Bris­tol-My­ers makes Op­di­vo pitch for front­line lung can­cer with open la­bel PhI­II study

De­spite a head start, when Bris­tol-My­ers Squibb and its pi­o­neer­ing check­point in­hibitor Op­di­vo suf­fered a key lung can­cer set­back in 2016, they found them­selves rel­e­gat­ed to the back­seat as Mer­ck’s Keytru­da seized the wheel on the road to im­munother­a­py star­dom. Bris­tol-My­ers has since suf­fered blow af­ter blow in its quest to take a big slice of the lu­cra­tive mar­ket, pep­pered with some small suc­cess­es. On Tues­day, the New Jer­sey drug­mak­er tout­ed pos­i­tive da­ta from a Phase III open-la­bel study in a bid to carve it­self a piece of the front­line lung can­cer mar­ket.

The study, dubbed Check­Mate -9LA, test­ed Bris­tol-My­ers’ Op­di­vo in com­bi­na­tion with its CT­LA-4 Yer­voy in ad­di­tion to chemother­a­py (two cy­cles) ver­sus chemother­a­py alone (up to four cy­cles fol­lowed by op­tion­al peme­trexed main­te­nance ther­a­py if el­i­gi­ble) as a first-line treat­ment in pa­tients with ad­vanced non-small cell lung can­cer (NSCLC) re­gard­less of PD-L1 ex­pres­sion.

The PD-L1 drug met the main tri­al goal of su­pe­ri­or over­all sur­vival at a pre­spec­i­fied in­ter­im analy­sis, the com­pa­ny said, adding that de­tailed da­ta will be pre­sent­ed at a fu­ture med­ical con­fer­ence. The com­pa­ny’s shares $BMY rose more than 5% to $55.94 in Tues­day pre­mar­ket trad­ing.

Sec­ondary end­points in­clud­ed pro­gres­sion-free sur­vival, over­all re­sponse rate, and ef­fi­ca­cy mea­sures ac­cord­ing to bio­mark­ers.

In Jan­u­ary, the com­pa­ny re­scind­ed its ap­pli­ca­tion to mar­ket the Op­di­vo/Yer­voy com­bo in front­line NSCLC cas­es with high tu­mor mu­ta­tion­al bur­den (TMB), af­ter dis­cus­sions with the agency sug­gest­ed they need­ed more da­ta to re­in­force the con­nec­tion be­tween TMB and PD-L1.

The ap­pli­ca­tion was based on the Check­Mate-227 study, in which re­searchers said they had ob­served a “high­ly” sig­nif­i­cant pro­gres­sion-free sur­vival rate in pa­tients with high TMB, re­gard­less of PD-L1 ex­pres­sion. The high TMB group ac­counts for 45% of all front­line pa­tients, the com­pa­ny es­ti­mat­ed at the time. Bris­tol-My­ers had re­designed the study to fo­cus on TMB af­ter stum­bling on a piv­otal tri­al that in­volved a broad­er pa­tient pop­u­la­tion.

Over­all sur­vival da­ta, pre­sent­ed months lat­er, showed that the haz­ard ra­tio in pa­tients get­ting the Op­di­vo/Yer­voy com­bo was com­pa­ra­ble whether they were high or low TMB pa­tients. How­ev­er, the me­di­an over­all sur­vival in pa­tients with high TMB was 23.03 months on the Op­di­vo/Yer­voy arm, ver­sus 16.72 months in the chemother­a­py group. In the low TMB group, the me­di­an OS was 16.20 months and was 12.42 months on the com­bi­na­tion and chemother­a­py arms, re­spec­tive­ly.

The re­sults of Check­Mate-227 sug­gest­ed that Yer­voy has ac­tiv­i­ty in lung can­cer when com­bined with Op­di­vo — but the da­ta sug­gest that pa­tients have to wait for some pe­ri­od of time for the ben­e­fit to man­i­fest, Wolfe Re­search’s Tim An­der­son wrote in a note.

“Chemother­a­py, when giv­en to lung can­cer pa­tients, of­ten shows a fast ini­tial re­sponse, but one that lacks dura­bil­i­ty.  But by com­bin­ing chemother­a­py+Op­di­vo+Yer­voy, BMY may have (fi­nal­ly) found a cock­tail of drugs that de­liv­ers both near- and longer-term ben­e­fit, lead­ing to an ear­ly re­sponse and im­proved long-term sur­vival.”

How­ev­er, An­der­son was cau­tious about the cock­tail’s safe­ty pro­file in Check­Mate -9LA.

“Op­di­vo+Yer­voy by it­self shows tox­i­c­i­ty and adding chemother­a­py in­to the mix will on­ly in­crease this,” he said.  “The com­mer­cial val­ue of CM-9LA will, there­fore, de­pend on the bal­ance be­tween the clin­i­cal ben­e­fit and the tox­i­c­i­ty.  It will on­ly be once full re­sults are pre­sent­ed that this risk:ben­e­fit as­sess­ment will be pos­si­ble.  Ad­di­tion­al­ly, adding a third drug in­to the mix al­so rais­es the cost of ther­a­py some­what.”

Mean­while, the com­pa­ny’s hunt for adop­tion in small cell lung can­cer (SCLC) mar­ket has al­so been punc­tu­at­ed with fail­ure.

Last year saw an Op­di­vo/Yer­voy com­bo miss the pri­ma­ry end­point for over­all sur­vival in the Check­Mate-451 study, where the Bris­tol-My­ers drugs were be­ing eval­u­at­ed as a main­te­nance ther­a­py for SCLC, fol­low­ing an ini­tial round of chemother­a­py. The re­sults came just over a month af­ter the drug­mak­er un­veiled an Op­di­vo flop in the Check­Mate-331 study, which test­ed the im­munother­a­py against the sec­ond-line small cell lung can­cer stan­dard-of-care.

Still, over the years, Op­di­vo has seen some lung can­cer suc­cess — in­clud­ing the ap­proval of the drug in squa­mous NSCLC pa­tients whose can­cer has pro­gressed de­spite plat­inum-based chemother­a­py as well as pa­tients with metasta­t­ic SCLC pa­tients, whose can­cer has pro­gressed af­ter plat­inum-based chemother­a­py and at least one oth­er line of ther­a­py.

The re­sults of Check­Mate -9LA could have an im­pact on As­traZeneca, which is run­ning the PO­SEI­DON tri­al, An­der­son added.

The tri­al is struc­tural­ly sim­i­lar to CM-9LA but with one key dif­fer­ence — in­stead of on­ly giv­ing a short course of chemother­a­py in ad­di­tion to its own check­point in­hibitor Imfinzi  and CT­LA-4 treme­li­mum­ab, it gives chemother­a­py con­tin­u­ous­ly, he said.

“This may or may not be a good thing – it can be pre­dict­ed that more chemother­a­py like­ly yields more tox­i­c­i­ty, but will it yield more ben­e­fit?  Fur­ther­more, AZN’s an­ti-CT­LA4 ther­a­py (treme­li­mum­ab) has yet to show it works in any tu­mor type (by con­trast, BMY’s Yer­voy is al­ready ap­proved in dif­fer­ent set­tings) po­ten­tial­ly re­flec­tive of the fact that it has slight­ly dif­fer­ent prop­er­ties ver­sus Yer­voy.”

Op­di­vo, which is al­so ap­proved for use in a host of oth­er can­cers, gen­er­at­ed about $3.6 bil­lion in the first half of this year. By 2025, Op­di­vo is set to be the fourth best-sell­ing drug in the world with an­nu­al sales fore­cast­ed to hit $12 bil­lion. King Keytru­da, how­ev­er, is ex­pect­ed to take top spot and rake in more than $22 bil­lion, ac­cord­ing to Glob­al­Da­ta cal­cu­la­tions.

Vas Narasimhan (Photographer: Jason Alden/Bloomberg via Getty Images)

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