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Background: The role of adding immune checkpoint inhibitors to chemotherapy in tyrosine kinase inhibitor (TKI)-resistant, epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) remains unknown. We carried out a meta-analysis to comprehensively assess the role of chemoimmunotherapy combinations, with and without vascular endothelial growth factor (VEGF) inhibition, in TKI-resistant, EGFR-mutant NSCLC., Materials and Methods: We systemically searched PubMed/MEDLINE and the proceedings of key annual meetings between 2018 and 2024 to identify randomized studies that evaluated chemoimmunotherapy combinations and included patients with EGFR-mutant NSCLC. Six randomized, phase III trials (CheckMate-722, KEYNOTE-789, ORIENT-31, IMpower150, IMpower151, and ATTLAS) were included in the meta-analysis. To compare progression-free survival (PFS) and overall survival (OS) outcomes, we extracted hazard ratio (HR) and 95% confidence interval (CI) for PFS and OS for EGFR-mutant subgroups from each study. We used the fixed effects model with inverse variance weighting to estimate the overall effect sizes for PFS and OS for chemoimmunotherapy combinations (with and without VEGF inhibitors) versus control arms., Results: A total of 1772 patients with EGFR-mutant NSCLC were included. Adding programmed death-ligand 1 [PD-(L)1] inhibitors to chemotherapy significantly improved PFS (HR 0.77, 95% CI 0.67-0.88, P = 0.0002). This effect was greater when both PD-(L)1 and VEGF inhibition were utilized (PFS: HR 0.62, 95% CI 0.52-0.73, P < 0.0001). The pooled OS HR was 0.86 (95% CI 0.75-1.00, P = 0.0429) with the chemotherapy + PD-(L)1 combinations and 0.98 (95% CI 0.79-1.22, P = 0.8463) with dual PD-(L)1/VEGF inhibition., Conclusions: Despite modest improvements in PFS, most pronounced when both PD-(L)1 and VEGF inhibitors are added to chemotherapy, neither strategy led to clinically meaningful improvements in OS. Our results do not support the broad use of chemoimmunotherapy combinations in TKI-resistant, EGFR-mutant lung cancer. Novel immunotherapy approaches are urgently needed for oncogene-driven NSCLC., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: First-line nivolumab plus ipilimumab prolongs survival versus chemotherapy in advanced non-small-cell lung cancer (NSCLC). We further characterized clinical benefit with this regimen in a large pooled patient population and assessed the effect of response on survival., Patients and Methods: Data were pooled from four studies of first-line nivolumab plus ipilimumab in advanced NSCLC (CheckMate 227 Part 1, 817 cohort A, 568 Part 1, and 012). Overall survival (OS), progression-free survival (PFS), objective response rate, duration of response, and safety were assessed. Landmark analyses of OS by response status at 6 months and by tumor burden reduction in responders to nivolumab plus ipilimumab were also assessed., Results: In the pooled population (N = 1332) with a minimum follow-up of 29.1-58.9 months, median OS was 18.6 months, with a 3-year OS rate of 35%; median PFS was 5.4 months (3-year PFS rate, 17%). Objective response rate was 36%; median duration of response was 23.7 months, with 38% of responders having an ongoing response at 3 years. In patients with tumor programmed death-ligand 1 (PD-L1) <1%, ≥1%, 1%-49%, or ≥50%, 3-year OS rates were 30%, 38%, 30%, and 48%. Three-year OS rates were 30% and 38% in patients with squamous or non-squamous histology. Efficacy outcomes in patients aged ≥75 years were similar to the overall pooled population (median OS, 20.1 months; 3-year OS rate, 34%). In the pooled population, responders to nivolumab plus ipilimumab at 6 months had longer post-landmark OS than those with stable or progressive disease; 3-year OS rates were 66%, 22%, and 14%, respectively. Greater depth of response was associated with prolonged survival; in patients with tumor burden reduction ≥80%, 50% to <80%, or 30% to <50%, 3-year OS rates were 85%, 72%, and 44%, respectively. No new safety signals were identified in the pooled population., Conclusion: Long-term survival benefit and durable response with nivolumab plus ipilimumab in this large patient population further support this first-line treatment option for advanced NSCLC., Competing Interests: Disclosure HB reports advisory/consulting fees, travel, accommodation, and expenses from Amgen, Bristol Myers Squibb, Genentech, Lilly, Merck, and Novartis; advisory/consulting fees from AbbVie, AstraZeneca, BioNTech AG, Boehringer Ingelheim, Cantargia AB, EMD Serono, Genmab, HUYA Bioscience International, Nuclaei, Pfizer, PharmaMar, Regeneron, Rgenix, Sonnet, Takeda, and Trovagene; honoraria from Amgen, Axiom Biotechnologies, Bristol Myers Squibb, Celgene, and Pfizer; research funding from Bristol Myers Squibb, Celgene, Lilly, Merck, and Millennium; stock interest with Nuclaei, Rgenix, and Sonnet; travel, accommodation, and expenses from Clovis Oncology; data safety monitoring board with Incyte and University of Pennsylvania; and ad boards with Guardant, Natera, and OncoCyte. TEC reports advisory/consulting fees, travel, accommodation, and expenses from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Janssen, Merck Sharp & Dohme (MSD), Novartis/GlaxoSmithKline, Pfizer, Roche, Sanofi, and Servier. J-SL reports advisory/consulting fees from AstraZeneca and Ono Pharmaceutical. AP reports speaker fees, expert testimony, travel, accommodation, and expenses from Boehringer Ingelheim, Bristol Myers Squibb, and MSD; speaker fees and expert testimony from Roche, speaker fees from Pfizer; and speaker fees, travel, accommodation, and expenses from AstraZeneca. RBC reports advisory/consulting fees from AstraZeneca, Bristol Myers Squibb, MSD, Roche, and Takeda. MG reports advisory fees from Celularity and Guardant 360; and speaker fees from Guardant 360. YO reports advisory/consulting fees, honoraria, and research funding from AstraZeneca and Ono Pharmaceutical; and honoraria and research funding from Bristol Myers Squibb Japan. MN reports advisory/consulting fees, honoraria, and research funding from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Lilly, MSD, Ono Pharmaceuticals, Taiho Pharmaceutical, and Takeda; advisory/consulting fees from AbbVie and Teijin Pharma; honoraria and research funding from Janssen, Merck, Novartis, and Pfizer; and honoraria from Boehringer Ingelheim and Nippon Kayaku. JG reports grant support from Advaxis, AstraZeneca, Bristol Myers Squibb, Genentech, Merck, and Pfizer; consulting and writing fees from Bristol Myers Squibb; and consulting fees from AstraZeneca, Genentech, and Pfizer. NR reports consulting fees and honoraria from AstraZeneca, Bristol Myers Squibb, G1 Therapeutics, Genentech, Merck, and Roche; research funding from Merck; honoraria from Novartis and Celgene; expert testimony fees from Bristol Myers Squibb and Celgene; speaker’s bureau fees from Bristol Myers Squibb; personal fees from AbbVie, Amgen, Jazz, Regeneron, and Sanofi; other fees from AbbVie; and a grant from Amgen. DRS reports grant support from Aeglea BioTherapeutics, Agios, Apollomics, Arcus, Arrys Therapeutics, Astellas Pharma, Bayer, BeiGene, BIND Therapeutics, BioNTech, Blueprint Medicine, Calithera, Celgene, Celldex, Clovis Oncology, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, Eli Lilly, EMD Serono, Evelo, G1 Therapeutics, GlaxoSmithKline, GRAIL, Hutchinson MediPharma, ImClone Systems, ImmunoGen, Incyte, Ipsen, Janssen, Kronos Bio, Loxo Oncology, MacroGenics, MedImmune, Merck, Molecular Partners, Molecular Templates, Nektar, Neon Therapeutics, Novocure, Oncologie, PTC Therapeutics, PureTech Health, Razor Genomics, Repare Therapeutics, Rgenix, Takeda, Tesaro, Tizona Therapeutics, Transgene, University of Texas-Southwestern, and Verastem; and consulting support from Amgen, BeiGene, Curio Science, Eli Lilly, EMD Serono, Evidera, Exelixis, GlaxoSmithKline, Intellisphere, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, Molecular Templates, Novocure, Puma Biotechnology, Regeneron, and Sanofi-Aventis. SSR reports advisory/consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sanyo, Eisai, Genentech/Roche, GlaxoSmithKline, Lilly, Merck, Sanofi, Takeda; and research funding from Advaxis, AstraZeneca, Bristol Myers Squibb, EMD Serono, Genmab, GlaxoSmithKline, Merck, Takeda, Tesaro. LGPA reports travel, accommodation, and expenses from AstraZeneca, Bristol Myers Squibb, MSD, Pfizer, Roche, and Takeda; honoraria from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Lilly, Merck Serono, Mirati, MSD, Novartis, Pfizer, PharmaMar, Roche/Genetech, Sanofi, Servier, and Takeda; speaker fees from Bristol Myers Squibb, Lilly, Merck Serono, MSD Oncology, Pfizer, and Roche/Genentech; research funding from AstraZeneca, Bristol Myers Squibb, MSD, PharmaMar; and personal fees from Altum Sequencing and Genomica. JFG reports consulting fees and honoraria from AstraZeneca, Blueprint, Bristol Myers Squibb, EMD Serono, Gilead, Glyde Bio, iTeos, Karyopharm, Loxo/Lilly, Merck, Moderna, Novartis, Oncorus, Pfizer, Regeneron, Silverback Therapeutics, and Takeda; grant support from Adaptimmune, Alexo, Array Biopharma, Blueprint, Bristol Myers Squibb, Jounce, Merck, Moderna, Novartis, and Tesaro; and an immediate family member who is an employee with equity at Ironwood Pharmaceuticals. MR reports advisory/consulting fees, travel, accommodation, and expenses from AbbVie and Amgen; advisory/consulting fees, speaker fees, expert testimony, travel, accommodation, and expenses from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Merck, MSD, Novartis, Pfizer, and Roche; and advisory/consulting fees from Samsung. MM reports advisory/consulting fees Alfasigma, Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Incyte, iOnctura, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, and SciClone. KJO reports advisory/consulting fees, speaker fees, expert testimony, honoraria, travel, accommodation, and expenses from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Lilly Oncology, MSD, Pfizer, and Roche; advisory/consulting fees, speaker fees, expert testimony and honoraria from Novartis; advisory/consulting fees, speaker fees, and honoraria from Teva; advisory/consulting fees and honoraria from Natera, Takeda, Tristar, and Yuhan; and being a shareholder at Carpe Vitae Pharmaceuticals, DGC diagnostics, Foundation Medicine, and RepLuca Pharmaceuticals. AM reports employment and stock interest with Bristol Myers Squibb. FN reports employment at Bristol Myers Squibb; and ownership/stock interest with AstraZeneca, Johnson & Johnson, and Eli Lilly. PT reports employment and stock interest with Bristol Myers Squibb. MDH reports advisory/consulting fees from Achilles, Adagene, Adicet, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Da Volaterra, Eli Lilly, Genentech, Genzyme/Sanofi, Immunai, Instill Bio, Janssen, Mana Therapeutics, Merk, Mirati, Pact Pharma, Regeneron, Roche, and Shattuck Labs; research funding from Bristol Myers Squibb; stock interest with Arcus, Factorial, Immunai, and Shattuck Labs; a patent filed by Memorial Sloan Kettering related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from Personal Genome Diagnostics (PGDx); after the completion of this work, MDH began as an employee (and equity holder) at AstraZeneca. JRB reports advisory/consultancy fees and research funding from Bristol Myers Squibb; advisory/consultancy fees from Amgen, AstraZeneca, Genentech, GlaxoSmithKline, Merck, Regeneron, and Sanofi; consultancy fees and honoraria from Janssen; and advisory/consultancy fees and other from Roche/Genentech. SA has declared no conflicts of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Background: RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study., Patients and Methods: ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety., Results: Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs., Conclusions: Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending., Competing Interests: Disclosure FG has consulted or provided expert opinion for Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Celgene, GSK, Lilly, MSD, Novartis, Pfizer, Roche, Siemens, and Takeda; has received fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Celgene, GSK, Lilly, MSD, Novartis, Pfizer, Roche, Siemens, and Takeda; and has received funding for scientific research from Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Celgene, GSK, Lilly, MSD, Novartis, Pfizer, Roche, Siemens, and Takeda. GC has consulted and/or had advisory roles for AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, Foundation Medicine, GlaxoSmithKline, Lilly, Novartis, Pfizer, Roche/Genentech, Samsung, and Seattle Genetics; served on speakers’ bureaus for Daiichi Sankyo, Foundation Medicine, Lilly, Novartis, Pfizer, Roche/Genentech, and Samsung; received travel, accommodations, and expenses from Pfizer, Roche/Genentech; received honoraria from Ellipses Pharma and research funding from Merck; and is supported by the OPTIMA [grant number 101034347]. MT has received honoraria for scientific meetings (self) from AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Novartis, Pfizer, Roche, and Takeda; advisory-board honoraria (self) from AstraZeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Novartis, Pfizer, Roche, and Takeda; travelling support (self) from AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Novartis, Pfizer, Roche, and Takeda; and has received research funding (institution) from AstraZeneca, BMS, Roche, and Takeda. VS reports research funding/grant support for clinical trials from AbbVie, Agensys, Alfa-sigma, Altum, Amgen, Bayer, Berg Health, Biotherapeutics, Blueprint Medicines Corporation, Boston Biomedical, Boston Pharmaceuticals, Celgene, D3, Dragonfly Therapeutics, Exelixis, Fujifilm, GSK, Idera Pharma, Incyte, Inhibrx, Loxo Oncology, MedImmune, MultiVir, Nanocarrier, National Comprehensive Cancer Network, NCI-CTEP, Novartis, Northwest Biotherapeutics, Pfizer, PharmaMar, Roche/Genentech, Takeda, Turning Point Therapeutics, UT MD Anderson Cancer Center, and Vegenics; travel support from ASCO, ESMO, Helsinn, Incyte, Novartis, and PharmaMar; consultancy/advisory board participation for Helsinn, Incyte, Loxo Oncology/Eli Lilly, MedImmune, Novartis, R-Pharma US, QED Pharma; and other relationship with Medscape. CSB has received consulting fees from AstraZeneca, Blueprint Medicines Corporation, Daiichi Sankyo, Turning Point Therapeutics, Guardant, Regeneron, Silverback, and Takeda; and has received research funding to their institution from AbbVie, AstraZeneca, Blueprint Medicines Corporation, Daiichi Sankyo, Genentech Inc., Janssen, Lilly, Loxo Oncology, Novartis, Pfizer, Rain Therapeutics, Spectrum Pharmaceuticals, and Turning Point Therapeutics. DSWT has consulted and/or had advisory roles for AstraZeneca, Bayer, Lilly, Loxo Oncology, Merrimack, Novartis, Pfizer, and Takeda; received honoraria from Boehringer Ingelheim, Merck, and Roche; and research funding to their institution from AstraZeneca, Bayer, GSK, and Novartis. DHL has received personal fees from AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Chong Keun Dang, CJ Healthcare, Genexine, Janssen, Lilly, Merck, Menarini, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm, ST Cube, and Takeda; and non-financial support from Blueprint Medicines Corporation and Takeda. DM has consulted and/or had advisory roles at scientific meetings for AstraZeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Novartis, Roche, Sanofi, and Takeda (institution, no personal honoraria). EG has consulted and/or had advisory roles for Alkermes, BMS, Boehringer Ingelheim, Ellipses Pharma, Janssen, NeoMed, Roche, Seattle Genetics, TFS, Thermo Fisher Scientific; served on speakers’ bureaus for MSD, Roche, and Thermo Fisher Scientific; received travel and accommodation expenses from BMS, Glycotope GmbH, Menarini, and MSD; research funding to their institution from Novartis, Roche, and Thermo Fisher Scientific; and is supported by a grant from the ‘la Caixa’ Foundation [grant number LCF/PR/CE07/50610001]. DWK has received travel and accommodation expenses from Amgen and Daiichi Sankyo; and research funding to their institution from Alpha Biopharma, Amgen, AstraZeneca/MedImmune, Boehringer Ingelheim, Daiichi Sankyo, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, and Yuhan. AJvdW reports research funding/grant support for clinical trials from AstraZeneca [grant number ESR-16-12212], Boehringer Ingelheim, Pfizer, Roche, and Takeda [grant number 2019N0853/2020N0366]; and consultancy/advisory board participation for AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Pfizer, Roche, and Takeda. JFG has an immediate family member who is an employee of Ironwood Pharmaceuticals; has consulted and/or had advisory roles for Agios, Amgen, Array BioPharma, Blueprint Medicines Corporation, BMS, Genentech, Gilead Sciences, Jounce Therapeutics, Lilly, Loxo Oncology, Merck, Mirati, Silverback Therapeutics, GlydeBio, Moderna Therapeutics, Oncorus, Regeneron, Takeda, and Theravance; has stock and ownership in Ironwood Pharmaceuticals; has received honoraria from ARIAD, Incyte, Merck, Novartis, Pfizer, and Takeda; and research funding from Adaptimmune, ALX Oncology, ARIAD, Array BioPharma, AstraZeneca, Blueprint Medicines Corporation, BMS, Genentech, Jounce Therapeutics, Merck, Novartis, and Tesaro. LPA has a leadership role in ALTUM Sequencing and Genomica; served on speakers’ bureaus for AstraZeneca, BMS, Lilly, MSD Oncology, Merck Serono, Pfizer, Roche/Genentech; received travel, accommodation, and expenses from AstraZeneca, BMS, MSD, Pfizer, Roche, and Takeda; honoraria from Amgen, AstraZeneca, Bayer, Blueprint Medicines Corporation, BMS, Celgene, Ipsen, Lilly, Merck Serono, Mirati Therapeutics, MSD, Novartis, Pfizer, PharmaMar, Roche/Genentech, Sanofi, Servier, and Takeda; research funding to their institution from AstraZeneca, BMS, Kura Oncology, MSD, and PharmaMar; other relationships with Roche; and an immediate family member has other relationships with Amgen, Ipsen, Merck Novartis, Pfizer, Sanofi, Servier, and Roche. SVL served as a consultant or advisory board member to Amgen, AstraZeneca, Bayer, BeiGene, Blueprint Medicines Corporation, BMS, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Lilly, Merck/MSD, Novartis, Regeneron, Sanofi, Takeda, and Turning Point Therapeutics; received research funding (to institution) from Alkermes, Bayer, Blueprint Medicines Corporation, BMS, Elevation Oncology, Genentech, Lilly, Merck, Merus, Pfizer, Rain Therapeutics, RAPT Therapeutics, Turning Point Therapeutics; and is supported by the National Cancer Institute [grant number UM1CA186691]. GPK received research grants from Blueprint Medicines Corporation, Merck, AbbVie, Takeda, Daiichi, and Cullinan. DWB served on an advisory board for Blueprint Medicines Corporation. ASM received research funding from DoD, Mark Foundation, NIH, Novartis, and Verily; honoraria to institution for participation in advisory boards: AbbVie, BeiGene, BMS, Genentech, Inc., Janssen; travel support from: Roche; is a non-remunerated member of the Mesothelioma Applied Research Foundation Board of Directors; and is supported by the Mark Foundation for Cancer Research ASPIRE Award, the National Cancer Institute [grant number R21 CA251923], and Department of Defense Concept Award [grant number W81XWH-22-1-0021]. JJL served as a compensated consultant or advisory board member for Genentech, C4 Therapeutics, Blueprint Medicines Corporation, Nuvalent, Bayer, Elevation Oncology, Novartis, Mirati Therapeutics, and Turning Point Therapeutics; received honorarium and travel support from Pfizer; received institutional research funding from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche, Linnaeus Therapeutics, Nuvalent, and Novartis; and received CME funding from OncLive, MedStar Health, and Northwell Health. VSm is an employee and/or equity holder of F. Hoffmann-La Roche, Ltd. AR is an employee and/or equity holder of F. Hoffmann-La Roche, Ltd and equity holder of Merck/MSD. SK is a former employee and/or equity holder of F. Hoffmann-La Roche, Ltd. AZ, MLG and ALB are employees and/or equity holders of Blueprint Medicines Corporation. JM has provided expertise for Amgen, AstraZeneca, Blueprint Medicines Corporation, BMS, Daiichi Sankyo, Hengrui, MSD, Novartis, Pierre Fabre, Roche, and Takeda; and received research funding from AstraZeneca, BMS, Pierre Fabre, and Roche. YH has declared no conflicts of interest. Data sharing The anonymized derived data from this study that underlie the results reported in this article will be made available, beginning 12 months and ending 5 years after this article’s publication, to any investigators who sign a data access agreement and provide a methodologically sound proposal to medinfo@blueprintmedicines.com. The trial protocol will also be made available, as will a data fields dictionary., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Alectinib, a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is highly effective in advanced ALK-rearranged non-small-cell lung cancer and represents a standard first-line therapy. New strategies are needed, however, to delay resistance. We conducted a phase I/II study to assess the safety and efficacy of combining alectinib with bevacizumab, a monoclonal antibody against vascular endothelial growth factor., Patients and Methods: Patients with advanced ALK-rearranged non-squamous non-small-cell lung cancer were enrolled. The phase I portion employed a dose de-escalation strategy with alectinib and bevacizumab starting at the individual standard doses. The primary objective was to determine the recommended phase II dose (RP2D). In phase II, the primary objective was to evaluate the safety of the combination at the RP2D; the secondary objective was to determine extracranial and intracranial efficacy., Results: Eleven patients were enrolled between September 2015 and February 2020. Most patients (82%) had baseline brain metastases. Six patients (55%) were treatment-naive; five (46%) had received prior ALK TKIs (crizotinib, n = 3; ceritinib, n = 1; crizotinib then brigatinib, n = 1). No dose-limiting toxicities occurred. RP2D was determined as alectinib 600 mg orally twice daily plus bevacizumab 15 mg/kg intravenously every 3 weeks. Three patients experienced grade 3 treatment-related adverse events: pneumonitis related to alectinib, proteinuria related to bevacizumab, and hypertension related to bevacizumab. Treatment-related intracranial hemorrhage was not observed. Six (100%) of six treatment-naive patients and three (60%) of five ALK TKI-pretreated patients had objective responses; median progression-free survival was not reached (95% confidence interval, 9.0 months-not reached) and 9.5 months (95% confidence interval, 4.3 months-not reached), respectively. Intracranial responses occurred in four (100%) of four treatment-naive and three (60%) of five TKI-pretreated patients with baseline brain metastases. The study was stopped prematurely because of slow accrual., Conclusions: Alectinib plus bevacizumab was well tolerated without unanticipated toxicities or dose-limiting toxicities., Competing Interests: Disclosure JJL has served as a compensated consultant for Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Bayer, Novartis, and Turning Point Therapeutics; received honorarium and travel support from Pfizer; received institutional research funds from Roche/Genentech, Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Linnaeus Therapeutics, and Novartis; received CME funding from OncLive, MedStar Health, and Northwell Health. CGA has participated in advisory boards with Pfizer, Regeneron/Sanofi-Genzyme, AstraZeneca, Takeda, Daiichi-Sankyo, Jazz, and Bristol-Myers Squibb. LVS has received consulting fees from AstraZeneca, Genentech, Pfizer, and Janssen, and has received institutional research support from Boehringer-Ingelheim, Novartis, AstraZeneca, and Genentech. IDJ has received honoraria from Foundation Medicine, American Lung Association, ASCO Post, OncLive, DAVA Oncology, Creative Education Concepts, Medscape, and Total Health Conferencing; consulting fees from Bayer, Boehringer Ingelheim, BostonGene, AstraZeneca, Pfizer, Xcovery, Catalyst, Novocure, Genentech, and Syros; research support from Array, Genentech, Novartis, Pfizer, and Guardant Health; and travel support from Array and Pfizer. ATS has served as a compensated consultant or received honoraria from Achilles, Archer, Ariad/Takeda, Bayer, Blueprint Medicines, Chugai, Daiichi-Sankyo, EMD Serono, Foundation Medicine, Guardant, Ignyta, KSQ Therapeutics, Loxo Oncology, Natera, Novartis, Pfizer, Roche-Genentech, Servier, Syros, Taiho Pharmaceutical, and TP Therapeutics; received institutional research funding from Ariad, Ignyta, Novartis, Pfizer, Roche-Genentech, and TP Therapeutics; received travel support from Genentech and Pfizer; and is currently employed by and owns stock in Novartis. JFG has served as a compensated consultant or received honoraria from Bristol-Myers Squibb, Genentech/Roche, Ariad/Takeda, Loxo/Lilly, Blueprint, Oncorus, Regeneron, Gilead, AstraZeneca, Pfizer, Incyte, Karyopharm, Novartis, Merck, Agios, Amgen, iTeos, GlydeBio, Moderna, and Array; research support from Novartis, Genentech/Roche, and Ariad/Takeda; institutional research support from Bristol-Myers Squibb, Tesaro, Moderna, Blueprint, Jounce, Array Biopharma, Merck, Adaptimmune, Novartis, and Alexo; and has an immediate family member who is an employee of Ironwood Pharmaceuticals. All remaining authors have declared no potential conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Acquired resistance (AR) to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] blockade is frequent in non-small-cell lung cancer (NSCLC), occurring in a majority of initial responders. Patients with AR may have unique properties of persistent antitumor immunity that could be re-harnessed by investigational immunotherapies. The absence of a consistent clinical definition of AR to PD-(L)1 blockade and lack of uniform criteria for ensuing enrollment in clinical trials remains a major barrier to progress; such clinical definitions have advanced biologic and therapeutic discovery. We examine the considerations and potential controversies in developing a patient-level definition of AR in NSCLC treated with PD-(L)1 blockade. Taking into account the specifics of NSCLC biology and corresponding treatment strategies, we propose a practical, clinical definition of AR to PD-(L)1 blockade for use in clinical reports and prospective clinical trials. Patients should meet the following criteria: received treatment that includes PD-(L)1 blockade; experienced objective response on PD-(L)1 blockade (inclusion of a subset of stable disease will require future investigation); have progressive disease occurring within 6 months of last anti-PD-(L)1 antibody treatment or rechallenge with anti-PD-(L)1 antibody in patients not exposed to anti-PD-(L)1 in 6 months., Competing Interests: Disclosure AJS reports consulting/advising role to J&J and Perceptive Advisors. SJA reports consulting/advising role from Bristol-Myers Squibb, Merck, CBMG, AstraZeneca, Memgen, RAPT, and Venn, Achilles Therapeutics, Celsius, Samyang Biopharma, Glaxo Smith Klein, Amgen, other from Bristol-Myers Squibb, Merck, Rapt, Achilles Therapeutics, Celsius, GlaxoSmithKline, Amgen, grants from Novartis; expenses from Bristol-Myers Squibb, Merck, CBMG, AstraZeneca, Memgen, RAPT, and Venn, Achilles Therapeutics, Celsius, Samyang Biopharma, Glaxo Smith Klein, Amgen, other from Bristol-Myers Squibb, Merck, Rapt, Achilles Therapeutics, Celsius, GlaxoSmithKline, Amgen, grants from Novartis. MMA reports grants and personal fees from Genentech, grants and personal fees from Bristol-Myers Squibb, personal fees from Merck, grants and personal fees from AstraZeneca, grants from Lilly, personal fees from Maverick, personal fees from Blueprint Medicine, personal fees from Syndax, personal fees from Ariad, personal fees from Nektar, personal fees from Gritstone, personal fees from ArcherDx, personal fees from Mirati, personal fees from NextCure, personal fees from EMD Serono. EF reports personal fees from AbbVie, personal fees from Amgen, personal fees from AstraZeneca, personal fees from Bayer, personal fees from Blue Print Medicines, personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers Squibb, personal fees from Eli Lilly, personal fees from GSK, personal fees from Janssen, personal fees from Medscape, personal fees from Merck KGaA, personal fees from Merck Sharp & Dohme, personal fees from Novartis, personal fees from Roche, personal fees from PeerVoice, personal fees from Pfizer, personal fees from prIME Oncology, personal fees from Puma Biotechnology, personal fees from Roche, personal fees from Sanofi Genzyme, personal fees from Springer, personal fees from Takeda, personal fees from TouchIME, grants from Grant for Oncology Innovation (GOI), grants from Fundación Merck Salud, outside the submitted work; and Grífols: Independent Member of the Board. JG reports grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Genentech/Roche, personal fees from Takeda, grants and personal fees from Blueprint, grants and personal fees from Loxo, personal fees from Oncorus, personal fees from Regeneron, personal fees from Pfizer, personal fees from Incyte, grants and personal fees from Novartis, grants and personal fees from Merck, personal fees from Agios, personal fees from Amgen, grants from Array, grants from Tesaro, grants from Moderna, grants from Adaptimmune, grants from Alexo, personal fees from Ironwood Pharmaceuticals, personal fees from Gilead, personal fees from EMD Serono, personal fees from AstraZeneca, personal fees from Mirati. SNG reports personal fees and other from Bristol Myers Squibb, personal fees from Nektar, other from Genentech, other from Ariad/Takeda, other from Iovance Biotherapeutics, during the conduct of the study. FSH reports grants, personal fees and other from Bristol-Myers Squibb, personal fees from Merck, personal fees from EMD Serono, grants, personal fees and other from Novartis, personal fees from Surface, personal fees from Compass Therapeutics, personal fees from Apricity, personal fees from Aduro, personal fees from Sanofi, personal fees from Pionyr, personal fees from 7 Hills Pharma, personal fees from Verastem, personal fees from Torque, personal fees from Rheos, personal fees from Kairos, personal fees from Bicara, from Psioxus Therapeutics, other from Pieris Pharmaceutical, from Zumutor, from Corner Therapeutics, personal fees from Eisai, personal fees from Checkpoint Therapeutics, outside the submitted work; In addition, FSH has a patent Methods for Treating MICA-Related Disorders (#20100111973) with royalties paid, a patent Tumor antigens and uses thereof (#7250291) issued, a patent Angiopoiten-2 Biomarkers Predictive of Anti-immune checkpoint response (#20170248603) pending, a patent Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms (#20160340407) pending, a patent Therapeutic peptides (#20160046716) pending, a patent Therapeutic Peptides (#20140004112) pending, a patent Therapeutic Peptides (#20170022275) pending, a patent Therapeutic Peptides (#20170008962) pending, a patent Therapeutic Peptides Patent number: 9402905 issued, a patent Methods of using pembrolizumab and trebananib pending, a patent Vaccine compositions and methods for restoring NKG2D pathway function against cancers Patent number: 10279021 issued, a patent Antibodies that bind to MHC class I polypeptide-related sequence A Patent number: 10106611 issued, and a patent Anti- galectin antibody biomarkers predictive of anti-immune checkpoint and anti-angiogenesis responses. Publication number: 20170343552 pending. MLJ reports other from Achilles Therapeutics, grants and other from AstraZeneca, grants and other from Atreca, grants and other from Boehringer Ingelheim, grants and other from Calithera Biosciences, grants and other from EMD Serono, grants and other from Roche/Genentech, grants and other from GlaxoSmithKline, grants and other from Gritstone Oncology, grants and other from Guardant Health, grants and other from Incyte, grants and other from Janssen Research and Development, grants and other from Lilly, grants and other from Merck, grants and other from Mirati Therapeutics, grants and other from Novartis, grants and other from Pfizer, grants and other from Sanofi-Aventis, grants from AbbVie, grants from Acerta Pharma, grants from Adaptimmune, grants and other from Amgen, grants from Apexigen, grants from Array BioPharma, grants from BeiGene, grants from Checkpoint Therapeutics, grants from Corvus Pharmaceuticals, grants from CytomX, grants and other from Daiichi Sankyo, grants from Dynavax Technologies, grants from Genmab, grants from Genocea Biosciences, grants from Hengrui Therapeutics, grants from Immunocore, grants from Jounce Therapeutics, grants from Kadmon Pharmaceuticals, grants from Loxo Oncology, grants from Lycera, grants from Neovia Oncology, grants from OncoMed Pharmaceuticals, grants from Regeneron Pharmaceuticals, grants from Shattuck Labs, grants from Stem CentRx, grants from Syndax Pharmaceuticals, grants from Takeda Pharmaceuticals, grants from Tarveda, grants from University of Michigan, grants and other from WindMIL Therapeutics, grants from TCR2 Therapeutics, grants from Arcus Biosciences, grants and other from Ribon Therapeutics, grants from Seven and Eight Biopharmaceuticals, other from Bristol-Myers Squibb, personal fees from Astellas, personal fees from Otsuka, grants from BerGenBio, grants from Foundation Medicine, other from G1 Therapeutics, grants from Tmunity Therapeutics. NBL reports grants and personal fees for CME lectures from MSD and BMS. CML reports other from Cepheid, other from Syros, other from Foundation Medicine, other from Novartis, other from Astra Zeneca, other from Takeda, other from Amgen, other from Blueprints Medicine, other from Genentech, other from Eli Lilly/Loxo, other from Pfizer, other from Roche, other from Achilles, from null, outside the submitted work. TM reports personal fees from AbbVie, Inc., personal fees and other from ACEA Pharma, personal fees and other from Alpha Biopharma Co. Ltd., personal fees and other from Amgen, personal fees and other from Amoy Diagnostics Co. Ltd., grants, personal fees and other from AstraZeneca, personal fees and other from BeiGene, personal fees and other from Boehringer Ingelheim, grants, personal fees and other from Bristol-Myers Squibb, personal fees and other from Blueprint Medicines Corporation, personal fees and other from CStone Pharmaceuticals, personal fees and other from Daiichi Sankyo, personal fees and other from Eisai, personal fees and other from Fishawack Facilitate Ltd., other from geneDecode, personal fees and other from Gritstone Oncology Inc., personal fees and other from Guardant Health, personal fees and other from Hengrui Therapeutics, personal fees and other from Ignyta Inc., personal fees and other from IQVIA, personal fees and other from Incyte Corporation, personal fees from InMed Medical Communication, personal fees and other from Janssen, personal fees and other from Lilly, personal fees and other from Loxo-Oncology, personal fees and other from Lunit, Inc., personal fees from MD Health (Brazil), personal fees from Medscape/WebMD, grants, personal fees and other from Merck Serono, grants, personal fees and other from Merck Sharp & Dohme, 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, personal fees from Physicians' Education Resource, personal fees from P. Permanyer SL, grants, personal fees and other from Pfizer, Inc, personal fees from prIME Oncology, personal fees and other from Puma Technology Inc, personal fees from Research to Practice, grants, personal fees and other from Roche, personal fees and other from Sanofi-Aventis R&D, 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, other from Hutchison Chi-Med, other from Sanomics Ltd., grants from Clovis Oncology, grants from SFJ Pharmaceuticals, grants from XCovery, outside the submitted work. MP reports grants, personal fees and non-financial support from Roche, grants, personal fees and non-financial support from AstraZeneca, personal fees from ELI LILLY, personal fees and non-financial support from Pfizer, grants, personal fees and non-financial support from Boehringer Ingelheim, personal fees and non-financial support from B Bristol Myers Squibb, personal fees and non-financial support from Merck Sharp & Dohme, personal fees from Novartis, grants and personal fees from Takeda, personal fees and non-financial support from Chugai, personal fees from Amgen, personal fees from Illumina, personal fees from Gritstone, outside the submitted work. MR reports personal fees from Amgen, personal fees from AstraZeneca, personal fees from BMS, personal fees from Boehringer-Ingelheim, personal fees from Lilly, personal fees from Merck, personal fees from MSD, personal fees from Mirati, personal fees from Novartis, personal fees from Pfizer, personal fees from Roche, personal fees from Samsung, outside the submitted work. BS reports personal fees from Roche/Genentech, personal fees from Novartis, personal fees from AstraZeneca, personal fees from Amgen, personal fees from Eli Lilly, personal fees from Loxo Oncology, personal fees from Merck, personal fees from Bristol Myers Squibb, personal fees from PharmaMar, personal fees from Pfizer, outside the submitted work. J-CS reports other from AstraZeneca, other from AstraZeneca, during the conduct of the study; other from Gritstone Oncology, other from Daiichi Sankyo, other from Relay Therapeutics, outside the submitted work. DSWT reports grants and personal fees from Novartis, grants and personal fees from Bayer, personal fees from Boehringer Ingelheim, personal fees from Celgene, grants and personal fees from Astra Zeneca, personal fees from Eli Lilly, personal fees from LOXO, personal fees from Merck, grants and personal fees from Pfizer, personal fees from Roche, personal fees from Takeda, grants from GlaxoSmithKline, personal fees from Merrimack, outside the submitted work. SP reports personal fees from AbbVie, personal fees from Amgen, personal fees from AstraZeneca, personal fees from Bayer, personal fees from Biocartis, personal fees from Boehringer-Ingelheim, personal fees from Bistrol-Myers Squibb, personal fees from Clovis, personal fees from Daiichi Sankyo, personal fees from Debiopharm, personal fees from Eli Lilly, personal fees from F. Hoffmann-La Roche, personal fees from Foundation Medicine, personal fees from Illumina, personal fees from Janssen, personal fees from Merck Sharp and Dohme, personal fees from Merck Serono, personal fees from Merrimack, personal fees from Novartis, personal fees from Pharma Mar, personal fees from Pfizer, personal fees from Regeneron, personal fees from Sanofi, personal fees from Seattle Genetics and Takeda, personal fees from AstraZeneca, personal fees from Boehringer-Ingelheim, personal fees from Bristol-Myers Squibb, personal fees from Eli Lilly, personal fees from F. Hoffmann-La Roche, personal fees from Merck Sharp and Dohme, personal fees from Novartis, personal fees from Pfizer, personal fees from Takeda, non-financial support from Sponsored by Amgen, non-financial support from AstraZeneca, non-financial support from Boehringer-Ingelheim, non-financial support from Bristol-Meyers Squibb, non-financial support from Clovis, non-financial support from F. Hoffmann-La Roche, non-financial support from Illumina, non-financial support from Merck Sharp and Dohme, non-financial support from Merck Serono, non-financial support from Novartis, non-financial support from Pfizer, non-financial support from Sanofi, personal fees from Bioinvent, outside the submitted work. All fees to institution. MDH reports personal fees from Merck, personal fees from Genentech/Roche, grants, personal fees and non-financial support from BMS, personal fees and non-financial support from AstraZeneca, personal fees from Mirati, personal fees from Syndax, personal fees and other from Shattuck Labs, personal fees from Nektar, personal fees and other from Immunai, personal fees and other from Arcus, from Eli Lilly, during the conduct of the study; In addition, Dr. Hellmann has a patent A patent filed by Memorial Sloan Kettering related to the use of tumor mutational burden to predict response to immunotherapy (PCT/US2015/062208) licensed to PGDx., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Aberrant activation of RET is a critical driver of growth and proliferation in diverse solid tumours. Multikinase inhibitors (MKIs) showing anti-RET activities have been tested in RET-altered tumours with variable results. The low target specificity with consequent increase in side-effects and off-target toxicities resulting in dose reduction and drug discontinuation are some of the major issues with MKIs. To overcome these issues, new selective RET inhibitors such as pralsetinib (BLU-667) and selpercatinib (LOXO-292) have been developed in clinical trials, with selpercatinib recently approved by the Food and Drug Administration (FDA). The results of these trials showed marked and durable antitumour activity and manageable toxicity profiles in patients with RET-altered tumours. The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) launched a collaborative project to review the available methods for the detection of RET gene alterations, their potential applications and strategies for the implementation of a rational approach for the detection of RET fusion genes and mutations in human malignancies. We present here recommendations for the routine clinical detection of targetable RET rearrangements and mutations., Competing Interests: Disclosure NN: Speaker's fee and/or advisory boards: Amgen, AstraZeneca, Bayer, Biocartis, BMS, Boehringer Ingelheim, Eli Lilly, Illumina, Incyte, Merck, MSD, Qiagen, Roche, Thermo Fisher, Sanofi; Institutional financial interests (financial support to research projects): AstraZeneca, Biocartis, BMS, Illumina, Merck, Qiagen, Roche, Sysmex, Thermo Fisher; non-financial interests: President of the International Quality Network for Pathology (IQN Path); President of the Italian Cancer Society (SIC). JYS: Leadership role (nonremunerated): President of the National Board of Pathology, France. JSR-F: Consultant with paid fees: Goldman Sachs, Repare Therapeutics and Paige.AI; Member of the scientific advisory board: Volition RX, Repare Therapeutics and Paige.AI; Ad hoc member of the scientific advisory board: Roche Tissue Diagnostics, Roche, Genentech, inviCRO and Novartis; Member of the Board of Directors of Grupo Oncoclinicas. JFG: Compensated consultant or received honoraria: Bristol-Myers Squibb, Genentech, Ariad/Takeda, Loxo/Lilly, Blueprint, Oncorus, Regeneron, EMD Serono, Gilead, AstraZeneca, Pfizer, Incyte, Novartis, Merck, Agios, Amgen and Array; Research support: Novartis, Genentech/Roche and Ariad/Takeda; Institutional research support: Bristol-Myers Squibb, Tesaro, Moderna, Blueprint, Jounce, Array Biopharma, Merck, Adaptimmune, Novartis and Alexo; Immediate family member: an employee of Ironwood Pharmaceuticals. AD: Honoraria/Advisory Boards: Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millennium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, BeiGene, BerGenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, AbbVie, 14ner/Elevation Oncology, Remedica Ltd., ArcherDX, Monopteros, Roche, Novartis, EMD Serono, MJH, Faculty RTP, Medendi; Associated research paid to institution: Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, Pharma Mar; Research: Foundation Medicine; Royalties: Wolters Kluwer; Other: Merck - Food/Beverage, Puma - Food/Beverage, Merus - Food/Beverage, Boehringer Ingelheim; CME honoraria: Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, PeerView Institute, Paradigm Medical Communications, WebMD. AS: Speakers bureau: Ipsen, Astra Zeneca, Amgen, MSD, GSK; Consulting: INCYTE Biosciences. GC: Honoraria for speaker's engagement: Roche, Seattle Genetics, Novartis, Lilly, Pfizer, Foundation Medicine, NanoString, Samsung, Celltrion, BMS, MSD; Honoraria for providing consultancy: Roche, Seattle Genetics, NanoString; Honoraria for participating in Advisory Board: Roche, Lilly, Pfizer, Foundation Medicine, Samsung, Celltrion, Mylan; Honoraria for writing engagement: Novartis, BMS; Honoraria for participation in Ellipsis Scientific Affairs Group; Institutional research funding for conducting phase I and II clinical trials: Pfizer, Roche, Novartis, Sanofi, Celgene, Servier, Orion, AstraZeneca, Seattle Genetics, AbbVie, Tesaro, BMS, Merck Serono, Merck Sharp Dome, Janssen-Cilag, Philogen, Bayer, Medivation, Medimmune. All remaining authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited., Patients and Methods: This study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by next-generation sequencing (NGS) or MET FISH., Results: We analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received an RET-selective inhibitor (selpercatinib, n = 10; pralsetinib, n = 7; pralsetinib followed by selpercatinib, n = 1, with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months [95% confidence interval 3.6-10.8 months]. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small-cell histologic transformation., Conclusions: RET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients., Competing Interests: Disclosure JJL has served as a compensated consultant or received honorarium from Chugai Pharma, Boehringer-Ingelheim, Pfizer, C4 Therapeutics, Nuvalent, Turning Point Therapeutics, Blueprint Medicines, and Genentech; received institutional research funds from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Roche/Genentech, Pfizer, and Novartis; received CME funding from OncLive, MedStar Health, and Northwell Health; and received travel support from Pfizer. SVL served as a compensated consultant or on the advisory board for AstraZeneca, Blueprint, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, G1 Therapeutics, Genentech/Roche, Guardant Health, Inivata, Janssen, Jazz, Lilly, Merck/MSD, PharmaMar, Pfizer, Regeneron, and Takeda; and received institutional research funding from Alkermes, AstraZeneca, Blueprint, Bristol-Myers Squibb, Corvus, Genentech, Lilly, Merck, Pfizer, Rain Therapeutics, RAPT, Spectrum, and Turning Point Therapeutics. CEM received honorarium from Novartis and Guardant Health; served on the advisory board for Genentech; and received research funding from Novartis and Revolution Medicines. ACT has served as a compensated consultant or received honorarium from Thermo Fisher. ID-J has received honoraria from Foundation Medicine; consulting fees from Boehringer Ingelheim and AstraZeneca; research support from Array, Genentech, Novartis, Pfizer, and Guardant Health; and travel support from Array and Pfizer. LJW has received personal fees from Bayer, Blueprint Medicines, Cue Biopharma, Exelixis, Genentech, and Rakuten Medical; received personal fees and nonfinancial support from Eisai, Lilly, Loxo Oncology, and Merck; and received institutional research funding from Loxo Oncology. ANH has received research support from Amgen, Pfizer, Novartis, Blueprint Medicines, Eli Lilly, Roche/Genentech, and Relay Therapeutics. MM-K has served as a compensated consultant for H3 Biomedicine and AstraZeneca; received institutional research support from Novartis. S-HIO has received personal fees from Pfizer, Merck, Takeda, AstraZeneca, Roche/Genentech, Daiichi Sankyo, Blueprint Medicines, and Janssen JNJ; and has stock ownership in Turning Point Therapeutics. DS-WT has served as a compensated consultant or received honorarium from Amgen, Boehringer-Ingelheim, Pfizer, C4 Therapeutics, Takeda, Bristol-Myers Squibb, MSD, Bayer, and Novartis; received institutional research funds from AstraZeneca, Pfizer, and Amgen; and received travel support from Pfizer and MSD. JFG has served as a compensated consultant or received honoraria from Bristol-Myers Squibb, Genentech, Ariad/Takeda, Loxo/Lilly, Blueprint, Oncorus, Regeneron, Gilead, AstraZeneca, Pfizer, Incyte, Novartis, Merck, Agios, Amgen, and Array; research support from Novartis, Genentech/Roche, and Ariad/Takeda; institutional research support from Bristol-Myers Squibb, Tesaro, Moderna, Blueprint, Jounce, Array Biopharma, Merck, Adaptimmune, Novartis, and Alexo; and has an immediate family member who is an employee of Ironwood Pharmaceuticals. All remaining authors have declared no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) are standard therapies for patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50%. Tumor mutation burden (TMB) also predicts response to ICIs but is often not available in real time for decision making in the first-line setting. Smoking exposure can be a proxy for TMB in NSCLC. The impact of smoking status on efficacy of PD-1 blockade in NSCLC patients with PD-L1 TPS ≥50% has not been well defined., Patients and Methods: To investigate the relationship between smoking and activity of ICIs in NSCLC, we retrospectively studied 315 patients with NSCLC and PD-L1 TPS ≥50% at five USA academic medical centers. Objective response rates (ORRs), progression-free survival (PFS), and duration of response (DOR) were compared between never (<100 lifetime cigarettes), light (≤10 pack-years), and heavy (>10 pack-years) smokers. A subset of patients underwent next-generation sequencing to estimate TMB., Results: We identified 36 (11%) never, 42 (13%) light, and 237 (75%) heavy smokers with NSCLC and PD-L1 TPS ≥50% treated with ICIs. Objective responses were observed in 27%, 40%, and 40% of never, light, and heavy smokers, respectively (P = 0.180 never versus heavy; P = 1.000 light versus heavy). Median PFS and median DOR were numerically shorter in never and light smokers compared with heavy smokers (PFS 3.0 versus 4.0 versus 5.4 months; median DOR 6.9 versus 10.8 versus 17.8 months), but were not statistically different [PFS: hazard ratio (HR) 1.37, P = 0.135 and HR 1.24, P = 0.272; DOR: HR 1.92, P = 0.217 and HR 1.79, P = 0.141]., Conclusions: PD-(L)1 inhibitors are associated with antitumor activity in NSCLC with PD-L1 TPS ≥50% regardless of smoking status. Nevertheless, there is a signal of potentially decreased durability among never and light smokers that should be further evaluated. Distinct immunobiologic features may affect initial response versus durability of antitumor immunity to programmed cell death 1 (PD-1) blockade., Competing Interests: Disclosure JFG: consultant or received honoraria from Bristol-Myers Squibb, Genentech/Roche, Ariad/Takeda, Loxo, Pfizer, Incyte, Novartis, Merck, Agios, Amgen, Regeneron, Oncorus, Array, Jounce, and Clovis Oncology, research support from Novartis, Genentech/Roche, and Ariad/Takeda, and institutional research support from Bristol-Myers Squibb, Tesaro, Moderna, Blueprint, Jounce, Array Biopharma, Merck, Adaptimmune, Novartis, and Alexo. JAR: consultant and equity in Genprex. BPL: Elsevier textbook author and editor, and receives royalties for his work. KA: consultant or received honoraria from AstraZeneca and Jackson Laboratory. JA: owns stock in Merck, Pfizer, and Thermo Fischer Scientific. MMK: consultant for Merimack Pharmaceuticals and H3 Biomedicine. ATS: consultant or received honoraria from Pfizer, Novartis, Chugai, Genentech/Roche, Ariad/Takeda, Ignyta, LOXO, Blueprint Medicines, KSQ Therapeutics, Daiichi Sankyo, EMD Serono, Taiho Pharmaceutical, TP Therapeutics, Bayer, Foundation Medicine, Guardant, and Natera. Institutional research funding from: Pfizer, Novartis, Roche/Genentech, Ariad, Ignyta, and TP Therapeutics. MMA: consultant or received honoraria from Merck, Bristol-Myers Squibb, Genentech, AstraZeneca, Nektar, Blueprint, Maverick, and Syndax and research support from Bristol-Myers Squibb, AstraZeneca, Lilly, and Genentech. MDH: has received research funding from Bristol-Myers Squibb; is a paid consultant to Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Shattuck Labs, and Immunai; has received travel support/honoraria from AztraZeneca and BMS; and a patent has been filed by MSK related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. The remaining authors have no conflicts of interest to disclose., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In non-small-cell lung cancers with programmed death-ligand 1 (PD-L1) expression on ≥50% of tumor cells, first-line treatment with the PD-1 inhibitor pembrolizumab improves survival compared with platinum-doublet chemotherapy. Whether higher PD-L1 levels within the expression range of 50%-100% predict for even greater benefit to pembrolizumab is currently unknown., Patients and Methods: In this multicenter retrospective analysis, we analyzed the impact of PD-L1 expression levels on the overall response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) in patients who received commercial pembrolizumab as first-line treatment of non-small-cell lung cancer (NSCLC) with a PD-L1 expression of ≥50% and negative for genomic alterations in the EGFR and ALK genes ., Results: Among 187 patients included in this analysis, the ORR was 44.4% [95% confidence interval (CI) 37.1% to 51.8%], the mPFS was 6.5 months (95% CI 4.5-8.5), and the mOS was not reached. The median PD-L1 expression level among patients who experienced a response to pembrolizumab was significantly higher than among patients with stable or progressive disease (90% versus 75%, P < 0.001). Compared with patients with PD-L1 expression of 50%-89% (N = 107), patients with an expression level of 90%-100% (N = 80) had a significantly higher ORR (60.0% versus 32.7%, P < 0.001), a significantly longer mPFS [14.5 versus 4.1 months, hazard ratio (HR) 0.50 (95% CI 0.33-0.74), P < 0.01], and a significantly longer mOS [not reached versus 15.9 months, HR 0.39 (95% CI 0.21-0.70), P = 0.002]., Conclusion: Among patients with NSCLC and PD-L1 expression of ≥50% treated with first-line pembrolizumab, clinical outcomes are significantly improved in NSCLCs with a PD-L1 expression of ≥90%. These findings have implications for treatment selection as well as for clinical trial interpretation and design., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Preclinical evidence suggests that MEK inhibition promotes accumulation and survival of intratumoral tumor-specific T cells and can synergize with immune checkpoint inhibition. We investigated the safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a programmed cell death 1 ligand 1 (PD-L1) inhibitor, atezolizumab, in patients with solid tumors., Patients and Methods: This phase I/Ib study treated PD-L1/PD-1-naive patients with solid tumors in a dose-escalation stage and then in multiple, indication-specific dose-expansion cohorts. In most patients, cobimetinib was dosed once daily orally for 21 days on, 7 days off. Atezolizumab was dosed at 800 mg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary end points included objective response rate, progression-free survival, and overall survival., Results: Between 27 December 2013 and 9 May 2016, 152 patients were enrolled. As of 4 September 2017, 150 patients received ≥1 dose of atezolizumab, including 14 in the dose-escalation cohorts and 136 in the dose-expansion cohorts. Patients had metastatic colorectal cancer (mCRC; n = 84), melanoma (n = 22), non-small-cell lung cancer (NSCLC; n = 28), and other solid tumors (n = 16). The most common all-grade treatment-related adverse events (AEs) were diarrhea (67%), rash (48%), and fatigue (40%), similar to those with single-agent cobimetinib and atezolizumab. One (<1%) treatment-related grade 5 AE occurred (sepsis). Forty-five (30%) and 23 patients (15%) had AEs that led to discontinuation of cobimetinib and atezolizumab, respectively. Confirmed responses were observed in 7 of 84 patients (8%) with mCRC (6 responders were microsatellite low/stable, 1 was microsatellite instable), 9 of 22 patients (41%) with melanoma, and 5 of 28 patients (18%) with NSCLC. Clinical activity was independent of KRAS/BRAF status across diseases., Conclusions: Atezolizumab plus cobimetinib had manageable safety and clinical activity irrespective of KRAS/BRAF status. Although potential synergistic activity was seen in mCRC, this was not confirmed in a subsequent phase III study., Clinicaltrials.gov Identifier: NCT01988896 (the investigators in the NCT01988896 study are listed in the supplementary Appendix, available at Annals of Oncology online)., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: There are currently no approved targeted therapies for non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 insertions (ins20), a subgroup of EGFR mutations that are generally refractory to first/second generation EGFR inhibitors. We report the final results of a phase II trial evaluating the activity of the Hsp90 inhibitor luminespib (AUY922) in NSCLC patients with EGFR ins20., Patients and Methods: Twenty-nine patients with stage IV NSCLC with EGFR ins20 identified on local testing and at least one prior therapy were enrolled on the trial between August 2013 and October 2016. The primary end point was objective response rate (ORR), with a pre-determined target rate of effectiveness [defined as the rate of partial response (PR) plus stable disease (SD) lasting ≥3 months] of 20%. Secondary end points were PFS, overall survival (OS), safety and response by EGFR ins20 subtype., Results: Among the 29 patients (18 females, median age 60 years) the ORR was 17%, median progression-free survival was 2.9 months (95% CI 1.4-5.6) and median OS (mOS) was 13 months (95% CI 4.9-19.5). The results exceeded the pre-determined target rate of effectiveness with 11/29 (38%) patients having a PR or an SD ≥3 months. The most common luminespib-related toxicities were diarrhea (83%), visual changes (76%) and fatigue (45%). All study treatment was stopped on 28 February 2017 due to dissolution of study drug availability; 3 patients were on treatment at study termination., Conclusion: The study met its primary end point, suggesting that luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of luminespib and other hsp90 inhibitors in this population is warranted., Study Registration (clinicaltrials.gov): NCT01854034.

Background: Long-term data with immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are limited. Two phase III trials demonstrated improved overall survival (OS) and a favorable safety profile with the anti-programmed death-1 antibody nivolumab versus docetaxel in patients with previously treated advanced squamous (CheckMate 017) and nonsquamous (CheckMate 057) NSCLC. We report results from ≥3 years' follow-up, including subgroup analyses of patients with liver metastases, who historically have poorer prognosis among patients with NSCLC., Patients and Methods: Patients were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or discontinuation. The primary end point of each study was OS. Patients with baseline liver metastases were pooled across studies by treatment for subgroup analyses., Results: After 40.3 months' minimum follow-up in CheckMate 017 and 057, nivolumab continued to show an OS benefit versus docetaxel: estimated 3-year OS rates were 17% [95% confidence interval (CI), 14% to 21%] versus 8% (95% CI, 6% to 11%) in the pooled population with squamous or nonsquamous NSCLC. Nivolumab was generally well tolerated, with no new safety concerns identified. Of 854 randomized patients across both studies, 193 had baseline liver metastases. Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio, 0.68; 95% CI, 0.50-0.91), consistent with findings from the overall pooled study population (hazard ratio, 0.70; 95% CI, 0.61-0.81). Rates of treatment-related hepatic adverse events (primarily grade 1-2 liver enzyme elevations) were slightly higher in nivolumab-treated patients with liver metastases (10%) than in the overall pooled population (6%)., Conclusions: After 3 years' minimum follow-up, nivolumab continued to demonstrate an OS benefit versus docetaxel in patients with advanced NSCLC. Similarly, nivolumab demonstrated an OS benefit versus docetaxel in patients with liver metastases, and remained well tolerated., Clinical Trial Registration: CheckMate 017: NCT01642004; CheckMate 057: NCT01673867.

Background: We previously demonstrated that patients with metastatic KRAS mutant lung cancers have a shorter survival compared with patients with KRAS wild-type cancers. Recent reports have suggested different clinical outcomes and distinct activated signaling pathways depending on KRAS mutation subtype. To better understand the impact of KRAS mutation subtype, we analyzed data from 677 patients with KRAS mutant metastatic lung cancer., Methods: We reviewed all patients with metastatic or recurrent lung cancers found to have KRAS mutations over a 6-year time period. We evaluated the associations among KRAS mutation type, clinical factors, and overall survival in univariate and multivariate analyses. Any significant findings were validated in an external multi-institution patient dataset., Results: Among 677 patients with KRAS mutant lung cancers (53 at codon 13, 624 at codon 12), there was no difference in overall survival for patients when comparing KRAS transition versus transversion mutations (p = 0.99), smoking status (p = 0.33), or when comparing specific amino acid substitutions (p = 0.20). In our dataset, patients with KRAS codon 13 mutant tumors (n = 53) had shorter overall survival compared with patients with codon 12 mutant tumors (n = 624) (1.1 versus 1.3 years, respectively; p = 0.009), and the findings were confirmed in a multivariate Cox model controlling for age, sex, and smoking status (hazard ratio: 1.52, 95% confidence interval: 1.11-2.08; p = 0.008). In an independent validation set of tumors from 682 patients with stage IV KRAS mutant lung cancers, there was no difference in survival between patients with KRAS codon 13 versus codon 12 mutations (1.0 versus 1.1 years, respectively; p = 0.41)., Conclusions: Among individuals with KRAS mutant metastatic lung cancers treated with conventional therapy, there are no apparent differences in outcome based on KRAS mutation subtype.

Background: Personalizing non-small-cell lung cancer (NSCLC) therapy toward oncogene addicted pathway inhibition is effective. Hence, the ability to determine a more comprehensive genotype for each case is becoming essential to optimal cancer care., Methods: We developed a multiplexed PCR-based assay (SNaPshot) to simultaneously identify >50 mutations in several key NSCLC genes. SNaPshot and FISH for ALK translocations were integrated into routine practice as Clinical Laboratory Improvement Amendments-certified tests. Here, we present analyses of the first 589 patients referred for genotyping., Results: Pathologic prescreening identified 552 (95%) tumors with sufficient tissue for SNaPshot; 51% had ≥1 mutation identified, most commonly in KRAS (24%), EGFR (13%), PIK3CA (4%) and translocations involving ALK (5%). Unanticipated mutations were observed at lower frequencies in IDH and β-catenin. We observed several associations between genotypes and clinical characteristics, including increased PIK3CA mutations in squamous cell cancers. Genotyping distinguished multiple primary cancers from metastatic disease and steered 78 (22%) of the 353 patients with advanced disease toward a genotype-directed targeted therapy., Conclusions: Broad genotyping can be efficiently incorporated into an NSCLC clinic and has great utility in influencing treatment decisions and directing patients toward relevant clinical trials. As more targeted therapies are developed, such multiplexed molecular testing will become a standard part of practice.