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Purpose: The ETOP 10-16 BOOSTER study was a randomized phase II trial of osimertinib and bevacizumab therapy versus osimertinib therapy in patients with an acquired EGFR T790M mutation. The mechanisms of acquired resistance to osimertinib and bevacizumab have not been described previously., Experimental Design: Next-generation sequencing (Guardant360) was conducted in serial plasma samples. The association between ctDNA and efficacy outcomes was explored, and molecular alterations at progression were described., Results: A total of 136 patients (88% of 155 randomized) had plasma samples at baseline (68 per arm), 110 (71%) at week 9, and 65 (42%) at progression. In a multivariable model for progression-free survival (PFS), the treatment effect was found to differ by smoking status (interaction P = 0.046), with the effect of smoking also differing by baseline EGFR T790M (interaction P = 0.033), whereas both TP53 at baseline and the tissue EGFR exon 21 L858R mutation were significantly associated with worse PFS outcome. Smokers (current/former) without baseline EGFR T790M showed a significant improvement in PFS under combination treatment, albeit with small numbers (P = 0.015). Week-9 EGFR T790M clearance was associated with improved PFS in the osimertinib arm (P = 0.0097). Acquired EGFR C797S mutations were detected in 22% and 13% of patients in the combination and osimertinib arms, respectively., Conclusions: The differential effect of treatment by smoking was not explained by TP53 mutations or other molecular alterations examined. Molecular mechanisms of acquired resistance were detected, but no novel molecular alterations were identified in the combination arm., (©2024 American Association for Cancer Research.)

Introduction: Pleural mesothelioma (PM) is an aggressive malignancy with increasing prevalence and poor prognosis. Real-life data are a unique approach to reflect the reality of PM epidemiology, treatment, and prognosis in Europe., Methods: A joint analysis of the European Thoracic Oncology Platform Mesoscape and the European Society of Thoracic Surgeons (ESTS) databases was performed to better understand the characteristics and epidemiology of PM, including histologic subtype, staging, and treatment. Overall survival (OS) was assessed, adjusting for parameters of clinical interest., Results: The analysis included 2766 patients (Mesoscape: 497/10 centers/ESTS: 2269/77 centers). The primary histologic subtype was epithelioid (71%), with 57% patients on stages III to IV. Within Mesoscape, the patients received either multimodality (59%) or palliative intention treatment (41%). The median follow-up was 47.2 months, on the basis of 1103 patients (Mesoscape: 491/ESTS: 612), with 823 deaths, and median OS was 17.4 months. In multivariable analysis, female sex, epithelioid subtype, and lower stage were associated with longer OS, when stratifying by cohort, age, and Eastern Cooperative Oncology Group Performance Status. Within Mesoscape, multimodality treatment including surgery was predictive of longer OS (hazard ratio = 0.56, 95% confidence interval: 0.45-0.69), adjusting for sex, histologic subtype, and Eastern Cooperative Oncology Group Performance Status. Overall, surgical candidates with a macroscopic complete resection had a significantly longer median OS compared with patients with R2 (25.2 m versus 16.4 m; log-rank p < 0.001)., Conclusions: This combined European Thoracic Oncology Platform/ESTS database analysis offers one of the largest databases with detailed clinical and pathologic outcome. Our finding reflects a benefit for selected patients that undergo multimodality treatment, including macroscopic complete resection, and represents a valuable resource to inform the epidemiology and treatment options for individual patients., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: While osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is the standard treatment in patients with advanced non-small-cell lung cancer (NSCLC) with sensitising EGFR and acquired T790M mutations, progression inevitably occurs. The angiogenic pathway is implicated in EGFR TKI resistance., Patients and Methods: BOOSTER is an open-label randomised phase II trial investigating the efficacy and safety of combined osimertinib 80 mg daily and bevacizumab 15 mg/kg every 3 weeks, versus osimertinib alone, in patients with EGFR-mutant advanced NSCLC and acquired T790M mutations after failure on previous EGFR TKI therapy. Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR) and adverse events (AEs)., Results: Between May 2017 and February 2019, 155 patients were randomised (combination: 78; osimertinib: 77). At data cut-off of 22 February 2021, median follow-up was 33.8 months [interquartile range (IQR): 26.5-37.6 months] and 129 (83.2%) PFS events were reported in the intention-to-treat population. There was no difference in median PFS between the combination [15.4 months; 95% confidence interval (CI) 9.2-18.0 months] and osimertinib arm (12.3 months; 95% CI 6.2-17.2 months; stratified log-rank P = 0.83), [hazard ratio (HR) = 0.96; 95% CI 0.68-1.37]. Median OS was 24.0 months (95% CI 17.8-32.1 months) in the combination arm and 24.3 months (95% CI 16.9-37.0 months) in the osimertinib arm (stratified log-rank P = 0.91), (HR = 1.03; 95% CI 0.67-1.56). Exploratory analysis revealed a significant interaction of smoking history with treatment for PFS (adjusted P = 0.0052) with a HR of 0.52 (95% CI 0.30-0.90) for smokers, and 1.47 (95% CI 0.92-2.33) for never smokers. ORR was 55% in both arms and the median time to treatment failure was significantly shorter in the combination than in the osimertinib arm, 8.2 months versus 10.8 months, respectively (P = 0.0074). Safety of osimertinib and bevacizumab was consistent with previous reports with grade ≥3 treatment-related AEs (TRAEs) reported in 47% and 18% of patients on combination and osimertinib alone, respectively., Conclusions: No difference in PFS was observed between osimertinib plus bevacizumab and osimertinib alone. Grade ≥3 TRAEs were more common in patients on combination., Competing Interests: Disclosure RAS reports advisory role for Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Lily, Merck, Novartis, Pfizer, Roche, Taiho, Takeda and Yuhan and grants from AstraZeneca, Boehringer Ingelheim, outside the submitted work. UD reports honorarium as Member of the Tumor Agnostic Evidence Generation working Group of Roche, outside the submitted work. BCC reports grants from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, Abbvie, Medpacto, GI Innovation, Eli Lilly, Blueprint medicines, Interpark Bio Convergence Corp, personal fees from Novartis, AstraZeneca, Champions Oncology, Janssen, Yuhan, Ono, MSD, Medpacto, Eli Lilly, Blueprint medicines, Interpark Bio Convergence Corp, Boehringer Ingelheim, Roche, BMS, Pfizer, Takeda, KANAPH Therapeutic Inc., Bridgebio therapeutics, Cyrus therapeutics, Guardant Health, Joseah BIO, Gencurix Inc., and other from Interpark Bio Convergence Corp, KANAPH Therapeutic Inc., Bridgebio therapeutics, Cyrus therapeutics, Gencurix Inc, DAAN, TheraCanVac Inc., outside the submitted work. EN reports grants, personal fees and non-financial support from Roche, personal fees and non-financial support from AstraZeneca, grants, personal fees and non-financial support from Bristol-Myers-Squibb, personal fees and non-financial support from Merck Sharp Dohme, grants and personal fees from Merck Serono, personal fees from Takeda, grants, personal fees and non-financial support from Pfizer, personal fees from Lilly, personal fees from Bayer, personal fees from Amgen, personal fees from Boehringer Ingelheim, outside the submitted work. EC reports personal fees from AstraZeneca, Amgen, BMS, MSD and Roche, outside the submitted work. JdC reports grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme and Hoffmann-La Roche, personal fees from Bayer, Boehringer Ingelheim, Glaxosmithkline, Jansen-Cilag, Lilly, Novartis, Pfizer and Takeda, outside the submitted work. MAS reports advisory role for Roche and Boehringer Ingelheim, speaker role for Pierre Fabre and travel grants from Roche and PharmaMar, outside the submitted work. RB reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Roche, AstraZeneca, BMS, AMGEN and MSD, participation on Data Safety Monitoring Board or Advisory Board for AstraZeneca, BMS and Roche. LC reports advisory role for AstraZeneca, Roche and Daichi, outside the submitted work. MPP reports grants, personal fees and non-financial support from AstraZeneca, BMS and ROCHE, personal fees from MSD and TAKEDA, outside the submitted work. RGC reports Advisory Board, Consultancy or Speaker honoraria from MSD, Bristol-Myers Squibb, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Janssen and Sanofi. SC reports non-financial support from Pfizer, Roche, MSD and BMS, outside the submitted work. MF reports grants from Astra Zeneca and BMS and other support from AstraZeneca, BMS, Boehringer Ingelheim, Janssen, MSD, Pfizer, Roche and Takeda, outside the submitted work. JGS reports grants for consulting or advisory role from Roche, Boehringer Ingelheim, EUSA Pharma, research funding from Roche and travel, and accommodation expenses from Roche, BMS, Merck Sharp & Dohme and Pfizer, outside the submitted work. MD reports personal fees from AstraZeneca, BMS, Boehringer Ingelheim, MSD, Pfizer, Roche and Takeda, outside the submitted work. MM reports grants and personal fees from Bristol-Myers Squibb, Pierre Fabre, personal fees and non-financial support from AstraZeneca, Boehringer Ingelheim, F. Hoffman – La Roche, Merck Sharp and Dohme, and personal fees from Kyowa Kirin, outside the submitted work. JMST reports personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Roche, Takeda and MSD, outside the submitted work. CB reports consulting or advisory role for AstraZeneca, Pfizer, Roche, Takeda, Janssen-Cilag and Boehringer Ingelheim, as well as travel support from AstraZeneca and Takeda, outside the submitted work. MP reports grants from AstraZeneca, BMS, Boehringer Ingelheim, Roche, Takeda, Vifor, and personal fees from Abbvie, AstraZeneca, BMS, Boehringer Ingelheim, Eisei, MSD, Novartis, Pfizer, Roche, Takeda, Merck and Janssen, outside the submitted work. RAS reports consultant or advisory role for AstraZeneca, BMS, Janssen, MSD, Pfizer, Regeneron, Roche, Seattle Genetics and Takeda, speaker honoraria from Amgen, AstraZeneca, Blueprint, Eli Lilly, GSK, MSD, Novartis, Roche and Sandoz, DMC role from Genentech/Roche and Takeda, and financial support for ETOP and IBCSG trials, where he is president and scientific chair, from AstraZeneca, BMS, Ipsen, MSD, Novartis, Pierre Fabre, Roche and Pfizer. SP reports grants from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffman – La Roche, Illumina, Novartis, Pfizer, Merck Sharp and Dohme, personal fees from Amgen, Abbvie, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffman – La Roche, Foundations Medicine, Illumina, Janssen, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, Merck Sharp and Dohme, Merck Serono, Merrimack, Medscape, Phosphoplatin Therapeutics, Beigene and Imedex, outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Introduction: KRAS mutations, the most frequent gain-of-function alterations in NSCLC, are currently emerging as potential predictive therapeutic targets. The role of KRAS-G12C (Kr&#95;G12C) is of special interest after the recent discovery and preclinical analyses of two different Kr&#95;G12C covalent inhibitors (AMG-510, MRTX849)., Methods: KRAS mutations were evaluated in formalin-fixed, paraffin-embedded tissue sections by a microfluidic-based multiplex polymerase chain reaction platform as a component of the previously published European Thoracic Oncology Platform Lungscape 003 Multiplex Mutation study, of clinically annotated, resected, stage I to III NSCLC. In this study, -Kr&#95;G12C mutation prevalence and its association with clinicopathologic characteristics, molecular profiles, and postoperative patient outcome (overall survival, relapse-free survival, time-to-relapse) were explored., Results: KRAS gene was tested in 2055 Lungscape cases (adenocarcinomas: 1014 [49%]) with I or II or III stage respective distribution of 53% or 24% or 22% and median follow-up of 57 months. KRAS mutation prevalence in the adenocarcinoma cohort was 38.0% (95% confidence interval (CI): 35.0% to 41.0%), with Kr&#95;G12C mutation representing 17.0% (95% CI: 14.7% to 19.4%). In the "histologic-subtype" cohort, Kr&#95;G12C prevalence was 10.5% (95% CI: 9.2% to 11.9%). When adjusting for clinicopathologic characteristics, a significant negative prognostic effect of Kr&#95;G12C presence versus other KRAS mutations or nonexistence of KRAS mutation was identified in the adenocarcinoma cohort alone and in the "histologic-subtype" cohort. For overall survival in adenocarcinomas, hazard ratio (HR) G12C versus other KRAS is equal to 1.39 (95% CI: 1.03 to 1.89, p = 0.031) and HR G12C versus no KRAS is equal to 1.32 (95% CI: 1.03 to 1.69, p = 0.028) (both also significant in the "histologic-subtype" cohort). For time-to-relapse, HR G12C versus other KRAS is equal to 1.41 (95% CI: 1.03 to 1.92, p = 0.030). In addition, among all patients, for relapse-free survival, HR G12C versus no KRAS is equal to 1.27 (95% CI: 1.04 to 1.54, p = 0.017)., Conclusions: In this large, clinically annotated stage I to III NSCLC cohort, the specific Kr&#95;G12C mutation is significantly associated with poorer prognosis (adjusting for clinicopathologic characteristics) among adenocarcinomas and in unselected NSCLCs., (Copyright © 2021 International Association for the Study of Lung Cancer. All rights reserved.)

Background: Cancer cases among the population of the canton Zurich, are registered in the Cancer Registry of the cantons of Zurich and Zug (KKR). The Thoracic Oncology Center, founded in 2011 is one of 17 multidisciplinary centers within the Comprehensive Cancer Center Zurich (CCCZ)., Methods: The aim of the current study is to quantify the mortality risk of patients with NSCLC and identify differences on survival and other factors between patients receiving their primary treatment at the CCCZ and those treated elsewhere and registered by KKR. The differential effect between CCCZ and KKR cohorts on survival: overall, by stage, sex and age, is explored. Stratified log-rank and Wilcoxon tests, Cox models and restricted mean survival times (RMST) are estimated. Propensity score matching (PSM) is also used to adjust for confounding factors., Results: Analysis included 848 NSCLC cases from the CCCZ and 1759 from the KKR, diagnosed between January 2011 and December 2015. At a median follow-up of 57 months, overall survival (OS) was significantly superior for patients treated at the CCCZ compared to KKR [Median OS: 36.0 months (95%CI: 31.0-45.0) and 12.0 months (95%CI: 11.0-13.0), respectively, stratified log-rank p < 0.001; adjusted HR = 1.31, (95% CI: 1.18-1.46), difference in RMST up to 72 months: 13.8 months (95%CI: 11.5-16.2), p < 0.001]. The effect of cohort was significant for stages III and IV (overall and also by sex and age). After PSM OS remained significantly superior for patients treated at the CCCZ compared to KKR., Conclusions: The survival probability for patients in the CCCZ cohort was superior to that of patients in the canton Zürich treated outside the center. This analysis provides further evidence of the importance of the volume of experience and the availability of a multidisciplinary organization and research environment, as delivered by a comprehensive cancer center, on the outcome of patients with NSCLC., Competing Interests: Declaration of Competing Interest Dr. Stahel reports grants from BMS, personal fees from Abbvie, grants and personal fees from Astra Zeneca, personal fees from Boehringer Ingelheim, personal fees from Eli Lilly, grants and personal fees from MSD, grants and personal fees from Pfizer, personal fees from Regeneron, personal fees from Roche, personal fees from Seattle Genetics, personal fees from Takeda, grants and personal fees from Genentech/Roche, outside the submitted work. Dr. Curioni reports other from Astra Zeneca, other from Bristol Meyer Squibb, other from Boehringer Ingelheim, other from Pfizer, other from Roche, other from Takeda, other from MSD, outside the submitted work. Dr. Andratschke reports personal fees from AstraZeneca, personal fees from Debiopharm, grants from Brainlab, personal fees from ViewRay, outside the submitted work. Dr. Rohrmann, Dr. Dafni, Dr. Sandner, Prof. Opitz, Dr. Franzen, Dr. Dimopoulou, Dr. Matthes, Prof. Kohler, Prof. Guckenberger and Prof. Weder have nothing to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)