FDA snubs Keytruda in early breast cancer after harsh review as Merck looks to next data analysis

Keytruda
The FDA has issued a complete response letter to Merck's application for PD-1 inhibitor Keytruda as a treatment both before and after surgery in high-risk early triple-negative breast cancer. (Merck)

The other shoe has dropped for Merck’s U.S. application of Keytruda in high-risk early-stage triple-negative breast cancer.

As expected, the FDA has rejected the blockbuster PD-1 inhibitor’s use both before and after surgery in that disease to prevent tumors from returning. Merck said it’s reviewing the complete response letter and will discuss next steps with the FDA.

The knock-back came after the FDA had already made clear its concern over an approval in a review document, and an independent FDA oncology expert panel had backed it up with a unanimous vote to defer a decision until more mature clinical data are available.

The problem centers on the surrogate biomarker data Merck relied on for this submission. In the phase 3 Keynote-522 trial, Merck showed adding Keytruda to chemotherapy ahead of surgery in the neoadjuvant setting could help significantly more patients achieve the so-called pathological complete response (pCR), in which no residual cancer cells are present in tissue samples removed during surgery.

But both the FDA and the advisory committee have doubts about whether pCR is a good indicator of Keytruda’s ability to delay disease recurrence or prolong patients’ lives; and, if it is, just how much of a pCR advantage is needed to translate into a hard survival benefit is also unknown.

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An interim analysis from Keynote-522 unveiled at ESMO 2019 also showed a positive trend in favor of Keytruda for extending the time patients enjoyed before cancer recurrence or death, but this event-free survival data weren’t mature at the moment. Patients in the study also got solo Keytruda as an adjuvant therapy after surgery while the control group received placebo.

Recurrence-free survival did previously help Keytruda snag an FDA green light for the adjuvant treatment of melanoma following surgery, and updated data unveiled at ESMO 2020 further backed that use up by showing Keytruda could prevent cancer from spreading.

RELATED: ESMO: Merck's Keytruda posts first-in-class victory in pre-surgery breast cancer

For now, Merck’s counting on the next interim analysis of Keynote-522, being planned for the third quarter, to read a clearer sign of event-free survival. But those data, as well as the final overall survival results, could take a long time to read out; the Keynote-522 trial bears a primary completion date in September 2025, as Merck noted analyses of those two endpoints could take up to about eight years.

Those aren’t the only hoops Merck has to jump through to win over the FDA. The agency and the experts took issues with Keynote-522’s trial design, arguing it muddies the water when reading into Keytruda’s specific role in neoadjuvant and adjuvant settings separately. The trial won’t be able to answer the question of whether patients really need to get Keytruda in both settings, which is important given the additional toxicity that comes with extended exposure to a PD-1 agent.

Industry watchers have remained optimistic of Keynote-522’s eventual success, but the question is, just how long will that take?