Bris­tol-My­ers Squibb has had a hard time win­ning an­a­lysts over to its strat­e­gy for carv­ing out a high­er mar­ket share for its check­point com­bo in non-small cell lung can­cer. And now you can add the FDA to the list of skep­tics re­quir­ing more da­ta to con­vince them.

In their Q4 re­lease Thurs­day morn­ing Bris­tol-My­ers Squibb says it is yank­ing its BLA for Op­di­vo com­bined with Yer­voy for front­line NSCLC cas­es with high tu­mor mu­ta­tion­al bur­den — or TMB — af­ter talks with the agency con­vinced them they need­ed more da­ta to high­light the con­nec­tion be­tween TMB and PD-L1.

Their state­ment:

This analy­sis will re­quire avail­abil­i­ty of the fi­nal da­ta from Check­mate -227, Part 1a (Op­di­vo plus low-dose Yer­voy or Op­di­vo monother­a­py ver­sus chemother­a­py in pa­tients whose tu­mors ex­press PD-L1), which the com­pa­ny an­tic­i­pates will be avail­able in the first-half of 2019. Since these da­ta from Check­mate -227, Part 1a, will not be avail­able with­in the re­view cy­cle of the cur­rent ap­pli­ca­tion the com­pa­ny de­cid­ed to with­draw.

Bris­tol-My­ers’ stock took a 2.4% hit in trad­ing ahead of the open­ing bell.

Long­time ob­servers have been puz­zling out the whole TMB ap­proach, which As­traZeneca has al­so been turn­ing to in the wake of its own PD-L1/CT­LA-4 set­backs with Imfinzi and treme­li­mum­ab. Bris­tol-My­ers re­designed its crit­i­cal late-stage tri­al to shift to TMB, and it has not played out in their fa­vor — so far.

Af­ter Mer­ck seized the lead in lung can­cer with its su­pe­ri­or Keytru­da/chemo com­bo, Bris­tol-My­ers’ team led by R&D chief Tom Lynch has been strug­gling to make a come­back. Typ­i­cal­ly, the FDA has been wide open — at least in re­cent years — to ac­cel­er­at­ed ap­provals for can­cer drugs. In this case, Bris­tol-My­ers found that the bar has been raised as physi­cians em­ploy a grow­ing num­ber of PD-1/L1s in their prac­tice.

Cred­it Su­isse’s bio­phar­ma team took at look at the news and con­clud­ed that, on bal­ance, Bris­tol-My­ers’ move rais­es fresh con­cerns.

We did not think an ap­proval for that fil­ing would have made much of a near-term com­mer­cial im­pact any­way, but it does raise new ques­tions on the com­pa­ny’s over­all strat­e­gy and ap­proach in 1L NSCLC.

In an up­date last Oc­to­ber, re­searchers for Bris­tol-My­ers not­ed that the haz­ard ra­tio for their com­bo was roughy iden­ti­cal for high and low TMB groups get­ting the com­bo, but the over­all sur­vival rate was 23 months for high TMB pa­tients at 16.7 months in a chemo arm with high TMB. There was al­so a dif­fer­ence of a few months for the low TMB group.

The set­back comes just weeks af­ter Bris­tol-My­ers an­nounced its plan to ac­quire Cel­gene for $74 bil­lion. And to­day there was a big fo­cus on the top late-stage drugs they will gain from Cel­gene: Ozan­i­mod, with a Q1 re­fil­ing plan; the CAR-T Liso-cel (JCAR017 from the Juno buy­out), with an H2 2019 fil­ing plan; and the an­ti-BC­MA CAR-T bb2121 part­nered with blue­bird, fil­ing in H1 2020. All that has to counter ques­tions re­volv­ing around the IP for Revlim­id.

The lat­est prob­lem with the Op­di­vo fran­chise over­shad­owed the com­pa­ny’s Q4 and 2018 fi­nan­cial re­port, which high­light­ed a 10% hike in sales. Op­di­vo it­self earned $6.7 bil­lion last year, up from just un­der $5 bil­lion in 2017. The rest of the ap­proved slate pf PD-1/L1s has been strug­gling to get in­to the same league with Mer­ck and Bris­tol-My­ers Squibb.

Im­age: Thomas Lynch at BIO 2018. ROB TAN­NEN­BAUM for END­POINTS NEWS

The EMA released updated recommendations today for the use of JAK inhibitors (JAKi) after reviewing data from several clinical trials that showed increased incidents of issues in certain patients who have rheumatoid arthritis and other risk factors.

The EMA noted malignancy, major adverse cardiovascular events (MACE), serious infections, venous thromboembolism (VTE) and mortality in some patients.