Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2021 Mar 1;7(3):386-394.
doi: 10.1001/jamaoncol.2020.6758.

Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Patients With EGFR T790M-Mutated Non-Small Cell Lung Cancer Previously Treated With Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor: West Japan Oncology Group 8715L Phase 2 Randomized Clinical Trial

Hiroaki Akamatsu  1 , Yukihiro Toi  2 , Hidetoshi Hayashi  3 , Daichi Fujimoto  4 , Motoko Tachihara  5 , Naoki Furuya  6 , Sakiko Otani  7 , Junichi Shimizu  8 , Nobuyuki Katakami  9 , Koichi Azuma  10 , Naoko Miura  11 , Kazumi Nishino  12 , Satoshi Hara  13 , Shunsuke Teraoka  1 , Satoshi Morita  14 , Kazuhiko Nakagawa  3 , Nobuyuki Yamamoto  1
Affiliations
Clinical Trial

Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Patients With EGFR T790M-Mutated Non-Small Cell Lung Cancer Previously Treated With Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor: West Japan Oncology Group 8715L Phase 2 Randomized Clinical Trial

Hiroaki Akamatsu et al. JAMA Oncol. .

Abstract

Importance: Although treatment with first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) plus antiangiogenic inhibitor has shown promising efficacies in patients with EGFR-mutated lung adenocarcinoma, recent single-arm studies have suggested that osimertinib plus antiangiogenic inhibitor might not work synergistically.

Objective: To explore the efficacy and safety of osimertinib plus bevacizumab compared with osimertinib alone in patients with lung adenocarcinoma with EGFR T790M mutation.

Design, setting, and participants: Patients with advanced lung adenocarcinoma that progressed with prior EGFR-TKI treatment (other than third-generation TKI) and acquired EGFR T790M mutation were enrolled. This study comprises a lead-in part with 6 patients and a subsequent phase 2 part. In phase 2, patients were randomized to osimertinib plus bevacizumab or osimertinib alone in a 1:1 ratio.

Interventions: The combination arm received oral osimertinib (80 mg, every day) plus intravenous bevacizumab (15 mg/kg, every 3 weeks) until progression or unacceptable toxic effects. The control arm received osimertinib monotherapy.

Main outcomes and measures: The primary end point was progression-free survival (PFS) assessed by investigators. Secondary end points consisted of overall response rate, time to treatment failure, overall survival, and safety.

Results: From August 2017 through September 2018, a total of 87 patients were registered (6 in the lead-in part and 81 in the phase 2 part [intention-to-treat population]). Among those randomized, the median (range) age was 68 (41-82) years; 33 (41%) were male; 37 (46%) had an Eastern Cooperative Oncology Group performance status of 0; and 21 (26%) had brain metastasis. Although the overall response rate was better with osimertinib plus bevacizumab than osimertinib alone (68% vs 54%), median PFS was not longer with osimertinib plus bevacizumab (9.4 months vs 13.5 months; adjusted hazard ratio, 1.44; 80% CI, 1.00 to 2.08; P = .20). Median time to treatment failure was also shorter in the combination arm vs the osimertinib arm (8.4 months vs 11.2 months; P = .12). Median overall survival was not different in the combination arm vs osimertinib arm (not reached vs 22.1 months; P = .96). In the combination arm, common adverse events of grade 3 or higher were proteinuria (n = 9; 23%), hypertension (n = 8; 20%).

Conclusions and relevance: In this randomized clinical trial comparing osimertinib plus bevacizumab vs osimertinib alone, the combination arm failed to show prolongation of PFS in patients with advanced lung adenocarcinoma with EGFR T790M mutation.

Trial registration: UMIN Clinical Trials Registry Identifier: UMIN000023761.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Akamatsu reported receiving grants and personal fees from Chugai Pharmaceutical and MSD KK and personal fees from AstraZeneca KK, Boehringer Ingelheim Japan Inc, Bristol Myers Squibb, Eli Lilly Japan KK, Novartis Pharma KK, Ono Pharmaceutical, and Taiho Pharmaceutical outside the submitted work. Dr Toi reported receiving personal fees from AstraZeneca, Bristol Myers Squibb, MSD, and Ono Pharmaceutical during the conduct of the study. Dr Hayashi reported receiving grants and personal fees from AstraZeneca KK and Chugai Pharmaceutical during the conduct of the study; and grants and personal fees from Boehringer Ingelheim Japan, Ono Pharmaceutical, and Bristol Myers Squibb and personal fees from Eli Lilly Japan KK, Kyorin Pharmaceutical, Merck Biopharma, MSD KK, Novartis Pharmaceuticals KK, Pfizer Japan Inc, Shanghai HaiHe Biopharma, and Taiho Pharmaceutical outside the submitted work. Dr Fujimoto reported receiving grants and personal fees from AstraZeneca KK and personal fees from Boehringer Ingelheim Japan Inc, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan KK, MSD KK, Novartis Pharma KK, Ono Pharmaceutical, and Taiho Pharmaceutical outside the submitted work. Dr Tachihara reported receiving grants and personal fees from AstraZeneca KK and personal fees from Boehringer Ingelheim Japan Inc, Chugai Pharmaceutical, Eli Lilly Japan KK, MSD KK, and Olympus outside the submitted work. Dr Furuya reported receiving personal fees from Eli Lilly Japan, Chugai, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim Japan, Taiho, Ono Pharmaceutical, and Pfizer Japan outside the submitted work. Dr Shimizu reported receiving honoraria from AstraZeneca KK, MSD KK, Ono Pharmaceutical, Taiho Pharmaceutical, and Chugai Pharmaceutical outside the submitted work. Dr Katakami reported receiving grants and personal fees from AstraZeneca KK, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan KK, MSD KK, and Ono Pharmaceutical, and personal fees from Boehringer Ingelheim Japan, Novartis Pharma KK, and Taiho Pharmaceutical outside the submitted work. Dr Azuma reported receiving personal fees from Chugai Pharma, AstraZeneca, MSD, Bristol Myers Squibb, and Ono Pharmaceutical outside the submitted work. Dr Nishino reported receiving personal fees from Nippon Boehringer Ingelheim, AstraZeneca KK, Novartis Pharma KK, Eli Lilly Japan KK, Roche Diagnostics KK, Chugai Pharma, and Ono Pharmaceutical outside the submitted work. Dr Teraoka reported receiving personal fees from AstraZeneca and Chugai Pharmabody Research outside the submitted work. Dr Morita reported receiving personal fees from AstraZeneca KK, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan KK, MSD KK, Pfizer Japan, Taiho Pharmaceutical, and Ono Pharmaceutical outside the submitted work. Dr Nakagawa reported receiving grants and personal fees from AstraZeneca KK, Astellas Pharma, MSD KK, Nippon Boehringer Ingelheim, Novartis Pharma KK, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, and Merck Serono/Merck Biopharma and grants, personal fees, and other from Ono Pharmaceutical, Pfizer Japan, and Eli Lilly Japan KK, during the conduct of the study; grants from inVentiv Health Japan, ICON Japan KK, Gritstone Oncology, Parexel International, Kissei Pharmaceutical, EPS Corporation, Syneos Health, Pfizer R&D Japan GK, A2 Healthcare, Quintiles/IQVIA Services JAPAN KK, EP-CRSU, Linical, Eisai, CMIC Shift Zero KK, Kyowa Hakko Kirin, Bayer Yakuhin, EPS International, and Otsuka Pharmaceutical; grants and personal fees from Takeda Pharmaceutical, Taiho Pharmaceutical, and SymBio Pharmaceuticals; personal fees from Clinical Trial Co, Medicus Shuppan Publishers, Care Net, Reno Medical KK, Medical Review, Roche Diagnostics KK, Bayer Yakuhin, Medical Mobile Communications, 3H Clinical Trial, Nichi-Iko Pharmaceutical, Nanzando, Yodosha, Nikkei Business Publications, Thermo Fisher Scientific KK, Yomiuri Telecasting Corporation, and Nippon Kayaku; personal fees and other from Kyorin Pharmaceutical; and grants and personal fees from AbbVie outside the submitted work. Dr Yamamoto reported receiving grants from AstraZeneca during the conduct of the study; grants from Astellas, Shionogi, Tumura, AbbVie GK, Amgen, Kyorin, Eisai, Terumo, Toppan Printing, and Tosoh; grants and personal fees from Eli Lilly, AstraZeneca, Ono Pharmaceutical, Daiichi Sankyo, Taiho, Takeda, Chugai, MSD, Novartis, Pfizer, and Boehringer Ingelheim; personal fees from Bristol Myers Squibb, Thermo Fisher Scientific, Life Technologies Japan, Nippon Kayaku, and Merck Biopharma, outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Patient Flow of the Trial
Figure 2.
Figure 2.. Waterfall Plot of Each Arm Showing Best Percentage Change in Tumor Burden From Baseline
A, Complete response (n = 2), partial response (n = 21), stable disease (n = 17), and disease progression (n = 1). B, Complete response (n = 2), partial response (n = 25), stable disease (n = 11), disease progression (n = 1), not evaluable (n = 1).
Figure 3.
Figure 3.. Kaplan-Meier Curves of Progression-Free Survival
A, Kaplan-Meier curves of progression-free survival in the osimertinib arm (n = 41) and combination arm (n = 40). B, Subgroup analysis according to any history of anti–vascular endothelial growth factor (VEGF) therapy.
Figure 4.
Figure 4.. Kaplan-Meier Curves of Time to Treatment Failure and Overall Survival
Kaplan-Meier curves of time to treatment failure (A) and overall survival (B) in the osimertinib arm (n = 41) and combination arm (n = 40).
See this image and copyright information in PMC

Comment in

References

    1. Lee CK, Davies L, Wu YL, et al. . Gefitinib or erlotinib vs chemotherapy for EGFR mutation-positive lung cancer: individual patient data meta-analysis of overall survival. J Natl Cancer Inst. 2017;109(6). doi:10.1093/jnci/djw279 - DOI - PubMed
    1. Sequist LV, Yang JC, Yamamoto N, et al. . Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327-3334. doi:10.1200/JCO.2012.44.2806 - DOI - PubMed
    1. Sequist LV, Waltman BA, Dias-Santagata D, et al. . Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26. doi:10.1126/scitranslmed.3002003 - DOI - PMC - PubMed
    1. Yver A. Osimertinib (AZD9291)—a science-driven, collaborative approach to rapid drug design and development. Ann Oncol. 2016;27(6):1165-1170. doi:10.1093/annonc/mdw129 - DOI - PubMed
    1. Mok TS, Wu Y-L, Ahn M-J, et al. ; AURA3 Investigators . Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376(7):629-640. doi:10.1056/NEJMoa1612674 - DOI - PMC - PubMed

Publication types

MeSH terms