PMID- 34839016 OWN - NLM STAT- MEDLINE DCOM- 20220303 LR - 20220603 IS - 1569-8041 (Electronic) IS - 0923-7534 (Linking) VI - 33 IP - 2 DP - 2022 Feb TI - A randomised phase II study of osimertinib and bevacizumab versus osimertinib alone as second-line targeted treatment in advanced NSCLC with confirmed EGFR and acquired T790M mutations: the European Thoracic Oncology Platform (ETOP 10-16) BOOSTER trial. PG - 181-192 LID - S0923-7534(21)04825-0 [pii] LID - 10.1016/j.annonc.2021.11.010 [doi] AB - 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. CI - Copyright (c) 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved. FAU - Soo, R A AU - Soo RA AD - Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore. FAU - Han, J-Y AU - Han JY AD - National Cancer Center, Center for Lung Cancer, Goyang, Republic of Korea. FAU - Dafni, U AU - Dafni U AD - National and Kapodistrian University of Athens, Athens, Greece; Frontier Science Foundation Hellas, Athens, Greece. FAU - Cho, B C AU - Cho BC AD - Yonsei Cancer Center, Yonsei University College of Medicine, Division of Medical Oncology, Seoul, Republic of Korea. FAU - Yeo, C M AU - Yeo CM AD - Medical Oncology Department, Tan Tock Seng Hospital, Singapore, Singapore. FAU - Nadal, E AU - Nadal E AD - Medical Oncology Department, ICO L'Hospitalet, Barcelona, Spain. FAU - Carcereny, E AU - Carcereny E AD - Medical Oncology Department, Institut Catala d'Oncologia Badalona Hospital Germans Trias i Pujol, B-ARGO Group, Badalona, Spain. FAU - de Castro, J AU - de Castro J AD - Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain. FAU - Sala, M A AU - Sala MA AD - Medical Oncology Department, Hospital Universitario Basurto, Bilbao, Spain. FAU - Bernabe, R AU - Bernabe R AD - Medical Oncology Department, Hospital Virgen del Rocio, Sevilla, Spain. FAU - Coate, L AU - Coate L AD - Mid-Western Cancer Centre and University Hospital Limerick, Limerick, Ireland. FAU - Provencio Pulla, M AU - Provencio Pulla M AD - Hospital Puerta de Hierro, Majadahonda Medical Oncology Service, Madrid, Spain. FAU - Garcia Campelo, R AU - Garcia Campelo R AD - Medical Oncology Department, Hospital Teresa Herrera, La Coruna, Spain. FAU - Cuffe, S AU - Cuffe S AD - Department of Medical Oncology, St. James's Hospital, Dublin, Ireland. FAU - Hashemi, S M S AU - Hashemi SMS AD - Department of Pulmonary Diseases, Amsterdam UMC, VU University Medical Center, Amsterdam, Netherlands. FAU - Fruh, M AU - Fruh M AD - Cantonal Hospital St. Gallen, Oncology and Hematology, St. Gallen, Switzerland; Department of Oncology, Inselspital Bern, Bern, Switzerland. FAU - Massuti, B AU - Massuti B AD - Medical Oncology Department, Hospital General Universitario Alicante, Alicante, Spain. FAU - Garcia-Sanchez, J AU - Garcia-Sanchez J AD - Medical Oncology Service, Hospital Arnau Vilanova, Valencia, Spain. FAU - Domine, M AU - Domine M AD - Department of Oncology, Hospital Universitario Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain. FAU - Majem, M AU - Majem M AD - Medical Oncology Department, Hospital De La Santa Creu I Sant Pau, Barcelona, Spain. FAU - Sanchez-Torres, J-M AU - Sanchez-Torres JM AD - Medical Oncology Department, Hospital Universitario de la Princesa, Madrid, Spain. FAU - Britschgi, C AU - Britschgi C AD - Department of Medical Oncology and Hematology, University Hospital Zurich, Comprehensive Cancer Center Zurich, Zurich, Switzerland. FAU - Pless, M AU - Pless M AD - Cantonal Hospital Winterthur, Oncology and Haematology, Winterthur, Switzerland. FAU - Dimopoulou, G AU - Dimopoulou G AD - Frontier Science Foundation Hellas, Athens, Greece. FAU - Roschitzki-Voser, H AU - Roschitzki-Voser H AD - European Thoracic Oncology Platform (ETOP), Coordinating Office, Bern, Switzerland. FAU - Ruepp, B AU - Ruepp B AD - European Thoracic Oncology Platform (ETOP), Coordinating Office, Bern, Switzerland. FAU - Rosell, R AU - Rosell R AD - Germans Trias i Pujol Research Institute (IGTP), Badalona, Barcelona, Spain; Catalan Institute of Oncology (ICO), Honorary Consultant, Barcelona, Spain. FAU - Stahel, R A AU - Stahel RA AD - European Thoracic Oncology Platform (ETOP), Coordinating Office, Bern, Switzerland. Electronic address: Rolf.Stahel@etop-eu.org. FAU - Peters, S AU - Peters S AD - Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne, Switzerland. CN - ETOP 10-16 BOOSTER Collaborators LA - eng PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20211126 PL - England TA - Ann Oncol JT - Annals of oncology : official journal of the European Society for Medical Oncology JID - 9007735 RN - 0 (Acrylamides) RN - 0 (Aniline Compounds) RN - 0 (Protein Kinase Inhibitors) RN - 2S9ZZM9Q9V (Bevacizumab) RN - 3C06JJ0Z2O (osimertinib) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Acrylamides MH - Aniline Compounds/adverse effects MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects MH - Bevacizumab/adverse effects MH - *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics MH - ErbB Receptors/genetics MH - Humans MH - *Lung Neoplasms/drug therapy/genetics MH - Mutation MH - Protein Kinase Inhibitors/adverse effects OTO - NOTNLM OT - EGFR mutations OT - NSCLC OT - bevacizumab OT - osimertinib OT - randomised controlled trial COIS- 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. FIR - Stahel, Rolf IR - Stahel R FIR - Peters, Solange IR - Peters S FIR - Soo, Ross IR - Soo R FIR - Han, Ji-Youn IR - Han JY FIR - Fruh, Martin IR - Fruh M FIR - Provencio, Mariano IR - Provencio M FIR - Coate, Linda IR - Coate L FIR - Dafni, Urania IR - Dafni U FIR - Hiltbrunner, Anita IR - Hiltbrunner A FIR - Ruepp, Barbara IR - Ruepp B FIR - Roschitzki-Voser, Heidi IR - Roschitzki-Voser H FIR - Hiltbrunner, Anita IR - Hiltbrunner A FIR - Gasca-Ruchti, Adriana IR - Gasca-Ruchti A FIR - Giacomelli, Nino IR - Giacomelli N FIR - Kammler, Rosita IR - Kammler R FIR - Marti, Nesa IR - Marti N FIR - Nobs, Lionel IR - Nobs L FIR - Pardo-Contreras, Mariana IR - Pardo-Contreras M FIR - Pfister, Rita IR - Pfister R FIR - Piguet, Anne-Christine IR - Piguet AC FIR - Ribeli-Hofmann, Sabrina IR - Ribeli-Hofmann S FIR - Martinez, Virginia Rodriguez IR - Martinez VR FIR - Roschitzki-Voser, Heidi IR - Roschitzki-Voser H FIR - Roux, Susanne IR - Roux S FIR - Ruepp, Barbara IR - Ruepp B FIR - Sanchez-Hohl, Magdalena IR - Sanchez-Hohl M FIR - Schneider, Mirjam IR - Schneider M FIR - Schweri, Robin IR - Schweri R FIR - Troesch, Sandra IR - Troesch S FIR - Zigomo, Isabel IR - Zigomo I FIR - Dafni, Urania IR - Dafni U FIR - Tsourti, Zoi IR - Tsourti Z FIR - Zygoura, Panagiota IR - Zygoura P FIR - Kassapian, Marie IR - Kassapian M FIR - Vervita, Katerina IR - Vervita K FIR - Dimopoulou, Georgia IR - Dimopoulou G FIR - Andriakopoulou, Charitini IR - Andriakopoulou C FIR - Fernandez, Maria IR - Fernandez M FIR - Pereira, Eva IR - Pereira E FIR - Simona, Carolina IR - Simona C FIR - Tucker, Lisa IR - Tucker L FIR - Burnes, Jillian IR - Burnes J FIR - Barrett, Aisling IR - Barrett A FIR - McGrillen, Meghan IR - McGrillen M FIR - Berset, Catherine IR - Berset C FIR - Biaggi, Christine IR - Biaggi C FIR - Reist, Martin IR - Reist M FIR - Rentsch, Priska IR - Rentsch P FIR - Coate, Linda IR - Coate L FIR - Cuffe, Sinead IR - Cuffe S FIR - Hashemi, Sayed IR - Hashemi S FIR - Nadal, Ernest IR - Nadal E FIR - Carcereny, Enric IR - Carcereny E FIR - de Castro, Javier IR - de Castro J FIR - Sala, Maria Angeles IR - Sala MA FIR - Reyes, Bernabe IR - Reyes B FIR - Pulla, Mariano Provencio IR - Pulla MP FIR - Campelo, Rosario Garcia IR - Campelo RG FIR - Massuti, Bartomeu IR - Massuti B FIR - Garcia, Jose IR - Garcia J FIR - Domine, Manuel IR - Domine M FIR - Majem, Margarita IR - Majem M FIR - Sanchez, Jose Miguel IR - Sanchez JM FIR - Fruh, Martin IR - Fruh M FIR - Britschgi, Christian IR - Britschgi C FIR - Pless, Miklos IR - Pless M FIR - Peters, Solange IR - Peters S FIR - Soo, Ross IR - Soo R FIR - Yeo, Chong Ming IR - Yeo CM FIR - Han, Ji-Youn IR - Han JY FIR - Cho, Byoung Chul IR - Cho BC EDAT- 2021/11/29 06:00 MHDA- 2022/03/04 06:00 CRDT- 2021/11/28 20:56 PHST- 2021/08/23 00:00 [received] PHST- 2021/11/16 00:00 [revised] PHST- 2021/11/18 00:00 [accepted] PHST- 2021/11/29 06:00 [pubmed] PHST- 2022/03/04 06:00 [medline] PHST- 2021/11/28 20:56 [entrez] AID - S0923-7534(21)04825-0 [pii] AID - 10.1016/j.annonc.2021.11.010 [doi] PST - ppublish SO - Ann Oncol. 2022 Feb;33(2):181-192. doi: 10.1016/j.annonc.2021.11.010. Epub 2021 Nov 26.