Clinical and Genetic Tumor Characteristics of Responding and Non-Responding Patients to PD-1 Inhibition in Hepatocellular Carcinoma

SIMPLE SUMMARY: Immune checkpoint inhibitors are dramatically reshaping cancer treatments in a multitude of advanced cancers, including hepatocellular carcinoma (HCC). However, only a subgroup of patients with HCC currently benefits from immunotherapy. Therefore, we performed a multicenter exploratory in-detail characterization of 99 patients with HCC and programmed cell death protein 1 (PD-1) blockade to identify markers associated with therapy response. Our study observed a better outcome for patients with low levels of alpha-fetoprotein, progression-free survival > 6 months, and relevant treatment responses in both Child–Pugh A and B patients. Genetic factors were analyzed in a subset of patients: Neither specific genetic patterns nor tumor mutational burden were associated with treatment response. Our cohort´s main finding suggests that the application of antibiotics 30 days before or after therapy initiation is associated with a worse outcome, indicating a possible influence of the host-microbiome modulation on the outcome of PD-1/PD-L1-targeted immunotherapy in HCC. ABSTRACT: Immune checkpoint inhibitors (ICIs) belong to the therapeutic armamentarium in advanced hepatocellular carcinoma (HCC). However, only a minority of patients benefit from immunotherapy. Therefore, we aimed to identify indicators of therapy response. This multicenter analysis included 99 HCC patients. Progression-free (PFS) and overall survival (OS) were studied by Kaplan-Meier analyses for clinical parameters using weighted log-rank testing. Next-generation sequencing (NGS) was performed in a subset of 15 patients. The objective response (OR) rate was 19% median OS (mOS)16.7 months. Forty-one percent reached a PFS > 6 months; these patients had a significantly longer mOS (32.0 vs. 8.5 months). Child-Pugh (CP) A and B patients showed a mOS of 22.1 and 12.1 months, respectively. Ten of thirty CP-B patients reached PFS > 6 months, including 3 patients with an OR. Tumor mutational burden (TMB) could not predict responders. Of note, antibiotic treatment within 30 days around ICI initiation was associated with significantly shorter mOS (8.5 vs. 17.4 months). Taken together, this study shows favorable outcomes for OS with low AFP, OR, and PFS > 6 months. No specific genetic pattern, including TMB, could identify responders. Antibiotics around treatment initiation were associated with worse outcome, suggesting an influence of the host microbiome on therapy success.