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.

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

What lured Hal Bar­ron away?; Top FDA minds on ac­cel­er­at­ed ap­proval re­forms; ‘Dead wrong’ Aduhelm ad blitz; 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.

Nothing can really compete with Hal Barron’s departure from GlaxoSmithKline as the news of the week, but we do have plenty of original reporting and analysis from the Endpoints team in this edition. Enjoy and have a nice weekend.

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Dan O'Day, Gilead CEO (Jim Watson/AFP via Getty Images)

Fail­ing to con­firm clin­i­cal ben­e­fit, Gilead pulls 2 ac­cel­er­at­ed ap­proval in­di­ca­tions for can­cer drug

Gilead recently decided to pull two indications for its cancer drug Zydelig — in relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic leukemia (SLL) — after failing to complete the confirmatory trials required as part of the accelerated approvals from 2014.

“As the treatment landscape for FL and SLL has evolved, enrollment into the confirmatory study has been an ongoing challenge,” Gilead said in a statement, noting it formally notified the FDA of its decision to voluntarily withdraw these indications.

Executive Director of the EMA Emer Cooke (AP Photo/Geert Vanden Wijngaert)

Eu­ro­pean Par­lia­ment signs off on strength­en­ing drug reg­u­la­tor's abil­i­ty to tack­le short­ages

The European Parliament on Thursday endorsed a plan to increase the powers of the European Medicines Agency, which will be better equipped to monitor and mitigate shortages of drugs and medical devices.

By a vote of 655 to 31, parliament signed off on a provisional agreement reached with the European Council from last October, in which the EMA will create two shortage steering groups (one for drugs, the other for devices), a new European Shortages Monitoring Platform to facilitate data collection and increase transparency, and on funding for the work of the steering groups, task force, working parties and expert panels that are to be established.

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Mer­ck wins le­gal bat­tle over in­sur­ance cov­er­age af­ter ran­somware at­tack

Merck has emerged victorious from a years-long legal battle with insurers over the coverage of more than a billion dollars in losses from the malware NotPetya, with a New Jersey Superior Court judge concluding that the responsibility is on insurers to clarify their policies around cyber attacks.

The pharma giant was one of several victims of a global cyber attack back in 2017 that also hit Danish shipping company Maersk, American food company Mondelēz, French construction giant Saint-Gobain and even the systems monitoring the Chernobyl nuclear power stations, Bloomberg reported back in 2019.

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Crit­ics push back on Alzheimer’s As­so­ci­a­tion ad blitz to get Medicare to change its Aduhelm rul­ing: 'Dead wrong'

The latest Alzheimer’s Association advertising campaign encourages people to fight.

Not against the disease or for more research or treatments, but against the Centers for Medicare and Medicaid Services. More specifically, CMS’ recent reimbursement decision to only pay for Biogen and Eisai’s controversial Alzheimer’s drug Aduhelm for patients in clinical trials.

With CMS’ preliminary decision now in a 30-day comment period, patient advocates’ goal is to convince CMS to reverse its decision with a marketing blitz and public pressure.

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Richard Pazdur (via AACR)

Time lim­its on ac­cel­er­at­ed ap­provals? FDA's on­col­o­gy chief Rick Paz­dur eyes po­ten­tial re­forms via in­ter­na­tion­al ap­proach­es

The spotlight on the accelerated approval pathway continues to shine bright, with the FDA’s top oncology official writing in an opinion that the pathway may be strengthened with bits and pieces of what other regulators in Europe and elsewhere have done with their expedited approval pathways, such as adding expiration dates for these faster approvals to ensure they confirm clinical benefit in a timely manner.

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FDA+ roundup: FDA's neu­ro­science deputy de­parts amid on­go­ing Aduhelm in­ves­ti­ga­tions; Califf on the ropes?

Amid increased scrutiny into the close ties between FDA and Biogen prior to the controversial accelerated approval of Aduhelm, the deputy director of the FDA’s office of neuroscience has called it quits after more than two decades at the agency.

Eric Bastings will now take over as VP of development strategy at Ionis Pharmaceuticals, the company said Wednesday, where he will provide senior clinical and regulatory leadership in support of Ionis’ pipeline.

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Sec­ondary patents prove to be key in biosim­i­lar block­ing strate­gies, re­searchers find

While the US biosimilars industry has generally been a disappointment since its inception, with FDA approving 33 biosimilars since 2015, just a fraction of those have immediately followed their approvals with launches. And more than a handful of biosimilars for two of the biggest blockbusters of all time — AbbVie’s Humira and Amgen’s Enbrel — remain approved by FDA but still have not launched because of legal settlements.