Immunotherapy biomarkers for HCC: contemporary challenges and emerging opportunities.

Clinical management of advanced unresectable HCC has indelibly changed with the advent of immune checkpoint inhibitor (ICI) antibody therapy. The CheckMate-040 multi-cohort trial first demonstrated the effectiveness of an anti-PD1 antibody (nivolumab) in patients with clinically advanced HCC previously treated with sorafenib, reporting an approximately 20% overall objective response rate in such patients [1] . Another anti-PD1 agent, pembrolizumab, demonstrated similar response rates in its phase 2 trial [2] , and both agents subsequently received accelerated regulatory approval for second-line systemic treatment of HCC. The CheckMate-040 trial later showed up to a 32% objective response rate in patients treated with nivolumab plus ipilimumab (an antibody targeting CTLA-4), leading to approval of this combination regimen for second-line therapy [3] . With regards to first-line treatment of locally advanced or metastatic and/or unresectable HCC, the IMbrave150 phase 3 randomized trial associated the combination of bevacizumab plus atezolizumab (an anti-PD-L1 antibody) with improved overall survival over first-line sorafenib, with an objective response rate of 30% (95%CI: 25%–35%) and median duration of response of 18.1 months based on a recent extended efficacy and safety analysis of the trial [4] . Although remarkable for the setting of advanced HCC, these findings congruously show that most patients eligible to receive ICI therapy will not experience an objective benefit and that predictive biomarkers of treatment response will be necessary to optimize the risk-benefit ratio of immunotherapy treatment in this setting. Notable efforts had been made to identify predictive biomarkers within the cohorts of these and other HCC immunotherapy trials. In the Keynote-040 trial, tumor PD-L1