Treatment options for advanced hepatocellular carcinoma (HCC) are limited, with the multikinase inhibitors sorafenib (first-line) and regorafenib (second-line) as the only approved systemic therapies. In the prospective, global, noncomparative phase I/II dose expansion and dose escalation CheckMate 040 trial, the programmed death receptor 1 (PD-1) inhibitor, nivolumab, demonstrated a manageable safety profile with encouraging response rates and overall survival (OS) in patients with advanced HCC.
The dose escalation phase examined nivolumab at doses ranging from 0.1 mg/kg to 10 mg/kg every two weeks (q 2 w) in 48 patients with advanced HCC. Previous sorafenib treatment was allowed, but prior exposure to T-cell–stimulating immunotherapy was not. The most common treatment-related adverse events (AEs) observed in more than 10% of the patients were rash, increase of liver and pancreatic enzymes, and pruritus. Serious AEs occurred in 25% of patients, including 3 that were deemed to be treatment-related (pemphigoid, adrenal insufficiency, and liver disorder). AEs were not associated with treatment dose and no maximum tolerated dose was identified. Treatment with nivolumab was associated with an ORR of 15%, including 3 complete responses (CR) and 4 partial responses (PR). Responses were durable with a median 17.4-month duration of response (DoR). Median OS was 15 months.
Based on results from this dose-escalation phase and studies in other tumor types, a dose of 3 mg/kg q 2 w was selected for the dose-expansion phase, which included 214 patients. In these patients, treatment with nivolumab yielded an overall response rate of 20%, including 3 CRs, 39 PRs, and a disease control rate of 64%. Baseline PD-L1 expression status did not impact responses. The median DoR was 9.9 months and the 9-month OS rate was 74%; median survival was not reached.
Of note, patients responded regardless of chronic viral infection and previous treatment with sorafenib. In those without viral hepatitis, ORR was 23% in patients who had not previously received sorafenib and 21% in patients with prior sorafenib treatment. In patients with hepatitis B virus (HBV) infections the ORR was 14%, and in patients with hepatitis C virus (HCV) infections ORR was 20%.
In The Lancet, where these findings were published, the authors commented that these results are very promising, particularly given the limited treatment options and low response rates seen with standard therapies (2% to 3% with first-line sorafenib, and 7% with second-line regorafenib). However, they indicated that comparative studies are needed to explore the potential of nivolumab in advanced HCC, such as the current ongoing randomized phase III CheckMate-459 trial investigating front-line nivolumab in comparison to sorafenib.