Combinatie atezolizumab, varlilumab en cobimetinib verbetert overleving niet bij eerder behandelde biliaire tumoren

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.