Merck's Keytruda again bags industry-first cervical cancer nod—with limitation

After crowning Keytruda as the first immunotherapy for advanced cervical cancer back in 2021, the FDA has awarded the drug another industry-first designation in an earlier stage of the tumor type. But again, the achievement was not perfect for Merck.

Thanks to a new FDA nod, Merck’s Keytruda is the first PD-1 drug to be approved in combination with chemoradiotherapy to treat patients with stage 3 to 4a cervical cancer, the New Jersey pharma giant said Friday. This marks Keytruda’s 39th indication in the U.S.

The approval, however, was narrower than expected. It came on the back of results from the Keynote-A18 trial, which showed a tumor progression benefit for the Keytruda-chemoradiation regimen in a broader patient population with earlier-stage cervical cancer.

Keynote-A18 tested the Keytruda combo in patients whose cancer was as early as stage 1b2. Among the entire trial population, adding Keytruda to chemoradiotherapy slashed the risk of progression or death by 30%.

But the progression-free survival benefit was markedly more pronounced in those with stage 3 to 4a disease, the approved FDA indication, where Keytruda’s addition was associated with a 41% improvement in the trial endpoint. In those with stage 1b2 to 2b disease, the benefit was just 9%, according to data presented at the European Society of Medical Oncology annual meeting in October.

Data on whether Keytruda can extend patients’ lives remained immature at the time, as less than half of deaths for the final overall survival analysis had occurred. At the first interim analysis, the Keytruda-chemoradiation pairing showed a favorable trend, reducing the risk of death by 27% in the entire trial population. Subgroup analyses of overall survival were unavailable. Overall survival is another primary endpoint of Keynote-A18.  

Investigators are following the overall survival endpoint of Keynote-A18. “If positive, an assessment of the benefit of this regimen for early stage patients will be conducted,” a Merck spokesperson told Fierce Pharma.

The imperfect nod for Keytruda tracks with an emerging trend from the FDA’s oncology department, which is increasingly looking for patient subgroups who didn’t benefit from large, inclusive trials. Drug companies often find that their strategy of asserting a statistically powered, overall trial win to seek a broad label—despite weak subgroup performances—no longer works with the FDA.

Back in 2021, the FDA greenlit Keytruda, used alongside chemo, with or without Roche’s Avastin, to treat patients with advanced cervical cancer, but only for those whose tumors express PD-L1. That PD-L1 restriction came despite the Keynote-826 trial showing a significant progression-free survival improvement in the overall trial population, which also included PD-L1-negative patients.

When the final overall survival came at last year’s American Society of Clinical Oncology meeting, the PD-L1-negative population was still holding back the overall trial result with comparatively worse outcomes. And Merck Research Laboratories’ chief medical officer, Eliav Barr, M.D., said that a label expansion to include those patients was unlikely because the FDA probably wouldn’t change its interpretation of the previous primary analysis.

The FDA’s scrutiny doesn’t stop with immuno-oncology agents. In November, the FDA surprisingly limited its approval for AstraZeneca’s Truqap to a small subgroup of HR-positive, HER2-negative breast cancer patients, allowing the first-in-class small-molecule AKT inhibitor only for those whose cancer carries one of three gene alternations. At the time, AstraZeneca’s oncology business chief David Fredrickson told Fierce Pharma that a final overall survival analysis may give AZ an opportunity to expand the nod to a larger group of patients.

The FDA’s move “may suggest a change in sentiment that requires the sponsor to have the burden of demonstrating prospectively and conclusively that all patients derive a benefit in order to be granted a broad label,” Leerink Partners analysts said at the time.

Editor's Note: The story has been updated with a statement from Merck on the overall survival endpoint and a potential expansion.