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

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.

Preferential Expression of Programmed Death Ligand 1 Protein in Tumor-Associated Macrophages and Its Potential Role in Immunotherapy for Hepatocellular Carcinoma

“…In the aforementioned study, the association between the frequency of total intratumoral CD68 + macrophages and OS was not significant [ 21 ]. In addition, another recent study demonstrated that specific genetic patterns or tumor mutational burdens were not related to treatment response [ 22 ].…”

Biomarkers and Future Perspectives for Hepatocellular Carcinoma Immunotherapy

“…Recently, a posttreatment decline in serum AFP levels was reported to be associated with higher ICI treatment efficacy in advanced HCC (119,120). In addition, Spahn et al reported that baseline levels of AFP of <400 µg/L at the start of ICI treatment were associated with higher rates of CR or partial response (PR) as best responses (121). However, the results of the checkmate040 clinical trial showed that although baseline AFP <400 µg/L was associated with longer OS compared with AFP ≥400 µg/L, the ORR and DCR were similar regardless of baseline AFP levels (29).…”

“…They observed that fecal samples from patients responding to immunotherapy showed higher taxonomic richness and greater gene counts compared with those of nonresponders; microbial composition remained relatively stable in the responder group, whereas in nonresponders, Proteobacteria abundance markedly increased from week 3 and became predominant at week 12. In addition, antibiotic administration at the initiation of ICI treatment was reportedly associated with worse outcomes, indicative of the influence of the gut microbiota on HCC treatment ( 121 ). A clinical trial (NCT03785210) to evaluate the effects of combined antibiotic (vancomycin) and ICI therapies is currently underway.…”

Genetic Heterogeneity, Therapeutic Hurdle Confronting Sorafenib and Immune Checkpoint Inhibitors in Hepatocellular Carcinoma

“…Both studies identified an HCC cluster with β-catenin mutations that were characterized by an immunosuppressive phenotype. On the other hand, Spahn et al performed a retrospective multicenter analysis for in-depth characterization of responding and non-responding HCC patients receiving PD-1 inhibitors [133]. This study performed NGS in a subset of 15 HCC patients and revealed that 4 patients have alterations in WNT/β-catenin, 1 of which showed shorter PFS than median PFS for the whole cohort.…”