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.

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His­toric drug pric­ing re­forms pass; Pfiz­er ac­quires GBT; The long search for non-opi­oid pain drugs; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

The Endpoints Weekly has officially crossed the 60,000 mark on subscribers — thanks to all of your support. As the editorial team grows, we’ve been able to do a lot more, with many of those on display this week. Be sure to check out Lei Lei Wu’s deep dive on pain R&D. If you missed it, you may also rewatch her companion panel here.

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Gold for adults, sil­ver for in­fants: Pfiz­er's Pre­vnar 2.0 head­ed to FDA months af­ter Mer­ck­'s green light

Pfizer was first to the finish line for the next-gen pneumococcal vaccine in adults, but Merck beat its rival with a jab for children in June.

Now, two months after Merck’s 15-valent Vaxneuvance won the FDA stamp of approval for kids, Pfizer is out with some late-stage data on its 20-valent shot for infants.

Known as Prevnar 20 for adults, Pfizer’s 20vPnC will head to the FDA by the end of this year for an approval request in infants, the Big Pharma said Friday morning. Discussions with the FDA will occur first and more late-stage pediatric trials are expected to read out soon, informing the regulatory pathway in other countries and regions.

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Seagen interim CEO Roger Dansey and Daiichi Sankyo CEO Sunao Manabe

Paving the way for Mer­ck­'s buy­out, Seagen los­es ar­bi­tra­tion dis­pute with Dai­ichi over ADC tech

As Seagen awaits a final buyout offer from Merck that could be in the territory of $40 billion, Seagen revealed Friday afternoon that it lost an arbitration dispute with Daiichi Sankyo relating to the companies’ 2008 collaboration around the use of antibody-drug conjugate (ADC) technology.

But that loss likely won’t matter much when it comes to Merck’s deal.

After breaking off its pact with Daiichi in mid-2015, the two companies battled over “linker” tech — a chemical bridge between an ADC’s antibody component and the cytotoxic payload — that Seagen claims Daiichi would improve upon and implement in its current generation of ADCs.

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FDA ap­proves sec­ond in­di­ca­tion for As­traZeneca and Dai­ichi's En­her­tu in less than a week

AstraZeneca and Daiichi Sankyo’s antibody-drug conjugate Enhertu scored its second approval in less than a week, this time for a subset of lung cancer patients.

Enhertu received accelerated approval on Thursday to treat adults with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, and who have already received a prior systemic therapy.

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Elcin Barker Ergun, Menarini Group CEO

Amid Roche and Sanofi's oral SERD set­backs, Menar­i­ni gets speedy re­view at FDA

Menarini and Radius Health are getting a speedy review at the FDA for their oral SERD breast cancer drug months after the field opened up with competitors failing and fleeing.

It was a one-two-three punch in March, April and May as Sanofi flunked its first big test for its oral selective estrogen receptor degrader (SERD), Roche also flamed out in a Phase II and G1 Therapeutics ended its program after scoping out the data and potential partners.

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Senate Finance Committee Chair Ron Wyden (D-OR) (Francis Chung/E&E News/POLITICO via AP Images)

Sen­ate Fi­nance chair con­tin­ues his in­ves­ti­ga­tion in­to phar­ma tax­es with re­quests for Am­gen

Amgen is the latest pharma company to appear on the radar of Senate Finance Committee Chair Ron Wyden (D-OR), who is investigating the way pharma companies are using subsidiaries in low- or zero-tax countries to lower their tax bills.

Like its peers Merck, AbbVie and Bristol Myers Squibb, Wyden notes how Amgen uses its Puerto Rico operations to consistently pay tax rates that are substantially lower than the U.S. corporate tax rate of 21%, with an effective tax rate of 10.7% in 2020 and 12.1% in 2021.

J&J to re­move talc prod­ucts from shelves world­wide, re­plac­ing with corn­starch-based port­fo­lio

After controversially spinning out its talc liabilities and filing for bankruptcy in an attempt to settle 38,000 lawsuits, Johnson & Johnson is now changing up the formula for its baby powder products.

J&J is beginning the transition to an all cornstarch-based baby powder portfolio, the pharma giant announced on Thursday — just months after a federal judge ruled in favor of its “Texas two-step” bankruptcy to settle allegations that its talc products contained asbestos and caused cancer. An appeals court has since agreed to revisit that case.

CSL is gathering its four business units under a unified brand identity strategy (Credit: CSL company site)

CSL brings Se­qirus, Vi­for un­der par­ent um­brel­la brand in iden­ti­ty re­vamp

CSL is gathering its brands under the family name umbrella, renaming its vaccine and newly acquired nephrology specialty businesses with the parent initials.

CSL Seqirus and CSL Vifor join CSL Plasma and CSL Behring as the four now uniformly branded business units of the global biopharma. The Seqirus vaccine division was formed in 2015 with the combination of bioCSL and its purchase of Novartis’ flu vaccine business. CSL picked up Vifor Pharma late last year in an $11.7 billion deal for the nephrology, iron deficiency and cardio-renal drug developer.

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