UP­DAT­ED: Mer­ck, Roche and Bris­tol My­ers nab 4 of 6 pos­i­tive ODAC votes for ‘dan­gling’ ac­cel­er­at­ed ap­provals

What looked at the out­set like a prime op­por­tu­ni­ty for the FDA to cri­tique in­dus­try over failed con­fir­ma­to­ry tri­als for lag­ging ac­cel­er­at­ed ap­provals end­ed up be­ing most­ly a tri­umph for the large bio­phar­ma com­pa­nies.

The FDA’s On­co­log­ic Drugs Ad­vi­so­ry Com­mit­tee vot­ed in fa­vor of keep­ing on the mar­ket four of the six “dan­gling” ac­cel­er­at­ed ap­provals pre­sent­ed to it over the last three days. Even de­spite the failed tri­als, com­pa­nies and their physi­cians raised con­cerns about un­met treat­ment needs and the long du­ra­tion of re­spons­es for the check­point in­hibitors be­fore each of the six votes.

The two ODAC votes that didn’t re­ceive a ma­jor­i­ty of “yes” votes from the out­side ex­perts were Mer­ck’s Keytru­da (pem­brolizum­ab) as a third-line treat­ment for stom­ach can­cer and Bris­tol My­ers Squibb’s Op­di­vo (nivolum­ab) as a sec­ond line treat­ment for liv­er can­cer. In both cas­es, Richard Paz­dur, di­rec­tor of the FDA’s On­col­o­gy Cen­ter of Ex­cel­lence, raised con­cerns with the com­mit­tee, while not­ing the un­in­tend­ed con­se­quences of keep­ing Keytru­da on the mar­ket and ques­tion­ing BMS da­ta (see more be­low).

Leerink se­nior re­search an­a­lyst Daina Gray­bosch said in an in­vestor note on Fri­day, “We be­lieve mar­ket im­pact from the two in­di­ca­tions rec­om­mend­ed for with­draw­al are in­con­se­quen­tial, with a small and shrink­ing num­ber of pa­tients el­i­gi­ble” for Keytru­da as a third-line treat­ment for gas­tric can­cer (~1,000), and as there’s an op­por­tu­ni­ty for Bris­tol My­ers to shift pa­tients from Op­di­vo to the com­bi­na­tion of Op­di­vo and Yer­voy (ip­il­i­mum­ab), which al­so won ac­cel­er­at­ed ap­proval last year as a sec­ond-line treat­ment in he­pa­to­cel­lu­lar car­ci­no­ma (HCC).

Gray­bosch called the FDA “ob­jec­tive, but al­so force­ful in a cou­ple ar­gu­ments with spon­sors” dur­ing the three days, in line with re­cent ob­ser­va­tions from the agency. He al­so not­ed that Paz­dur made a “pow­er­ful case for with­draw­al in two cas­es, which seemed to sway the ODAC vote.”

Over­all, how­ev­er, the main take­away from the last three days seemed to be that if you’re a bio­phar­ma com­pa­ny that has won an ac­cel­er­at­ed ap­proval and your con­fir­ma­to­ry tri­al has failed, it may be un­wise to vol­un­tar­i­ly with­draw that ap­proval. Tak­ing the de­ci­sion to ODAC may end up with a thumbs up to re­main on the mar­ket while fu­ture tri­als are be­ing con­duct­ed.

Some out­side on­col­o­gists raised se­ri­ous con­cerns about main­tain­ing the in­tegri­ty of the ac­cel­er­at­ed ap­proval path­way if com­pa­nies and the FDA don’t get rid of cer­tain drug in­di­ca­tions that have failed in con­fir­ma­to­ry tri­als.

“If the drugs re­main on the mar­ket, the very na­ture of ac­cel­er­at­ed ap­proval should fall in­to ques­tion,” Vinay Prasad, on­col­o­gist at UCSF, told End­points. “Per­haps we can­not re­al­is­ti­cal­ly give con­di­tion­al ap­proval be­cause no one will ever have the courage to pull the drugs.”

Keytru­da in stom­ach can­cer

On Thurs­day morn­ing, ODAC vot­ed 6-2 against keep­ing Keytru­da as a third-line treat­ment for stom­ach can­cer. Pan­elists vot­ing no point­ed to the chang­ing treat­ment land­scape as ear­li­er this month an­oth­er check­point in­hibitor, Bris­tol My­ers Squibb’s Op­di­vo (nivolum­ab), won full ap­proval from the FDA and showed pos­i­tive over­all sur­vival ben­e­fit as a first line treat­ment for stom­ach can­cer.

The ac­cel­er­at­ed ap­proval first came in Sep­tem­ber 2017, but the FDA not­ed in its pre­sen­ta­tion Thurs­day that two fol­low-up tri­als did not con­firm the ben­e­fit that was ini­tial­ly seen.

Poo­ja Bha­gia, VP of on­col­o­gy re­search at Mer­ck, coun­tered that these two stud­ies were eval­u­at­ing Keytru­da as first- and sec­ond-line treat­ments for stom­ach can­cer. She al­so ex­plained how four on­go­ing Phase 3 tri­als (three of which are ei­ther ful­ly en­rolled or greater than 90% en­rolled) have the po­ten­tial to con­firm clin­i­cal ben­e­fit of Keytru­da in stom­ach can­cer be­fore the end of 2024.

Pe­ter En­zinger of the Dana Far­ber Can­cer In­sti­tute and a paid con­sul­tant to Mer­ck and oth­er physi­cians raised con­cerns about the lack of treat­ment op­tions in the third line, es­pe­cial­ly since Keytru­da is the on­ly im­munother­a­py avail­able.

But Paz­dur, FDA’s head of on­col­o­gy, shift­ed the tone of the morn­ing meet­ing and of­fered the agency’s per­spec­tive, stress­ing the un­in­tend­ed con­se­quences of keep­ing Keytru­da in this in­di­ca­tion as physi­cians might see check­point in­hibitors as op­tions in the first or third line, even though pos­i­tive over­all sur­vival re­sults have on­ly been seen in the first line with Op­di­vo.

And as more re­ceive check­point in­hibitors in the first line set­ting, few­er will re­ceive it in the third line set­ting, Steven Lemery, act­ing di­rec­tor of FDA’s Di­vi­sion of On­col­o­gy 3, added. He al­so not­ed im­mune-re­lat­ed ad­verse events with Keytru­da, how most pa­tients do not ben­e­fit from Keytru­da in this in­di­ca­tion, and he ques­tioned the rel­e­vance of the four pro­posed con­fir­ma­to­ry tri­als for this third-line in­di­ca­tion as they all are study­ing Keytru­da in com­bo with chemo.

“Many of these po­ten­tial con­fir­ma­to­ry tri­als won’t be avail­able for years. Would we grant this in­di­ca­tion at this time? The de­fin­i­tive an­swer is no,” Paz­dur said.

He al­so stressed that even if Keytru­da is pulled for this in­di­ca­tion, pa­tients who might be caught in lim­bo be­tween treat­ments may still be able to ac­cess Keytru­da be­cause the FDA can set up an ex­pand­ed ac­cess pro­to­col.

Keytru­da in HCC

The sit­u­a­tion turned against the FDA again in the af­ter­noon, al­though the agency isn’t oblig­ed to fol­low the ad­vice of its ad­vi­so­ry com­mit­tees.

In the first ses­sion, ODAC vot­ed unan­i­mous­ly, 8-0, to main­tain Keytru­da’s ac­cel­er­at­ed ap­proval for pa­tients with he­pa­to­cel­lu­lar car­ci­no­ma (HCC), a com­mon type of liv­er can­cer, as a sec­ond line treat­ment.

Mer­ck first won that ac­cel­er­at­ed ap­proval in No­vem­ber 2018, and the com­pa­ny made the case for why Keytru­da should re­main on the mar­ket as, even with the new ap­proval in the first line set­ting for the com­bi­na­tion of ate­zolizum­ab and be­va­cizum­ab, and the two new sec­ond-line ac­cel­er­at­ed ap­provals in this in­di­ca­tion, there’s a need for an­ti-PD-1 monother­a­py in the sec­ond line set­ting.

The FDA ar­gued that the treat­ment land­scape changed af­ter the ate­zolizum­ab-be­va­cizum­ab com­bo was ap­proved in the first-line set­ting.

Richard Finn, a pro­fes­sor of med­i­cine at UCLA and paid con­sul­tant for Mer­ck, said there does not seem to be any ben­e­fit to pulling this ac­cel­er­at­ed ap­proval for Keytru­da while two oth­er con­fir­ma­to­ry re­sults are ex­pect­ed soon. One of those re­sults from a tri­al in Asia is ex­pect­ed to read out in June or Ju­ly, and is in the same set­ting as the ac­cel­er­at­ed ap­proval.

FDA’s Steve Lemery not­ed that if this larg­er study in Asia is neg­a­tive, it’s un­clear if an­oth­er tri­al could be use­ful as a con­fir­ma­to­ry study as there would then be two neg­a­tive con­fir­ma­to­ry tri­als against place­bo. He al­so not­ed that while some pa­tients did see long du­ra­tion of re­sponse, most pa­tients do not ben­e­fit from the treat­ment. And he raised ques­tions, giv­en the chang­ing treat­ment land­scape, if Keytru­da would win ac­cel­er­at­ed ap­proval in this sec­ond line set­ting to­day.

Op­di­vo in HCC

In the late af­ter­noon ses­sion, ODAC vot­ed 5 to 4 to not main­tain Bris­tol My­ers Squibb’s Op­di­vo’s (nivolum­ab) in­di­ca­tion for the monother­a­py use of nivolum­ab in pa­tients pre­vi­ous­ly treat­ed with so­rafenib pend­ing the con­duct or com­ple­tion of ad­di­tion­al tri­al(s).

Pan­elist An­tho­ny Sung, as­sis­tant pro­fes­sor of med­i­cine at Duke Uni­ver­si­ty School of Med­i­cine, vot­ed “no” and said he didn’t think the da­ta was there on the whole. Su­san Ha­l­abi, a pro­fes­sor of bio­sta­tis­tics at Duke, al­so vot­ed no and said that al­though there’s an un­met need, she wasn’t con­vinced there was a clin­i­cal ben­e­fit.

Back in Sep­tem­ber 2017, Bris­tol My­ers Squibb’s Op­di­vo (nivolum­ab) won ac­cel­er­at­ed ap­proval as a sec­ond-line treat­ment for HCC. Two years lat­er, a con­fir­ma­to­ry study did not meet sta­tis­ti­cal sig­nif­i­cance in its pri­ma­ry end­point of over­all sur­vival and oth­er treat­ments for this in­di­ca­tion made their way to the mar­ket.

As seen with Keytru­da in the pri­or ses­sion, the al­tered treat­ment land­scape was a ques­tion for Op­di­vo, part­ly be­cause the drug al­so won an­oth­er, sep­a­rate ac­cel­er­at­ed ap­proval in com­bi­na­tion with Yer­voy (ip­il­i­mum­ab) last March for the same set­ting — pa­tients with HCC who have been pre­vi­ous­ly treat­ed with so­rafenib.

Bris­tol My­ers dis­cussed the sig­nif­i­cant un­met need in the sec­ond line treat­ment space for HCC and some long re­sponse rates with Op­di­vo.

An­tho­ny El-Khoueiry, as­so­ciate pro­fes­sor of med­i­cine at the Uni­ver­si­ty of South­ern Cal­i­for­nia, said Op­di­vo of­fers a more fa­vor­able ben­e­fit-risk pro­file than sec­ond-line an­ti-VEGF tar­get­ed op­tions.

Lemery pre­sent­ed again for FDA, ex­plain­ing the failed con­fir­ma­to­ry tri­al and not­ing that the agency found the com­bo of Op­di­vo and Yer­voy to be “high­ly rel­e­vant” giv­en the con­sid­er­ably low­er re­sponse rate for monother­a­py.

But Thomas Abrams, an as­so­ci­at­ed pro­fes­sor at Har­vard Med­ical School and paid Mer­ck con­sul­tant, said the com­bo treat­ment is re­al­ly re­served for the fit­ter pa­tients who failed a TKI (ty­ro­sine ki­nase in­hibitor) in the first line. For monother­a­py with Op­di­vo, Abrams said the pa­tients have more co­mor­bidi­ties, and “they re­al­ly are two dif­fer­ent pa­tient pop­u­la­tions.”

FDA’s Paz­dur again weighed in, claim­ing that BMS is es­sen­tial­ly try­ing to make the case for Op­di­vo as a monother­a­py for those who can­not tol­er­ate the Op­di­vo and Yer­voy com­bi­na­tion. But when Paz­dur pressed BMS on da­ta around the re­sponse rate for this pop­u­la­tion, BMS said it didn’t have the da­ta.

“You’re ad­vo­cat­ing for a new in­di­ca­tion, please pro­vide the re­sponse rate – not anec­do­tal in­for­ma­tion,” Paz­dur said.

Leerink’s Gray­bosch said ODAC’s vote to with­draw nivolum­ab from this in­di­ca­tion “seemed some­what un­fair as ODAC vot­ed unan­i­mous­ly ear­li­er to keep ac­cel­er­at­ed ap­proval for pem­brolizum­ab in the same in­di­ca­tion. Three dif­fer­ences, how­ev­er, were that Mer­ck did share ORR [over­all re­sponse rate] da­ta for pem­brolizum­ab in pa­tients who would be con­sid­ered in­el­i­gi­ble for be­va­cizum­ab, placed more em­pha­sis on com­pa­ra­ble ef­fi­ca­cy in 2L to TKIs, and has an on­go­ing, ran­dom­ized tri­al that could con­firm monother­a­py ef­fi­ca­cy.”

Last two days

Thurs­day’s meet­ing fol­lowed three oth­er votes on Tues­day and Wednes­day to main­tain Keytru­da and Tecen­triq ac­cel­er­at­ed ap­provals in oth­er in­di­ca­tions.

On Wednes­day morn­ing, ODAC vot­ed 5-3 in fa­vor of keep­ing Keytru­da’s ac­cel­er­at­ed ap­proval alive as a first line blad­der can­cer treat­ment for those who are cis­platin-in­el­i­gi­ble and car­bo­platin-in­el­i­gi­ble, even af­ter a Mer­ck con­fir­ma­to­ry tri­al failed.

And on Wednes­day af­ter­noon, ODAC vot­ed 10-1 in fa­vor of keep­ing Genen­tech’s Tecen­triq (ate­zolizum­ab) as a first-line treat­ment of cis­platin-in­el­i­gi­ble pa­tients with ad­vanced/metasta­t­ic blad­der can­cer pend­ing fi­nal over­all sur­vival re­sults from a con­fir­ma­to­ry tri­al, known as IMvig­or130.

Com­mit­tee mem­bers on Tues­day al­so vot­ed 7-2 to main­tain the ac­cel­er­at­ed ap­proval for Tecen­triq plus Abrax­ane (nab-pa­cli­tax­el) in metasta­t­ic triple neg­a­tive breast can­cer while ad­di­tion­al con­fir­ma­to­ry tri­als are on­go­ing.

These votes add to four oth­er vol­un­tary ac­cel­er­at­ed ap­proval with­drawals for Op­di­vo and Keytru­da as third-line treat­ments in small cell lung can­cer, and Tecen­triq and As­traZeneca’s Imfinzi (dur­val­um­ab) as sec­ond-line treat­ments for blad­der can­cer.

Look­ing for­ward

The FDA is not ob­lig­at­ed to fol­low the ad­vice of ODAC, but the agency will be faced with some dif­fi­cult de­ci­sions, par­tic­u­lar­ly on the prece­dent that might be set if some com­pa­nies are al­lowed to con­duct or wait for an ad­di­tion­al con­fir­ma­to­ry tri­al to read out be­fore their ac­cel­er­at­ed ap­proval in­di­ca­tions are pulled or con­vert­ed to a full ap­proval.

Al­though none of the drugs will be pulled en­tire­ly from the mar­ket, mean­ing all can be used off-la­bel for these in­di­ca­tions no mat­ter what hap­pens, this three-day meet­ing may push the FDA, and pos­si­bly even Con­gress, to re­assess the ac­cel­er­at­ed ap­proval path­way over­all and what should oc­cur when a con­fir­ma­to­ry tri­al fails.

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