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. Cancer 2019;125:3603-3614.

Biomarkers in Hepatocellular Carcinoma: Diagnosis, Prognosis and Treatment Response Assessment

“…There is no robust data reporting the effect of PD-L1 tumor expression as a predictive marker of response to pembrolizumab. Data on PD-L1 tissue expression as a predictive tool with pembrolizumab was previously reported in a single center uncontrolled intervention study in 29 patients with advanced HCC who had developed disease progression or were intolerant to sorafenib [ 174 ]. In this study, serum pro and anti-inflammatory cytokines, as well as serum levels of PD-1 and PD-L1 and PD-L2, were measured at baseline.…”

“…In only 10 patients there was tumor tissue available and only 4 were positive to PD-L1 staining, showing higher levels of plasma INF-y or IL-10 but PD-L1 staining was not correlated with plasma PD-L1 concentration. Plasma tumor-growth factor β (TGF-β) levels were associated with overall survival [ 174 ].…”

Predictive Factors for Response to PD-1/PD-L1 Checkpoint Inhibition in the Field of Hepatocellular Carcinoma: Current Status and Challenges

“…Thus, a fraction of PD-L1-negative HCC patients showed objective clinical responses, demonstrating no significant difference compared to PD-L1 positive patients. This was recently confirmed by a study where the response to anti-PD-1 did not correlate with PD-L1 tumor staining in advanced HCC [27]. However, archival tissue samples were used and the number of evaluable patients in this study was very limited ( n = 10).…”

Immune Phenotype and Immune Checkpoint Inhibitors for the Treatment of Human Hepatocellular Carcinoma

“…Detection of activating mutation in CTNNB1 should also be informative to know immune cold phenotype and lack of response to ICIs in HCC [41]. On the other hand, Feun et al indicated that baseline plasma TGF-β level could be a predictive biomarker for the response to pembrolizumab [80], and clinical trials of combined blockade of PD-1/PD-L1 and TGF-β axis are ongoing (Table 3). Dong et al analyzed multiple tumors of the same patients for genetic structure, neoantigens, T cell receptor repertoires, and immune infiltrates, and found that only a few tumors were under the control of immunosurveillance and the majority carry a variety of immune escape mechanisms, even in a single case [81].…”