Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers

Abstract

BACKGROUND. MEK inhibitors have limited activity in biliary tract cancers (BTCs) as monotherapy but are hypothesized to enhance responses to programmed death ligand 1 (PD-L1) inhibition. METHODS.This open-label phase II study randomized patients with BTC to atezolizumab (anti-PD-L1) as monotherapy or in combination with cobimetinib (MEK inhibitor). Eligible patients had unresectable BTC with 1 to 2 lines of prior therapy in the metastatic setting, measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1. The primary endpoint was progression-free survival (PFS). RESULTS.Seventy-seven patients were randomized and received study therapy. The trial met its primary endpoint, with a median PFS of 3.65 months in the combination arm versus 1.87 months in the monotherapy arm (HR 0.58, 90% CI 0.35-0.93, 1-tail P = 0.027). One patient in the combination arm (3.3%) and 1 patient in the monotherapy arm (2.8%) had a partial response. Combination therapy was associated with more rash, gastrointestinal events, CPK elevations, and thrombocytopenia. Exploratory analysis of tumor biopsies revealed enhanced expression of antigen processing and presentation genes and an increase in CD8/FoxP3 ratios with combination treatment. Patients with higher baseline or lower fold changes in expression of certain inhibitory ligands (LAG3, BTLA, VISTA) on circulating T cells had evidence of greater clinical benefit from the combination. CONCLUSION.The combination of atezolizumab plus cobimetinib prolonged PFS as compared with atezolizumab monotherapy, but the low response rate in both arms highlights the immune-resistant nature of BTCs. TRIAL REGISTRATION. ClinicalTrials.gov NCT03201458.

An antigen processing and presentation signature for prognostic evaluation and immunotherapy selection in advanced gastric cancer

“…The cleavage of Caspase-1 by CTSB activates caspase-1, which promotes the secretion of interleukin-1b (IL-1b), leading to an inflammatory response (69, 70). Compared with atezolizumab monotherapy for biliary tract cancer, TAPBP expression was higher in the combined treatment group (71). Compared with attezolzumab monotherapy for biliary tract cancer, TAPBP expression was higher in the combined treatment group (atezolizumab + MEK inhibitor).…”

Feasibility and tolerability of sintilimab plus anlotinib as the second‐line therapy for patients with advanced biliary tract cancers: An open‐label, single‐arm, phase II clinical trial

“…Meanwhile, Targeted or targeted combination immunotherapy regimen also has unsatisfactory outcomes. In a trial of atezolizumab with or without cobimetinib in BTCs, mPFS of combination arm was 3.65 months while the monotherapy arm was 1.87 months 42 . By contrast, our combination regimen of sintilimab plus anlotinib exhibited a mOS of 12.3 months with a 12‐month OS rate of 55.0%, a mPFS of 6.5 months, an ORR of 30%, and a DCR of 95%.…”

VISTA expression and patient selection for immune-based anticancer therapy

“…VISTA can be found on ~5% of CD4+ and CD8+ T cells within the TME of breast cancer ( 39 ). VISTA expression on circulating, non-tumoral T cells is also observed ( 46 ). VISTA expression level on tumor-infiltrating Tregs is higher than Tregs from peripheral lymph nodes, indicating that VISTA expressed on Tregs within the TME might play a role in suppressing tumor-specific immunity ( 47 ).…”