First-line treatment with atezolizumab and bevacizumab plus chemotherapy provides progression-free survival (PFS) advantage vs atezolizumab plus placebo and chemotherapy for patients with advanced biliary tract cancer, according to findings from the phase 2 IMbrave151 trial. These findings were presented by Anthony El-Khoueiry, MD, USC Norris Comprehensive Cancer Center, Los Angeles, California, during the 2024 ASCO Gastrointestinal Cancers Symposium in San Francisco, California.

The IMbrave151 trial is a randomized, double-blinded, global proof-of-concept phase 2 trial evaluating atezolizumab combined with bevacizumab and chemotherapy (cisplatin and gemcitabine) for the first-line treatment of patients with advanced biliary tract cancer. 

A total of 162 patients were enrolled and randomized in a 1:1 ratio to receive atezolizumab plus bevacizumab and chemotherapy (n = 79) or atezolizumab plus placebo and chemotherapy (n = 83) for up to 8 cycles and, followed by atezolizumab plus bevacizumab or placebo until disease progression or unacceptable toxicity. 

The primary end point of the study was PFS. Secondary end points included overall survival (OS), objective response rate (ORR), duration of response (DOR), and safety. Final analysis for OS was performed when around 90 deaths occurred or when all patients reached ≥2 years of follow-up.

Researchers performed transcriptome analysis and mutation profiling on baseline tumor samples. This signal-seeking trial had no formal hypothesis testing but estimated the treatment effect in each arm. This update reports updated clinical data and molecular correlates of response and resistance. 

The updated PFS hazard ratio (HR) was 0.67 (95% confidence interval [CI], 0.46 to 0.95) in favor of atezolizumab plus bevacizumab. The updated median PFS was 8.35 months in the atezolizumab plus bevacizumab arm vs 7.9 months in the placebo arm. The 6-month PFS rates were 78% and 63%, respectively. 

The updated OS HR was 0.97 (95% CI, 4.3 to 6.7), with a median OS of 14.9 months for atezolizumab and bevacizumab vs 14.6 months with placebo. The confirmed ORR was 26.6% for atezolizumab plus bevacizumab vs 26.5% for placebo, with median DOR of 10.28 (95% CI, 6.7 to 16.7) and 6.18 (95% CI, 4.3 to 6.7) months, respectively. 

The incidence of grade 3/4 adverse events (AEs) was 73% with atezolizumab plus bevacizumab and 74% with atezolizumab plus placebo. 

Results from the molecular analysis showed that high VEGFA gene expression was associated with improved PFS (HR, 0.43; 95% CI, 0.22 to 0.83) and OS (HR, 0.66; 95% CI, 0.31 to 1.4) in favor of atezolizumab plus bevacizumab. In addition, hepatocytes high gene signature was associated with improved PFS (HR, 0.47; 95% CI, 0.24 to 0.92) and OS (HR, 0.66; 95% CI, 0.31 to 1.4), also in favor of atezolizumab plus bevacizumab. 

Authors noted that patients who had PI3k/AKT pathway mutations appeared to have worse OS than those without these mutations (HR, 3.7; 95% CI, 1.5 to 9.1) with atezolizumab plus bevacizumab.

In conclusion, this final analysis of the IMbrave151 trial indicated that atezolizumab and bevacizumab combined with chemotherapy is associated with a modest PFS benefit in patients with advanced biliary tract cancer. 

“The trial is limited by small numbers and a non-comparative design. Exploratory analysis of correlative biomarkers suggests that high VEGF-A gene expression and hepatocytes high gene signature may be predictive markers of benefit with atezolizumab/bevacizumab, warranting further investigation,” Dr El-Khoueiry and colleagues concluded.

Source:

El-Khoueiry AB, Ren Z, Chon HJ, et al. Atezolizumab plus chemotherapy with or without bevacizumab in advanced biliary tract cancer: Results from a randomized proof-of-concept phase II trial (IMbrave151). Presented at 2024 ASCO Gastrointestinal Cancer Symposium; January 18-20, 2024; San Francisco, California. Abstract 435.