Pegylated Granulocyte Colony Stimulating Factor Combined with Anti-Pd-1/Pd-L1 Inhibitors in the Treatment of Recurrent or Metastatic Biliary Tract Cancer

Abstract

Background: Biliary tract cancer (BTC) is a malignancy with an extremely poor prognosis. For patients with recurrent or metastatic BTC who have failed first-line chemotherapy, treatment options are limited. Although anti-PD-1/PD-L1 inhibitors have shown efficacy in various tumors, their single-agent activity in BTC is limited, particularly in previously treated patients. Preclinical evidence suggests that granulocyte-colony stimulating factor (G-CSF) may enhance the efficacy of anti-PD-1/PD-L1 inhibitors by remodeling the tumor immune microenvironment. This study aimed to evaluate whether the addition of long-acting G-CSF (pegylated recombinant human G-CSF, pegfilgrastim) could restore or enhance the efficacy of anti-PD-1/PD-L1 inhibitors in patients with resistant BTC.

Methods
This was a single-arm, prospective, Phase II clinical trial. The inclusion criteria were histologically confirmed recurrent or metastatic BTC that had
progressed after at least one line of systemic chemotherapy. All patients received an anti-PD-1 inhibitor (sintilimab 200mg IV q3w) or an anti-PD-L1
inhibitor (atezolizumab 1200mg IV q3w). On day 2 of each cycle, pegfilgrastim (6mg subcutaneously) was administered. The primary endpoint was the Objective Response Rate (ORR) as assessed by the investigator according to RECIST v1.1. Secondary endpoints included Disease Control Rate (DCR), Progression-Free Survival (PFS), Overall Survival (OS), duration of response (DoR), and safety.

Results
A total of 42 patients were enrolled. The median follow-up time was 12.8 months (95% CI: 10.5-15.1 months). The confirmed ORR was 21.4% (95% CI:
10.3%-36.8%), with 1 patient achieving a complete response (CR) and 8 patients achieving a partial response (PR). The DCR was 66.7% (95% CI: 50.5%- 80.4%). The median PFS was 4.2 months (95% CI: 3.1-5.3 months), and the median OS was 11.5 months (95% CI: 9.2-13.8 months). The most common treatment-related adverse events (TRAEs) of any grade were leukopenia (45.2%), neutropenia (40.5%), and fatigue (31.0%). Grade 3 or higher TRAEs occurred in 19.0% of patients, with the most common being neutropenia (9.5%) and anemia (4.8%). No treatment-related deaths were reported. Exploratory biomarker analysis suggested that patients with a baseline neutrophil-to-lymphocyte ratio (NLR) < 3 had a higher ORR and longer PFS.

Conclusion
For patients with recurrent or metastatic BTC who have progressed on prior chemotherapy, the combination of long-acting G-CSF and anti-PD-1/PD-L1 inhibitors demonstrated promising anti-tumor activity and a manageable safety profile. This regimen appears to be a viable therapeutic option, capable of restoring sensitivity to immunotherapy in this difficult-to-treat population. Further validation from randomized controlled trials is warranted.