A piv­otal lung can­cer tri­al test­ing Tagris­so, As­traZeneca’s best­selling on­col­o­gy ther­a­py, has been halt­ed due to “over­whelm­ing” ef­fi­ca­cy.

The 682 pa­tient-tri­al, ADAU­RA, was eval­u­at­ing the drug against a place­bo in non-small cell lung can­cer pa­tients with EGFR mu­ta­tions who had un­der­gone tu­mor re­sec­tion and op­tion­al, stan­dard post­op­er­a­tive ad­ju­vant chemother­a­py. In the Tagris­so arm, pa­tients were to be treat­ed with the 80 mg drug once-dai­ly for three years, or un­til the can­cer re­turned — and the da­ta read­out was sched­uled for 2022.

The tri­al, in which the main goal was dis­ease-free sur­vival (DFS), was stopped on the rec­om­men­da­tion of an in­de­pen­dent da­ta mon­i­tor­ing com­mit­tee based on its de­ter­mi­na­tion of “over­whelm­ing ef­fi­ca­cy,” the British drug­mak­er said, adding that the com­pa­ny would con­tin­ue to as­sess the sec­ondary end­point of over­all sur­vival.

José Basel­ga

No new safe­ty con­cerns were re­port­ed, and de­tailed da­ta will be pre­sent­ed at a lat­er date. Plans for reg­u­la­to­ry sub­mis­sions are al­so un­der­way. “Lung can­cer is a dev­as­tat­ing di­ag­no­sis and for the first time an EGFR-tar­get­ed med­i­cine can now pro­vide the hope of a cure,” said José Basel­ga, ex­ec­u­tive VP of On­col­o­gy R&D, in a state­ment.

Tagris­so, known chem­i­cal­ly as os­imer­tinib, gen­er­at­ed sales of more than $3 bil­lion in 2019, is one of As­traZeneca’s flag­ship on­col­o­gy ther­a­pies.

The drug is al­ready ap­proved as the first line of de­fense in pa­tients with metasta­t­ic EGFR mu­ta­tion-pos­i­tive NSCLC.

Lung can­cer is the lead­ing cause of can­cer death glob­al­ly, ac­cord­ing to the WHO. The two main types of lung can­cer are non-small cell and small cell, and NSCLC ac­counts for about 85% of all cas­es. Mu­ta­tions in the EGFR gene oc­cur in 10% to 35% of pa­tients with NSCLC — and the use of EGFR ty­ro­sine ki­nase in­hibitors (TKIs) has trans­formed the ar­se­nal of tools used to fight the dead­ly dis­ease.

De­spite ini­tial ben­e­fit with first-gen­er­a­tion EGFR TKIs, such as er­lotinib (Roche’s Tarce­va) and gefi­tinib (As­traZeneca’s own Ires­sa), most pa­tients de­vel­op drug re­sis­tance with­in one year. The use of sec­ond-gen­er­a­tion TKIs such as afa­tinib (Boehringer In­gel­heim’s Gilotrif) and da­comi­tinib (Pfiz­er’s Viz­im­pro) showed promis­ing pre­clin­i­cal ac­tiv­i­ty, dose-lim­it­ing tox­i­c­i­ty pre­clud­ed their use in NSCLC pa­tients.

Tagris­so is a third-gen­er­a­tion EGFR TKI. This Tagris­so tri­al is the first to demon­strate the ben­e­fit of tar­get­ed EGFR in­hi­bi­tion in the ad­ju­vant NSCLC set­ting and the drug will like­ly gain ap­proval in this in­di­ca­tion by 2021 with no com­peti­tors in sight, wrote Cowen an­a­lyst Steve Scala in a note.

The ad­di­tion of re­sect­ed stage (IB-II­IA) NSCLC pa­tients to the Tagris­so la­bel could in­crease the glob­al ad­dress­able pop­u­la­tion by over 60,000 pa­tients (in­clud­ing Chi­na; cur­rent­ly >250,000 in the metasta­t­ic set­ting), and du­ra­tion of treat­ment may ex­ceed that in ad­vanced pa­tients (me­di­an 20.7 months in the FLAU­RA tri­al). Ad­vanced NSCLC typ­i­cal­ly presents in the metasta­t­ic set­ting, so the can­ni­bal­iza­tion of ex­ist­ing sales is not ex­pect­ed, he said.

“The pos­i­tive DFS was ob­served about 2 years ahead of the 2022 es­ti­mat­ed pri­ma­ry com­ple­tion date, in­di­cat­ing ro­bust ef­fi­ca­cy that in­creas­es the like­li­hood of ul­ti­mate­ly achiev­ing OS…ADAU­RA was pow­ered to de­tect DFS HR of 0.78, but like­ly sur­passed this val­ue. This news al­so rais­es the prospect of an ear­ly read­out for Phase III LAU­RA in EGFRm un­re­sectable Stage III NSCLC (cur­rent­ly due in 2022), rep­re­sent­ing ~70,000 ad­di­tion­al pa­tients.”

To­geth­er with LAU­RA, ADAU­RA ap­proval is crit­i­cal for Tagris­so to sur­pass As­traZeneca’s ini­tial peak sales pro­jec­tions of $4 bil­lion to $5 bil­lion, he added, es­ti­mat­ing the drug is poised to eclipse $8 bil­lion in peak sales in 2025.

Con­sid­ered one of the most com­mer­cial­ly re­ward­ing con­di­tions to treat, As­traZeneca had pinned its hopes on the com­bi­na­tion of its check­point in­hibitor Imfinzi with its in-house CT­LA-4 drug treme­li­mum­ab in the keen­ly watched MYS­TIC tri­al in 2018, but that bet proved cost­ly. Imfinzi is now in de­vel­op­ment as a monother­a­py, as well as a treme­li­mum­ab and/or chemother­a­py com­bi­na­tion, in var­i­ous tri­als for lung can­cer pa­tients with­out a known ge­net­ic mu­ta­tion.

In late 2018, As­traZeneca ex­e­cut­ed a num­ber of deals prun­ing its port­fo­lio and rein­vig­o­rat­ing its fo­cus on new flag­ship prod­ucts, no­tably can­cer drugs such as Lyn­parza, Imfinzi, Tagris­so, and Calquence. By 2019, CEO Pas­cal So­ri­ot al­so re­vamped the com­pa­ny’s struc­ture — dis­solv­ing the com­pa­ny’s Med­Im­mune sub­sidiary, en­shrin­ing the on­col­o­gy fran­chise un­der one roof, and shift­ing the rest of the pipeline un­der a sep­a­rate di­vi­sion.

Buoyed by the per­for­mance of its on­col­o­gy drugs, last year As­traZeneca bet big to part­ner with Dai­ichi Sankyo on a can­cer drug, with $1.35 bil­lion up­front in a deal worth up to rough­ly $7 bil­lion. Rough­ly 8 months lat­er, as 2019 drew to a close, the FDA swift­ly ap­proved the drug — trastuzum­ab derux­te­can — for use in breast can­cer, months ahead of the ex­pect­ed de­ci­sion date.

Following a promise last year to go “big and fast in breast cancer,” Gilead has secured a win for Trodelvy in the most common form.

The drug was approved to treat HR-positive, HER2-negative breast cancer patients who’ve already received endocrine-based therapy and at least two other systemic therapies for metastatic cancer, Gilead announced on Friday.

Trodelvy won its first indication in metastatic triple-negative breast cancer back in 2020, and has since added urothelial cancer to the list. HR-positive HER2-negative breast cancer accounts for roughly 70% of new breast cancer cases worldwide per year, according to senior VP of oncology clinical development Bill Grossman, and many patients develop resistance to endocrine-based therapies or worsen on chemotherapy.