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.

• Authors: Lynn G Feun, Ying-Ying Li, Chunjing Wu, Medhi Wangpaichitr, Patricia D Jones, Stephen P Richman, Beatrice Madrazo, Deukwoo Kwon, Monica Garcia-Buitrago, Paul Martin, Peter J Hosein, Niramol Savaraj
• Journal: Cancer (Cancer) Vol. 125 Issue 20 Pg. 3603-3614 (Oct 15 2019) ISSN: 1097-0142 [Electronic] United States
• PMID: 31251403 (Publication Type: Clinical Trial, Phase II, Journal Article)
• Copyright: © 2019 American Cancer Society.

Chemical References

• Antibodies, Monoclonal, Humanized
• B7-H1 Antigen
• CD274 protein, human
• IFNG protein, human
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Transforming Growth Factor beta
• Interleukin-10
• Interferon-gamma
• pembrolizumab

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects)
• B7-H1 Antigen (blood)
• Carcinoma, Hepatocellular (blood, diagnostic imaging, drug therapy, pathology)
• Disease Progression
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Interferon-gamma (blood)
• Interleukin-10 (blood)
• Kaplan-Meier Estimate
• Liver Neoplasms (blood, diagnostic imaging, drug therapy, pathology)
• Male
• Middle Aged
• Programmed Cell Death 1 Receptor (blood)
• Progression-Free Survival
• Prospective Studies
• Tomography, Emission-Computed
• Transforming Growth Factor beta (blood)
• Treatment Outcome