- Merck & Co. disclosed Tuesday its cancer drug Keytruda failed a Phase 3 study in advanced liver cancer, less than four months after the immunotherapy gained an accelerated approval for a similar indication.
- Results showed treatment with Keytruda plus best supportive care failed to significantly improve either overall or progression-free survival compared to placebo, falling short of both co-pimary endpoints in the confirmatory KEYNOTE-240 trial. The study enrolled 413 patients with advanced hepatocellular carcinoma (HCC) who were previously treated with systemic therapy.
- In a statement, Merck Research Laboratories chief medical officer Roy Baynes called the efficacy results "generally consistent with findings from the Phase 2 study." Patients in the Keytruda arm showed improvement in overall survival and "directionally favorable" results for progression-free survival, although neither cleared the necessary statistical bar to declare a significant difference versus control.
In the fast-moving field of immunotherapy, the trial failure could bring some uncertainty to use of Keytruda (pembrolizumab) as a treatment for patients with the advanced liver cancer.
Accelerated drug approvals from the Food and Drug Administration generally come with a requirement to verify benefit through a confirmatory study. In the case of Keytruda, the November approval was based on data from KEYNOTE-224, a single-arm study which evaluated 104 patients with HCC and showed a 17% overall response rate to treatment.
In this Phase 3 study, Merck did not formally test overall response rate, a secondary endpoint, since the study failed to reach its primary goals. The pharma noted Keytruda's safety profile was in line with previous studies, and Baynes' statement cast results as comparable to KEYNOTE-224, touting the positive — though not statistically significant — trend in survival.
Yet the clinical failure poses a broader question of whether the FDA would issue a warning or caution against use of Keytruda as a second-line treatment for HCC.
Just last month, for example, the FDA advised doctors to not start certain cancer patients on Eli Lilly's Lartruvo (olaratumab) after that drug failed to show a survival benefit in Phase 3 testing. The agency had granted Lartruvo an accelerated approval in October 2016.
Merck has another Phase 3 study, dubbed KEYNOTE-394, testing Keytruda as monotherapy in Asian patients with previously treated advanced HCC. Clinicaltrials.gov, a federal database of clinical studies, lists KEYNOTE-394's estimated primary completion date as Dec. 23, 2019.
Further out, the pharma and partner Eisai are also testing Keytruda in combination with Lenvima (lenvatinib) as a first-line therapy, with a targeted completion date set for 2022.
Past failures of confirmatory studies of cancer immunotherapies have not resulted in immediate FDA action or cautions.
In July 2017, for example, Keytruda failed a head and neck squamous cell carcinoma study after gaining an accelerated approval for that indication a little less than a year prior.
In that case, Keytruda subsequently showed a survival benefit in first-line treatment of the cancer type, according to study results from last October.
Other immunotherapy companies have faced similar scenarios. Bristol-Myers Squibb's Opdivo (nivolumab), for instance, failed to show a survival benefit in a pair of small cell lung cancer studies last year, after winning an OK for third-line treatment of the cancer.
Merck stated it has shared the study results with the FDA for discussion and plans to present the data at an upcoming medical meeting. In a statement, a spokesperson for the FDA's drugs division said the agency had nothing to add when asked about the drug's status.