CheckMate 040 Backs Further Nivolumab Investigation In Advanced HCC

Nivolumab could be a potential treatment option for patients with advanced hepatocellular carcinoma

medwireNews: Nivolumab is well tolerated and elicits durable responses in patients with advanced hepatocellular carcinoma (HCC), say the CheckMate 040 researchers who believe that the checkpoint inhibitor warrants additional investigation in this patient population.

The phase I/II study started with a dose escalation stage in which 48 participants, with or without chronic viral hepatitis, were given nivolumab every 2 weeks at doses ranging from 0.1–10.0 mg/kg. Prior sorafenib treatment was permitted and the majority (77%) had received the multikinase inhibitor.

One patient experienced a dose-limiting toxicity – grade 2 hepatic impairment – but it resolved within a week, and a maximum tolerated dose was not reached.

During the subsequent dose expansion stage, 214 participants stratified by sorafenib treatment history and viral hepatitis status received the programmed cell death protein 1 (PD-1) inhibitor at 3 mg/kg every 2 weeks.

Treatment-related toxicities of grade 3 or 4 occurred in a quarter of the patients in the dose escalation phase and in 19% of those in the dose expansion phase. The corresponding rates of serious adverse effects attributable to treatment were 6% and 4%.

And no new safety signals were identified, say Anthony El-Khoueiry, from USC Norris Comprehensive Cancer Center in Los Angeles, California, USA, and fellow investigators in The Lancet.

In the dose escalation phase, three participants achieved a complete response and four had a partial response, giving an objective response rate (ORR) of 15%, while the ORR in the dose expansion stage was 20%, including three complete and 39 partial responses. The disease control rates were 58% and 64%, respectively.

The CheckMate 040 investigators highlight that these ORRs are higher than the 2–3% rates observed with first-line sorafenib, the only drug approved for advanced HCC worldwide, and the 7% rate seen with second-line regorafenib .

The responses also appeared to be durable with a median duration of response of 17.0 months in the dose escalation phase and 9.9 months in the dose expansion phase. Of note, two-thirds (67%) of the responders in the latter phase had an ongoing response at data cutoff.

Furthermore, responses were observed regardless of whether patients had progressed on sorafenib or were naïve or intolerant to the drug, the study authors point out. Similarly, neither HCC aetiology (hepatitis C or hepatitis B virus infection or no viral hepatitis), nor baseline programmed cell death ligand 1 (PD-L1) levels had an effect on response rates, although the team notes that PD-L1 data were only available for 81% of the participants of the dose expansion phase.

In a linked comment, Marcus-Alexander Wörns and Peter Galle, both from the University Medical Centre of the Johannes Gutenberg-University in Mainz, Germany, say: “Despite the non-randomised study design and the current lack of complete biomarker analysis, we believe the results of CheckMate 040 will considerably affect the future landscape of systemic treatment in hepatocellular carcinoma.”

They continue that these findings “have already opened paths for potential combination therapies on the basis of good tolerance—instrumental in patients with liver disease—and rational synergistic strategies such as the combination of different immunotherapeutics or complementary to targeted therapies.”

However, “a randomised trial with a control arm is required to fully appreciate the magnitude of benefit nivolumab might provide for patients with hepatocellular carcinoma”, write the commentators who eagerly await the results of the ongoing phase III trial pitting nivolumab against sorafenib in the first-line setting.


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; Advance online publication 20 April 2017. doi:

Wörns M-A, Galle PR. Immune oncology in hepatocellular carcinoma—hype and hope. Lancet; Advance online publication 20 April 2017. doi:

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