Phase 3 Keytruda Trial Fails Primary Objectives in Liver Cancer Patients Who Received Prior Nexavar

Immune checkpoint inhibitor Keytruda (pembrolizumab) did not significantly improve the survival outcomes of previously treated hepatocellular carcinoma patients on best supportive care, results from a Phase 3 trial show.

While a trend was seen toward extended survival and delayed disease progression or death, the results did not meet statistical significance, with the KEYNOTE-240 trial (NCT02702401) failing both its primary objectives.

“While we are disappointed KEYNOTE-240 did not meet its co-primary endpoints, the results for overall survival, progression-free survival and objective response rate are generally consistent with findings from the Phase 2 study, KEYNOTE-224, which led to the accelerated approval of Keytruda for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib,” Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said in a press release.

Keytruda, developed by Merck (known as MSD outside the U.S. and Canada), is an immune checkpoint inhibitor, meant to help the immune system recognize and fight cancer. It binds to a protein called PD-1 on immune T-cells, preventing interaction with its ligand, PD-L1, produced by cancer cells to avoid immune surveillance.

After results from the KEYNOTE-224 Phase 2 trial (NCT02702414), the treatment received accelerated approval as a treatment for patients with hepatocellular carcinoma (HCC) — the most common type of liver cancer — who previously had received Nexavar (sorafenib).

However, like most accelerated approvals, which are based on promising response rates and duration of response, a full approval is contingent on additional data confirming the treatment’s benefits.

Therefore, KEYNOTE-240 was designed to determine if adding Keytruda to best supportive care could improve the survival outcomes of HCC patients who had failed or were intolerant to Nexavar. These patients lack options to treat their condition and are often given best supportive care, which includes management of pain and other potential complications.

The trial included 413 patients who received Keytruda plus best supportive care, or a placebo plus best supportive care. Treatment was given for up to two years, or until disease progression or signs of intolerable toxicity.

In addition to the primary goals of measuring overall survival and the time to disease progression or death, researchers also examined the response rate, duration of response, disease control rate, and time to progression as secondary measures.

While the full findings have not been disclosed, the researchers reported a 22% reduction in both the risk of death and the risk of disease progression. While favorable, the results were not statistically significant, researchers say.

Since both primary objectives were not met, researchers did not formally analyze the number of patients who achieved a response to treatment, though they said response rates were similar to those of KEYNOTE-224.

Results have been shared with the FDA and will be presented at an upcoming medical meeting.

“We sincerely thank the patients and investigators for their participation in this study and are committed to helping patients diagnosed with this common and difficult-to-treat type of liver cancer,” Baynes said.

A similar Phase 3 trial (NCT03062358) is testing a combination of Keytruda and best supportive care in Asian HCC patients who received prior Nexavar. The trial is recruiting participants across China, Korea, Malaysia, and Taiwan. More information is available here.