Early discovery of liver disease improves chances to cure liver cancer
Breakthroughs
Fifteen years ago, there was no treatment for liver cancer that prolonged overall survival.
“We gave chemotherapy to patients with advanced disease, really for no reason other than we wanted to do something for them,” Richard S. Finn, MD, professor of medicine in the division of hematology/oncology at David Geffen School of Medicine at University of California, Los Angeles, and Jonsson Comprehensive Cancer Center, told Healio Gastroenerology.
The breakthrough clinicians needed arrived in 2007, when Josep M. Llovet, MD, founder and director of the liver cancer program and professor of medicine at Mount Sinai School of Medicine, presented results of the SHARP trial at the ASCO Annual Meeting.
In the phase 3, double-blind, randomized trial that included 602 patients with advanced disease, those who received sorafenib had a 44% increase in OS compared with those assigned placebo (median OS, 10.7 months vs. 7.9 months; HR = 0.69; 95% CI, 0.55-0.87).
“It was the first time we had a systemic therapy for HCC,” Llovet told Healio Gastroenterology. “People were standing up and clapping. It was very, very nice.”
These data ushered in a period of intense clinical development in liver cancer research, according to Finn.
“[The SHARP trial] showed that sorafenib improved survival by a median of about 3 months,” he said. “Tumors didn’t necessarily shrink, but it improved survival, which is ultimately the most important thing. It set the stage for progress. The results showed you can develop a drug for liver cancer, that you can be successful in a well-designed study.”
Still, the progress that followed moved slowly at first.
“We had 10 years of additional drugs being tested and all trials were negative. We were shocked,” Llovet said. “Some were negative because the drug was powerful but toxic, like sunitinib [Sutent, Pfizer], and others were not powerful enough.”
The next breakthrough occurred in April 2017.
Stivarga (regorafenib, Bayer) — a kinase inhibitor that works by blocking several enzymes that promote cancer growth — became the first FDA-approved treatment for advanced liver cancer since sorafenib. Sixteen months later, based on data from the phase 3 REFLECT trial, Lenvima (lenvatinib, Eisai) received FDA approval, becoming the first front-line therapy approved for unresectable HCC in a decade. Within a year, FDA approved two more multi-kinase inhibitors, Cabometyx (cabozantinib, Exelixis) and Cyramza (ramucirumab, Eli Lilly).
Three additional treatments received accelerated approval — the anti-PD-1 antibodies Opdivo (nivolumab, Bristol Myers Squibb) and Keytruda (pembrolizumab, Merck), and nivolumab plus the anti-CTLA-4 antibody Yervoy (ipilimumab, Bristol Myers Squibb) — although these approvals have been the subject of an FDA review.
After a decade-long drought, the tidal wave of drugs approved for HCC from 2017 to 2020 opened the window to a myriad of opportunities for advancing research and improving outcomes.
“We’ve learned some things from what we did during those negative studies in regard to trial design and the natural history of liver cancer,” Finn said. “It took time and trial and error to develop these more active drugs.”
Finn led the phase 3 IMbrave150 trial, which compared the PD-L1 inhibitor Tecentriq (atezolizumab, Genentech/Roche) plus the VEGF inhibitor Avastin (bevacizumab, Genentech/Roche) with sorafenib among patients with unresectable HCC. Results of the trial, published in May in The New England Journal of Medicine, are considered the next milepost in research and led to FDA approval of the combination for this patient population.
An updated analysis presented in January after median follow-up of 15.6 months showed the combination reduced the risk for death by 34% (median OS, 19.2 months vs. 13.4 months; HR = 0.66; 95% CI, 0.52-0.85).
“It’s the dawn of a new era of combinations, a true breakthrough,” Llovet said. “The first HR reported [from IMbrave150] was 0.58, which is outstanding. With longer follow-up there was some regression to the HR, to 0.66, which is still outstanding. The objective response rate of approximately 30% is very, very good.”作者: StephenW 时间: 2021-10-22 17:33