Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma

Abstract

Background: Checkpoint inhibitors have shown modest activity in patients with advanced hepatocellular carcinoma (HCC). Herein, the authors report a prospective single-institution clinical/translational phase 2 study of pembrolizumab in patients with advanced HCC and circulating biomarkers closely related to response.

Methods: Pembrolizumab was administered at a dose of 200 mg intravenously every 3 weeks among patients who may have developed disease progression while receiving, were intolerant of, or refused sorafenib. The circulating levels of cytokines, chemokines, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and PD-L2 were correlated with response, tumor PD-L1 expression, and other clinicopathological features.

Results: A total of 29 patients were treated and 28 patients were evaluable for response. The most common laboratory grade 3/4 adverse events were increases in aspartate aminotransferase and/or alanine aminotransferase and serum bilirubin, which for the most part were reversible. In terms of efficacy, one patient achieved a complete response and 8 patients achieved partial responses for an overall response rate of 32%. Four other patients had stable disease. The median progression-free survival was 4.5 months and the median overall survival was 13 months. Response did not correlate with prior sorafenib therapy, PD-L1 tumor staining, or a prior history of hepatitis. Correlative studies revealed that high baseline plasma TGF-β levels (≥200 pg/mL) significantly correlated with poor treatment outcomes after pembrolizumab. Tumor PD-L1 and plasma PD-L1/PD-1 levels were associated with plasma IFN-γ or IL-10.

Conclusions: Pembrolizumab was found to demonstrate activity in patients with advanced HCC. Toxicity generally was tolerable and reversible. A set of immunological markers in blood plasma as well as PD-L1 staining indicated that baseline TGF-β could be a predictive biomarker for response to pembrolizumab.

Keywords: circulating biomarkers; clinical trial; hepatocellular carcinoma; pembrolizumab; programmed death-ligand 1 (PD-L1) expression; sorafenib.

Conflict of interest statement

CONFLICT OF INTEREST DISCLOSURES

Paul Martin has received research support and acted as a paid consultant for AbbVie, Merck, and Gilead for work performed outside of the current study. The other authors made no disclosures.

© 2019 American Cancer Society.

Figures

Figure 1.

Computed tomography scans demonstrating response to pembrolizumab.

Figure 2.

Computed tomography scans demonstrating pseudoprogression.

Figure 3.

Pembrolizumab benefits both overall survival (OS) and progression-free survival (PFS) rates in patients with hepatocellular carcinoma (HCC) with low baseline levels of TGF-β. (A) OS and PFS rates in patients with HCC receiving pembrolizumab. (B) Twenty-four patients with HCC were divided based on the cutoff value of baseline plasma TGF-β (200 pg/mL).

Figure 4.

Baseline IFN-γ or IL-10 levels were found to correlate with plasma programmed cell death protein 1 (PD-1)/programmed death–ligand 1 (PD-L1) levels in patients with hepatocellular carcinoma. Correlations between CXCL9, IFN-γ, IL-10, PD-1, PD-L1, and programmed death–ligand 2 (PD-L2) were analyzed using linear regression. r2 indicates correlation coefficient.

Figure 5.

Baseline plasma IFN-γ or IL-10 levels were found to be associated with tumor programmed death–ligand 1 (PD-L1) expression. Correlations between plasma biomarkers and tumor PD-L1 expression in 9 patients with hepatocellular carcinoma were analyzed using the 2-tailed Student t test. PD-1, programmed cell death protein 1; PD-L2, programmed death–ligand 2.

Figure 6.

Alterations in plasma biomarker levels over time in 24 patients with hepatocellular carcinoma. Plasma biomarker levels detected at pretreatment (baseline) and posttreatment (on day 60-day 90) were shown. Blue lines represented responders (R) and gray lines represented nonresponders (NR). PD-1, programmed cell death protein 1; PD-L1, programmed death–ligand 1; PD-L2, programmed death–ligand 2.