Assessment of Inflammation Biomarkers in Relation to Clinical Outcomes in Nivolumab-Treated Patients With Advanced Hepatocellular Carcinoma in CheckMate 040

Abstract

Introduction: Nivolumab (NIVO), a programmed death-1 (PD-1) inhibitor, demonstrated durable responses, manageable safety, and promising long-term survival in patients (pts) with advanced hepatocellular carcinoma (HCC), regardless of etiology, with/without prior sorafenib treatment in CheckMate 040 (El-Khoueiry, Lancet 2017). NIVO is approved in several countries for the treatment of sorafenib-experienced pts with advanced HCC. We report findings on additional exploratory biomarker analyses from NIVO-treated pts with advanced HCC from CheckMate 040.

Methods: In CheckMate 040, pts with advanced HCC received NIVO monotherapy in the phase 1/2 dose-escalation (ESC; 0.1–10 mg/kg) and dose-expansion (EXP; 3 mg/kg) phases every two weeks, regardless of programmed death ligand 1 (PD-L1) status and HCC etiology. For pts in the ESC and EXP phases receiving NIVO 3 mg/kg, baseline tumor biopsy samples were analyzed using immunohistochemistry for the following markers: expression of PD-L1, PD-1, T-cell markers (CD3, CD4, CD8, FOXP3), and macrophages (CD68, CD163). Baseline tumor biopsy samples from a subset of pts in the ESC and EXP phases were evaluated using RNA sequencing to assess inflammatory signatures. Results were correlated with clinical outcomes: response (complete response [CR] + partial response [PR] vs stable disease [SD] or progressive disease [PD]) and overall survival (OS). Associations with characteristics such as etiology and geographical region (non-Asia vs Asia) were also assessed. The data cutoff date was June 2018.

Results: In pts with evaluable data (n = 184), increased tumor cell PD-L1 expression was significantly associated with response (CR+PR vs SD [P = 0.00009]; CR+PR vs PD [P = 0.0007]) and OS (P = 0.03). Increased PD-1 expression was also significantly associated with response (CR+PR vs SD [P = 0.05]; CR+PR vs PD [P = 0.009]) and OS (P = 0.05). Of the T-cell markers assessed, CD3 expression was significantly associated with response (n = 182, CR+PR vs SD; P = 0.05). In pts positive for CD3 or CD8, there was a trend towards improved survival (P = 0.08). No association between CD68- and CD163-expression and clinical outcomes was observed. For the subset of pts for whom RNA sequencing data was available (n = 37), the median Bristol-Myers Squibb (BMS) inflammatory signature score was significantly higher in pts with a PR vs SD (P = 0.05) and was correlated with improved OS (P = 0.01). For all of the inflammation markers assessed, there was no association with HCC etiology or geographical region.

Conclusions: In pts with advanced HCC, improved survival and response to nivolumab may be associated with higher PD-L1, PD-1 and CD3 expression, and higher BMS inflammatory signature scores. These data support the role of PD-1 inhibition in the treatment of HCC. Further investigation of these biomarkers is required.