Current Perspectives on the Use of Adjuvant Pembrolizumab for Hepatocellular Carcinoma

Despite implementation of surveillance in at-risk populations and the availability of potentially curative treatment such as resection or ablation, recurrence of hepatocellular carcinoma (HCC) remains a frequent clinical challenge driven by both occult residual disease and de novo carcinogenesis, and can have a major impact on patients' quality of life. Current evidence does not support adjuvant therapy after curative treatment in early-stage HCC, and active surveillance remains the standard of care. Following the historical failure of adjuvant tyrosine kinase inhibitors, the integration of immune checkpoint inhibitors (ICIs) in advanced HCC treatment has renewed interest in their application in the curative-intent setting, particularly for their potential to eradicate microscopic residual disease. Preliminary evidence on adjuvant PD-1-based combinations supported the plausibility of immune modulation, although most of today's evidence derives from retrospective heterogeneous cohorts including multiple anti-PD-1 agents. Pembrolizumab, a monoclonal anti-PD-1 antibody that restores antitumor T-cell activity, has recently attracted growing interest on the postoperative management of early- and intermediate-stage HCC. KEYNOTE-937 was a Phase III trial comparing pembrolizumab to placebo after curative treatment whose results failed to demonstrate improvement in recurrence-free survival. This outcome suggested that postoperative PD-1 blockade alone may be insufficient to prevent tumor relapse, especially without proper selection on residual disease or treatment sensitivity. Conversely, pembrolizumab-based strategies administered in the neoadjuvant or perioperative setting remain underexplored. As persistence of tumor antigens with intact tumor burden may offer a more favorable immunological context, this setting may be better suited for enhancing antitumor immune priming. In conclusion, the negative findings of KEYNOTE-937 provide a useful foundation for refining future PD-1-based strategies in HCC. Progress will require integration of molecular residual disease assessment with pathological risk stratification and liver disease etiology, in order to identify patients with immunologically targetable residual disease who may derive meaningful benefit from adjuvant pembrolizumab.