PD-1 inhibitors monotherapy in hepatocellular carcinoma: Meta-analysis and systematic review

Abstract

Background: Immunity plays a major role in carcinogenesis and this is the case also for hepatocellular carcinomas (HCC). Checkpoint inhibitors, novel drugs that enhance the immune system's ability to attack cancers, have been successfully introduced for the therapy of various malignancies including HCC. An important target of these drugs is the PD-L1/PD-1 ligand/receptor pair and several clinically available inhibitors of this pair exist.

Data sources: A search of the literature until April 20, 2019 was performed in the MEDLINE/PubMed database, the Embase database and the Cochrane Central Register of Controlled Trials. The clinical studies describing treatment with PD-L1/PD-1 inhibitors as monotherapy in HCC patients were retrieved. Patient characteristics with relevance for treatment efficacy, such as liver function, disease extend and previous treatment, were extracted from identified articles. Response and survival outcomes were the primary focus of the meta-analysis. Summary estimates of response rates and survival were calculated using a random or fixed effect model, depending on heterogeneity. Most common adverse effects were also recorded and summarized.

Results: Three studies (two on nivolumab and one on pembrolizumab) with a total of 400 patients were included in the analysis. The summary response rate (RR) was 17.3% [95% confidence interval (CI): 13.2%-21.4%]. The summary disease control rate (DCR) was 56.6% (95% CI: 44.7%-68.5%). Summary progression free survival (PFS) was 3.5 months (95% CI: 2.8-4.2 months). Summary overall survival (OS) was 10.4 months (95% CI: 3.5-17.2 months). Adverse effect rate was low and also consistent with the adverse effect profile of PD-L1/PD-1 inhibitors in other disease locations.

Conclusions: Pembrolizumab and nivolumab are the only checkpoint inhibitors with data in HCC. Meta-analysis of their effectiveness discloses rates not dissimilar to other systemic therapies available for this disease. Of interest also are the observed long responses in a sub-set of responders. Further development is clearly warranted.

Keywords: Hepatocellular carcinoma; Immune checkpoint inhibitors; Meta-analysis; Nivolumab; Pembrolizumab.