“Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma.”

— Anthony B. El-Khoueiry, MD

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NIVOLUMAB (OPDIVO) has been found to produce durable responses in patients with advanced hepatocellular carcinoma in the phase I/II CheckMate 040 trial. These findings were reported in The Lancet by Anthony B. El-Khoueiry, MD, of USC Norris Comprehensive Cancer Center, and colleagues.¹ Currently, sorafenib (Nexavar) is the only systemic treatment option for patients in this setting. 

Study Details 

THE PHASE I/II dose-escalation and expansion trial was performed in patients with advanced hepatocellular carcinoma who were not amenable to curative surgery or local treatment with or without hepatitis C or B virus (HCV or HBV) infection. Patients were enrolled between November 2012 and August 2016. Previous sorafenib treatment was permitted. Patients who had been treated with immune checkpoint pathway inhibitors were excluded. Patients with HBV infection had to be receiving effective antiviral therapy; antiviral therapy was not required for patients with HCV infection. Patients had to have Child-Pugh scores of ≤ 7 for the dose-escalation phase and ≤ 6 for the dose-expansion phase and an Eastern Cooperative Oncology Group performance status of 0 or 1. The dose-escalation phase was conducted at 7 sites in the United States, Spain, Hong Kong, and Singapore, and the dose-expansion phase was conducted at an additional 39 sites in Canada, UK, Germany, Italy, Japan, South Korea, and Taiwan. 

Dose-Escalation Phase 

IN THE DOSE-ESCALATION phase, 48 patients received nivolumab at 0.1 to 10 mg/kg every 2 weeks. Prior sorafenib had been received by 77%. 

Response was observed in seven patients (15%), including complete response in three, and the disease control rate was 58%. Median time to disease progression was 3.4 months. Median duration of response was 17 months. Overall survival was 66% at 6 months and 9 months, and median overall survival was 15.0 months. Grade 3 or 4 treatment-related adverse events occurred in 25% of patients, and 6% had treatment-related serious adverse events. The incidence of treatment-related adverse events did not appear to be dose-related, and no maximum tolerated dose was reached. 

Dose-Expansion Phase 

NIVOLUMAB at 3 mg/kg given every 2 weeks was selected for the dose-expansion phase. Overall, 214 patients received treatment, including 56 who had not received sorafenib or were intolerant to it and did not have viral hepatitis, 57 whose disease progressed on sorafenib without viral hepatitis, 50 with HCV infection, and 51 with HBV infection. Overall, 68% had received prior sorafenib, including 84% of those with HCV infection, 60% of those with HBV infection, and 27% of the subgroup who were intolerant to sorafenib and had no viral hepatitis. 

Responses: Response was observed in 42 patients (20%), including a complete response in 3 patients; stable disease was observed in 45%, yielding a disease control rate of 64%. Responses occurred within 3 months in 69% of responders. The Kaplan-Meier median duration of response was 9.9 months; 67% of responders had an ongoing response at data cutoff. The median time to disease progression was 4.1 months. Overall survival was 83% at 6 months and 74% at 9 months, and median overall survival was not reached. Progression-free survival was 37% at 6 months and 28% at 9 months. 

The response rate among 145 patients who had previously received sorafenib was 19%. On retrospective assessment in 174 patients with available data, 20% of patients had programmed cell death ligand 1 (PD-L1)–positive status, defined as membrane expression on ≥ 1% of tumor cells. Response rates were 26% in PD-L1–positive patients and 19% among those with PD-L1 expression < 1%. 

Among the 56 patients in the group without viral hepatitis who did not receive sorafenib or were intolerant to it, the response rate was 23%; the median duration of response was 8.4 months, with 62% of responders having an ongoing response at data cutoff; and the disease control rate was 75%. Among the 57 patients without viral hepatitis whose disease progressed on sorafenib, the response rate was 21%; the median duration of response was not reached, with 58% of responses ongoing; and the disease control rate was 61%. Among the 50 patients with HCV infection, the response rate was 20%; the median duration of response was 9.9 months, with 80% of responses ongoing; and the disease control rate was 66%. Among the 51 patients with HBV infection, the response rate was 14%; the median duration of response was not reached, with 71% of responses ongoing; and the disease control rate was 55%. Median overall survival was 13.2 months in the uninfected progressor group and not reached in the other groups. 

Adverse Events: The most common treatment-related adverse events were fatigue (23%), pruritus (21%), and rash (15%). Grade 3 or 4 treatment-related adverse events occurred in 19% of patients, with no single type of event occurring in > 1%. Treatment-related grade 3 or 4 laboratory abnormalities consisted of aspartate transaminase increase in 4% and alanine transaminase increase in 2%. Grade 3 or 4 treatment-related serious adverse events occurred in 4%. Symptomatic treatment-related adverse events were similar in patients with and without HCV or HBV infection. Treatment-related adverse events led to treatment discontinuation in 11% of patients. No treatment-related deaths occurred. 

The investigators concluded: “Nivolumab had a manageable safety profile, and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma.” ■

DISCLOSURE: The study was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit www.thelancet.com. 

REFERENCE 

1. El-Khoueiry AB, Sangro B, Yau T, et al: Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389:2492-2502, 2017.