The FDA recently expanded label indications for regorafenib to include treating patients with advanced hepatocellular carcinoma whose disease has progressed on the standard of care, sorafenib. Until now, these patients have had no other treatment options. Regorafenib is the first drug to be approved for liver cancer in a decade.

The FDA recently expanded label indications for regorafenib (Stivarga; Bayer) to include treating patients with advanced hepatocellular carcinoma (HCC) whose disease has progressed on the standard of care, sorafenib (Nexavar; Bayer). Until now, these patients have had no other treatment options. This approval also marks the first new therapy for liver cancer in a decade.

Regorafenib and sorafenib primarily block angiogenesis; each targets a slightly different combination of the RAF, VEGFR, and PDGFR families. Between 2012 and 2013, regorafenib garnered its first agency nods to treat metastatic colorectal cancer and gastrointestinal stromal tumors, respectively. However, the drug carries a black-box warning about potentially severe liver toxicity—a chief reason why clinicians have been slow to evaluate it in HCC, says Nevena Damjanov, MD, director of gastrointestinal oncology at Penn Presbyterian Medical Center in Philadelphia, PA.

Extensive cirrhosis often underlies advanced, inoperable HCC, Damjanov explains, so with regorafenib, “physicians face the difficult situation of trying to shrink tumors with a therapy that could result in the patient's already poor liver function deteriorating still faster.”

Recruitment for the phase III study (RESORCE) on which the FDA based its decision took time, she adds, because “patients had to have been able to tolerate sorafenib first, long enough to experience disease progression—and the side effects of sorafenib are not always easy to manage.”

RESORCE investigators reported that among 573 patients randomly assigned to receive regorafenib or placebo, the median overall survival was 10.6 months for those given the drug, and 7.8 months in the control arm (Lancet 2017;389:56–66). The median progression-free survival was 3.1 months versus 1.5 months, and the objective response rates were 11% versus 4%.

As with sorafenib, patients on regorafenib experienced a slew of side effects, including diarrhea, nausea, hypertension, fatigue, and hand–foot skin reaction. Having this drug as a second-line treatment for HCC is not unlike “treating an ulcer that hasn't responded to Zantac with Tagamet instead,” Damjanov observes. “If possible, you'd rather try something completely different.”

Even so, the survival benefit seen with regorafenib makes it “a big deal, especially considering that HCC still very much lags behind other cancers in terms of good therapeutic options,” Damjanov says. She hopes immune checkpoint inhibitors will come to the fore in this difficult-to-treat disease, and is awaiting results from a phase III trial comparing nivolumab (Opdivo; Bristol-Myers Squibb) with sorafenib as first-line therapy for advanced HCC. –Alissa Poh

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©2017 American Association for Cancer Research.
2017
American Association for Cancer Research.