FDA busts Merck's Keytruda in triple-negative breast cancer with a CRL — not unexpected given its disastrous adcomm
Merck and the FDA have engaged in a high-noon standoff over checkpoint inhibitor Keytruda in triple-negative breast cancer after the agency roundly panned its results in high-risk patients. Now, with a decisive adcomm supporting its criticisms, the FDA has shown Keytruda the door in that indication.
The FDA slapped Keytruda with a CRL in high-risk triple-negative breast cancer after the agency’s Oncologic Drugs Advisory Committee handed out a rather gentle slapdown on the I/O drug’s application last month, Merck said Monday.
Keytruda’s chances as monotherapy after a regimen of Keytruda and chemo and surgery in triple-negative breast cancer were always a longshot after the FDA offered a stinging rebuke of the drug’s pivotal dataset, which it called “questionable” given immature OS data and some wishy-washy efficacy numbers, according to ODAC briefing documents at the time.
What really riled up the agency, however, was that they explicitly asked Merck not to submit for approval after expressing their concerns with the maturity of the dataset after multiple meetings. The CRL doesn’t affect Keytruda’s approval as a combination therapy with chemo in locally advanced, PD-1 expressing TNBC tumors that are metastatic or cannot be surgically removed.
The basis for Merck’s submission was KEYNOTE-522, which tested Keytruda as a post-surgical monotherapy following a combo of Keytruda and platinum-based chemotherapy. The study’s event-free survival primary endpoint over placebo was too immature to judge — a quick red flag — as researchers hadn’t watched patients long enough after treatment to determine EFS and OS. At the time of third check-in, just 53% of targeted EFS events had occurred and 32% of OS events.
The agency also pushed back on the study’s pCR co-primary endpoint, which Keytruda hit, calling efficacy over placebo “small.”
The 10-0 ODAC vote, however, wasn’t a nail in the coffin. The advisory committee advocated waiting out final safety figures, and Merck said another interim look-in on the KEYNOTE-522 data was coming up in the third quarter.
Does any of that “wait-and-see” mentality mean the FDA will change its mind and welcome Keytruda back in these patients? That’s unclear. But a win on EFS and OS could be enough to swing a vote given the FDA’s recent history of rewarding drugs that don’t hit the primary endpoint in pivotal studies. Calling an adcomm on data it seemed never likely to approve, however, looked a lot like the FDA and OCE director Richard Pazdur publicly putting an overzealous drugmaker in the penalty box.
Merck, for its part, found the drug’s interim survival data to show a “strong and durable” trend, the drugmaker said in February.
Editor’s Note: This story has been updated to clarify details of KEYNOTE-522’s design.