A randomized phase 2 study of combination atezolizumab and varlilumab (CDX-1127) with or without cobimetinib in previously-treated unresectable biliary tract cancer
Thatcher Ross. Heumann, Jiayun Lu, Hao Wang, Mitch Phelps, Qingfeng Zhu, Robert Anders, Sarah Mitchell, James Leatherman, Nicole Abbott, Kyeongmin Kim, Teresa Imhof, Zhiliang Xie, Alexandra Partey, Daneng Li, Paul Raymond. Kunk, Renuka V. Iyer, Farshid Dayyani, Lionel Aurelien Kankeu, Aparna Kalyan, Olumide B. Gbolahan, Milind M. Javle, S. Lindsey. Davis, Vaia Florou, Kristen Spencer, Elad Sharon, Mark Yarchoan, Gregory B. Lesinski, Nilofer Saba. AzadAbstract
Purpose: The addition of MEK inhibition to PD-L1 blockade improves progression-free survival (PFS) in patients with advanced biliary tract cancer (BTC). While 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 anti-tumor immunity in this combination. Patients and Methods: We conducted a randomized, phase 2 trial evaluating atezolizumab (840mg IV days 1,15) in combination with the CD27 co-stimulatory mAb (CDX-1127/varlilumab [3mg/kg IV days 1, 15]), with/without the addition of a MEK inhibitor (cobimetinib [60mg oral daily days 1-21, off 22-28]) in unresectable BTC following at least 1 metastatic therapy. Overall response rate (ORR) and PFS were co-primary endpoints. Treatment-related changs in CD8+ tumor infiltrating lymphocytes (TIL) was the primary correlative outcome. Results: The trial was closed early following interim preplanned ORR analysis. At closure, 57 patients had been enrolled (n=29[CAV],n=28[AV]. 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]). Median PFS was 2.40(CAV) and 1.84(AV) months (HR 0.67,95%CI[0.38,1.18]). Among immunotherapy-experienced patients, 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 BTC treated in the later lines. Correlative tissue studies validated preclinical work that MEK inhibition increases CD8+TILs.