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Background Interleukin-1β (IL-1β) inhibition with canakinumab was associated with a significant reduction in the incidence of lung cancer and lung cancer mortality in pts with atherosclerosis in CANTOS trial. Inhibition of IL-1β driven inflammation may lead to a tumor microenvironment more susceptible to anti-PD-(L)1 therapies. Recent studies have shown that low levels of CRP at baseline or decreased levels over time correlated with improved responses to anti-PD-(L)1 agents, providing rationale for combining canakinumab and PEM. Trial design CANOPY-1 (NCT03631199) is a double-blind, randomized, placebo (Pb)-controlled, phase III trial to determine efficacy and safety of PEM + platinum-based Ctx ± canakinumab in untreated stage IIIB/IIIC-IV squamous and non-squamous NSCLC pts. It is a 2 part study- In part 1 (open-label safety run-in with 3 cohorts of ∼9 pts each), pts received canakinumab 200 mg s.c (Q3W) + PEM 200 mg i.v (Q3W) + platinum-based Ctx [Cohort A (non-squamous), carboplatin (CBCDA) + pemetrexed (PTX); Cohort B (non-squamous), cisplatin + PTX; Cohort C (squamous or non-squamous), CBCDA + paclitaxel]. In part 2 (with ∼600 pts), pts will be randomize to receive canakinumab/Pb + PEM + platinum-based Ctx (non-squamous, CBCDA or cisplatin + PTX; squamous, CBCDA + paclitaxel or nab-paclitaxel). PEM and platinum-based Ctx will be administered at their approved doses. Randomization (1:1) will be stratified by PD-L1 status, region, and histology. In both parts, pts will receive 4 cycles of induction therapy (canakinumab/Pb + PEM + Ctx) followed by maintenance therapy (PEM + canakinumab/Pb +/- PTX) until progressive disease. Primary objectives: confirm recommended phase 3 (RP3R) for canakinumab combination (part 1), compare PFS and OS between treatment arms (part 2). Secondary objectives (part 1 and 2): ORR, DCR, safety, PK and DOR. Part 1 is completed and part 2 is ongoing based on the confirmation of canakinumab 200 mg Q3W + PEM and platinum-doublet Ctx as RP3R. Clinical trial identification CACZ885U2301/NCT03631199. Legal entity responsible for the study Novartis. Funding Novartis. Disclosure D.S.W. Tan: Advisory / Consultancy: Novartis, Pfizer, AstraZeneca; Research grant / Funding (self): Novartis ; Advisory / Consultancy: Novartis; Research grant / Funding (self): Pfizer, AstraZeneca. T.M. Kim: Advisory / Consultancy: AstraZeneca, Novartis, Takeda, Sanofi, and Bayer ; Research grant / Funding (self): AstraZeneca-KHIDI outside this work. B.J. Solomon: Advisory / Consultancy: Roche/Genentech; AstraZeneca; Novartis; Pfizer; Merck; Bristol-Myers Squibb; Loxo Oncology; Gritstone Oncology; Honoraria (self): Roche/Genentech; AstraZeneca; Novartis; Pfizer; Merck; Bristol-Myers Squibb; Loxo Oncology; Gritstone Oncology. W.L. Tan: Travel / Accommodation / Expenses: Boehringer Ingelheim for WCLC in Toronto Sept 2018. S. Geater: Honoraria (self): AstraZeneca, Boehringer Ingelheim, Roche; Advisory / Consultancy: Boehringer Ingelheim; Research grant / Funding (institution): AstraZeneca, Boehringer Ingelheim, Roche, MSD; Travel / Accommodation / Expenses: AstraZeneca, Boehringer Ingelheim, Roche. G. De Castro Jr.: Honoraria (self): Bristol-Myers Squibb; Merck Serono Serbia; MSD; Advisory / Consultancy: Bristol-Myers Squibb; MSD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Merck Serono Serbia; MSD; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Merck Serono Serbia; MSD. A. Greystoke: Speaker Bureau / Expert testimony: Novartis, AstraZeneca, Boehringer Ingelheim, BMS, MSD, Takeda, Pfizer; Advisory / Consultancy: Novartis, AstraZeneca, Boehringer Ingelheim, BMS, MSD, Takeda, Pfizer. E. Felip: Advisory / Consultancy: AbbVie; AstraZeneca; Blueprint Medicines; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; Guardant Health; Lilly; Merck KGaA; Merck Sharp & Dohme; Novartis; Pfizer; Roche; Takeda; Speaker Bureau / Expert testimony: AbbVie; AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Lilly; Merck KGaA; Merck Sharp & Dohme; Novartis; Pfizer; Roche; Takeda; Research grant / Funding (self): EMD Serono (Inst); Fundación Merck Salud (Inst). B.E. Johnson: Advisory / Consultancy: Novartis Steering Committee and Array Biopharma Steering Committee; Research grant / Funding (self): Research Grants from Novartis and Cannon Medical Imaging. A-L. Louveau: Full / Part-time employment: Novartis. V.Q. Passos: Full / Part-time employment: Novartis. B.C. Cho: Shareholder / Stockholder / Stock options: TheraCanVac Inc; Honoraria (self): AstraZeneca; Bayer; Champions Oncology; Dizal Pharma; Dong-A ST; Janssen; MOGAM Institute; MSD; Novartis; Ono Pharmaceutical; Yuhan; Advisory / Consultancy: AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Janssen; Lilly; MSD; Novartis; Ono Pharmaceutical; Pfizer; Roche; Takeda; Yuhan; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (self): AstraZeneca; Bayer; Champions Oncology; Dizal Pharma; Dong-A ST; Janssen; MOGAM Institute; MSD; Novartis; Ono Pharmaceutical; Yuhan; Licensing / Royalties: Champions Oncology. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Genomic rearrangements involving neurotrophic tropomyosin receptor kinase 1, 2, or 3 (NTRK1/2/3) result in constitutively active tropomyosin receptor kinase (TRK) fusion proteins that are oncogenic drivers in multiple pediatric and adult cancers. Larotrectinib is a selective TRK inhibitor approved by the US Food and Drug Administration in 2018 for the treatment of TRK fusion cancer based on a primary analysis in 55 patients from 3 clinical trials [Drilon et al. NEJM 2018]. Here, we report median duration of response (DOR) data in the primary cohort and updated data in an expanded cohort of 159 patients with TRK fusion cancer treated with larotrectinib, with 153 (55 primary + 98 supplemental) evaluable for efficacy. Methods Patients with TRK fusion cancer detected by local molecular profiling were treated with larotrectinib across 3 studies (NCT02122913, NCT02637687, NCT02576431). Disease status was assessed by investigators using RECIST 1.1. Data cut-off was February 19, 2019. Results In the primary cohort of 55 patients with a median follow-up of 26 months, the median DOR in 44 patients with complete or partial responses was 35.2 months (95% CI 21.2–not evaluable [NE]), with 17 progression events and 27 responses ongoing (range 1.6–44 months). Median progression-free survival in the primary cohort was 25.8 months (95% CI 9.9–NE), with 27 patients having progressed. In the expanded combined dataset, the most common tumor types included soft tissue sarcoma (n = 36), infantile fibrosarcoma (n = 29), thyroid carcinoma (n = 26), salivary gland carcinoma (n = 21), and lung cancer (n = 12). Median age was 43 years, ranging from < 1 month to 84 years; 33% < 18 years. The overall response rate was 79% (95% CI 72–85), with complete responses in 16%. Adverse events were mostly grade 1–2; 13% of patients had a grade 3–4 event related to larotrectinib. Only one patient discontinued due to an adverse event related to larotrectinib. Conclusions These data confirm the marked tissue-agnostic efficacy and long durability of response in patients with TRK fusion cancer treated with larotrectinib. Larotrectinib demonstrated a favorable long-term safety profile. Screening patients for NTRK gene fusions should be considered. Clinical trial identification NCT02122913, NCT02637687, NCT02576431. Legal entity responsible for the study Bayer. Funding Bayer. Disclosure F. Doz: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Research grant / Funding (self): Celgene; Advisory / Consultancy: Bayer; Advisory / Consultancy: Loxo Oncology; Advisory / Consultancy: Servier. L. Mascarenhas: Speaker Bureau / Expert testimony: Bayer. J. Berlin: Research grant / Funding (institution): PsiOxus; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): AbbVie (pharamcyclics); Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): FivePrime; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Macrogenics; Honoraria (self): Nestle; Advisory / Consultancy: Rafeal; Advisory / Consultancy: Seattle Genetics; Honoraria (self): Eisai; Advisory / Consultancy: Taiho; Advisory / Consultancy: Armo. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

BACKGROUND RET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown. METHODS We enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS In the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event. CONCLUSIONS Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-OOl ClinicalTrials.gov number, NCT03157128.) [ABSTRACT FROM AUTHOR]

BACKGROUND Among patients with non–small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and MET amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation. METHODS We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with MET-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and MET status (MET exon 14 skipping mutation or MET amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments. RESULTS A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a MET exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with MET amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with MET amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2. CONCLUSIONS Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a MET exon 14 skipping mutation, particularly in those not treated previously. The efficacy in MET-amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.) [ABSTRACT FROM AUTHOR]

BACKGROUND RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown. METHODS We enrolled patients with RET-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS In the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events. CONCLUSIONS In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-OOl ClinicalTrials.gov number, NCT03157128.) [ABSTRACT FROM AUTHOR]

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of metastatic non-small-cell lung cancer (NSCLC) was published in 2016. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Chinese Society of Clinical Oncology (CSCO) to convene a special guidelines meeting immediately after the Chinese Thoracic Oncology Group Annual Meeting 2018, in Guangzhou, China. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic NSCLC cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic NSCLC representing the oncological societies of China (CSCO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the six participating Asian countries. During the review process, the updated ESMO 2018 Clinical Practice Guidelines for metastatic NSCLC were released and were also considered, during the final stages of the development of the Pan-Asian adapted Clinical Practice Guidelines. [ABSTRACT FROM AUTHOR]

Background There is an expanding list of therapeutically relevant biomarkers for NSCLC and effective molecular profiling is paramount. We sought to comprehensively and prospectively evaluate the molecular epidemiology of NSCLC in Asia and ascertain the extent of access to relevant therapies. The study is being conducted by the Asian Thoracic Oncology Research Group (ATORG) – an academic co-operative lung cancer trials group in Asia. Methods ATORG-001 is a prospective, multi-centre study of NSCLC patients (pts) throughout Asia. Eligible pts must have good performance status (ECOG ≤2), adequate organ function and ≤3 prior lines of cytotoxic chemotherapy. Archival tissue specimens are sent to a central laboratory in Singapore (Singapore General Hospital) for profiling, consisting of NGS with the Oncomine Focus Assay (52 gene panel including fusions) and PD-L1 immunohistochemistry. Results are returned to investigators in a clinically relevant timeframe. Baseline demographics, pre-existing molecular profile and prior treatment details are collected. Treatment and pt outcomes are followed for 2 years. Recruitment commenced in Jan 2019 in 3 sites (National Cancer Centre Singapore, Chinese University of Hong Kong, University Malaya Medical Centre). We report an interim analysis for the first 27 of a planned 500 pts. Results As of 01 Jul 2019, 27 pts have enrolled with median age 67 yrs (range 46-79), 59% male, 81% adenocarcinoma, 52% stage IV, 37% non-smokers, median lines of prior therapy 1 (range 0-6) and 85% with no known oncogenic driver. Pre-existing mutation status was known in 89% for EGFR and 63% for ALK. Median turnaround time from tissue acquisition to profiling results was 22 days (range 15-74). New alterations were most common in KRAS (19%), MYC (15%), CDK4 (7%) and ERBB2 (7%). Potentially actionable new alterations were found in 7 (26%) pts, including KRAS G12C mutation (7%), BRAF G469A mutation (4%), ERBB2 exon 20 insertion (4%), ERBB2 amplification (4%), FGFR2 amplification (4%) and MET exon 14 skipping mutation (4%). Conclusions Enrolment is ongoing with additional sites and countries planned to comprehensively evaluate the molecular epidemiology of NSCLC in Asia. Legal entity responsible for the study Asian Thoracic Oncology Research Group. Funding Asian Thoracic Oncology Research Group, Novartis. Disclosure A.C. Tan: Travel / Accommodation / Expenses: ASLAN Pharmaceuticals. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Introduction: Next-generation sequencing (NGS) diagnostics have shown clinical utility in predicting survival benefits in patients with certain cancer types who are undergoing targeted drug therapies. Currently, there are no guidelines or recommendations for the use of NGS in patients with metastatic cancer from an Asian perspective. In this article, we present the Asia-Pacific Oncology Drug Development Consortium (APODDC) recommendations for the clinical use of NGS in metastatic cancers., Methods: The APODDC set up a group of experts in the field of clinical cancer genomics to (i) understand the current NGS landscape for metastatic cancers in the Asia-Pacific (APAC) region; (ii) discuss key challenges in the adoption of NGS testing in clinical practice; and (iii) adapt/modify the European Society for Medical Oncology guidelines for local use. Nine cancer types [breast cancer (BC), gastric cancer (GC), nasopharyngeal cancer (NPC), ovarian cancer (OC), prostate cancer, lung cancer, and colorectal cancer (CRC) as well as cholangiocarcinoma and hepatocellular carcinoma (HCC)] were identified, and the applicability of NGS was evaluated in daily practice and/or clinical research. Asian ethnicity, accessibility of NGS testing, reimbursement, and socioeconomic and local practice characteristics were taken into consideration., Results: The APODDC recommends NGS testing in metastatic non-small-cell lung cancer (NSCLC). Routine NGS testing is not recommended in metastatic BC, GC, and NPC as well as cholangiocarcinoma and HCC. The group suggested that patients with epithelial OC may be offered germline and/or somatic genetic testing for BReast CAncer gene 1 (BRCA1), BRCA2, and other OC susceptibility genes. Access to poly (ADP-ribose) polymerase inhibitors is required for NGS to be of clinical utility in prostate cancer. Allele-specific PCR or a small-panel multiplex-gene NGS was suggested to identify key alterations in CRC., Conclusion: This document offers practical guidance on the clinical utility of NGS in specific cancer indications from an Asian perspective., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Combinations of avelumab [anti-programmed death-ligand 1 (anti-PD-L1)] or talazoparib [poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor] with binimetinib (MEK inhibitor) were expected to result in additive or synergistic antitumor activity relative to each drug administered alone. Here, we report phase Ib results from JAVELIN PARP MEKi, which investigated avelumab or talazoparib combined with binimetinib in metastatic pancreatic ductal adenocarcinoma (mPDAC)., Patients and Methods: Patients with mPDAC that had progressed with prior treatment received avelumab 800 mg every 2 weeks plus binimetinib 45 mg or 30 mg two times daily (continuous), or talazoparib 0.75 mg daily plus binimetinib 45 mg or 30 mg two times daily (7 days on/7 days off). The primary endpoint was dose-limiting toxicity (DLT)., Results: A total of 22 patients received avelumab plus binimetinib 45 mg (n = 12) or 30 mg (n = 10). Among DLT-evaluable patients, DLT occurred in five of 11 patients (45.5%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in three of 10 patients (30.0%) at the 30-mg dose. Among patients treated at the 45-mg dose, one (8.3%) had a best overall response of partial response. Thirteen patients received talazoparib plus binimetinib 45 mg (n = 6) or 30 mg (n = 7). Among DLT-evaluable patients, DLT occurred in two of five patients (40.0%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in two of six patients (33.3%) at the 30-mg dose. No objective responses were observed., Conclusions: Combinations of avelumab or talazoparib plus binimetinib resulted in higher-than-expected DLT rates. However, most DLTs were single occurrences, and the overall safety profiles were generally consistent with those reported for the single agents., Clinical Trial Registration: ClinicalTrials.govNCT03637491; https://clinicaltrials.gov/ct2/show/NCT03637491., Competing Interests: Disclosure JRA reports nonfinancial support and reasonable reimbursement for travel from the European Society for Medical Oncology; has received travel and accommodation expenses from Ellipses Pharma, IONCTURA, Kelun Pharmaceuticals/KLUS Pharma, Molecular Partners, and Peptomyc; has served in consulting or advisory roles for Boxer Capital, Chinese University of Hong Kong, Ellipses Pharma, IONCTURA (including serving on a scientific advisory board), Kelun Pharmaceuticals/KLUS Pharma, Molecular Partners, Peptomyc, Vall d’Hebron Institute of Oncology/Ministerio De Empleo Y Seguridad Social, and Tang Advisors; has received research funding from Black Diamond Therapeutics, Blueprint Medicines, Hummingbird, MSD, Vall d’Hebron Institute of Oncology/Cancer Core Europe, and Yingli; and has served as investigator in clinical trials with Aadi Bioscience, Amgen, Bayer, BioAtla, BioMed Valley Discoveries, Bicycle Therapeutics, Cancer Core Europe, Cellestia, Curis, CytomX, Deciphera, Fore Biotherapeutics, Genmab, GSK, Hummingbird, Hutchison MediPharma, IDEAYA, Kelun-Biotech, Loxo Oncology, Merus, Mirati Linnaeus Therapeutics, Novartis, Nuvation, Pfizer, Roche Pharmaceuticals, Spectrum Pharmaceuticals, Symphogen, Taiho, Takeda-Millennium, Tango Therapeutics, and Yingli. DSWT has received institutional research funding from AstraZeneca, GSK, and Novartis; has received honoraria from BMS, Novartis, Pfizer, Roche, and Takeda; has served in consulting or advisory roles for AstraZeneca, Loxo, MSD, Novartis, Pfizer, and Roche; and has received travel and accommodation expenses from Boehringer Ingelheim, Pfizer, and Roche. IGL has served in consulting or advisory roles for Array BioPharma, Eisai, Jazz Pharmaceuticals, Kanaph, OncXerna, SOTIO, and Sumitomo; and has received institutional research funding from ARMO BioSciences, Bayer, BMS, BridgeBio, GSK, Glenmark, Halozyme, Ignyta, Incyte, Lilly, MedImmune, NewLink Genetics, Novartis, OncoMed, and Pfizer. WH has received research funding from AI Therapeutics. JTB has received research funding from Novartis and Pfizer. NB has served in consulting or advisory roles for AstraZeneca, BMS, Celgene, and Exelixis. ZZ reports stock and other ownership interests in and was employed by Pfizer at the time of study. SD, KK, CW, and RJL report employment by and stock and other ownership interests in Pfizer. NP reports stock and other ownership interests in and was employed by Pfizer at the time of study. WAM has served in consulting or advisory roles for Five Prime Therapeutics (DMSC), Zymeworks (DMSC), and QED Therapeutics (DMSC); and has received institutional research funding from ALX Oncology, AstraZeneca, BeiGene, EDDC/D3, Exelixis, Fate Therapeutics, Pfizer, Roche/Genentech, and Takeda. AB, SR, NK have declared no conflicts of interest. Data sharing Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual deidentified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information. Ethics approval and consent to participate The trial was conducted in accordance with the Declaration of Helsinki, the International Council for Harmonisation Guideline for Good Clinical Practice, and the International Ethical Guidelines for Biomedical Research Involving Human Subjects. All patients provided written informed consent before enrollment. The protocol, amendments, and informed consent forms were approved by the institutional review board or independent ethics committee at each center., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.)

Objectives: To better understand genetic determinants of response to ceritinib, an exploratory analysis was conducted using tumor biopsies from anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small-cell lung cancer (NSCLC) patients treated with ceritinib at doses of ≥ 300 mg in the ASCEND-1 study., Methods: ASCEND-1 was an open-label, multicentre, phase 1, dose-escalation and expansion study of ceritinib (fasted) in ALK inhibitor (ALKi)-naïve or ALKi-pretreated patients with locally advanced or metastatic ALK + NSCLC. Biopsies were assayed by next-generation sequencing (NGS) using a Foundation Medicine panel targeting 295 genes. Somatic alterations were correlated with clinical outcome (cut-off 14-Apr-2014). A total of 285 ALK + NSCLC patients were treated with ceritinib at doses ≥ 300 mg., Results: NGS data were generated for 85 pts (ALKi-pretreated [n = 54]; ALKi-naïve [n = 31]), 57 were collected from patients before exposure to any ALKi. NGS did not detect ALK rearrangement in 14 of 85 patients; several of these ALK NGS negative cases harbored alternative drivers, e.g. EGFR mutation. Of the 71 biopsies with NGS confirmed ALK rearrangement, the most frequently detected rearrangements were EML4-ALK variant 1 (V1) and EML4-ALK V3 (36.6% [26/71] and 32.4% [23/71] respectively). Eight (six crizotinib-pretreated and two pretreated with crizotinib followed by alectinib) of the 21 ALKi-pretreated patients carried a point mutation of the ALK TKD, and had the biopsy collected between 1 and 14 days before ceritinib; with the exception of one patient with a G1202R point mutation, all patients derived clinical benefit from ceritinib treatment. Of the 14 ALKi-naïve patients, ceritinib was effective in almost all patients, including a patient carrying a concomitant ERBB4 and HGF amplification., Conclusions: This exploratory analysis highlights the potential role of NGS in improving our understanding of response and resistance to ceritinib. It also illustrates that ceritinib is active against almost all ALK resistance mutations found in ALKi-pretreated patients., Trial Registration: ClinicalTrials.gov, NCT01283516. Registered January 26, 2011, https://clinicaltrials.gov/ct2/show/NCT01283516., (Copyright © 2021. Published by Elsevier B.V.)

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.)

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.)

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of early and locally-advanced non-small-cell lung cancer (NSCLC) was published in 2017, and covered the diagnosis, staging, management and treatment of both early stage I and II disease and locally-advanced stage III disease. At the ESMO Asia Meeting in November 2018, it was decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special face-to-face guidelines meeting in 2019 in Seoul. The aim was to adapt the ESMO 2017 guidelines to take into account potential differences related to ethnicity, cancer biology and standard practices associated with the treatment of locally-advanced, unresectable NSCLC in Asian patients. These guidelines represent the consensus opinions reached by those experts in the treatment of patients with lung cancer who represented the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and it was independent of both local current treatment practices and the treatment availability and reimbursement situations in the individual participating Asian countries., (Copyright © 2019 European Society for Medical Oncology. All rights reserved.)