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Background: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd., Patients and Methods: Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC., Results: In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% [95% confidence interval (CI) 30.0% to 52.7%], median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified., Conclusions: In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy., Competing Interests: Disclosure HAY has received consulting fees from AstraZeneca, Daiichi Sankyo, Cullinan, Blueprint Medicines, Janssen, Black Diamond, and Takeda. CB has received consulting fees from AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Takeda, Turning Point Therapeutics, Guardant Health, Regeneron, and Silverback Therapeutics; institutional research funding grants/contracts from Loxo, AstraZeneca, Pfizer, Spectrum Pharmaceuticals, Blueprint Medicines, Daiichi Sankyo, Rain Therapeutics, AbbVie, Turning Point Therapeutics, Lilly, and Janssen. D-WK has received institutional research funding grants/contracts from Alpha Biopharma, AstraZeneca, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, Turning Point Therapeutics, Xcovery, Yuhan, Boehringer Ingelheim, Amgen, Daiichi Sankyo, Chong Kun Dang Pharmaceutical, BridgeBio Pharma, GSK, and Merck. MLJ has received consulting fees from Genentech/Roche, AstraZeneca, Calithera Biosciences, Merck, Sanofi, Mirati Therapeutics, Ribon Therapeutics, AbbVie, GSK, Gritstone Bio, Janssen Oncology, Lilly, Amgen, Daiichi Sankyo, Eisai, Axelia Oncology, Black Diamond Therapeutics, CytomX Therapeutics, EcoR1 Capital, Editas Medicine, Genmab, IDEAYA Biosciences, ITeos Therapeutics, Oncorus, Regeneron, Turning Point Therapeutics, Astellas Pharma, Checkpoint Therapeutics, Genocea Biosciences, Molecular Axiom, Novartis, Revolution Medicines, Takeda, and VBL Therapeutics; payment/honoraria from AbbVie, AstraZeneca, Genentech, Incyte, Merck, Pfizer, and Sanofi; research funding/grants from EMD Serono, Kadmon, Janssen, Mirati Therapeutics, Genmab, Pfizer, AstraZeneca, Stemcentrx, Novartis, Array BioPharma, Regeneron, Merck, Hengrui Pharmaceutical, Lycera, BeiGene, Tarveda Therapeutics, Loxo, AbbVie, Boehringer Ingelheim, Guardant Health, Daiichi Sankyo, Sanofi, CytomX Therapeutics, Dynavax Technologies, Corvus Pharmaceuticals, Incyte, Genocea Biosciences, Gritstone Bio, Amen, Genentech/Roche, Adaptimmune, Syndax, Neovia Oncology, Takeda, Shattuck Labs, GSK, Apexigen, Atreca, OncoMed, Lilly, Immunocore, University of Michigan, TCR2 Therapeutics, Arcus Biosciences, Ribon Therapeutics, BerGenBio, Calithera Biosciences, Tmunity Therapeutics, Seven and Eight Biopharmaceuticals, Rubius Therapeutics, Curis, Silicon Therapeutics, Dracen, PMV Pharma, Artios, BioAtla, Elicio Therapeutics, Erasca, Harpoon, Helsinn Healthcare, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Memorial Sloan Kettering Cancer Center, NeoImmune Tech, Numab, RasCal Therapeutics, Relay Therapeutics, Revolution Medicines, Tempest Therapeutics, Tizona Therapeutics, Turning Point Therapeutics, Vyriad, Y-mAbs Therapeutics, Exelixis, Fate Therapeutics, Merus, Black Diamond Therapeutics, Kartos Therapeutics, Carisma Therapeutics, Rain Therapeutics, Nuvalent, Palleon Pharmaceuticals, IMPAC Medical Systems, and EQRx. HH has received grants/contracts from AstraZeneca K.K., Astellas Pharma, MSD K.K., Ono Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma K.K., Pfizer Japan, Bristol Myers Squibb, Eli Lilly Japan K.K., Chugai Pharmaceutical, Daiichi Sankyo, Merck Serono, Merck Biopharma, Takeda, Taiho Pharmaceutical, SymBio Pharmaceuticals, AbbVie, inVentiv Health Japan, ICON Japan K.K., Gritstone Bio, Parexel International, Kissei Pharmaceutical, EPS Corporation, Syneos Health, Pfizer R&D Japan G.K., A2 Healthcare, Quintiles/IQVIA Services Japan K.K., EP-CRSU CO, Linical, Eisai, CMIC Shift Zero K.K., Kyowa Hakko Kirin, Bayer Yakuhin, EPS International, and Otsuka Pharmaceutical; payment/honoraria from Amgen K.K, AstraZeneca K.K., Boehringer Ingelheim Japan, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan K.K., Guardant Health, Kyorin Pharmaceutical, Merck Biopharma, MSD K.K., Novartis Pharma K.K., Ono Pharmaceutical, Shanghai Haihe Biopharma, Taiho Pharmaceutical, Pfizer, and Takeda outside the submitted work. MN has received payment/honoraria from Pfizer, Bristol Myers Squibb Japan, Ono Pharmaceutical, Chugai Pharma, Taiho Pharmaceutical, AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Lilly, Nippon Kayaku, Takeda, Merck, Janssen, and Amgen; institutional research funding grants/contracts from Bristol Myers Squibb, Taiho Pharmaceutical, Pfizer, AstraZeneca, Lilly, MSD, Merck, Takeda, Amgen, and Janssen. JC-HY has received grants, personal fees, and advising/consulting institutional fees from AstraZeneca; personal fees and advising/consulting institutional fees from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Merck KGaA, MSD, Novartis, Roche/Genentech, Takeda, and Yuhan Pharmaceuticals; advising/consulting institutional fees from Eli Lilly and Johnson & Johnson; advising/consulting fees from Ono Pharmaceutical, Pfizer, Puma Technology, Gilead, and GSK. W-CS has received advising/consulting fees from Bayer Schering Pharma, MSD Oncology, Lilly, and Merck. KAG has received advising/consulting fees from Takeda, AstraZeneca, Rakuten Medical, Regeneron; research funding grants/contracts from Pharmacyclics, AstraZeneca, AbbVie, BerGenBio, and Pfizer. MK has received payment/honoraria from AstraZeneca and Celgene. EFS has received personal fees from AstraZeneca, Daiichi Sankyo, Merck KGaA, and Boehringer Ingelheim; advising/consulting and research funding grants/contracts and institutional fees from Lilly, AstraZeneca, Boehringer Ingelheim, Roche/Genentech, Bristol Myers Squibb, Merck KGaA, MSD Oncology, Takeda, Bayer, Novartis, Daiichi Sankyo, and Seattle Genetics. CES has received personal fees and advising/consulting from AbbVie, BerGenBio, ARMO BioSciences, Lilly, Mirati Therapeutics, Sanofi/Regeneron, Caris Life Sciences, and Merck; research funding grants/contracts from Vaccinex, Seattle Genetics, Daiichi Sankyo, and Infinity Pharmaceuticals. EF has received institutional research funding grants/contracts from Grant for Oncology Innovation, Merck Healthcare KGaA, and Fundación Merck Salud; consulting fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, GSK, Ipsen, Janssen, Merck Serono, MSD, Novartis, Peptomyc, Pfizer, Sanofi, Takeda, and Turning Point; payment/honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Janssen, Medical Trends, Medscape, Merck Serono, MSD, PeerVoice, Pfizer, Sanofi, Takeda, and Touch Oncology; other financial aid from Grifols as an independent member of the board. HM has received grants, personal fees, and advising/consulting institutional fees from Chugai Pharma, GAIA BioMedicine, Taiho Pharmaceutical, AstraZeneca, Lilly Japan, Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD, Takeda, Novartis, Daiicho Sankyo, Eisai, Nippon Kayaku, Pfizer, Boehringer Ingelheim, and AbbVie; institutional research funding grants/contracts from AstraZeneca, AbbVie, Takeda, Daiichi Sankyo, IQVIA, and Chugai Pharma. XS, SS, P-DF, MF, YT, PP, DWS, and DS are employees of and have stock ownership in Daiichi Sankyo. PAJ has received royalties for licenses from Labcorp; consulting fees from AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceutical, Eli Lilly, SFJ Pharmaceuticals, VORONOI, Daiichi Sankyo, Biocartis, Novartis, Sanofi, Takeda, Mirati Therapeutics, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, and AbbVie; had stock ownership in Gatekeeper Pharmaceuticals. S-WK has declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for both EGFR-TKI sensitizing ( EGFRm) and T790M resistance mutations. AURA (NCT01802632) is a phase I/II clinical trial to determine the dose, safety, and efficacy of osimertinib. This article reports the results from the phase II extension component. Patients and Methods Patients with EGFR-TKI-pretreated EGFRm- and T790M-positive advanced non-small-cell lung cancer (NSCLC) received once-daily osimertinib 80 mg. T790M status was confirmed by central testing from a tumor sample taken after the most recent disease progression. Patients with asymptomatic, stable CNS metastases that did not require corticosteroids were allowed to enroll. The primary end point was objective response rate (ORR) by independent radiology assessment. Secondary end points were disease control rate, duration of response, progression-free survival (PFS), and safety. Patient-reported outcomes comprised an exploratory objective. Results In total, 201 patients received treatment, with a median treatment duration of 13.2 months at the time of data cutoff (November 1, 2015). In evaluable patients (n = 198), ORR was 62% (95% CI, 54% to 68%), and the disease control rate was 90% (95% CI, 85 to 94). Median duration of response in 122 responding patients was 15.2 months (95% CI, 11.3 to not calculable). Median PFS was 12.3 months (95% CI, 9.5 to 13.8). The most common possibly causally related adverse events (investigator assessed) were diarrhea (43%; grade ≥ 3, < 1%) and rash (grouped terms; 40%; grade ≥ 3, < 1%). Interstitial lung disease (grouped terms) was reported in eight patients (4%; grade 1, n = 2; grade 3, n = 3; grade 5, n = 3). Conclusion In patients with EGFRm T790M advanced NSCLC who progress after EGFR-TKI treatment, osimertinib provides a high ORR, encouraging PFS, and durable response.

Purpose Patients with extensive-stage disease small-cell lung cancer (SCLC) have poor survival outcomes despite first-line chemotherapy with etoposide and platinum. This randomized, double-blind phase III study evaluated the efficacy and safety of ipilimumab or placebo plus etoposide and platinum in patients with newly diagnosed extensive-stage disease SCLC. Patients and Methods Patients were randomly assigned at a ratio of one to one to receive chemotherapy with etoposide and platinum (cisplatin or carboplatin) plus ipilimumab 10 mg/kg or placebo every 3 weeks for a total of four doses each in a phased induction schedule (chemotherapy in cycles one to four; ipilimumab or placebo beginning in cycle three up to cycle six), followed by ipilimumab or placebo maintenance every 12 weeks. Primary end point was overall survival (OS) among patients receiving at least one dose of blinded study therapy. Results Of 1,132 patients randomly assigned, 954 received at least one dose of study therapy (chemotherapy plus ipilimumab, n = 478; chemotherapy plus placebo, n = 476). Median OS was 11.0 months for chemotherapy plus ipilimumab versus 10.9 months for chemotherapy plus placebo (hazard ratio, 0.94; 95% CI, 0.81 to 1.09; P = .3775). Median progression-free survival was 4.6 months for chemotherapy plus ipilimumab versus 4.4 months for chemotherapy plus placebo (hazard ratio, 0.85; 95% CI, 0.75 to 0.97). Rates and severity of treatment-related adverse events were similar between arms, except for diarrhea, rash, and colitis, which were more frequent with chemotherapy plus ipilimumab. Rate of treatment-related discontinuation was higher with chemotherapy plus ipilimumab (18% v 2% with chemotherapy plus placebo). Five treatment-related deaths occurred with chemotherapy plus ipilimumab and two with chemotherapy plus placebo. Conclusion Addition of ipilimumab to chemotherapy did not prolong OS versus chemotherapy alone in patients with newly diagnosed extensive-stage disease SCLC. No new or unexpected adverse events were observed with chemotherapy plus ipilimumab. Several ongoing studies are evaluating ipilimumab in combination with programmed death-1 inhibitors in SCLC.

In this article the authors report on the short-term impact of incorporating biomarker feedback about exposure and genetic susceptibility into minimal-contact quit-smoking counseling (QSC). Four hundred and twenty-seven smokers were randomized to 1 of 3 treatments: (a) QSC, (b) QSC + exposure biomarker feedback (EBF) about carbon monoxide in exhaled breath, or (b) QSC + EBF + biomarker feedback about genetic susceptibility to lung cancer (SBF). We observed significant immediate positive effects of SBF, compared with EBF and QSC on perceived risk, perceived quitting benefits, and fear arousal. However, at the 2-month follow-up, there were no group differences in quit rates. SBF did lead to significant reductions in the number of cigarettes smoked for smokers who were in the preparation stage. Smokers in the EBF and QSC conditions showed reductions in depressive symptoms by 2 months, but smokers in the SBF condition did not. In the context of QSC, genetic feedback may heighten vulnerability and possibly promote distress, but may not immediately enhance quitting in most smokers.