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Clinical Trial
. 2024 Mar 1;10(3):315-324.
doi: 10.1001/jamaoncol.2023.5258.

Atezolizumab and Platinum Plus Pemetrexed With or Without Bevacizumab for Metastatic Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial

Yoshimasa Shiraishi  1 , Junji Kishimoto  2 , Shunichi Sugawara  3 , Hideaki Mizutani  4 , Haruko Daga  5 , Koichi Azuma  6 , Hirotaka Matsumoto  7 , Osamu Hataji  8 , Kazumi Nishino  9 , Masahide Mori  10 , Takehito Shukuya  11 , Haruhiro Saito  12 , Motoko Tachihara  13 , Hidetoshi Hayashi  14 , Asuka Tsuya  15 , Kazushige Wakuda  16 , Noriko Yanagitani  17 , Tomohiro Sakamoto  18 , Satoru Miura  19 , Akito Hata  20 , Morihito Okada  21 , Toshiyuki Kozuki  22 , Yuki Sato  23 , Taishi Harada  24 , Koichi Takayama  25 , Nobuyuki Yamamoto  26 , Kazuhiko Nakagawa  14 , Isamu Okamoto  1
Affiliations
Clinical Trial

Atezolizumab and Platinum Plus Pemetrexed With or Without Bevacizumab for Metastatic Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial

Yoshimasa Shiraishi et al. JAMA Oncol. .

Abstract

Importance: The combination of an antibody to programmed cell death-1 (PD-1) or to its ligand (PD-L1) with chemotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC). Bevacizumab is expected to enhance the efficacy not only of chemotherapy but also of PD-1/PD-L1 antibodies through blockade of vascular endothelial growth factor-mediated immunosuppression, but further data are needed to support this.

Objective: To evaluate the efficacy and safety of bevacizumab administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous NSCLC.

Design, setting, and participants: An open-label phase 3 randomized clinical trial was conducted at 37 hospitals in Japan. Patients with advanced nonsquamous NSCLC without genetic driver alterations or those with genetic driver alterations who had received treatment with at least 1 approved tyrosine kinase inhibitor were enrolled between January 20, 2019, and August 12, 2020.

Interventions: Patients were randomly assigned to receive either atezolizumab plus carboplatin with pemetrexed (APP) or atezolizumab, carboplatin plus pemetrexed, and bevacizumab (APPB). After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab was administered until evidence of disease progression, development of unacceptable toxic effects, or the elapse of 2 years from the initiation of protocol treatment.

Main outcomes and measures: The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the intention-to-treat (ITT) population.

Results: A total of 412 patients were enrolled (273 men [66%]; median age, 67.0 [range, 24-89] years) and randomly assigned, with 205 in the APPB group and 206 in the APP group of the ITT population after exclusion of 1 patient for good clinical practice violation. The median BICR-assessed PFS was 9.6 months with APPB vs 7.7 months with APP (stratified hazard ratio [HR], 0.86; 95% CI, 0.70-1.07; 1-sided stratified log-rank test; P = .92). According to prespecified subgroup analysis of BICR-assessed PFS, an improved PFS with APPB vs APP was apparent specifically in driver oncogene-positive patients (median, 9.7 vs 5.8 months; stratified HR, 0.67; 95% CI, 0.46-0.98). Toxic effects related to bevacizumab were increased in the APPB group.

Conclusions and relevance: The findings of this trial did not show superiority of APPB over APP for patients with nonsquamous NSCLC; however, this regimen showed a similar tolerability and improved survival relative to APP in patients with driver oncogenes.

Trial registration: Japan Registry of Clinical Trials Identifier: jRCT2080224500.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Shiraishi reported receiving personal fees from Ono Pharmaceutical, Taiho Pharmaceutical, AstraZeneca, Bristol-Myers Squibb, and Chugai Pharmaceutical outside the submitted work. Dr Sugawara reported receiving lecture fees from Chugai Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Nippon Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Eli Lilly and Company, Novartis, Kyowa Kirin, Takeda, Nippon Kayaku, Merck, Amgen, AbbVie, Otsuka, ThermoFisher Scientific, and Towa Pharmaceutical outside the submitted work. Dr Daga reported receiving personal fees from AstraZeneca outside the submitted work. Dr Azuma reported receiving lecture fees from AstraZeneca, Ono Pharmaceutical, MSD, Bristol-Myers Squibb, and Chugai Pharmaceutical outside the submitted work. Dr Matsumoto reported receiving personal fees from AstraZeneca KK, Chugai Pharmaceutical, Takeda, Boehringer Ingelheim Japan, Ono Pharmaceutical, and Taiho Pharmaceutical outside the submitted work. Dr Hataji reported receiving lecture fees from Chugai Pharmaceutical during the conduct of the study; lecture fees and grants from AstraZeneca, Daiichi Sankyo, Takeda Pharmaceutical, Novartis Pharma, and Eli Lilly; lecture fees from Boehringer Ingelheim, Kyowa Kirin, MSD, Ono Pharmaceutical, Taiho Pharmaceutical, Bayer Yakuhin, Merck, and Nippon Kayaku; and grants from AbbVie, Bristol-Myers Squibb, and Janssen Pharmaceutical KK outside the submitted work. Dr Nishino reported receiving grants from Chugai Pharmaceutical during the conduct of the study; personal fees and grants from AstraZeneca, Nippon Boehringer Ingelheim, Eli Lilly Japan, Merck Biopharma, Pfizer, Janssen Pharmaceutical, and Takeda Pharmaceutical; personal fees from Roche Diagnostics, Novartis Pharmaceuticals, Bristol-Myers Squibb, and Nippon Kayaku; and grants from Ono Pharmaceutical, Merus, Taiho Pharmaceutical, MSD, AbbVie, Daiichi Sankyo, Amgen, Eisai, and Sanofi outside the submitted work Dr Mori reported receiving personal fees from Chugai Pharmaceutical outside the submitted work. Dr Shukuya reported receiving grants from Chugai Pharmaceutical during the conduct of the study; grants and personal fees from AstraZeneca; grants from Boehringer Ingelheim, Novartis, and MSD; and personal fees from Chugai Pharmaceutical, Boehringer Ingelheim, Novartis, MSD, Taiho Pharma, Daiichi Sankyo, Ono Pharmaceutical, Bristol-Myers Squibb, Nippon Kayaku, Pfizer, Takeda, and Eli Lilly and Company outside the submitted work. Dr Saito reported receiving grants and personal fees from Chugai Pharma, AstraZeneca, Ono Pharma, and Bristol-Myers Squib; and personal fees from Boehringer Ingelheim and Pfizer Pharma outside the submitted work. Dr Tachihara reported receiving grants and personal fees from Chugai Pharmaceutical during the conduct of the study; personal fees and grants from AstraZeneca; and personal fees from Chugai Pharmaceutical, Eli Lilly Japan, MSD, Taiho Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Takeda Pharmaceutical, Nippon, Boehringer Ingelheim, Novartis Pharmaceuticals, and Pfizer Japan outside the submitted work. Dr Hayashi reported receiving personal fees from Ono Pharmaceutical, Merck Biopharma, Daiichi Sankyo, 3H Clinical Trial, AstraZeneca, Novartis Pharma, Chugai Pharmaceutical, Bristol-Myers Squibb, Eli Lilly Japan, Amgen, MSD, Sysmex, Pfizer Japan, Takeda Pharmaceutical, and Nippon Boehringer Ingelheim; grants from IQVIA Services Japan, Eisai, Syneos Health Clinical, EP-CRSU, EPS, Shionogi & Co, Nippon Kayaku, Otsuka Pharmaceutical, Takeda Pharmaceutical, GlaxoSmithKline, MSD, Sanofi, Amgen, Chugai Pharmaceutical, Taiho Pharmaceutical, Nippon Boehringer Ingelheim, Bristol-Myers Squibb, SRL Medisearch, Janssen Pharmaceutical, PRA Health Sciences, CMIC, Astellas Pharma, Pfizer R&D Japan, G.K. Ascent Development Services, Labcorp Development Japan, Eisai Inc, Kobayashi Pharmaceutical, Bayer Yakuhin, and Pfizer Japan; and personal fees from Guardant Health Japan outside the submitted work. Dr Wakuda reported receiving personal fees from Chugai Pharmaceutical, Taiho Pharmaceutical, Boehringer Ingelheim, Eli Lilly, Ono Pharmaceutical, MSD, AstraZeneca, Daiichi Sankyo, Janssen Pharmaceutical, and Takeda Pharmaceutical outside the submitted work. Dr Yanagitani reported receiving personal fees from Chugai Pharmaceutical during the conduct of the study; personal fees from Taiho, MSD, Ono Pharmaceutical, Bristol-Myers Squibb, Novartis, Pfizer, Eli Lilly, and Bayer AG outside the submitted work. Dr Sakamoto reported receiving personal fees from Chugai Pharmaceutical, Eli Lilly, Novartis, Ono Pharmaceutical, MSD, Merck, Taiho, Hisamitsu, Janssen, Amgen, Daiichi Sankyo, AstraZeneca, Kyowa Kirin, Takeda, and Illumina outside the submitted work. Dr Miura reported receiving personal fees from Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer, Eli Lilly, Boehringer-Ingelheim Japan, Ono Pharmaceutical, AstraZeneca, Novartis, MSD, Bristol-Myers Squibb, Kyowa Hakko Kirin, Daiichi Sankyo, Nippon Kayaku, Amgen, Merck, and Takeda Pharmaceutical outside the submitted work. Dr Hata reported receiving grants and personal fees from Chugai Pharmaceutical during the conduct of the study; personal fees and grants from MSD, AstraZeneca, Eli Lilly, Taiho, and Boehringer Ingelheim; personal fees from Pfizer; and grants from AbbVie outside the submitted work. Dr Kozuki reported receiving grants from Eli Lilly Japan, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Kyowa Hakko Kirin, Merck Biopharma, Daiichi Sankyo, Amgen, AbbVie, Sanofi, Eisai, and Labcorp Development Japan; personal fees from Chugai Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Pfizer Japan, Daiichi Sankyo, Bayer, AbbVie, Eli Lilly Japan, Taiho Pharmaceutical, Bristol-Myers Squibb, MSD, Kyowa Hakko Kirin, Nippon Boehringer Ingelheim, Merck Biopharma, Nippon Kayaku, Novartis, Takeda Pharmaceutical, Bayer, Sawai, and Amgen outside the submitted work. Dr Sato reported grants from Chugai Pharmaceutical during the conduct of the study; personal fees from AstraZeneca Honoraria, personal fees from MSD Honoraria, personal fees from Novartis Honoraria, personal fees from Chugai Pharmaceutical Honoraria, personal fees from Ono Pharmaceutical Honoraria, personal fees from Pfizer Honoraria, personal fees from Taiho Pharmaceutical Honoraria, personal fees from Nippon Kayaku Honoraria, personal fees from Bristol-Myers Squibb Honoraria, personal fees from Eli Lilly Honoraria, personal fees from Takeda Honoraria, and personal fees from Kyowa Kirin Honoraria outside the submitted work. Dr Takayama reported receiving personal fees from Chugai Pharmaceutical and Eli Lilly Lecture fee during the conduct of the study; personal fees from AstraZeneca, MSD, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Boehringer-Ingelheim, and Amgen; and grants from Taiho Pharmaceutical outside the submitted work. Dr Yamamoto reported receiving grants from Chugai Pharmaceutical during the conduct of the study; grants from Boehringer-Ingelheim, Taiho, Chugai Pharmaceutical, Shionogi, Eli Lilly Japan, Daiichi Sankyo, Tumura, Nippon Kayaku, Asahikasei-pharma, AstraZeneca, Janssen, Sanofi, Amgen, Novartis, Astellas, MSD, Esai, Bristol Myers Squibb, AbbVie, and Tosoh; and personal fees from MSD, AstraZeneca, Amgen, Ono Pharmaceutical, Otsuka, Guardant Health Japan, Tumura, Kyowa-Kirin, Kyorin, GlaxoSmithKline, Sanofi, Daiichi Sankyo, Taiho, Takeda, Chugai, Eli Lilly Japan, Nippon Kayaku, Boehringer-Ingelheim, Novartis, Pfizer, Bristol-Myers Squibb, Miyarisan, Merck, and Janssen outside the submitted work. Dr Nakagawa reported receiving grants from Amgen, MSD, Ono Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma, Pfizer Japan, Bristol-Myers Squibb, Eli Lilly Japan, Chugai Pharmaceutical, Daiichi Sankyo, AstraZeneca, Parexel International, PRA Health Sciences, EPS, Kissei Pharmaceutical, Taiho Pharmaceutical, PPD-SNBL SymBio Pharmaceuticals, IQVIA Services Japan, Syneos Health Clinical, Nippon Kayaku, EP-CRSU, Mebix, Janssen Pharmaceutical, Astellas Pharma, Bayer Yakuhin, Eisai, Mochida Pharmaceutical, Labcorp Development Japan (Covance Japan), Japan Clinical Research Operations, Takeda Pharmaceutical, GlaxoSmithKline, Sanofi, Sysmex, Medical Research Support, Otsuka Pharmaceutical, SRL, Pfizer R&D Japan, CMIC, Shionogi & Co, Kobayashi Pharmaceutical, and Ascent Development Services; and personal fees from Ono Pharmaceutical, Amgen, Nippon Kayaku, AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Pfizer Japan, Nippon Boehringer Ingelheim, Taiho Pharmaceutical, Bayer Yakuhin, CMIC ShiftZero, Life Technologies Japan, Neo Communication, Daiichi Sankyo, Incyte Biosciences Japan, Merck Biopharma, Kyowa Kirin, Takeda Pharmaceutical, 3H Clinical Trial, Care Net, Medical Review, Medical Mobile Communications, Yodosha, Nikkei Business Publications, Japan Clinical Research Operations, CMIC, Novartis Pharma, Taiyo Pharma, Janssen Pharmaceutical, and Bristol-Myers Squibb outside the submitted work; in addition, Dr Nakagawa had a patent for Daiichi Sankyo issued. Dr Okamoto reported receiving grants from Chugai Pharmaceutical during the conduct of the study; grants from Taiho Pharmaceutical, Ono Pharmaceutical, Eli Lilly, Bristol-Myers Squibb, Pfizer, AstraZeneca, Boehringer Ingelheim, MSD, Astellas, Novartis, and AbbVie; and personal fees from AstraZeneca, AbbVie, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, MSD, Bristol-Myers Squibb, Pfizer, Taiho Pharmaceutical, Ono Pharmaceutical, Eli Lilly, Novartis, and Chugai Pharmaceutical outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Consolidated Standards of Reporting Trials Diagram
APP indicates atezolizumab with carboplatin plus pemetrexed; APPB, atezolizumab with carboplatin plus pemetrexed with bevacizumab; NSCLC, non–small cell lung cancer. aOne patient with a good clinical practice violation was excluded from the intention-to-treat (ITT) population. Data cutoff was March 31, 2022.
Figure 2.
Figure 2.. Blinded Independent Central Review–Assessed Progression-Free Survival
Progression-free survival was assessed by blinded independent central review according to treatment arm for the intention-to-treat (ITT) population (A), driver oncogene–positive population (B), and driver oncogene–negative or –unknown population (C) and was measured from the date of random assignment. APP indicates atezolizumab plus carboplatin with pemetrexed; APPB, atezolizumab plus carboplatin with pemetrexed and bevacizumab.
Figure 3.
Figure 3.. Plots of Overall Survival
Overall survival was assessed according to treatment arm for the intention-to-treat (ITT) population (A), driver oncogene–positive population (B), and driver oncogene–negative or –unknown population (C) and was measured from the date of random assignment. APP indicates atezolizumab plus carboplatin with pemetrexed; APPB, atezolizumab plus carboplatin with pemetrexed and bevacizumab.
See this image and copyright information in PMC

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