Almost three years after whiffing in a confirmatory study, Merck touts new data for Keytruda in HCC
Keytruda’s accelerated approval in a common form of liver cancer looked shaky after the drug failed on two survival measures in a confirmatory study almost three years ago. Now Merck’s touting what could be a confirmatory win — but will three patient deaths mar its chances?
A regimen of Keytruda plus best supportive care reduced patients’ risk of death by 21% compared to placebo plus supportive care (p=0.0180), meeting the primary endpoint in the Phase III KEYNOTE-394 study, Merck announced on Tuesday. The trial enrolled 453 Asian patients with advanced hepatocellular carcinoma (HCC), who had previously been treated with sorafenib or oxaliplatin-based chemotherapy.
Patients in the Keytruda arm saw an overall survival of 14.6 months compared to 13 months in the placebo arm, and 34.3% of Keytruda patients were still alive at the two-year mark compared to 24.9% of placebo patients.
However, there were three deaths in the Keytruda arm “related to the study intervention,” Merck said, caused by gastrointestinal hemorrhage, autoimmune hepatitis and soft tissue infection. Patients in the Keytruda arm also saw higher rates of treatment-emergent side effects, including immune-mediated adverse events, according to Merck.
That could give Opdivo and Yervoy a leg up in this setting, where the drug combo posted one treatment-related death in the open-label CheckMate-040 trial (due to pneumonitis). However, Bristol Myers Squibb voluntarily pulled Opdivo from the market as a solo therapy for HCC back in July, as the FDA’s Oncologic Drugs Advisory Committee held an industry-wide evaluation of accelerated approvals for checkpoint inhibitors that have not met their post-marketing requirements to show confirmatory benefit.
Keytruda won accelerated approval in HCC back in 2018 based on some earlier mid-stage data. But when the drug failed the KEYNOTE-240 study a few months later, its future looked murky. That trial missed the mark on both overall survival as well as progression-free survival.
ODAC voted unanimously for keeping Keytruda on the market last April, as the adcomm continued its review of so-called “dangling approvals.” Merck had asserted the Keytruda regimen was still necessary for second-line patients despite a recent approval for a Tecentriq-Avastin combo in first-line HCC. Richard Finn, a professor of medicine at UCLA and paid consultant for Merck, said at the time that pulling the HCC approval didn’t make sense given more data were coming in just a few months.
Merck says it’s discussing the KEYNOTE-394 data with regulators around the world, and the trial will be evaluated as a potential confirmatory study in the US.
“Patients with advanced HCC still have a high unmet medical need with low survival rates, reinforcing the need for treatment options that can improve overall survival,” Scot Ebbinghaus, VP of clinical research at Merck Research Laboratories, said in a statement on Tuesday. “We are pleased to share these new data from KEYNOTE-394 and are committed to advancing research for patients with this difficult-to-treat cancer through our broad global program in HCC.”
Merck didn’t get so lucky with all of its Keytruda indications, as ODAC recommended against keeping Keytruda’s accelerated OK in third-line stomach cancer. The pharma giant subsequently pulled the drug in July.
Correction: Patients in KEYNOTE-394 received Keytruda along with best supportive care, not best standard-of-care.