Nivolumab Approved for Liver Cancer

The FDA granted accelerated approval on September 22 to the PD-1 inhibitor nivolumab (Opdivo; Bristol-Myers Squibb) for the treatment of hepatocellular carcinoma (HCC) in patients whose disease progressed despite treatment with the multikinase inhibitor sorafenib (Nexavar; Bayer), the standard of care. The decision comes 5 months after the agency approved another multikinase inhibitor, regorafenib (Stivarga; Bayer), the first new drug for HCC in a decade—and gives patients a third treatment option.

The approval of nivolumab was based on a 14% response rate observed among 154 participants in the single-arm phase I/II CheckMate-040 trial whose disease had progressed on sorafenib. Among the 22 responders, responses lasted from 3.2 months to more than 38.2 months; 55% of these patients had responses of at least 12 months.

“It's so good to see patients that had quite a bad prognosis now being on treatment with very few side effects—sometimes for years,” says Bruno Sangro, MD, of the Clinical University of Navarra in Spain, a co–principal investigator. “Some patients are even getting durable complete responses induced, which was totally unprecedented.”

The question now: Should patients who don't respond to sorafenib receive nivolumab or regorafenib?

One consideration is overall survival (OS). The latest findings from CheckMate-040—presented last month at the 2017 Annual Conference of the International Liver Cancer Association in Seoul, South Korea—showed that patients receiving nivolumab after sorafenib had a median OS of close to 16 months. In the pivotal phase III trials for sorafenib (first-line) and regorafenib (second-line), median OS was less than 11 months.

Other deciding factors are tolerability and durability. According to CheckMate-040 co–lead investigator Thomas Yau, MD, of the University of Hong Kong Li Ka Shing Faculty of Medicine, nivolumab was well tolerated, with a side-effect profile in patients with HCC similar to that reported for other tumor types. “Surprisingly,” Yau says, “we haven't seen much liver-related toxicity, hepatitis, or even a case of hepatic failure due to nivolumab.” In contrast, both sorafenib and regorafenib have been associated with debilitating side effects, including significant liver toxicity.

In addition, most responders to nivolumab have stayed in remission for over a year—compared with 3.5 months with regorafenib. Thus, Sangro says, there's “a good rationale” for trying nivolumab first and reserving regorafenib for nonresponders. (Even then, regorafenib would be appropriate only for those who tolerated sorafenib as a first-line therapy.)

Milind Javle, MD, of The University of Texas MD Anderson Cancer Center in Houston, who was not involved in the nivolumab trials, describes the approval of nivolumab as “the first time historically that we have seen something really significant in the management of advanced hepatocellular cancer.” However, because the therapy yields responses in only a minority of patients, “we will have to look for predictive markers,” he says. In CheckMate-040, PD-L1 expression did not correlate with response to nivolumab. However, some of the biomarkers being assessed in the phase III CheckMate-459 trial of front-line nivolumab versus sorafenib—including gene signatures in tumors, circulating cytokines, and PD-1/PD-L1 levels in tumor-infiltrating lymphocytes—could prove effective.

Another strategy for boosting response rates could be combination therapies. To that end, nivolumab is being evaluated with either the CTLA4 inhibitor ipilimumab (Yervoy; Bristol-Myers Squibb) or the kinase inhibitor cabozantinib (Cabometyx/Cometriq; Exelixis), and with ipilimumab and cabozantinib combined. “This approval is going to incentivize more of those kinds of combinatorial therapies,” Javle says, “because clearly that's the next step.” –Elie Dolgin