Combo Poised to Become Standard in HCC

After more than a decade, researchers may have identified a first-line treatment for hepatocellular carcinoma (HCC) that beats the current standard—the first one that involves an immune checkpoint inhibitor. In a phase III trial, atezolizumab (Tecentriq; Genentech) plus bevacizumab (Avastin; Genentech) extended median progression-free survival (PFS) and overall survival (OS) compared with sorafenib (Nexavar; Bayer), and was associated with a similar rate and severity of side effects.

“It's a major breakthrough in the management of liver cancer,” says Augusto Villanueva, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, NY, who was not involved in the trial. Results were presented at the ESMO Asia 2019 Congress in Singapore in late November.

According to senior author Richard Finn, MD, of the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, HCC presents a double challenge for treatment: It is often accompanied by underlying liver disease, and it is a molecularly diverse cancer. “We haven't been able to pin down, at least with any high frequency, a real molecular driver,” Finn says.

In recent years, several second-line treatment regimens have been approved, but as a first-line therapy, “we just had a string of failures—nothing could beat sorafenib.” Notably, a phase III trial comparing the PD-1 inhibitor nivolumab (Opdivo; Bristol-Myers Squibb) with sorafenib failed; the only success was a noninferiority trial of the tyrosine kinase inhibitor lenvatinib (Lenvima; Eisai).

High response rates in early trials of the PD-L1 inhibitor atezolizumab combined with the angiogenesis inhibitor bevacizumab in patients newly diagnosed with HCC led Finn and his colleagues to conduct the phase III IMbrave150 trial.

After a median follow-up of 8.6 months, patients treated with the combination had an overall response rate of 27%, had a median PFS of 6.8 months, and had not reached median OS, compared with 12%, 4.3 months, and 13.2 months, respectively, in patients who received sorafenib. In total, 57% of patients in the combination group experienced grade 3 to 4 adverse events, compared with 55% of those in the sorafenib group. Patient assessments of their quality of life showed that those who received sorafenib suffered physical deterioration more quickly than those who received the combination.

“I think this is a huge step, because now we have something that is clearly better” than sorafenib as an initial therapy, says Tim Greten, MD, of the NCI in Bethesda, MD, who was not involved in the trial. He and Villanueva are eager for longer term follow-up data—including median OS—but they agree that once the combination is approved for HCC, it is likely to become first-line standard of care. But then what?

“It's going to shake up the field because none of the second-line studies have been done in patients who failed first-line immunotherapy,” Greten says.

“The management gets a little bit messy because there are so many different options,” Villanueva adds. “It would be important to have a clear path on how to organize these different treatment lines.”

This question is likely to persist, especially as researchers continue combining immune checkpoint inhibitors with targeted therapies—for example, pembrolizumab plus lenvatinib, which is being tested in a phase III trial.

Greten and Villanueva also call for research on patients who respond to the combination. “To really deliver the right and effective treatment to the right patients, we have to be better at identifying patient populations that will benefit,” Greten says.

Villanueva adds, “That opens all the doors to develop biomarkers of response.” –Catherine Caruso