Atezolizumab Plus Chemotherapy With or Without Bevacizumab in Advanced Biliary Tract Cancer: Clinical and Biomarker Data From the Randomized Phase II IMbrave151 Trial

Abstract

Purpose: Biliary tract cancers (BTCs) harbor an immunosuppressed tumor microenvironment and respond poorly to PD-1/PD-L1 inhibitors. Bevacizumab (anti-vascular endothelial growth factor) plus chemotherapy can promote anticancer immunity, augmenting response to PD-L1 inhibition.

Patients and methods: This randomized, double-blind, proof-of-concept phase II study enrolled patients (n = 162) with previously untreated advanced BTC (IMbrave151; ClinicalTrials.gov identifier: NCT04677504). Patients were randomly assigned 1:1 to receive cycles of atezolizumab (1,200 mg) plus bevacizumab (15 mg/kg) or atezolizumab plus placebo once every 3 weeks until disease progression or unacceptable toxicity. All patients received cisplatin (25 mg/m²) plus gemcitabine (1,000 mg/m²; cisplatin plus gemcitabine [CisGem]) on days 1 and 8 once every 3 weeks for up to eight cycles. Stratification of patients was by disease status, geographic region, and primary tumor location. The primary end point was progression-free survival (PFS). No formal hypothesis testing was performed. Exploratory correlative biomarker analysis was undertaken using transcriptome analysis (n = 95) and mutation profiling (n = 102) on baseline tumor samples.

Results: Between February and September 2021, 162 patients were enrolled. Median PFS was 8.3 months in the bevacizumab arm and 7.9 months in the placebo arm (stratified hazard ratio [HR], 0.67 [95% CI, 0.46 to 0.95]). Median overall survival (OS) was 14.9 and 14.6 months in the bevacizumab and placebo arms, respectively (stratified HR, 0.97 [95% CI, 0.64 to 1.47]). The incidence of grade 3 or 4 adverse events was 74% in both arms. High VEGFA gene expression was associated with improved PFS (HR, 0.44 [95% CI, 0.23 to 0.83]) in the bevacizumab arm versus placebo.

Conclusion: In unselected patients with advanced BTC, adding bevacizumab to atezolizumab plus CisGem modestly improves PFS but not OS. High VEGFA gene expression may represent a predictive biomarker of benefit from atezolizumab/bevacizumab, warranting further investigation.

FIG 1.

CONSORT diagram. Atezo, atezolizumab; Bev, bevacizumab; CisGem, cisplatin plus gemcitabine; PBO, placebo.

FIG 2.

(A) PFS curve and (B) PFS forest plot. A patient in the Bev arm had a missing death date and was excluded from the Kaplan-Meier curve. ^aStratified analysis. ^bUnstratified Cox regression analysis. ^cPer VENTANA SP-263 PD-L1 assay. Atezo, atezolizumab; Bev, bevacizumab; CisGem, cisplatin plus gemcitabine; eCCA, extrahepatic cholangiocarcinoma; GBC, gall bladder carcinoma; HR, hazard ratio; iCCA, intrahepatic cholangiocarcinoma; PBO, placebo; PFS, progression-free survival; TAP, tumor area positivity score.

FIG 3.

(A) OS curve and (B) forest plot. A patient in the Bev arm had a missing death date and was excluded from the Kaplan-Meier curve. ^aStratified analysis. ^bUnstratified Cox regression analysis. ^cPer VENTANA SP-263 PD-L1 assay. Atezo, atezolizumab; Bev, bevacizumab; CisGem, cisplatin plus gemcitabine; eCCA, extrahepatic cholangiocarcinoma; GBC, gall bladder carcinoma; HR, hazard ratio; iCCA, intrahepatic cholangiocarcinoma; NE, not estimable; OS, overall survival; PBO, placebo; TAP, tumor area positivity score.

FIG 4.

(A) Top gene signature forest plot (PFS and OS) and (B) outcomes by VEGFA gene expression. (A) Forest plot shows VEGFA gene and other biologic pathways in association with PFS (left) and OS (right) in the bevacizumab arm (n = 46) compared with the placebo arm (n = 49). The effect measure used is HR with 95% CI. (B) Kaplan-Meier plots of PFS and OS stratified by treatment arms (atezolizumab + bevacizumab and cisplatin and gemcitabine v atezolizumab + placebo and cisplatin and gemcitabine) in patients with high or low (split by median) expression score of VEGFA (BEP, n = 95). Atezo, atezolizumab; BEP, biomarker evaluable population; Bev, bevacizumab; CisGem, cisplatin plus gemcitabine; HR, hazard ratio; NE, not estimable; OS, overall survival; PBO, placebo; PFS, progression-free survival.

FIG A1.

IMbrave151 study design. ^aPer investigator assessment by RECIST 1.1. BTC, biliary tract cancer; DOR, duration of response; eCCA, extrahepatic cholangiocarcinoma; ECOG PS, Eastern Cooperative Oncology Group performance status; EGD, esophagogastroduodenoscopy; GBC, gallbladder carcinoma; iCCA, intrahepatic cholangiocarcinoma; IV, intravenous; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; R, randomly assigned.

FIG A2.

DOR. Atezo, atezolizumab; Bev, bevacizumab; CisGem, cisplatin plus gemcitabine; DOR, duration of response; NE, not evaluable; PBO, placebo.

FIG A3.

(A) PFS and (B) OS according to CR/PR or SD. Atezo, atezolizumab; Bev, bevacizumab; CisGem, cisplatin plus gemcitabine; CR, complete response; HR, hazard ratio; NE, not evaluable; OS, overall survival; PBO, placebo; PFS, progression-free survival; PR, partial response; SD, stable disease. ^aStratified analysis.

FIG A4.

Common adverse events. ^aMaintenance phase started at Cycle 9 after the completion of 8 cycles of combination chemotherapy treatment administered on a 21-day cycle. Atezo, atezolizumab; Bev, bevacizumab; CisGem, cisplatin plus gemcitabine; PBO, placebo.

FIG A5.

Association between angiogenesis gene signature and clinical outcomes: (A) PFS and angiogenesis RCC high, (B) PFS and angiogenesis RCC low, (C) OS and angiogenesis RCC high, and (D) OS and angiogenesis RCC low. Atezo, atezolizumab; Bev, bevacizumab; CisGem, cisplatin plus gemcitabine; HR, hazard ratio; NE, not evaluable; OS, overall survival; PBO, placebo; PFS, progression-free survival; RCC, renal cell carcinoma.

FIG A6.

Pathways or gene signatures associated with bevacizumab benefit according to anatomic BTC subtype: (A) VEGFA, (B) xCell hepatocytes, (C) angiogenesis RCC, and (D) ratio myeloid Teff. BTC, biliary tract cancer; eCCA, extrahepatic cholangiocarcinoma; GBC, gallbladder cancer; iCCA, intrahepatic cholangiocarcinoma; RCC, renal cell carcinoma; Teff, effector T cell.

FIG A7.

(A) Summary of frequently mutated genes in baseline tumor samples, (B) OS by PI3K/AKT mutation status stratified by treatment arm, and (C) OS by according to PI3K/AKT mutation status within each treatment arm. One patient had missing OS data and was not included in the OS analysis. Atezo, atezolizumab; Bev, bevacizumab; CisGem, cisplatin plus gemcitabine; CNA, copy number alteration; HR, hazard ratio; NE, not evaluable; OS, overall survival; PBO, placebo; RA, rearrangement; SV, short variant.