Pembrolizumab plus Granulocyte Macrophage Colony-Stimulating Factor in Patients with Advanced Biliary Tract Cancer

March 2022, Vol 3, No 1

Immune checkpoint inhibitors used as monotherapy have demonstrated only modest activity in unselected patients with advanced biliary tract cancers, highlighting the need for novel strategies to improve patient outcomes. Granulocyte macrophage colony-stimulating factors (GM-CSF) show immunomodulatory effects and may therefore potentiate the activity of immune checkpoint inhibitors.

This rationale was the basis for a phase 2 clinical trial designed to evaluate the efficacy and safety of the checkpoint inhibitor pembrolizumab plus GM-CSF in patients with advanced biliary tract cancers. The results were presented by Robin Kate Kelley, MD, University of California, San Francisco during the 2022 ASCO GI Cancers Symposium.

This investigator-initiated, single-center, phase 2 study involved a Simon’s 2-stage design (stage 1 and stage 2) and an expansion cohort and included patients with advanced biliary tract cancer who received treatment at the University of California, San Francisco, between May 2016 and December 2019. The main inclusion criteria were a diagnosis of locally advanced or metastatic biliary tract cancer, including intrahepatic cholangiocarcinoma (CCA), extrahepatic CCA, gallbladder carcinoma, or combined hepatocellular CCA, after failure of ≥1 standard therapies; no previous use of a checkpoint inhibitor; and bilirubin levels up to 1.5 the upper limit of normal.

Eligible patients received intravenous pembrolizumab 200 mg every 21 days until disease progression (up to 24 months) plus subcutaneous GM-CSF 250 mcg on days 1 through 14 of every 21 days in cycles 2 and 3 in stage 1 and in the expansion cohort, or in cycles 1 and 2 of stage 2, for a total of 2 induction cycles.

The study’s primary end point was the objective response rate (ORR). The key secondary end points were safety, progression-free survival (PFS), overall survival (OS), and PD-L1 expression. Exploratory end points included the relationship between efficacy outcomes and anatomic subsite, risk factors, and tumor genotype.

A total of 42 patients were enrolled in the study; of these, 9 patients were enrolled in stage 1, 18 patients in stage 2, and 15 patients in the expansion cohort. The median age of the total study population was 61 years; the majority were female (57%), had a diagnosis of intrahepatic CCA (67%), stage IV disease (91%), and were microsatellite stable (81%).

Among the 42 patients evaluable for efficacy, 5 (12%) had a response to therapy, including 2 complete responses and 3 partial responses, with a median time to response of 111 days. The median PFS was 63 days, the 6-month PFS was 27%, and the median OS was 393 days.

No significant differences were found in the ORR, PFS, or OS by anatomic subsite or tumor PD-L1 expression. Patients with underlying hepatitis B or C virus infection had a trend toward higher ORR than the overall population (30% vs 6%, respectively; P = .08), longer median PFS (276 vs 63 days; P = .06), and longer OS (1033 vs 323 days; P = .052).

Although the 12% ORR did not meet the prespecified target rate of ≥20% for efficacy, this rate exceeds the expected ORR with pembrolizumab monotherapy.

The combination of pembrolizumab plus GM-CSF was safe and tolerable, with no unexpected adverse events. Overall, 3 (7%) patients had grade 3 or 4 treatment-related adverse events (TRAEs). Immune-related events were reported in 69% of the patients, all-cause serious adverse events in 31% of patients, serious TRAEs in 10% of patients, and 2 patients discontinued the study because of TRAEs.

These results show that the combination of pembrolizumab plus GM-CSF therapy is safe and well-tolerated, with higher ORR than for pembrolizumab monotherapy in patients with advanced biliary tract cancer, but this combination did not meet the study’s target ORR threshold for efficacy.


Kelley RK, Bracci PM, Keenan B, et al. Pembrolizumab (PEM) plus granulocyte macrophage colony stimulating factor (GM-CSF) in advanced biliary cancers (ABC): final outcomes of a phase 2 trial. Abstract 444.

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