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

ETOP 10-16 BOOSTER Collaborators

doi:10.1016/j.annonc.2021.11.010

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

ETOP 10-16 BOOSTER Collaborators

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

27 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	181-192
Number of pages	12
Journal	Annals of Oncology
Volume	33
Issue number	2
DOIs	https://doi.org/10.1016/j.annonc.2021.11.010
Publication status	Published - 2022 Feb

Bibliographical note

Funding Information:
We thank the 155 patients who participated in the trial and their families and caregivers, the BOOSTER investigators at the 23 clinical sites and their teams, Cancer Trials Ireland, the Spanish Lung Cancer Group (SLCG), the Swiss Group for Clinical Cancer Research (SAKK), the Central laboratory in Lausanne, the European Thoracic Oncology Platform Independent Data Monitoring Committee (IDMC), the coworkers at the ETOP Coordinating Office and the ETOP Statistical Office and AstraZeneca and F. Hoffmann-La Roche for supporting the trial. The BOOSTER trial was sponsored and coordinated by ETOP, in collaboration with Cancer Trials Ireland, the SLCG and the SAKK. BOOSTER received financial support for trial conduct from AstraZeneca, who also provided osimertinib for this study [grant number ESR-15-11666]. Bevacizumab was provided by F. Hoffmann-La Roche [grant number MO39447]. 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.

Funding Information:
The BOOSTER trial was sponsored and coordinated by ETOP , in collaboration with Cancer Trials Ireland , the SLCG and the SAKK . BOOSTER received financial support for trial conduct from AstraZeneca , who also provided osimertinib for this study [grant number ESR-15-11666 ]. Bevacizumab was provided by F. Hoffmann-La Roche [grant number MO39447 ].

Publisher Copyright:
© 2021 European Society for Medical Oncology

All Science Journal Classification (ASJC) codes

Hematology
Oncology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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ETOP 10-16 BOOSTER Collaborators (2022). 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. Annals of Oncology, 33(2), 181-192. https://doi.org/10.1016/j.annonc.2021.11.010

@article{46ce559506e04380b477d5ba1c7ef1db,

title = "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",

abstract = "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.",

author = "{ETOP 10-16 BOOSTER Collaborators} and Soo, {R. A.} and Han, {J. Y.} and U. Dafni and Cho, {B. C.} and Yeo, {C. M.} and E. Nadal and E. Carcereny and {de Castro}, J. and Sala, {M. A.} and R. Bernab{\'e} and L. Coate and {Provencio Pulla}, M. and {Garcia Campelo}, R. and S. Cuffe and Hashemi, {S. M.S.} and M. Fr{\"u}h and B. Massuti and J. Garcia-Sanchez and M. D{\'o}mine and M. Majem and Sanchez-Torres, {J. M.} and C. Britschgi and M. Pless and G. Dimopoulou and H. Roschitzki-Voser and B. Ruepp and R. Rosell and Stahel, {R. A.} and S. Peters and Rolf Stahel and Solange Peters and Han, {Ji Youn} and Martin Fr{\"u}h and Mariano Provencio and Linda Coate and Urania Dafni and Anita Hiltbrunner and Barbara Ruepp and Heidi Roschitzki-Voser and Adriana Gasca-Ruchti and Nino Giacomelli and Rosita Kammler and Nesa Marti and Lionel Nobs and Mariana Pardo-Contreras and Rita Pfister and Piguet, {Anne Christine} and Sabrina Ribeli-Hofmann and Martinez, {Virginia Rodriguez} and Susanne Roux",

note = "Funding Information: We thank the 155 patients who participated in the trial and their families and caregivers, the BOOSTER investigators at the 23 clinical sites and their teams, Cancer Trials Ireland, the Spanish Lung Cancer Group (SLCG), the Swiss Group for Clinical Cancer Research (SAKK), the Central laboratory in Lausanne, the European Thoracic Oncology Platform Independent Data Monitoring Committee (IDMC), the coworkers at the ETOP Coordinating Office and the ETOP Statistical Office and AstraZeneca and F. Hoffmann-La Roche for supporting the trial. The BOOSTER trial was sponsored and coordinated by ETOP, in collaboration with Cancer Trials Ireland, the SLCG and the SAKK. BOOSTER received financial support for trial conduct from AstraZeneca, who also provided osimertinib for this study [grant number ESR-15-11666]. Bevacizumab was provided by F. Hoffmann-La Roche [grant number MO39447]. 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. Funding Information: The BOOSTER trial was sponsored and coordinated by ETOP , in collaboration with Cancer Trials Ireland , the SLCG and the SAKK . BOOSTER received financial support for trial conduct from AstraZeneca , who also provided osimertinib for this study [grant number ESR-15-11666 ]. Bevacizumab was provided by F. Hoffmann-La Roche [grant number MO39447 ]. Publisher Copyright: {\textcopyright} 2021 European Society for Medical Oncology",

year = "2022",

month = feb,

doi = "10.1016/j.annonc.2021.11.010",

language = "English",

volume = "33",

pages = "181--192",

journal = "Annals of Oncology",

issn = "0923-7534",

publisher = "Oxford University Press",

number = "2",

}

ETOP 10-16 BOOSTER Collaborators 2022, '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', Annals of Oncology, vol. 33, no. 2, pp. 181-192. https://doi.org/10.1016/j.annonc.2021.11.010

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. / ETOP 10-16 BOOSTER Collaborators.

In: Annals of Oncology, Vol. 33, No. 2, 02.2022, p. 181-192.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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

T2 - the European Thoracic Oncology Platform (ETOP 10-16) BOOSTER trial

AU - ETOP 10-16 BOOSTER Collaborators

AU - Soo, R. A.

AU - Han, J. Y.

AU - Dafni, U.

AU - Cho, B. C.

AU - Yeo, C. M.

AU - Nadal, E.

AU - Carcereny, E.

AU - de Castro, J.

AU - Sala, M. A.

AU - Bernabé, R.

AU - Coate, L.

AU - Provencio Pulla, M.

AU - Garcia Campelo, R.

AU - Cuffe, S.

AU - Hashemi, S. M.S.

AU - Früh, M.

AU - Massuti, B.

AU - Garcia-Sanchez, J.

AU - Dómine, M.

AU - Majem, M.

AU - Sanchez-Torres, J. M.

AU - Britschgi, C.

AU - Pless, M.

AU - Dimopoulou, G.

AU - Roschitzki-Voser, H.

AU - Ruepp, B.

AU - Rosell, R.

AU - Stahel, R. A.

AU - Peters, S.

AU - Stahel, Rolf

AU - Peters, Solange

AU - Han, Ji Youn

AU - Früh, Martin

AU - Provencio, Mariano

AU - Coate, Linda

AU - Dafni, Urania

AU - Hiltbrunner, Anita

AU - Ruepp, Barbara

AU - Roschitzki-Voser, Heidi

AU - Gasca-Ruchti, Adriana

AU - Giacomelli, Nino

AU - Kammler, Rosita

AU - Marti, Nesa

AU - Nobs, Lionel

AU - Pardo-Contreras, Mariana

AU - Pfister, Rita

AU - Piguet, Anne Christine

AU - Ribeli-Hofmann, Sabrina

AU - Martinez, Virginia Rodriguez

AU - Roux, Susanne

N1 - Funding Information: We thank the 155 patients who participated in the trial and their families and caregivers, the BOOSTER investigators at the 23 clinical sites and their teams, Cancer Trials Ireland, the Spanish Lung Cancer Group (SLCG), the Swiss Group for Clinical Cancer Research (SAKK), the Central laboratory in Lausanne, the European Thoracic Oncology Platform Independent Data Monitoring Committee (IDMC), the coworkers at the ETOP Coordinating Office and the ETOP Statistical Office and AstraZeneca and F. Hoffmann-La Roche for supporting the trial. The BOOSTER trial was sponsored and coordinated by ETOP, in collaboration with Cancer Trials Ireland, the SLCG and the SAKK. BOOSTER received financial support for trial conduct from AstraZeneca, who also provided osimertinib for this study [grant number ESR-15-11666]. Bevacizumab was provided by F. Hoffmann-La Roche [grant number MO39447]. 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. Funding Information: The BOOSTER trial was sponsored and coordinated by ETOP , in collaboration with Cancer Trials Ireland , the SLCG and the SAKK . BOOSTER received financial support for trial conduct from AstraZeneca , who also provided osimertinib for this study [grant number ESR-15-11666 ]. Bevacizumab was provided by F. Hoffmann-La Roche [grant number MO39447 ]. Publisher Copyright: © 2021 European Society for Medical Oncology

PY - 2022/2

Y1 - 2022/2

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85121658815&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85121658815&partnerID=8YFLogxK

U2 - 10.1016/j.annonc.2021.11.010

DO - 10.1016/j.annonc.2021.11.010

M3 - Article

C2 - 34839016

AN - SCOPUS:85121658815

SN - 0923-7534

VL - 33

SP - 181

EP - 192

JO - Annals of Oncology

JF - Annals of Oncology

IS - 2

ER -

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

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