Phase 2 trial of pembrolizumab (PEM) plus granulocyte macrophage colony stimulating factor (GM-CSF) in advanced biliary cancers (ABC): Clinical outcomes and biomarker analyses.

4087 Background: The efficacy of immune checkpoint inhibition (CPI) has not been established in ABC. The combination of CPI plus the myeloid cytokine GM-CSF was safe with prolonged overall survival (OS) compared to CPI monotherapy in melanoma. This phase 2 trial evaluates the safety, efficacy, and biomarkers of PEM in combination with 2 cycles of low dose induction GM-CSF in ABC (NCT02703714). Methods: Design: Simon’s 2-stage. Key eligibility: ABC after ≥ 1 standard therapy, no prior CPI, bilirubin ≤ 1.5xULN. Treatment: PEM 200 mg IV Q3 weeks plus GM-CSF 250 µg SC days 1-14 Q3 weeks for 2 cycles. Endpoints: 1◦: Overall response rate (ORR) by RECIST 1.1 with H0 5% vs. H1 20%. Key 2◦: Safety, progression-free survival at 6 months (PFS6), OS, tumor PD-L1 expression. Exploratory: CA 19-9 levels, tumor microsatellite (in)stability (MSI, MSS), tumor mutation burden (TMB), tumor and peripheral immune cell profiling. Results: Accrual has completed with 27 patients enrolled 5/2016-9/2017: Stage 1/2 9/18; F/M 13/14; median age 61; intra-/extra-hepatic 74%/26%; stage IVA/B 85%, II/III 15%; median prior therapies 2 (range 1-6); MSI/MSS/unknown 1/19/7; TMB high+int./low/unknown 5/11/11. Adverse events (AE): Related ≥ grade (Gr)3 AE in 2 (7%) (1 each immune-related (ir)AE of Gr4 diabetes mellitus and Gr3 fever); irAE requiring steroids in 3 (11%); endocrine irAE in 8 (30%). Disposition: 20 pts discontinued for PD, 1 for Gr2 irAE neuropathy/arthralgia, 1 for unrelated AE; 5 remain on treatment. Median cycles: 6 cycles (range 2-28+). ORR: Confirmed partial response (cPR) in 5 (19%) (95% CI: 3-34%) (1 MSI, 4 MSS); cPR or stable disease (SD) ≥ 6 months in 9 (33%). PFS6: 35% (95% CI: 15-54%); median OS: not reached. Endocrine irAE, CA 19-9 changes ≥ 50%, hepatitis C virus (HCV), and TMB were associated with efficacy in univariate analyses. PD-L1+ in ≥ 1% cells was present in 3/10 (30%) pre-treatment samples but was not associated with ORR or PFS6; additional PD-L1 results are pending. Conclusions: PEM plus induction GM-CSF is safe and well-tolerated in ABC. Prolonged responses and PFS in MSS ABC along with candidate biomarkers warrant further study in larger sample. Clinical trial information: NCT02703714).