FDA busts Merck's Keytruda in triple-negative breast cancer with a CRL — not unexpected given its disastrous adcomm - Endpoints News

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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 a monother­a­py 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 missed its event-free sur­vival co-pri­ma­ry end­point over place­bo — a quick red flag — and 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.

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FDA busts Merck's Keytruda in triple-negative breast cancer with a CRL — not unexpected given its disastrous adcomm - Endpoints News
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