Bris­tol-My­ers with­draws Op­di­vo/Yer­voy lung can­cer EU ap­pli­ca­tion — but oth­ers are in­com­ing

Ear­ly in 2019, Bris­tol-My­ers Squibb re­scind­ed an FDA ap­pli­ca­tion to mar­ket its check­point in­hibitor Op­di­vo in com­bi­na­tion with its CT­LA-4 ther­a­py Yer­voy for front­line use in pa­tients with the most com­mon form of lung can­cer. One year lat­er — the com­pa­ny is tak­ing the same step with the Eu­ro­pean reg­u­la­tor.

De­spite a head start, when Bris­tol-My­ers’ 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. The drug­mak­er has since suf­fered a se­ries of blows in its quest to take a big slice of the lu­cra­tive mar­ket, pep­pered with some suc­cess­es.

This Op­di­vo/Yer­voy com­bo was meant to claw back some of that lost ground. Orig­i­nal­ly filed in 2018, the EU ap­pli­ca­tion was de­signed to al­low the use of the Op­di­vo/Yer­voy as a first-line reg­i­men in pa­tients with non-small cell lung can­cer (NSCLC) with high tu­mor mu­ta­tion­al bur­den (TMB) on the ba­sis of the Check­Mate-227 study.

In one arm of the tri­al, which com­pared the com­bo to chemother­a­py, 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, post­ed 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.

Since the OS da­ta came lat­er, the EU ap­pli­ca­tion was amend­ed ac­cord­ing­ly. A full as­sess­ment of the ap­pli­ca­tion by the EU reg­u­la­tor was not pos­si­ble fol­low­ing mul­ti­ple pro­to­col changes the com­pa­ny made, Bris­tol-My­ers’ said, cit­ing its re­sponse from the EU agency.

The com­pa­ny — which with­drew a sim­i­lar US ap­pli­ca­tion in Jan­u­ary 2019 af­ter it was un­able to con­vince the FDA of the con­nec­tion be­tween TMB and PD-L1 — has no plans to re­file this ap­pli­ca­tion in the EU, it said on Fri­day.

In­stead, Bris­tol-My­ers has tak­en a slight­ly dif­fer­ent ap­proach. Last month, the FDA grant­ed the com­pa­ny’s ap­pli­ca­tion for the Op­di­vo/Yer­voy com­bo for the first-line treat­ment of pa­tients with metasta­t­ic or re­cur­rent NSCLC with no EGFR or ALK ge­nom­ic tu­mor aber­ra­tions pri­or­i­ty re­view, on the ba­sis of the same Check­Mate-227 study.

In ad­di­tion, Bris­tol-My­ers plans to file ap­pli­ca­tions across the At­lantic fol­low­ing the re­sults of a Phase III open-la­bel study — Check­Mate -9LA — which eval­u­at­ed the im­pact of Op­di­vo/Yer­voy ad­min­is­tered con­comi­tant­ly with a lim­it­ed course of chemother­a­py for the first-line treat­ment of NSCLC.

Lung can­cer is the most lu­cra­tive on­col­o­gy mar­ket — and as such, check­point in­hibitors of all hues have been scram­bling to gain ground in the field. For now, Mer­ck’s Keytru­da re­mains way in front. Ac­cord­ing to 2024 pro­jec­tions com­piled by Cowen an­a­lysts, Op­di­vo is ex­pect­ed to gen­er­ate a meaty $12.4 bil­lion that year, while king Keytru­da is ex­pect­ed to reap a hefty $20.6 bil­lion.

Bris­tol-My­ers hunt for adop­tion in the small­er small cell lung can­cer (SCLC) mar­ket has al­so been punc­tu­at­ed with fail­ure. 2018 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 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 SCLC 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, whose can­cer has pro­gressed af­ter plat­inum-based chemother­a­py and at least one oth­er line of ther­a­py.

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2021 saw a record $600B in healthcare M&A activity. In 2022, there is an anticipated slowdown in activity, however, M&A prospects remain strong in the medium to long-term. What are future growth drivers for the healthcare sector? Where might we see innovations that drive M&A? RBC’s Andrew Callaway, Global Head, Healthcare Investment Banking discusses with Vito Sperduto, Global Co-Head, M&A.

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