated with amivantamab-chemotherapy were reversible hematologic and EGFR-related toxic effects; 7% of patients discontinued amivantamab owing to adverse reactions., Conclusions: The use of amivantamab-chemotherapy resulted in superior efficacy as compared with chemotherapy alone as first-line treatment of patients with advanced NSCLC with EGFR exon 20 insertions. (Funded by Janssen Research and Development; PAPILLON ClinicalTrials.gov number, NCT04538664.)., (Copyright © 2023 Massachusetts Medical Society.)

RET fusions occur as a rare mechanism of acquired resistance to osimertinib in patients with EGFR mutation-positive non-small cell lung cancer. Inhibiting RET alongside osimertinib shows promising clinical activity, but innovative approaches are needed to seek regulatory approvals in these rare treatment resistance settings. See related article by Rotow et al., p. 2979., (©2023 American Association for Cancer Research.)

Competing Interests: HO'S has received honorarium from Amgen and expenses from Takeda, all outside the scope of the submitted work. SP has received honoraria from Amgen, AstraZeneca, Bayer, Blueprint, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, EQRx, GlaxoSmithKline, Guardant Health, Incyte, Janssen, Lilly, Merck Serono, Merck, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, and Turning Point Therapeutics; honoraria for educational lectures from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche, and Takeda; and provided expert testimony for Roche and Merck Serono, all in the field of precision medicine and lung cancer drug development.

Objectives: The VISION trial showed durable activity of tepotinib in MET exon 14 (METex14) skipping non-small cell lung cancer. We analyzed health state utilities using patient-reported outcomes from VISION., Methods: 5-level version of EQ-5D (EQ-5D-5L) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 responses were collected at baseline, every 6 to 12 weeks during treatment, and at the end of treatment and safety follow-up. EQ-5D-5L and European Organisation for Research and Treatment of Cancer Quality of Life Utility Measure-Core 10 Dimensions (QLU-C10D) utilities were derived using United States, Canada, United Kingdom, and Taiwan value sets, where available. Utilities were analyzed with linear mixed models including covariates for progression or time-to-death (TTD)., Results: Utilities were derived for 273/291 patients (EQ-5D-5L, 1545 observations; QLU-C10D, 1546 observations). Mean (± SD) US EQ-5D-5L utilities increased after tepotinib initiation, from 0.687 ± 0.287 at baseline to 0.754 ± 0.250 before independently assessed progression, and decreased post progression (0.704 ± 0.288). US QLU-C10D utilities showed similar trends (0.705 ± 0.215, 0.753 ± 0.195, and 0.708 ± 0.209, respectively). Progression-based models demonstrated a statistically significant impact of progression on utilities and predicted higher utilities pre versus post progression. TTD-based models showed statistically significant associations of TTD with utilities and predicted declining utilities as TTD decreased. Prior treatment (yes/no) did not significantly predict utilities in progression- or TTD-based models. Utilities for Canada, United Kingdom, and Taiwan showed comparable trends., Conclusions: In this first analysis of health state utilities in patients with METex14 skipping non-small cell lung cancer, who received tepotinib, utilities were significantly associated with progression and TTD, but not prior treatment., (Copyright © 2023. Published by Elsevier Inc.)

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

Background and Objective: Distributional cost-effectiveness analysis (DCEA) facilitates quantitative assessments of how health effects and costs are distributed among population subgroups, and of potential trade-offs between health maximisation and equity. Implementation of DCEA is currently explored by the National Institute for Health and Care Excellence (NICE) in England. Recent research conducted an aggregate DCEA on a selection of NICE appraisals; however, significant questions remain regarding the impact of the characteristics of the patient population (size, distribution by the equity measure of interest) and methodologic choices on DCEA outcomes. Cancer is the indication most appraised by NICE, and the relationship between lung cancer incidence and socioeconomic status is well established. We aimed to conduct an aggregate DCEA of two non-small cell lung cancer (NSCLC) treatments recommended by NICE, and identify key drivers of the analysis., Methods: Subgroups were defined according to socioeconomic deprivation. Data on health benefits, costs, and target populations were extracted from two NICE appraisals (atezolizumab versus docetaxel [second-line treatment following chemotherapy to represent a broad NSCLC population] and alectinib versus crizotinib [targeted first-line treatment to represent a rarer mutation-positive NSCLC population]). Data on disease incidence were derived from national statistics. Distributions of population health and health opportunity costs were taken from the literature. A societal welfare analysis was conducted to assess potential trade-offs between health maximisation and equity. Sensitivity analyses were conducted, varying a range of parameters., Results: At an opportunity cost threshold of £30,000 per quality-adjusted life-year (QALY), alectinib improved both health and equity, thereby increasing societal welfare. Second-line atezolizumab involved a trade-off between improving health equity and maximising health; it improved societal welfare at an opportunity cost threshold of £50,000/QALY. Increasing the value of the opportunity cost threshold improved the equity impact. The equity impact and societal welfare impact were small, driven by the size of the patient population and per-patient net health benefit. Other key drivers were the inequality aversion parameters and the distribution of patients by socioeconomic group; skewing the distribution to the most (least) deprived quintile improved (reduced) equity gains., Conclusion: Using two illustrative examples and varying model parameters to simulate alternative decision problems, this study suggests that key drivers of an aggregate DCEA are the opportunity cost threshold, the characteristics of the patient population, and the level of inequality aversion. These drivers raise important questions in terms of the implications for decision making. Further research is warranted to examine the value of the opportunity cost threshold, capture the public's views on unfair differences in health, and estimate robust distributional weights incorporating the public's preferences. Finally, guidance from health technology assessment organisations, such as NICE, is needed regarding methods for DCEA construction and how they would interpret and incorporate those results in their decision making., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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

The implementation of immune checkpoint inhibitors (ICIs), with or without chemotherapy, as first-line treatment for patients who do not have actionable mutations has proved to be a major paradigm shift in the management of advanced non-small cell lung cancer (NSCLC). However, the transition of ICIs, such as pembrolizumab and nivolumab, to a first-line setting has left an unmet need for effective second-line treatment options, which is an area of intense research. In 2020, we reviewed the biological and mechanistic rationale for anti-angiogenic agents in combination with, or following, immunotherapy with the aim of eliciting a so called 'angio-immunogenic' switch in the tumor microenvironment. Here, we review the latest clinical evidence of the benefits of incorporating anti-angiogenic agents into treatment regimens. While there is a paucity of prospective data, several recent observational studies indicate that the marketed anti-angiogenic drugs, nintedanib or ramucirumab, are effective in combination with docetaxel following immuno-chemotherapy. Addition of anti-angiogenics, like bevacizumab, have also demonstrated clinical benefit when combined with first-line immuno-chemotherapy regimens. Ongoing clinical trials are assessing these agents in combination with ICIs, with encouraging early results (e.g., ramucirumab plus pembrolizumab in LUNG-MAP S1800A). Also, several emerging anti-angiogenic agents combined with ICIs are currently being assessed in phase III trials following immunotherapy, including lenvatinib (LEAP-008), and sitravatinib (SAPPHIRE) It is hoped that these trials will help expand second-line treatment options in patients with NSCLC. Areas of focus in the future will include further molecular dissection of the mechanisms of resistance to immunotherapy and the various response-progression profiles to immunotherapy observed in the clinic and the monitoring of the dynamics of immunomodulation over the course of treatment. Improved understanding of these phenomena may help identify clinical biomarkers and inform the optimal use of anti-angiogenics in the treatment of individual patients., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Martin Reck received fees for honoraria, consulting/advisory roles and speaker’s bureau from Boehringer Ingelheim. Sanjay Popat received personal fees from Bristol Myers Squibb, Roche, Takeda, AstraZeneca, Pfizer, Merck Sharp & Dohme, EMD Serono, Guardant Health, AbbVie, Boehringer Ingelheim, Tesaro, OncLive, Medscape. Christian Grohé has received sponsorship or research funding and payment or other financial remuneration from AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, F. Hoffmann-La Roche; and payment or other financial remuneration from Lilly. Silvia Novello received personal fees for advisor/speaker’s bureaus from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Takeda, Pfizer, Roche, Merck Sharp & Dohme, Eli Lilly, AbbVie. Wolfgang M. Brueckl received lecture and educational event (personal) fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Lilly, Merck Sharp & Dohme, Pfizer, Roche Pharmaceuticals, Takeda; congress (personal) fees from Boehringer Ingelheim, AstraZeneca, Roche Pharmaceuticals; and advisory board fees (personal) from AstraZeneca, Boehringer Ingelheim, Novartis, Merck Sharp & Dohme, Lilly Pharma, Bristol Myers Squibb, Roche. Dejan Radonjic and Rolf Kaiser are employees of Boehringer Ingelheim. Rolf Kaiser also has a patent EP 2994125 issued. John Heymach received fees for advisory roles from AstraZeneca, EMD Serono, Boehringer Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Hengrui Therapeutics, Eli Lilly, Spectrum, Sanofi, Takeda, Mirati Therapeutics, Bristol Myers Squibb, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, Pneuma Respiratory, RefleXion, Chugai Pharmaceuticals; fees for a Board of Directors role from Rexanna Foundation; corporate-sponsored research fees from AstraZeneca, Boehringer Ingelheim, Spectrum, Takeda; and royalties and licensing fees from Spectrum. Jesus Corral and Maya Gottfried report no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: We characterized the safety of first-line nivolumab plus ipilimumab (NIVO+IPI) in a large patient population with metastatic NSCLC and efficacy outcomes after NIVO+IPI discontinuation owing to treatment-related adverse events (TRAEs)., Methods: We pooled data from three first-line NIVO+IPI studies (NIVO, 3 mg/kg or 240 mg every 2 wk; IPI, 1 mg/kg every 6 wk) in metastatic NSCLC (CheckMate 227 part 1, CheckMate 817 cohort A, CheckMate 568 part 1). Safety end points included TRAEs and immune-mediated adverse events (IMAEs) in the pooled population and patients aged 75 years or older., Results: In the pooled population (N = 1255), any-grade TRAEs occurred in 78% of the patients, grade 3 or 4 TRAEs in 34%, and discontinuation of any regimen component owing to TRAEs in 21%. The most frequent TRAE and IMAE were diarrhea (20%; grade 3 or 4, 2%) and rash (17%; grade 3 or 4, 3%), respectively. The most common grade 3 or 4 IMAEs were hepatitis (5%) and diarrhea/colitis and pneumonitis (4% each). Pneumonitis was the most common cause of treatment-related death (5 of 16). Safety in patients aged 75 years or older (n = 174) was generally similar to the overall population, but discontinuation of any regimen component owing to TRAEs was more common (29%). In patients discontinuing NIVO+IPI owing to TRAEs (n = 225), 3-year overall survival was 50% (95% confidence interval: 42.6-56.0), and 42% (31.2-52.4) of 130 responders remained in response 2 years after discontinuation., Conclusions: First-line NIVO+IPI was well tolerated in this large population with metastatic NSCLC and in patients aged 75 years or older. Discontinuation owing to TRAEs did not reduce long-term survival., (Copyright © 2022. Published by Elsevier Inc.)

Genomic screening is routinely used to guide the treatment of cancer patients in many countries. However, several multi-layered factors make this effort difficult to deliver within a clinically relevant timeframe. Here we share the learnings from the CRUK-funded Stratified Medicine Programme for advanced NSCLC patients, which could be useful to better plan future studies., (© 2023. The Author(s).)

Central nervous system (CNS) metastases are common in non-small-cell lung cancer (NSCLC) and associated with poor prognosis and high disease burden. Effective options are needed to treat CNS metastases, and delay or prevent their formation. For epidermal growth factor receptor mutation-positive (EGFRm) advanced NSCLC and brain metastases, upfront EGFR-tyrosine kinase inhibitors (TKIs) are recommended by the joint European Association of Neuro-Oncology-European Society for Medical Oncology and experts. While early-generation EGFR-TKIs have limited CNS efficacy, the third-generation, irreversible, EGFR-TKI osimertinib has potent efficacy in NSCLC CNS metastases. This review discusses the CNS data of osimertinib in the context of therapeutic strategies and future prospects based on expert review of published literature and relevant clinical, real-world, and ongoing studies in this setting. Osimertinib penetrates the blood-brain barrier and achieves greater exposure in the brain compared with other EGFR-TKIs. Osimertinib has demonstrated CNS efficacy, including in leptomeningeal metastases, in EGFRm advanced disease. In EGFRm stage IB-IIIA NSCLC, adjuvant osimertinib reduced CNS disease recurrence versus placebo. The burden and poor prognosis of CNS metastases necessitate more therapeutic options for their management and reduced risk of recurrence in patients with EGFRm NSCLC. Clinical studies are ongoing in advanced disease to investigate osimertinib combinations with chemotherapy/radiation therapy and optimal treatment post-CNS progression with osimertinib. Further prospective research evaluating treatments using CNS-specific endpoints and evaluating CNS resistance is needed to improve outcomes for patients with CNS metastases., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Brigatinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor with demonstrated efficacy in locally advanced and metastatic non-small cell lung cancer (NSCLC) in crizotinib-refractory and ALK inhibitor-naive settings. This analysis assessed brigatinib in Asian vs. non-Asian patients from the first-line ALTA-1L trial., Patients and Methods: This was a subgroup analysis from the phase III ALTA-1L trial of brigatinib vs. crizotinib in ALK inhibitor-naive ALK+ NSCLC. The primary endpoint was progression-free survival (PFS) as assessed by blinded independent review committee (BIRC). Secondary endpoints included confirmed objective response rate (ORR) and overall survival (OS) in the overall population and BIRC-assessed intracranial ORR and PFS in patients with brain metastases., Results: Of the 275 randomized patients, 108 were Asian. Brigatinib showed consistent superiority in BIRC-assessed PFS vs. crizotinib in Asian (hazard ratio [HR]: 0.35 [95% CI: 0.20-0.59]; log-rank P = .0001; median 24.0 vs. 11.1 months) and non-Asian (HR: 0.56 [95% CI: 0.38-0.84]; log-rank P = .0041; median 24.7 vs. 9.4 months) patients. Results were consistent with investigator-assessed PFS and BIRC-assessed intracranial PFS. Brigatinib was well tolerated. Toxicity profiles and dose modification rates were similar between Asian and non-Asian patients., Conclusion: Efficacy with brigatinib was consistently better than with crizotinib in Asian and non-Asian patients with locally advanced or metastatic ALK inhibitor-naive ALK-+ NSCLC. There were no clinically notable differences in overall safety in Asian vs. non-Asian patients., (Copyright © 2022. Published by Elsevier Inc.)

Importance: The external validity of survival outcomes derived from clinical practice data from US patients with advanced non-small cell lung cancer (NSCLC) is not known and is of potential importance because it may be used to support regulatory decision-making and health technology assessment outside of the US., Objective: To evaluate whether overall survival (OS) estimates for a selected group of patients with advanced NSCLC from a large US clinical practice database are transportable to Canadian patients receiving the same systemic therapies., Design, Setting, and Participants: This retrospective multicenter cohort study used transportability analysis to assess whether adjustment for pretreatment characteristics of eligible patient cohorts could reliably approximate OS estimated from US-based samples to Canadian populations. A total of 17 432 eligible adult patients who were diagnosed de novo with advanced NSCLC on or after January 1, 2011, were included in the analysis and followed up until September 30, 2020. Because data on race and ethnicity were available in the US database but not the Canadian database and because racial and ethnic distribution was likely to be similar between US and Canadian patients, these characteristics were not analyzed., Exposures: Initiation of platinum-doublet chemotherapy or pembrolizumab monotherapy as first-line systemic treatment for advanced NSCLC., Main Outcomes and Measures: OS measured from the time of initiation of the respective treatment regimen., Results: Among 17 432 eligible patients, 15 669 patients from the US and 1763 patients from Canada were included in the analysis. Of those, 11 863 patients (sample size-weighted estimates of mean [SD] age, 68.0 [9.3] years; 6606 [55.7%] male; 10 100 from the US and 1763 from Canada) were included in the subset of patients with complete data for baseline covariates. A total of 13 532 US patients received first-line chemotherapy, and 2137 received first-line pembrolizumab monotherapy. Of those, 8447 patients (62.4%) in the first-line chemotherapy group and 1653 patients (77.3%) in the first-line pembrolizumab group had complete data on baseline covariates for outcome model estimation. A total of 1476 Canadian patients who received first-line chemotherapy and 287 patients who received first-line pembrolizumab monotherapy were identified from the target population. After standardization to baseline patient covariates in the Canadian cohorts, transported OS estimates revealed a less than 5% mean absolute difference from the observed OS in the target population (0.56% over 60 months of follow-up in the first-line chemotherapy group and 4.54% over 30 months of follow-up in the first-line pembrolizumab group). Negative control analysis using a mismatched outcome model revealed a 6.64% discrepancy and an incompatible survival curve shape. The results were robust to assumptions of random missingness for baseline covariates, to unadjusted differences in baseline metastases and comorbidities, and to differences in the standard of care between the US and Canada related to administration of second-line anti-programmed cell death 1 ligand 1 immunotherapy for patients who initiated first-line chemotherapy., Conclusions and Relevance: The results of this cohort study suggest that, under specific circumstances, OS estimates from US clinical practice data can be adjusted using baseline clinical characteristics to closely approximate OS in selected groups of Canadian patients with advanced NSCLC. These results may have implications for regulatory decision-making and health technology assessment in target populations outside of the US.

Background: Second-generation anaplastic lymphoma kinase ( ALK) gene targeted tyrosine kinase inhibitors (TKIs) alectinib and brigatinib have shown efficacy as front-line treatments for ALK -positive non-small cell lung cancer (NSCLC). No head-to-head data are currently available for brigatinib vs alectinib in the ALK-TKI-naive population., Objective: To estimate the relative overall survival (OS) for brigatinib vs alectinib with indirect treatment comparisons (ITCs) using ALEX and ALTA-1L clinical trial data., Methods: The latest aggregate data from the ALEX trial and final patient-level data from ALTA-1L were used. ITCs were conducted with/without treatment crossover adjustments to estimate relative OS. Bucher methods, anchored matching-adjusted indirect comparisons (MAICs) and unanchored MAICs were employed in ITCs without treatment crossover adjustments. An inverse probability of censoring weight Cox model, a marginal structure model and rank-preserving structural failure time models (with/without re-censoring) within an anchored MAIC were used in ITCs with treatment crossover adjustments. Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported., Results: HRs for brigatinib vs alectinib for relative OS generated from ITCs without treatment crossover adjustments ranged from 0.90 (95% CI: 0.59-1.38) in the unanchored MAIC to 1.20 (95% CI: 0.69-2.11) using the Bucher method. Methods employing treatment switching adjustments estimated HRs for relative OS ranging from 0.74 (95% CI: 0.38-1.45) to 1.11 (95% CI: 0.63-1.94). Results from all ITCs did not indicate statistically different survival profiles., Conclusion: Regardless of ITC methodology, OS is comparable for brigatinib vs alectinib in patients with ALK + NSCLC previously untreated with an ALK inhibitor.

Background: Genomic sequencing is necessary for first-line advanced non-small cell lung cancer (aNSCLC) treatment decision-making. Tissue next generation sequencing (NGS) is standard but tissue quantity, quality, and time-to-results remains problematic. Here, we compare upfront cell-free-DNA (cfDNA) NGS clinical utility against routine tissue testing in patients with aNSCLC., Methods: cfDNA-NGS was performed in consecutive, newly identified aNSCLC patients between December 2019-October 2021 alongside routine tissue genotyping. Variants were interpreted using AMP/ASCO/CAP guidelines. The primary endpoint was tier-1 variants detected on cfDNA-NGS. cfDNA-NGS results were compared to tissue results., Results: Of 311 patients, 282 (91%) had an informative cfDNA-NGS test; 118 (38%) patients had a tier-1 variant identified by cfDNA-NGS. Of 243 patients with paired tissue-cfDNA tests, 122 (50%) tissue tests were informative; 85 (35%) tissue tests identified a tier-1 variant. cfDNA-NGS detected 39 additional tier-1 variants compared to tissue alone, increasing the tier-1 detection rate by 46% (from 85 to 124). The sensitivity of cfDNA-NGS relative to tissue was 75% (25% tissue tier-1 variants were not detected on cfDNA-NGS); 33% of cfDNA tier-1 variants were not identified on tissue tests. Median time from request-to-report was shorter for cfDNA-NGS versus tissue (8 versus 22 days; p < 0.0001). A total of 245 (79%) patients received first-line systemic-therapy: 49 (20%) with cfDNA-NGS results alone. Median time from sampling-to-commencement of first-line treatment was shorter for cfDNA-NGS blood draw versus first tissue biopsy (16 versus 35 days; p < 0.0001)., Conclusions: cfDNA-NGS increased the tier-1 variant detection rate with high concordance with tissue, and halves time-to-treatment. 'Plasma-first' upfront cfDNA-NGS use should be considered routinely for aNSCLC., Competing Interests: Conflict of interest statement WC: WC reports honoraria from AstraZeneca, Janssen, Merck, and Pfizer; research grant funding from the Breast Cancer Trials group; and the Australian Government Research Training scholarship outside of the submitted work. CWM: CWM reports honoraria from AstraZeneca outside of the submitted work. HO: None. HL: None. AM: Has served on advisory boards for Janssen Pharmaceuticals, Merck Pharmaceuticals, Takeda Pharmaceuticals and Genmab Pharmaceuticals. Has received honoraria from Chugai Pharmaceuticals, Novartis Oncology, Faron Pharmaceuticals, Bayer Pharmaceuticals and Janssen Pharmaceuticals. Has received expenses from Amgen Pharmaceuticals and LOXO Oncology. JB: None. MD: None. NY: NY reports honoraria from AstraZeneca outside of the submitted work. SS: SS is an employee and stockholder at Guardant Health Inc. IF: IF is an employee and stockholder at Guardant Health Inc. MK: MK is an employee and stockholder at Guardant Health Inc. RN: RN is an employee and stockholder at Guardant Health Inc. MOB: reports personal fees from MSD, Amgen, Pierre Fabre and iTeos outside of the submitted work. SP: SP reports personal fees from AstraZeneca, Roche, Boehringer Ingelheim, Pfizer, Novartis, Takeda, BMS, MSD, EMD Serono, Bayer, Blueprint, Daiichi Sankyo, Guardant Health, Janssen, GSK, BeiGene, Incyte, Eli Lilly, Amgen outside of the submitted work., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The spleen is a lymphoid organ and we hypothesize that clinical benefit to immunotherapy may present with an increase in splenic volume during treatment. The purpose of this study was to investigate whether changes in splenic volume could be observed in those showing clinical benefit versus those not showing clinical benefit to pembrolizumab treatment in non-small cell lung cancer (NSCLC) patients., Materials and Methods: In this study, 70 patients with locally advanced or metastatic NSCLC treated with pembrolizumab; and who underwent baseline CT scan within 2 weeks before treatment and follow-up CT within 3 months after commencing immunotherapy were retrospectively evaluated. The splenic volume on each CT was segmented manually by outlining the splenic contour on every image and the total volume summated. We compared the splenic volume in those achieving a clinical benefit and those not achieving clinical benefit, using non-parametric Wilcoxon signed-rank test. Clinical benefit was defined as stable disease or partial response lasting for greater than 24 weeks. A p-value of <0.05 was considered statistically significant., Results: There were 23 responders and 47 non-responders based on iRECIST criteria and 35 patients with clinical benefit and 35 without clinical benefit. There was no significant difference in the median pre-treatment volume (175 vs 187 cm3, p = 0.34), post-treatment volume (168 vs 167 cm3, p = 0.39) or change in splenic volume (-0.002 vs 0.0002 cm3, p = 0.97) between the two groups. No significant differences were also found between the splenic volume of patients with partial response, stable disease or progressive disease (p>0.017). Moreover, there was no statistically significant difference between progression-free survival and time to disease progression when the splenic volume was categorized as smaller or larger than the median pre-treatment or post-treatment volume (p>0.05)., Conclusion: No significant differences were observed in the splenic volume of those showing clinical benefit versus those without clinical benefit to pembrolizumab treatment in NSCLC patients. CT splenic volume cannot be used as a potentially simple biomarker of response to immunotherapy., Competing Interests: I have read the journal’s policy and one of the authors of this manuscript (Anna Minchom) have the following competing interests: has served on advisory boards for Janssen Pharmaceuticals and Merck Pharmaceuticals, has received honoraria from Chugai Pharmaceuticals, Novartis Oncology, Faron Pharmaceuticals, Bayer Pharmaceuticals, has received expenses from Amgen Pharmaceuticals and LOXO Oncology. The other authors have declared that no competing interests exist. that this does not alter our adherence to PLOS ONE policies on sharing data and materials.

As advanced non-small cell lung cancer (aNSCLC) is being increasingly divided into rare oncogene-driven subsets, conducting randomised trials becomes challenging. Using real-world data (RWD) to construct control arms for single-arm trials provides an option for comparative data. However, non-randomised treatment comparisons have the potential to be biased and cause concern for decision-makers. Using the example of pralsetinib from a RET fusion-positive aNSCLC single-arm trial (NCT03037385), we demonstrate a relative survival benefit when compared to pembrolizumab monotherapy and pembrolizumab with chemotherapy RWD cohorts. Quantitative bias analyses show that results for the RWD-trial comparisons are robust to data missingness, potential poorer outcomes in RWD and residual confounding. Overall, the study provides evidence in favour of pralsetinib as a first-line treatment for RET fusion-positive aNSCLC. The quantification of potential bias performed in this study can be used as a template for future studies of this nature., (© 2022. The Author(s).)

Aim: To conduct an indirect treatment comparison (ITC) of the relative efficacy of brigatinib and alectinib for progression-free survival in people with tyrosine kinase inhibitor (TKI)-naive  ALK -positive non-small-cell lung cancer (NSCLC). Methods: Final aggregate and patient-level data from the ALTA-1L trial comparing brigatinib to crizotinib and published aggregate data from ALEX (comparing alectinib to crizotinib) were contrasted using Bucher ITC and matching-adjusted indirect comparisons (MAICs). Results: No statistically significant differences were identified between brigatinib and alectinib in reducing the risk of disease progression overall and in patients with baseline central nervous system metastases. Conclusion: Brigatinib appeared similar to alectinib in reducing risk of disease progression for people with TKI-naive ALK -positive NSCLC.

We hypothesize that the study of acute protein perturbation in signal transduction by targeted anticancer drugs can predict drug sensitivity of these agents used as single agents and rational combination therapy. We assayed dynamic changes in 52 phosphoproteins caused by an acute exposure (1 hour) to clinically relevant concentrations of seven targeted anticancer drugs in 35 non-small cell lung cancer (NSCLC) cell lines and 16 samples of NSCLC cells isolated from pleural effusions. We studied drug sensitivities across 35 cell lines and synergy of combinations of all drugs in six cell lines (252 combinations). We developed orthogonal machine-learning approaches to predict drug response and rational combination therapy. Our methods predicted the most and least sensitive quartiles of drug sensitivity with an AUC of 0.79 and 0.78, respectively, whereas predictions based on mutations in three genes commonly known to predict response to the drug studied, for example, EGFR, PIK3CA, and KRAS, did not predict sensitivity (AUC of 0.5 across all quartiles). The machine-learning predictions of combinations that were compared with experimentally generated data showed a bias to the highest quartile of Bliss synergy scores (P = 0.0243). We confirmed feasibility of running such assays on 16 patient samples of freshly isolated NSCLC cells from pleural effusions. We have provided proof of concept for novel methods of using acute ex vivo exposure of cancer cells to targeted anticancer drugs to predict response as single agents or combinations. These approaches could complement current approaches using gene mutations/amplifications/rearrangements as biomarkers and demonstrate the utility of proteomics data to inform treatment selection in the clinic., (©2022 The Authors; Published by the American Association for Cancer Research.)

Importance: There is a need to tailor treatments to patients who are most likely to derive the greatest benefit from them to improve patient outcomes and enhance cost-effectiveness of cancer therapies., Objective: To compare overall survival (OS) between patients with a current or former history of smoking with patients who never smoked and initiated pembrolizumab monotherapy as first-line (1L) treatment for advanced non-small lung cancer (NSCLC)., Design, Setting, and Participants: This retrospective cohort study compared patients diagnosed with advanced NSCLC aged 18 or higher selected from a nationwide real-world database originating from more than 280 US cancer clinics. The study inclusion period was from January 1, 2011, to October 1, 2019., Exposures: Smoking status at the time of NSCLC diagnosis., Main Outcomes and Measures: OS measured from initiation of 1L pembrolizumab monotherapy., Results: In this retrospective cohort study, a total of 1166 patients (median [IQR] age, 72.9 [15.3] years; 581 [49.8%] men and 585 [50.2%] women) were assessed in the primary analysis, including 91 patients [7.8%] with no history of smoking (ie, never-smokers) and 1075 patients [92.2%] who currently or formerly smoked (ie, ever-smokers). Compared with ever-smokers, never-smokers were older (median age [IQR] of 78.2 [12.0] vs 72.7 [15.5] years), more likely to be female (61 [67.0%] vs 524 [48.7%]) and to have been diagnosed with nonsquamous tumor histology (70 [76.9%] vs 738 [68.7%]). After adjustment for baseline covariates, ever-smokers who initiated 1L pembrolizumab had significantly prolonged OS compared to never-smokers (median OS: 12.8 [10.9-14.6] vs 6.5 [3.3-13.8] months; hazard ratio (HR): 0.69 [95% CI, 0.50-0.95]). This trend was observed across all sensitivity analyses for the 1L pembrolizumab cohort, but not for initiators of 1L platinum chemotherapy, for which ever-smokers showed significantly shorter OS compared with never-smokers (HR, 1.2 [95% CI, 1.07-1.33])., Conclusions and Relevance: In patients with advanced NSCLC who received 1L pembrolizumab monotherapy in routine clinical practices in the US, patients who reported a current or former history of smoking at the time of diagnosis had consistently longer OS than never-smokers. This finding suggests that in never-smoking advanced NSCLC, 1L pembrolizumab monotherapy may not be the optimal therapy selection, and genomic testing for potential genomically matched therapies should be prioritized over pembrolizumab in never-smokers.

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

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are standard of care for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) with common mutations (Del19 or L858R); however, 7%-23% of NSCLC tumors harbor uncommon EGFR mutations. These mutations are highly heterogeneous, and developments in detection techniques are helping to identify mutations with little or no clinical data., Patients and Methods: In this retrospective, global, multi-center study (NCT04179890), existing health records were identified for consecutive EGFR TKI-naïve patients with uncommon EGFR mutations (T790M, ex20ins, major uncommon [G719X, L861Q, or S768I], or "other" mutations; compound mutations) treated with erlotinib, gefitinib, afatinib, or osimertinib in first or second line. Endpoints included time-to-treatment failure (TTF), objective response rate (ORR), and overall survival (OS)., Results: Overall, 246 patients (median age: 69.5 years; Asian: 84%) were included from 9 countries. Most patients (92%) received an EGFR TKI as first-line therapy; 54%, 43% and 3% received afatinib, first-generation TKIs, and osimertinib, respectively. Median TTF and OS with EGFR TKIs were 9.9 and 24.4 months; ORR was 43%. In patients treated with first-line chemotherapy (n = 20), median TTF and ORR were 6.6 months and 41%. Outcomes were most favorable in patients with major uncommon or compound mutations. Overall, TTF was 11.3 months with afatinib and 8.8 months with first-generation EGFR TKIs across mutation categories. In most mutation categories, median OS was >2 years., Conclusion: In a real-world setting, EGFR TKIs were the preferred treatment option in patients with uncommon EGFR mutations; strongest outcomes were seen in patients with major uncommon and compound mutations., (© The Author(s) 2022. Published by Oxford University Press.)

Lung cancer classification has been radically transformed in recent years as genomic profiling has identified multiple novel therapeutic targets including MET exon 14 (METex14) alterations and MET amplification. Utilizing targeted therapies in patients with molecularly-defined NSCLC leads to remarkable objective response rates and improved progression-free survival. However, acquired resistance is inevitable. Several recent phase II trials have confirmed that METex14 NSCLC can be treated effectively with MET kinase inhibitors, such as crizotinib, capmatinib, tepotinib, and savolitinib. However, response rates for many MET TKIs are modest relative to the activity of targeted therapy in other oncogene-driven lung cancers, where ORRs are more consistently greater than 60%. In spite of significant gains in the field of MET inhibition in NSCLC, challenges remain: the landscape of resistance mechanisms to MET TKIs is not yet well characterized, and there may be intrinsic and acquired resistance mechanisms that require further characterization to enable increased MET TKI activity. In this review, we overview MET pathway dysregulation in lung cancer, methods of detection in the clinic, recent clinical trial data, and discuss current mechanisms of TKI resistance, exploring emerging strategies to overcome resistance., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard of care for EGFR mutation-positive non-small cell lung cancer (NSCLC). However, optimal sequence of treatment has yet to be defined. Overall survival (OS) is influenced by the availability/use of subsequent therapy after first-line treatment. Emergence of T790M is the main mechanism of resistance to afatinib and second-line osimertinib could be a treatment option in this instance., Methods: In this non-interventional, global study (NCT04179890), existing medical/electronic records were identified for consecutive EGFR TKI-naïve patients with EGFR mutation-positive NSCLC (Del19 or L858R) treated with first-line afatinib and second-line osimertinib in regular clinical practice (n = 191; all T790M-positive). The primary objective was time to treatment failure (TTF). Key secondary objectives were OS and objective response rate (ORR)., Results: At the start of afatinib treatment, median age (range) was 62 years (34-88). Fifty-five percent of patients were female and 67% were Asian. ECOG PS (0/1/≥2) was 31%/57%/12%. Fourteen percent of patients had brain metastases. At the start of osimertinib treatment, ECOG PS (0/1/≥2) was 25%/61%/14% and 14% had brain metastases (rising to 29% at the end of osimertinib treatment). The source of biopsy material (solid/liquid) was 86%/3% at the start of afatinib and 54%/33% at start of osimertinib. Mutations were mainly detected with PCR methods. Overall, median TTF was 27.7 months (95% CI: 24.0-30.2) and median OS was 36.5 months (95% CI: 32.9-41.8). ORR with afatinib and osimertinib was 74% and 45%. TTF, OS and ORR were generally consistent across subgroups., Conclusion: Sequential afatinib and osimertinib demonstrated encouraging activity in patients with EGFR mutation-positive NSCLC and acquired T790M. Activity was observed across all subgroups, including patients with poor ECOG PS or brain metastases. ECOG PS and incidence of brain metastases remained stable prior to, and after, afatinib treatment., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Crizotinib is highly efficacious and more tolerable than chemotherapy for ALK +  non-small-cell lung cancer (NSCLC), but its progression-free survival benefit and intracranial efficacy have limitations. Head-to-head comparisons of next-generation ALK inhibitors in patients with ALK + NSCLC progressing on crizotinib will contribute toward optimizing survival. This international, Phase III, randomized, open-label study (ALTA-3) will therefore assign patients with locally advanced or metastatic ALK + NSCLC progressing on crizotinib to receive either brigatinib 180 mg qd (7-day lead-in at 90 mg qd) or alectinib 600 mg twice daily. The primary end point is progression-free survival as assessed by a blinded Independent Review Committee; the key secondary end point is overall survival. Clinical trial registration number: NCT03596866 (ClinicalTrials.gov).

Background: Immune checkpoint inhibitors (ICIs) are standard of care in advanced non-small cell lung cancer (NSCLC), however their status in patients with poor performance status (PS) is poorly defined. We aimed to evaluate the efficacy and safety of ICIs in NSCLC patients with PS ≥ 2., Methods: We conducted a systematic review and meta-analysis of interventional and observational studies, which reported efficacy and safety data on ICIs in PS ≥ 2 comparing to PS ≤ 1 NSCLC patients. Efficacy endpoints included: Objective Response Rate (ORR), Disease-Control Rate (DCR), Overall Survival (OS), Progression-Free Survival (PFS). Safety endpoint was the incidence of severe (grade≥3) Adverse Events (AE). Random-effects model was applied for meta-analysis. Heterogeneity was assessed using I 2 . The review is registered on PROSPERO (CRD42020162668)., Findings: Sixty-seven studies (n = 26,442 patients) were included. In PS ≥ 2 vs. PS ≤ 1 patients, the pooled odds ratios were: for ORR 0.46 (95 %CI: 0.39-0.54, I 2 :0 %); for DCR 0.39 (95 %CI: 0.33-0.48, I 2 :50 %) and for AEs 1.12 (95 %CI: 0.84-1.48, I 2 :39 %). The pooled hazard ratio for PFS was 2.17 (95 %CI: 1.96-2.39, I 2 :65 %) and for OS was 2.76 (95 %CI: 2.43-3.14, I 2 :76 %). The safety profile was comparable regardless of the PS status., Interpretation: Patients with impaired PS status are, on average, twice less likely to achieve a response when exposed to ICIs when compared with representative PS ≤ 1 population. For lung cancer patients treated with ICIs, the impaired PS is not only prognostic, but also predictive for response, while the safety profile is not affected. Prospective randomized studies are indispensable to determine whether poor PS patients derive benefit from ICIs., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The next-generation ALK inhibitor brigatinib is approved for use in patients with ALK inhibitor-naïve ALK-positive advanced NSCLC and in patients previously treated with crizotinib. A phase II trial showed that brigatinib is active in patients with ALK-positive metastatic NSCLC (mNSCLC) who had progressed on prior crizotinib (response rate 56 %, median PFS 16.7 months, median OS 34.1 months). We report final data from the UVEA-Brig study of brigatinib in ALK inhibitor-pretreated ALK-positive mNSCLC in clinical practice., Methods: UVEA-Brig was a retrospective chart review of patients treated with brigatinib in Italy, Norway, Spain and the UK in an expanded access program. Adults with ALK-positive mNSCLC, including those with brain lesions, resistant to or intolerant of ≥1 prior ALK inhibitor and ECOG performance status ≤3 were eligible. Patients received brigatinib 180 mg once daily with a 7-day lead-in at 90 mg. The objectives were to describe patient characteristics, clinical disease presentation, treatment regimens used and clinical outcomes., Results: Data for 104 patients (male: 43 %; median age: 53 [29-80] years; ECOG performance status 0/1/2/3: 41/41/10/5 %; brain/CNS metastases: 63 %) were analyzed. Patients had received a median of 2 (1-6) lines of systemic therapy prior to brigatinib (37.5 % received ≥3) and a median of 1 (1-5) lines of prior ALK inhibitor-containing therapy (crizotinib 83.6 %; ceritinib 50.0 %; alectinib 6.7 %; lorlatinib 4.8 %). At the time of analysis, 77 patients had discontinued brigatinib. Overall, the response rate was 39.8 %, median PFS was 11.3 (95 % CI:8.6-12.9) months and median OS was 23.3 (95 % CI: 16.0-NR) months. Four patients discontinued brigatinib treatment due to adverse events. 53 patients received systemic therapy after brigatinib, 42 with an ALK inhibitor (lorlatinib, n = 34)., Conclusions: These real-world data indicate the activity and tolerability of brigatinib in patients with ALK-positive mNSCLC who were more heavily pretreated than patients included in clinical trials., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: In ALTA-1 L, first-line brigatinib versus crizotinib significantly prolonged progression-free survival in advanced ALK-positive (ALK+) non-small cell lung cancer (NSCLC). We report health-related quality of life (HRQOL) outcomes from ALTA-1 L., Materials and Methods: HRQOL was assessed using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and lung cancer-specific module (QLQ-LC13). HRQOL time to worsening, change from baseline, and duration of improvement were analyzed., Results: EORTC QLQ-C30 and QLQ-LC13 compliance was >90 % for both groups (n = 131 each). Brigatinib versus crizotinib significantly delayed time to worsening in the EORTC QLQ-C30 global health status (GHS)/QOL (median: 26.74 vs 8.31 months; hazard ratio [HR]: 0.70; 95 % CI: 0.49, 1.00; log-rank P = 0.0485); emotional functioning, social functioning, fatigue, nausea and vomiting, appetite loss, and constipation scales (log-rank P < 0.05); delays in time to worsening for the physical, role, and cognitive functioning scales were not statistically significant. Mean change from baseline showed greater improvement in GHS/QOL and most EORTC QLQ-C30 functional and symptom scales with brigatinib versus crizotinib. Among patients with GHS/QOL improvement, brigatinib had longer duration of improvement versus crizotinib (median: not reached vs 11.99 months); similar results were seen in the physical, role, emotional, and social functioning; fatigue; nausea and vomiting; and appetite loss scales. Median time to worsening in dyspnea (QLQ-LC13) was 23.98 versus 8.25 months (brigatinib vs crizotinib; HR: 0.64; 95 % CI: 0.39, 1.05)., Conclusion: Brigatinib significantly delayed time to worsening and prolonged duration of improvement in GHS/QOL versus crizotinib, supported by improvement in functional and symptom scores. These preliminary analyses suggest brigatinib is the first ALK inhibitor with better HRQOL versus another ALK inhibitor in ALK inhibitor-naive advanced ALK + NSCLC., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Non-small cell lung cancer (NSCLC) accounts for approximately one in five cancer-related deaths, and management requires increasingly complex decision making by health care professionals. Many centers have therefore adopted a multidisciplinary approach to patient care, using the expertise of various specialists to provide the best evidence-based, personalized treatment. However, increasingly complex disease staging, as well as expanded biomarker testing and multimodality management algorithms with novel therapeutics, have driven the need for multifaceted, collaborative decision making to optimally guide the overall treatment process. To keep up with the rapidly evolving treatment landscape, national-level guidelines have been introduced to standardize patient pathways and ensure prompt diagnosis and treatment. Such strategies depend on efficient and effective communication between relevant multidisciplinary team members and have both improved adherence to treatment guidelines and extended patient survival. This article highlights the value of a multidisciplinary approach to diagnosis and staging, treatment decision making, and adverse event management in NSCLC. IMPLICATIONS FOR PRACTICE: This review highlights the value of a multidisciplinary approach to the diagnosis and staging of non-small cell lung cancer (NSCLC) and makes practical suggestions as to how multidisciplinary teams (MDTs) can be best deployed at individual stages of the disease to improve patient outcomes and effectively manage common adverse events. The authors discuss how a collaborative approach, appropriately leveraging the diverse expertise of NSCLC MDT members (including specialist radiation and medical oncologists, chest physicians, pathologists, pulmonologists, surgeons, and nursing staff) can continue to ensure optimal per-patient decision making as treatment options become ever more specialized in the era of biomarker-driven therapeutic strategies., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Background: Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has shown clinical benefit in other tumour types, including first-line non-small-cell lung cancer. We hypothesised that this regimen would improve overall survival in MPM., Methods: This open-label, randomised, phase 3 study (CheckMate 743) was run at 103 hospitals across 21 countries. Eligible individuals were aged 18 years and older, with previously untreated, histologically confirmed unresectable MPM, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m 2 intravenously] plus cisplatin [75 mg/m 2 intravenously] or carboplatin [area under the concentration-time curve 5 mg/mL per min intravenously]) once every 3 weeks for up to six cycles. The primary endpoint was overall survival among all participants randomly assigned to treatment, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02899299, and is closed to accrual., Findings: Between Nov 29, 2016, and April 28, 2018, 713 patients were enrolled, of whom 605 were randomly assigned to either nivolumab plus ipilimumab (n=303) or chemotherapy (n=302). 467 (77%) of 605 participants were male and median age was 69 years (IQR 64-75). At the prespecified interim analysis (database lock April 3, 2020; median follow-up of 29·7 months [IQR 26·7-32·9]), nivolumab plus ipilimumab significantly extended overall survival versus chemotherapy (median overall survival 18·1 months [95% CI 16·8-21·4] vs 14·1 months [12·4-16·2]; hazard ratio 0·74 [96·6% CI 0·60-0·91]; p=0·0020). 2-year overall survival rates were 41% (95% CI 35·1-46·5) in the nivolumab plus ipilimumab group and 27% (21·9-32·4) in the chemotherapy group. Grade 3-4 treatment-related adverse events were reported in 91 (30%) of 300 patients treated with nivolumab plus ipilimumab and 91 (32%) of 284 treated with chemotherapy. Three (1%) treatment-related deaths occurred in the nivolumab plus ipilimumab group (pneumonitis, encephalitis, and heart failure) and one (<1%) in the chemotherapy group (myelosuppression)., Interpretation: Nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the USA as of October, 2020, for previously untreated unresectable MPM., Funding: Bristol Myers Squibb., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated superior progression-free survival (PFS) and improved health-related quality of life (QoL) versus crizotinib in advanced ALK inhibitor-naive ALK-positive non-small cell lung cancer (NSCLC) at first interim analysis (99 events; median brigatinib follow-up, 11.0 months) in the open-label, phase III ALTA-1L trial (ClinicalTrials.gov identifier: NCT02737501). We report results of the second prespecified interim analysis (150 events)., Methods: Patients with ALK inhibitor-naive advanced ALK-positive NSCLC were randomly assigned 1:1 to brigatinib 180 mg once daily (7-day lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was PFS as assessed by blinded independent review committee (BIRC). Investigator-assessed efficacy, blood samples for pharmacokinetic assessments, and patient-reported outcomes were also collected., Results: Two hundred seventy-five patients were randomly assigned (brigatinib, n = 137; crizotinib, n = 138). With median follow-up of 24.9 months for brigatinib (150 PFS events), brigatinib showed consistent superiority in BIRC-assessed PFS versus crizotinib (hazard ratio [HR], 0.49 [95% CI, 0.35 to 0.68]; log-rank P < .0001; median, 24.0 v 11.0 months). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31 to 0.61; median, 29.4 v 9.2 months). No new safety concerns emerged. Brigatinib delayed median time to worsening of global health status/QoL scores compared with crizotinib (HR, 0.70 [95% CI, 0.49 to 1.00]; log-rank P = .049). Brigatinib daily area under the plasma concentration-time curve was not a predictor of PFS (HR, 1.005 [95% CI, 0.98 to 1.031]; P = .69)., Conclusion: Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and QoL over crizotinib, making it a promising first-line treatment of ALK-positive NSCLC.

Background: Therapeutic blockade of the axis of programmed cell death 1 (PD-1) and its ligand (PD-L1) has transformed the management of non-small-cell lung cancer (NSCLC). Clinical trials with pembrolizumab have enrolled patients with performance status (PS) 0-1. However, around 18% of patients with NSCLC are PS2, and the activity and safety of pembrolizumab in these patients is unclear. We aimed to evaluate the safety and efficacy of pembrolizumab in these patients., Methods: We did a multicentre, single-arm, open-label, phase 2 trial (PePS2) in ten hospitals in the UK, in which patients with NSCLC and a rigorous ascription of PS2 were given pembrolizumab 200 mg every 3 weeks. No masking was used in this trial. We stratified the treatment evaluation by tumour proportion score (TPS) and line of therapy. Co-primary outcomes were: (1) durable clinical benefit (DCB), defined as the occurrence of complete response, partial response, or stable disease that continues until at least the second CT scan scheduled at 18 weeks; and (2) toxicity, defined as the occurrence at any time of treatment-related dose delay or treatment discontinuation due to an adverse event. Analysis included all patients who received any pembrolizumab. As well as reporting simple observed incidence for the co-primary outcomes, DCB and toxicity, we also estimated incidence using a model-based method for correlated binary outcomes. This study is registered with ClinicalTrials.gov, NCT02733159; EudraCT, 2015-002241-55; and ISRCTN, 10047797., Findings: Between Jan 4, 2017, and Feb 13, 2018, of 112 patients assessed for eligibility, we recruited 62 patients. 60 patients were evaluable for the co-primary outcomes. Median age was 72 years (IQR 65-75); 33 (55%) of participants were male and 27 (45%) were female. The observed incidence for DCB was 38% (95% CI 21-57) in first-line patients (n=24) and 36% (22-52) in subsequent-line patients (n=36); DCB was 22% (11-41) in patients with a TPS less than 1% (n=27), 47% (25-70) in patients with a TPS of 1-49% (n=15), and 53% (30-75) in patients with a TPS of 50% or greater (n=15). An increase in DCB incidences with TPS was also shown in model-based estimates. Toxicity was observed in 28% (95% CI 19-41) of patients, 11 (18%) of 60 due to dose delay and 6 (10%) of 60 due to drug discontinuation. No grade 5 treatment-related adverse events were observed and no early deaths were attributed to hyperprogression. The most common grade 3-4 adverse events were dyspnoea (n=9), hyponatraemia (n=5), and anorexia (n=4). There were ten serious adverse events considered to be related to treatment, comprising diarrhoea (n=3) and acute kidney injury, adrenal insufficiency, hyperbilirubinaemia, oral mucositis, rash, urinary tract infection, and vomiting (n=1 each)., Interpretation: Patients with NSCLC of PS2 are a group of patients of unmet therapeutic need. The PePS2 trial shows that pembrolizumab can be safely administered to these patients, with no increase in the risk of immune-related or other toxicities. Efficacy outcomes are at least as good as those in patients with PS0-1 and the data provides clinicians with the confidence to incorporate pembrolizumab into the treatment pathway of patients with NSCLC of PS2., Funding: Merck, Sharp & Dohme., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aims: The optimal management of stage III non-small cell lung cancer (NSCLC) is widely debated and is a rapidly evolving area. However, less than one in five stage III patients in England receive optimal multimodality treatment. The aim of this study was to map commonalities and differences in clinician judgement as well as infrastructure and resources for managing stage III NSCLC., Materials and Methods: We carried out a national survey of practice in stage III NSCLC management in the UK using a 30-min web-based survey. Invitations were sent via e-mail to the British Thoracic Oncology Group and the Society of Cardiothoracic Surgery membership and a healthcare professional market research panel., Results: In total, 160 respondents completed the survey. Although opinion was variable, there was a preference for surgery and adjuvant chemotherapy in stage III N2 (single station) NSCLC that could be treated with lobectomy, but this preference switched to chemoradiotherapy in single-station N2 requiring a pneumonectomy or multi-station N2. The PD-L1 status influenced the treatment decision in 'potentially resectable' N2 for a number of clinicians who opted for concurrent chemoradiotherapy with adjuvant durvalumab when PD-L1 ≥ 1%. A joint clinic with surgeons and oncologists was considered the most important factor for shared decision making with patients. There are barriers to recommending trimodality treatment, e.g. concerns over the negative impact on quality of life. A proportion of clinicians favoured palliative treatment in certain clinical scenarios, including supraclavicular fossa lymph node metastases, patients with borderline fitness or high PD-L1 expressors >50%., Discussion: This survey has highlighted the need for infrastructure development, such as reflex PD-L1 testing and joint surgical and oncology clinics. Further research into the impact of multimodality treatment on quality of life and education to improve confidence in multimodality treatment could all drive improvements in stage III NSCLC management., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are directed against oncogenic drivers that are more prevalent in patients with light exposure to tobacco smoke 1-3 . As this group represents around 20% of all patients with lung cancer, the discovery of stratified medicine options for tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline the investigation of genotype-based treatments by screening tumours for multiple genomic alterations and triaging patients to one of several genotype-matched therapeutic agents. Here we report the current outcomes of 19 drug-biomarker cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial in NSCLC. We use next-generation sequencing to match patients to appropriate targeted therapies on the basis of their tumour genotype. The Bayesian trial design enables outcome data from open cohorts that are still recruiting to be reported alongside data from closed cohorts. Of the 5,467 patients that were screened, 2,007 were molecularly eligible for entry into the trial, and 302 entered the trial to receive genotype-matched therapy-including 14 that re-registered to the trial for a sequential trial drug. Despite pre-clinical data supporting the drug-biomarker combinations, current evidence shows that a limited number of combinations demonstrate clinically relevant benefits, which remain concentrated in patients with lung cancers that are associated with minimal exposure to tobacco smoke.

In the past 10 years, a deeper understanding of the immune landscape of cancers, including immune evasion processes, has allowed the development of a new class of agents. The reactivation of host antitumor immune response offers the potential for long-term survival benefit in a portion of patients with thoracic malignancies. The advent of programmed cell death protein 1/programmed death ligand-1 immune checkpoint inhibitors (ICIs), both as single agents and in combination with chemotherapy, and more recently, the combination of ICI, anti-programmed cell death protein 1, and anticytotoxic T-lymphocyte antigen 4 antibody, have led to breakthrough therapeutic advances for patients with advanced NSCLC, and to a lesser extent, patients with SCLC. Encouraging activity has recently emerged in pretreated patients with thymic carcinoma (TC). Conversely, in malignant pleural mesothelioma, pivotal positive signs of activity have not been fully confirmed in randomized trials. The additive effects of chemoradiation and immunotherapy suggested intriguing potential for therapeutic synergy with combination strategies. This has led to the introduction of ICI consolidation therapy in stage III NSCLC, creating a platform for future therapeutic developments in earlier-stage disease. Despite the definitive clinical benefit observed with ICI, primary and acquired resistance represent well-known biological phenomena, which may affect the therapeutic efficacy of these agents. The development of innovative strategies to overcome ICI resistance, standardization of new patterns of ICI progression, identification of predictive biomarkers of response, optimal treatment duration, and characterization of ICI efficacy in special populations, represent crucial issues to be adequately addressed, with the aim of improving the therapeutic benefit of ICI in patients with thoracic malignancies. In this article, an international panel of experts in the field of thoracic malignancies discussed these topics, evaluating currently available scientific evidence, with the final aim of providing clinical recommendations, which may guide oncologists in their current practice and elucidate future treatment strategies and research priorities., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

The introduction of licensed front-line immunotherapies has heralded a new era for the treatment of non-oncogene-addicted, advanced non-small cell lung cancer (NSCLC). Yet as with all evolutions in clinical management, changes in practice can outpace the availability of the clinical evidence needed to inform subsequent therapeutic decision making. At the time of writing, there is limited available evidence on the optimum therapeutic options after progression on immunotherapy. Further research is needed to define mechanisms of immunotherapy resistance in patients with advanced NSCLC, and to understand the implications for subsequent treatment response. Pending the availability of robust clinical data and proven therapeutic options to underpin an optimized therapeutic pathway after progression on immunotherapy, attention must turn to the potential utility of currently licensed agents and any available supporting clinical data in this setting. Within this context we review the mechanistic arguments and supporting evidence for the use of anti-angiogenic agents as a means of targeting immunosuppression within the tumor microenvironment. We consider whether VEGF inhibition may help to normalize the tumor vasculature and to address immunosuppression - reinstating, and potentially enhancing, the effect of subsequent therapies. We also highlight evidence needs and signpost ongoing trials that should enable current clinical opinion in this area to be replaced by robust, evidence-based guidance., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: CheckMate 171 (NCT02409368) is an open-label, multicentre, phase 2 trial of nivolumab in previously treated advanced squamous non-small cell lung cancer (NSCLC), conducted as part of a post-approval commitment to the European Medicines Agency (EMA). We report outcomes from this trial., Methods: Patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 and disease progression during/after ≥1 systemic treatment (≥1 being platinum-based chemotherapy) for advanced or metastatic disease were treated with nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary end-point was incidence of grade 3-4 treatment-related select adverse events (AEs). Other end-points included overall survival (OS) and safety., Results: Of 811 patients treated, 103 had ECOG PS 2; 278 were aged ≥70 years and 125 were ≥75 years of age. Minimum follow-up was ~18 months. Safety was similar across populations; the most frequent grade 3-4 treatment-related select AEs in all treated patients were diarrhoea (1%), increased alanine aminotransferase (ALT, 1%), pneumonitis (0.7%), colitis (0.6%) and increased aspartate aminotransferase (AST, 0.5%). Median OS was similar in all treated patients and those aged ≥70 and ≥75: 10.0 months, 10.0 months and 11.2 months, respectively. Median OS was 5.2 months in patients with ECOG PS 2., Conclusion: These results suggest that nivolumab is well tolerated and active in patients with advanced, relapsed squamous NSCLC, including the elderly, with OS outcomes consistent with phase 3 data. In patients with ECOG PS 2, nivolumab had similar tolerability, but outcomes were worse, as expected in this difficult-to-treat, poor prognosis population., Clinical Trial Registration: NCT02409368., Competing Interests: Conflict of interest statement E.F. reports receiving personal fees from AbbVie, AstraZeneca, Blueprint medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, priME Oncology, Roche, Samsung, Springer, Takeda, and Touchtime, outside the submitted work. A.A. reports receiving personal fees from Boehringer Ingelheim, Eli Lilly, MSD, and Pfizer, grants from Celgene, and grants and personal fees from Bristol-Myers Squibb and Roche, outside the submitted work. T.C. reports receiving personal fees from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Ipsen, Janssen, MSD, Novartis/GSK, Pfizer, Roche, Sanofi, and Servier, outside the submitted work. M.C., K.L., M.S., E.C., M.A.G., D.I., and J.M. have nothing to disclose. R.C. reports receiving grants from Bristol-Myers Squibb during the conduct of the study, and personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly Oncology, MSD, Novartis, Pfizer, Roche, and Takeda, outside the submitted work. R.G. reports receiving personal fees from Bristol-Myers Squibb, outside the submitted work. L. P-A. reports receiving personal fees from Amgen, Bayer, Blueprint, Eli Lilly, Incyte, Merck, MSD, Novartis, Roche, and Takeda, and grants and personal fees from AstraZeneca and Bristol-Myers Squibb, outside the submitted work. R.D. reports receiving travel grants from Amgen and Roche, receiving travel grants and holding advisory position for Pfizer, and acting in an advisory role for Ely Lilly and Novartis, outside the submitted work. J.J. reports receiving personal fees from AstraZeneca, Bristol-Myers Squibb, MSD, Pfizer, Roche, and Takeda, and receiving travel support from Roche, outside the submitted work. W.A. reports receiving non-financial support from Boehringer Ingelheim and Bristol-Myers Squibb, personal fees from AstraZeneca and Pfizer, personal fees and non-financial support from Amgen and Roche, outside the submitted work. J.P.V.M. reports receiving travel support from Bristol-Myers Squibb and institutional grants from Pfizer, outside the submitted work. J.W. reports receiving personal fees from AbbVie, AstraZeneca, Blueprint, Boehringer Ingelheim, Chugai, Eli Lilly, Ignyta, Loxo, Roche, and Takeda, and grants and personal fees from Bristol-Myers Squibb, Janssen, MSD, Novartis, and Pfizer, outside the submitted work. A.L. and A.A. were employees of Bristol-Myers Squibb during the conduct of the study and A.A. has received company stock from Bristol-Myers Squibb. S.P. reports receiving personal fees from Bristol-Myers Squibb during the conduct of the study; personal fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Elsevier, EMD Serono, Guardant Health, Medscape, MSD, Novartis, OncLive, Pfizer, Roche, Takeda, and Tesaro, outside the submitted work., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)