Background

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide and shows minimal response to existing chemotherapies. Tumor mutational burden (TMB) and microsatellite instability (MSI) are predictive biomarkers of response to immune checkpoint inhibitors. Comprehensive genomic profiling (CGP) is a hybrid capture-based next-generation sequencing (NGS) test that may help optimize therapy regimens for advanced stage HCC patients.

Methods

CGP of up to 315 cancer-related genes was performed on 614 consecutive cases of hepatocellular carcinoma (2012-16) using a hybrid-capture, adaptor ligation based NGS assay and genomic alterations (GA: point mutations, small indels, copy number changes and rearrangements) were recorded. TMB was calculated from up to 1.1 megabase (Mb) of cancer genome as the number of somatic, coding point mutations and indels per Mb (low: <6; intermediate: 6-19; high: ≥20 mutations/Mb).

Results

In 614 HCC, the median age was 61 years and 70% were male. HBV/HCV infection status was not available. The most frequent GA occurred in TERT (51%), TP53 (34%), CTNNB1 (32%), MALT1 (14%), PASK (14%), CD36 (14%), MYC (13%), ARID1A (12%), CDKN2A (8.5%) and RB1 (7.6%). Potentially targetable GA involved CCND1 (5.5%), FGF19 (5.1%), FGF3/4 (4.2%), MET (2.0%), ERBB2 (1.1%), EGFR (0.7%), BRAF (0.5%) and ALK (0.4%). TMB was low in 394 (64%), intermediate in 214 (35%) and high in 6 (1.0%) patients. Of 378 patients with available MSI status, 1 HCC was MSI-H; GA involving MLH1 (0.4%), MSH2 (0.4%), MSH6 (1.1%) and POLE (0.2%) were also detected. Clinical examples of responders to everolimus and nivolumab will be presented.

Conclusions

CGP of HCC reveals rarer GA and small subsets of patients with high TMB and MSI that may open new avenues of medical treatment for select advanced HCC as well as understudied, recurrently altered genes such as PASK and MALT1, suggesting a role in the management of advanced-stage HCC.

Legal entity responsible for the study

Foundation Medicine, Inc.

Funding

None

Disclosure

J. Suh, E. Severson, G. Frampton, D. Fabrizio, J. Sun, S. Ali, V. Miller, P. Stephens, J. Ross: Foundation Medicine (employment, equity). All other authors have declared no conflicts of interest.

Background

Many patients (pts) with advanced HCC progress on sorafenib therapy, and limited treatment options are available. Nivolumab, a fully human IgG4 mAb inhibitor of PD-1, demonstrated durable responses (objective response rate [ORR], 20%; median duration of response [DOR], 9.9 mo; 9-mo overall survival [OS] rate, 74%) in pts with advanced HCC in the dose-expansion (EXP) phase of the CheckMate 040 study (El-Khoueiry, Sangro, et al. 2017). Here we present survival, durability of response, and safety data in Asian pts with advanced HCC in the CheckMate 040 study.

Methods

Pts naive to or previously treated with sorafenib received nivolumab in phase 1/2 dose-escalation (ESC; 0.1–10 mg/kg) and -EXP (3 mg/kg) cohorts every 2 weeks regardless of PD-L1 status. Primary endpoints were safety and tolerability (ESC) and ORR (EXP; reported by blinded independent central review) using RECIST v1.1. Secondary endpoints included DOR, disease control rate (DCR), and OS.

Results

Asian pts (N = 107) from Hong Kong (n = 25), Japan (n = 32), Korea (n = 13), Singapore (n = 15), and Taiwan (n = 22) were included in the analysis; median follow-up was 19.2 mo. Median age was 62 yr, and 99% had Child-Pugh scores of 5–6. Overall, 18% and 50% of pts were HCV or HBV infected, respectively; 32% were uninfected. In sorafenib-naive pts (n = 22), the ORR was 14% (Table), and the DCR was 41%. In sorafenib-experienced pts (n = 85), the ORR was 15%, and the DCR was 49%. Across the cohorts, the median DOR was 13.8 mo; 6 of 16 responses (38%) were ongoing. Treatment-related AEs (TRAEs; any grade) and grade 3/4 TRAEs occurred in 75% and 11% of pts, respectively; rates of grade 3/4 ALT and AST elevations were 1%–2%. Additional baseline, efficacy, and safety data, stratified by patient age (<65 and ≥65 yr), will be presented.Table: 195O

Nivolumab Efficacy in Asian Patients

Conclusions

Nivolumab demonstrated durable responses and manageable safety in Asian pts with advanced HCC with or without chronic viral hepatitis.

Clinical trial identification

NCT01658878

Legal entity responsible for the study

Bristol-Myers Squibb

Funding

Bristol-Myers Squibb

Disclosure

S.P. Choo: Advisory boards for Sirtex, Shire, BMS, Norvatis, Celgene; and received travel funding from Amgen and Merck. Y-K. Kang: Consulting/advisory role for Lilly/ImClone, Novartis, ONO Pharmaceutical, Roche/Genentech and Taiho Pharmaceutical; research funding from Bayer, Novartis and Roche/Genentech. W. Yeo: Honoraria from Bristol-Myers Squibb, Novartis and Pfizer; consulting/advisory role for Novartis and Pfizer; speakers\' bureau for Lilly. A. Chopra: Travel grant from BMS to travel to ASCO 2016 and 2017. Has also received fees for giving a talk at BASCO, Thailand in 2016 from BMS. Has also attended advisory board on invitation from BMS in 2016. A. Baakili, C. Dela Cruz, H. Zhao: Employment with Bristol-Myers Squibb. M. Kudo: Lectures for Bayer, Eisai, MSD, Ajinomoto, Kowa, Taiho; grants from Chugai, Otsuka, Takeda, Taiho, Sumitomo Dainippon, Daiichi, Sankyo, MSD, Eisai, Bayer, Abbvie, Medico’s Hirata, Astellas Pharma, Bristol-Myers Squibb, Eli Lilly, Pfizer, Novartis, Kaken and advisory consulting for Kowa, MSD, BMS, Bayer, Chugai, Taiho, Eisai, Ono. All other authors have declared no conflicts of interest.

Background

Advanced and unresectable hepatocellular carcinoma (HCC) carries a poor prognosis and systemic therapy provides marginal benefits. Most of the patients diagnosed as HCC are hepatitis C positive with no prior anti viral treatment. Sorafenib is standard of treatment for unresectable HCC with marginal survival benefit. The hypothesis that anti viral therapy with sofosbuvir and ribavirin could regress HCC in patients on sorafenib. This clinical study examined whether sofosbuvir and ribavirin improves the therapeutic efficacy of sorafenib in patients with advanced HCC in terms of tumor response, time to progression, one year survival and quality-of-life.

Methods

All HCC patients with Child Puge A and B, ECOG performance status 1 & 2 with hepatitis C positive and no history of prior chemotherapy and anti viral therapy. The treatment included oral administration of Sofosbuvir 400 mg daily with Ribavirin 500 mg twice daily and Sorafenib 400 mg daily was given between October 2016 to March 2017. AFP level was done monthly with CT scan 3 monthly for response assessment. Tumor response by Response Evaluation Criteria in Solid Tumors (RECIST), toxicity by Common Toxicity Criteria (CTC) version 4.0.

Results

Total 40 patients were recruited in this study. 10 patients stopped anti viral therapy due to poor tolerance. 30 patients completed their 6 month treatment. Significant disease reduction was seen after resolution of Hepatitis C with fall in AFP level. Overall 15 patients (50%) showed partial response (PR) and 12 patients (40%) had stable disease (SD) with 10% progressive disease (PD). Grade 3 fatigue, abdominal pain and vomiting was observed in 5% cases, but Grade 1 and 2 fatigue, nausea abdominal pain and anorexia was seen in almost all patients. Rest of 10 patients who did not tolerate the anti viral therapy were expired after 2 month of targeted therapy.

Conclusions

This study clearly showed that resolution of Hepatitis C infection can increase the efficacy of anti cancer treatment in HCC as compared to those patient with high infection load. One year survival will be assessed after completion of time.

Clinical trial identification

NO

Legal entity responsible for the study

Dr Rana Atique Anwar Principal investigator

Funding

None

Disclosure

The author has declared no conflicts of interest.