A randomized phase 2 study of combination atezolizumab and varlilumab (CDX-1127) with or without cobimetinib in previously-treated unresectable biliary tract cancer

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.

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Publication Details

Journal
Clinical Cancer Research
Published
2026-06-30
DOI
https://doi.org/10.1158/1078-0432.ccr-25-4893
Primary Topic
Cholangiocarcinoma and Gallbladder Cancer Studies
Type
article
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article

A randomized phase 2 study of combination atezolizumab and varlilumab (CDX-1127) with or without cobimetinib in previously-treated unresectable biliary tract cancer

Paul R. Kunk, S. Lindsey Davis, Qingfeng Zhu, Kyeongmin Kim et al.
Clinical Cancer Research
Cholangiocarcinoma and Gallbladder Cancer Studies
article

A randomized phase 2 study of combination atezolizumab and varlilumab (CDX-1127) with or without cobimetinib in previously-treated unresectable biliary tract cancer

Paul R. Kunk, S. Lindsey Davis, Qingfeng Zhu, Kyeongmin Kim, Elad Sharon, Farshid Dayyani, Robert A. Anders, Lionel Aurelien Kankeu Fonkoua, Gregory B. Lesinski, Daneng Li, Vaia Florou, Milind M. Javle, Renuka Iyer, Jiayun Lu, Nilofer S. Azad, Mitch A. Phelps, Thatcher Heumann, James M. Leatherman, Mark Yarchoan, Kristen Spencer, Hao Wang, Nicole Abbott, Alexandra Partey, Zhiliang Xie, Olumide B. Gbolahan, Teresa Imhof, Aparna Kalyan, Sarah Mitchell
article en

Abstract

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.

Clinical Cancer Research
Northwestern University (US), Roswell Park Comprehensive Cancer Center (US), City Of Hope National Medical Center (US), Mayo Clinic (US), The University of Texas MD Anderson Cancer Center (US), Johns Hopkins University (US), Emory University (US), Vanderbilt University (US), University of California, Irvine (US), Johns Hopkins Medicine (US), Huntsman Cancer Institute (US), The Ohio State University Wexner Medical Center (US), Johns Hopkins University Applied Physics Laboratory (US), University of California, Irvine Medical Center (US), Piedmont Cancer Institute (US), Northwestern University (PH), Dana-Farber Cancer Institute (US), Mayo Clinic in Arizona (US), University of Virginia Medical Center (US), Mayo Clinic in Florida (US), Johns Hopkins Hospital (US), Sidney Kimmel Comprehensive Cancer Center (US), University of Colorado Anschutz Medical Campus (US), The Ohio State University (US), New York University (US)
Good health and well-being
Openalex Percentile: Top 6%
Cholangiocarcinoma and Gallbladder Cancer Studies
DOIOpen Access PDFOpenAlex
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