Prevalence of established and emerging biomarkers of immune checkpoint inhibitor response in advanced hepatocellular carcinoma

// Celina Ang 1 , Samuel J. Klempner 2 , Siraj M. Ali 3 , Russell Madison 3 , Jeffrey S. Ross 3 , Eric A. Severson 3 , David Fabrizio 3 , Aaron Goodman 4 , Razelle Kurzrock 4 , James Suh 3 and Sherri Z. Millis 3 1 Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA 2 Department of Medicine, Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA 3 Foundation Medicine, Cambridge, MA, USA 4 Department of Medicine, Division of Hematology and Oncology, Moores Cancer Center, University of California San Diego, San Diego, CA, USA Correspondence to: Celina Ang, email: [email protected] Keywords: immunotherapy; biomarkers; hepatocellular carcinoma; tumor mutation burden Received: January 16, 2019     Accepted: May 20, 2019     Published: June 18, 2019 ABSTRACT The clinical deployment of immune checkpoint inhibitors (ICIs) has created a tandem drive for the identification of biomarkers linked to benefit. Comprehensive genomic profiling was performed to evaluate the frequency of genomic biomarkers of ICI response in 755 patients with advanced hepatocellular carcinoma (HCC). Median age was 62 years’ old, 73% were male, 46% had extrahepatic disease, 107 had documented hepatitis C, 96 had hepatitis B and 4 patients were coinfected. Median tumor mutation burden (TMB) was 4 mutations/Mb and only 6 tumors (0.8%) were TMB-high. Out of 542 cases assessed for microsatellite instability (MSI), one (0.2%) was MSI-high and TMB-high. Twenty-seven (4%) patients had POLE/D alterations. One patient had a pathogenic POLE R762W mutation but TMB was 4 mutations/Mb. Forty percent had DNA damage response gene alterations. In a small case series (N=17) exploring the relationship between biomarkers and ICI response, one patient (TMB 15 mutations/Mb, MSI-low) had a sustained complete response to nivolumab lasting > 2 years. Otherwise there were no significant genomic or TMB differences between responders, progressors, and those with stable disease. Overall, markers of genomic instability were infrequent in this cohort. Larger clinically annotated datasets are needed to explore genomic and non-genomic determinants of ICI response in HCC.