Chemotherapy with gemcitabine/cisplatin (GemCis) plus the immune checkpoint inhibitor durvalumab has become first-line standard of care for patients with advanced biliary tract cancer (BTC); however, efforts are underway to further optimize outcomes in these patients. It has been hypothesized that VEGF blockade coupled with cytotoxic chemotherapy can enhance responses to PD-L1 inhibition by promoting an immune-permissive tumor microenvironment.
Dr Anthony El-Khoueiry presented results from IMbrave 151, a randomized, double-blind, phase 2 trial evaluating the PD-L1 inhibitor atezolizumab (atezo), VEGF inhibitor bevacizumab (bev), and GemCis as first-line treatment for patients with advanced BTC.
Patients had histologically confirmed intrahepatic cholangiocarcinoma (iCCA), extrahepatic CCA, or gallbladder cancer and no prior systemic treatment. Results were stratified by location of primary tumor, presence of metastatic disease, and geographic region. Patients were randomly assigned 1:1 to GemCis plus bev (15 mg/kg IV every 3 weeks) and atezo (1200 mg IV every 3 weeks) or GemCis plus placebo and atezo (1200 mg IV every 3 weeks) for 8 cycles followed by continued maintenance with atezo and bev or atezo and placebo until disease progression, unacceptable toxicity, or loss of benefit. The primary end point was progression-free survival (PFS), and secondary end points included objective response rate (ORR), duration of response (DOR), disease control rate (DCR), overall survival (OS), safety, and patient-reported outcomes/quality of life.
A total of 162 patients with previously untreated advanced BTC were randomly assigned: 79 patients received atezo and bev plus GemCis, and 83 patients received atezo and placebo plus GemCis. Median age was 63 years, and 54% of patients had iCCA, 82% of patients had metastatic disease, and 56% were PD-L1 negative.
In a subgroup analysis of PFS, atezo and bev plus GemCis was favored in a majority of subgroups, but a notable benefit was seen in women, patients treated outside of Asia, patients with locally advanced disease, and those without prior BTC surgery.
The median PFS was 8.3 months with the addition of bev versus 7.9 months without bev (hazard ratio [HR], 0.76; 95% confidence interval, 0.51-1.14), and 6-month PFS rates were 78% and 63%, respectively. In a subgroup analysis of PFS, atezo and bev plus GemCis was favored in a majority of subgroups, but a notable benefit was seen in women, patients treated outside of Asia, patients with locally advanced disease, and those without prior BTC surgery.
The ORR for patients treated with atezo and bev plus GemCis was 24% versus 25% in patients treated with atezo and placebo plus GemCis. The DCR was 78.5% versus 75.9% in the bev arm versus the placebo arm, and the median DOR was not reached in the bev group and 5.8 months with placebo. The median OS has not been reached in the GemCis plus atezo and bev arm, and it was 11.4 months in the GemCis plus atezo and placebo arm.
In a subgroup analysis of PFS in patients with a complete response or partial response, the median PFS was not reached in the bev arm, and it was 8.3 months in the placebo arm (HR, 0.51). In patients with stable disease, the median PFS was 8.3 months in the bev arm and 8.4 months in the placebo arm (HR, 1.00).
Grade 3/4 treatment-related adverse events (TRAEs) occurred in 57% of patients in the bev arm and 60% in the placebo arm. The most common grade 3/4 (≥20%) TRAEs in both groups were anemia, decreased neutrophil count, and neutropenia. All-grade adverse events occurred more frequently during the chemotherapy phase than in the maintenance phase.
Follow-up is ongoing for OS; however, these data suggest that atezo and bev plus GemCis may provide a clinical benefit in a subset of patients and has a manageable safety profile and minimal additional toxicity.
Source: El-Khoueiry A, Ren Z, Chon HJ, et al. A phase 2 randomized, double-blind, placebo-controlled study of bevacizumab in combination with atezolizumab and gemcitabine/cisplatin in patients with advanced biliary tract cancer: IMbrave 151. Oral abstract presented at: ASCO Gastrointestinal Cancers Symposium, January 19-21; San Francisco, CA. Abstract 491.
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