Citations 1
A Randomized Phase II Study of Combination Atezolizumab and Varlilumab (CDX-1127) with or without Cobimetinib in Previously Treated Unresectable Biliary Tract Cancer
Heumann, Thatcher , Lu, Jiayun , Wang, Hao , Phelps, Mitch A. , Zhu, Qingfeng , Anders, Robert A. , Mitchell, Sarah , Leatherman, James M. , Abbott, Nicole , Kim, Kyeongmin , Imhof, Teresa , Xie, Zhiliang , Partey, Alexandra , Kunk, Paul R. , Iyer, Renuka , Fonkoua, Lionel Aurelien Kankeu , Kalyan, Aparna , Gbolahan, Olumide B., Javle, Milind , Davis, S. Lindsey , Spencer, Kristen , Azad, Nilofer S. , Heumann, Thatcher Ross , Phelps, Mitch , Anders, Robert , Leatherman, James , Li, Daneng , Kunk, Paul Raymond , Iyer, Renuka , Dayyani, Farshid , Fonkoua, Lionel Aurelien A Kankeu , Kalyan, Aparna , Gbolahan, Olumide B , Javle, Milind M , Davis, S Lindsey , Florou, Vaia , Spencer, Kristen , Sharon, Elad , Yarchoan, Mark , Lesinski, Gregory B , Azad, Nilofer , Wang, Hao , Mitchell, Sarah , Li, Daneng , Dayyani, Farshid , Sharon, Elad , Yarchoan, Mark
Clinical Cancer Research | June 30, 2026 | Volume: No volume available | Issue: No issue available | Pages: OF1-OF12
Abstract Purpose: The addition of MEK inhibition (MEKi) to programmed cell death ligand 1 (PD-L1) blockade improves progression-free survival (PFS) in patients with advanced biliary tract cancer. Although MEK inhibitors may increase tumor cell immunogenicity, they can impair T-cell priming/effector function, limiting combination efficacy. We hypothesized that the addition of a CD27 agonist could restore T-cell function and enhance antitumor immunity in this combination. Patients and Methods: We conducted a randomized, phase II trial evaluating atezolizumab (840 mg, intravenously, days 1 and 15) in combination with the CD27 costimulatory monoclonal antibody [CDX-1127/varlilumab (3 mg/kg, intravenously, days 1 and 15)], with/without the addition of an MEK inhibitor [cobimetinib (60 mg, orally, daily, days 1–21, off days 22–28)] in unresectable biliary tract cancer following at least one metastatic therapy. Overall response rate (ORR) and PFS were coprimary endpoints. Treatment-related changes in CD8+ tumor-infiltrating lymphocytes (TIL) were the primary correlative outcomes. Results: The trial was closed early following interim preplanned ORR analysis. At closure, 57 patients had been enrolled [n = 29 in the cobimetinib + atezolizumab + varlilumab (CAV) arm; n = 28 in the atezolizumab + varlilumab (AV) arm]. A majority (67%) had intrahepatic cholangiocarcinoma, and 32% were immunotherapy experienced. Both regimens were well tolerated without new safety signals. Objective responses were rare [0% (CAV); 3.8% (AV)]. The median PFS (mPFS) was 2.40 (CAV) and 1.84 (AV) months [hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.38–1.18]. Among immunotherapy-experienced patients, the mPFS was 3.62 (CAV) and 1.84 (AV) months (HR, 0.54; 95% CI, 0.18–1.62). Treatment with CAV increased intratumoral CD8+ T-cell density compared with treatment with AV. Conclusions: The combinations of atezolizumab and varlilumab with/without cobimetinib were safe, but neither meaningfully improved outcomes in biliary tract cancer treated in the later lines. Correlative tissue studies validated preclinical work that MEKi increases CD8+ TILs.