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

Shiraishi, Yoshimasa; Kishimoto, Junji; Sugawara, Shunichi; Mizutani, Hideaki; Daga, Haruko; Azuma, Koichi; Matsumoto, Hirotaka; Hataji, Osamu; Nishino, Kazumi; Mori, Masahide; Shukuya, Takehito; Saito, Haruhiro; Tachihara, Motoko; Hayashi, Hidetoshi; Tsuya, Asuka; Wakuda, Kazushige; Yanagitani, Noriko; Sakamoto, Tomohiro; Miura, Satoru; Hata, Akito; Okada, Morihito; Kozuki, Toshiyuki; Sato, Yuki; Harada, Taishi; Takayama, Koichi; Yamamoto, Nobuyuki; Nakagawa, Kazuhiko; Okamoto, Isamu

doi:10.1001/jamaoncol.2023.5258

Cited by 54Lung Cancer Treatments and MutationsCancer Immunotherapy and BiomarkersLung Cancer Diagnosis and Treatment

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

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Shiraishi, Yoshimasa, Kishimoto, Junji, Sugawara, Shunichi, Mizutani, Hideaki, Daga, Haruko, Azuma, Koichi, Matsumoto, Hirotaka, Hataji, Osamu +20 more·2024·JAMA Oncology

DOI 10.1001/jamaoncol.2023.5258

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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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The randomised phase III APPLE trial failed to demonstrate benefit from adding bevacizumab to platinum-doublet chemotherapy plus atezolizumab in metastatic or recurrent non-squamous NSCLC.
“However, the large randomised phase III APPLE trial failed to demonstrate benefit from adding bevacizumab to platinum‐doublet chemotherapy plus atezolizumab in metastatic or recurrent nsqNSCLC. 4”
From Bevacizumab plus nab‐paclitaxel and platinum as second‐line therapy for driver‐gene‐negative non‐squamous non‐small cell lung cancer after immunochemotherapy: A prospective single‐arm single‐centre study (2026) · cites this paper as [4]

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Bevacizumab plus nab‐paclitaxel and platinum as second‐line therapy for driver‐gene‐negative non‐squamous non‐small cell lung cancer after immunochemotherapy: A prospective single‐arm single‐centre study
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Authors: Shiraishi, Y., Kishimoto, J., Sugawara, S., Mizutani, H., Daga, H., Azuma, K., Matsumoto, H., Hataji, O., Nishino, K., Mori, M., Shukuya, T., Saito, H., Tachihara, M., Hayashi, H., Tsuya, A., Wakuda, K., Yanagitani, N., Sakamoto, T., Miura, S., Hata, A., Okada, M., Kozuki, T., Sato, Y., Harada, T., Takayama, K., Yamamoto, N., Nakagawa, K., & Okamoto, I.
Affiliations: Kyushu University (JP)
Sendai Kousei Hospital (JP)
Saitama Cancer Center (JP)
Osaka City General Hospital (JP)
Kurume University (JP)
Hyogo Prefectural Amagasaki General Medical Center (JP)
Matsusaka City Hospital (JP)
Osaka International Cancer Institute (JP)
Toneyama National Hospital (JP)
Juntendo University (JP)
Kanagawa Cancer Center (JP)
Kobe University (JP)
Kindai University Hospital (JP)
Izumi City General Hospital (JP)
Shizuoka Cancer Center (JP)
The Cancer Institute Hospital (JP)
Tottori University (JP)
Niigata Cancer Center Hospital (JP)
Department of Thoracic Oncology, Kobe Minimally Invasive Cancer Center, Hyogo, Japan
Hiroshima University (JP)
Shikoku Cancer Center (JP)
Kobe City Medical Center General Hospital (JP)
Kyushu Hospital (JP)
Kyoto Prefectural University of Medicine (JP)
Wakayama Medical University (JP)
Corresponding author: Okamoto, Isamu
ORCID: Shiraishi, Yoshimasa
Kishimoto, Junji
Sugawara, Shunichi
Daga, Haruko
Azuma, Koichi
Matsumoto, Hirotaka
Hataji, Osamu
Nishino, Kazumi
Mori, Masahide
Shukuya, Takehito
Saito, Haruhiro
Tachihara, Motoko
Hayashi, Hidetoshi
Wakuda, Kazushige
Yanagitani, Noriko
Sakamoto, Tomohiro
Miura, Satoru
Hata, Akito
Okada, Morihito
Kozuki, Toshiyuki
Sato, Yuki
Harada, Taishi
Takayama, Koichi
Yamamoto, Nobuyuki
Nakagawa, Kazuhiko
Okamoto, Isamu
Venue: JAMA Oncology
Publisher: American Medical Association (AMA)
Published: 2024-03-01
Volume: 10
Issue: 3
Pages: 315
ISSN: 2374-2437 (ISSN-L)
DOI: 10.1001/jamaoncol.2023.5258
OpenAlex: W4390061478
Cited by: 54
References: 25
Citations by year: 2026: 22 · 2025: 22 · 2024: 10
FWCI: 9.95
Type: journal article
Language: en
Open access: green
pmc.ncbi.nlm.nih.gov
Locations: JAMA Oncology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (publishedVersion)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
Keywords: atezolizumab, bevacizumab, pemetrexed, carboplatin, PD-L1 blockade, first-line therapy, progression-free survival, maintenance therapy, vascular endothelial growth factor, immune checkpoint inhibitors, treatment safety, immune-related adverse events, neutropenia
MeSH terms: Bevacizumab, Pemetrexed, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Platinum, Carboplatin, Vascular Endothelial Growth Factor A, Young Adult, B7-H1 Antigen, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized

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

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