IMbrave151: A phase 2, randomized, double-blind, placebo-controlled study of atezolizumab with or without bevacizumab in combination with cisplatin plus gemcitabine in patients with untreated, advanced biliary tract cancer.

Abstract

491 Background: VEGF blockade coupled with cytotoxic chemotherapy can promote an immune-permissive tumor microenvironment that can augment response to PD-L1 inhibition. IMbrave151 (NCT04677504) is a randomized, double-blind, global Phase II study evaluating the efficacy of atezolizumab (atezo), bevacizumab (bev) and cisplatin and gemcitabine (CisGem) as first-line treatment for patients with advanced biliary tract cancer (aBTC). Methods: Patients with previously untreated aBTC were randomized 1:1 to receive atezo (1200 mg every 3 weeks [q3w]) + bev (15 mg/kg q3w) or placebo + CisGem (cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 on Days 1 and 8 q3w) for up to 8 cycles, followed by atezo (1200 mg q3w) + bev (15 mg/kg q3w) or placebo until disease progression or unacceptable toxicity. Patients were stratified by disease status, geographic region and primary tumor location. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), disease control rate and safety. No formal hypothesis testing was performed. Results: In total, 162 patients were randomized to receive either atezo + bev + CisGem (n=79) or atezo + placebo + CisGem (n=83). Median age 63 years, Asia/Rest of World (43/57%), ECOG PS 0/1 (53/48%), intrahepatic/extrahepatic cholangiocarcinoma and gallbladder (54/19/27%), and metastatic/locally advanced stage (82/18%). The HR for PFS was 0.76 (95% CI: 0.51, 1.14). Median PFS was 8.4 months for atezo + bev + CisGem and 7.9 months for atezo + placebo + CisGem; the 6-month PFS rates were 78% and 63%, respectively. The confirmed ORR was 24% for atezo + bev + CisGem and 25% for atezo + placebo + CisGem. DOR ≥6 months was 89% for atezo + bev + CisGem vs 47% for atezo + placebo + CisGem. The incidence of Grade 3 or 4 adverse events was 73% and 74% with atezo + bev + CisGem and atezo + placebo + CisGem, respectively. Median OS is not reached. Conclusions: Both combinations of IMbrave151 showed a manageable safety profile. The aggregate of data suggests that combining atezo with bev and chemotherapy may provide clinical benefit in a subset of patients with aBTC. Follow-up is ongoing for OS. Clinical trial information: NCT04677504 .

Early Decision Making in a Randomized Phase II Trial of Atezolizumab in Biliary Tract Cancer Using a Tumor Growth Inhibition‐Survival Modeling Framework

“…The OS data was highly immature with even fewer number of events in the study, although an encouraging trend existed. The confirmed ORR in the Atezo + Bev + CisGem arm of 24.1% was similar to the Atezo + PBO + CisGem arm (25.3%), although bevacizumab was seen to have a profound impact on duration of response, where 31.6% of events vs. 61.9% between the respective arms was seen 5 . Traditional RECIST‐based end points, including ORR and PFS, have limitations in predicting the survival benefit with immunotherapy which might not adequately measure efficacy 26 .…”

“…In IMbrave151 the predicted OS HR (95% PI) by the TGI‐OS model was 0.76 (0.47–1.17) vs. observed 0.76 and following simulation, the expected HR for OS with 500 patients/arm (resampled from the current study patients) comparing Atezo + Bev + CisGem vs. Atezo + PBO + CisGem, shows the expected HR (95%) PI of 0.77 (0.64–0.93) predictive of clinically meaningful difference between the tentative arms suggestive of a positive phase III outcome. Further, although not reported herein, the treatment was generally well‐tolerated, with manageable toxicities, a comparable safety profile between the two arms, and a safety profile consistent with the known risks of the individual study treatments with no new safety signals reported 5 …”

“…The confirmed ORR in the Atezo + Bev + CisGem arm of 24.1% was similar to the Atezo + PBO + CisGem arm (25.3%), although bevacizumab was seen to have a profound impact on duration of response, where 31.6% of events vs. 61.9% between the respective arms was seen. 5 Traditional RECIST-based end points, including ORR and PFS, have limitations in predicting the survival benefit with immunotherapy which might not adequately measure efficacy. 26 Several immune checkpoint inhibitors granted accelerated approval across multiple indications based on…”

“…Further, although not reported herein, the treatment was generally well-tolerated, with manageable toxicities, a comparable safety profile between the two arms, and a safety profile consistent with the known risks of the individual study treatments with no new safety signals reported. 5 The interim analysis allowed for evaluation of PFS benefit with Atezo + Bev + CisGem compared with Atezo + PBO + CisGem in addition to the confirmed ORR, response durability, and preliminary trends in OS. In our study, we found that early assessment at an interim analysis for PFS allowed for robust decision making supported by the TGI-OS modeling framework with early characterization of favorable tumor dynamics and predicted OS benefit of the Atezo + Bev + CisGem combination.…”

“…Recent studies indicate a role for immunotherapy with PD‐1/PD‐L1 inhibitor‐based combinations in advanced BTC 3 . The combination of atezolizumab, bevacizumab, and chemotherapy were evaluated in a randomized phase II study (IMbrave151) 4,5 . Herein, we assess the longitudinal tumor growth inhibition (TGI) metrics and OS predictions applied to IMbrave151 (NCT04677504).…”