A Phase II Trial of Pembrolizumab plus Granulocyte Macrophage Colony Stimulating Factor in Advanced Biliary Cancer [CITE-Seq]

Immune checkpoint inhibitors have limited activity as monotherapy in biliary cancers. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic immune cell growth factor which resulted in prolonged survival when combined with ipilimumab in melanoma. We conducted a single-center, phase II trial to evaluate the efficacy and safety of combining GM-CSF with pembrolizumab in patients with advanced biliary cancers after prior standard chemotherapy but no prior immune checkpoint inhibitor. Pembrolizumab 200 mg was administered intravenously in 21-day cycles, along with two cycles of GM-CSF 250 µg subcutaneously days 1 through 14. The primary endpoint was objective response rate. Among 42 patients enrolled, the median age was 61 years, 67% had intrahepatic cholangiocarcinoma, 90% had stage IV disease, and 24% had underlying viral hepatitis. The confirmed objective response rate was 12% (95% confidence interval: 4, 26), including two patients with complete response, and 26% of patients had progression-free survival ongoing at 6 months. Treatment was well-tolerated with treatment-related grade 3-4 events in 7% and treatment-related serious adverse events in 10%. Tumor PD-L1 expression was present in 46% and was associated with a higher rate of 6-month progression-free survival. Paired tumor biopsies showed upregulation of CD8+ T cell populations and antigen processing pathways after the addition of GM-CSF. In conclusion, the addition of GM-CSF to pembrolizumab was well-tolerated but did not meet the pre-specified response rate for efficacy. A subset of patients experienced deep responses and prolonged stable disease. GM-CSF elicited changes in the tumor immune microenvironment that could guide future combination approaches.