The end of Exkivity is another win for Rybrevant

The FDA has been getting tough on accelerated approvals that fail to get the backing of confirmatory trials, and last night it was Takeda’s turn to feel the pain. The group’s Exkivity got an accelerated US nod in 2021 for second-line NSCLC harbouring EGFR exon 20 insertions, but Takeda says its confirmatory Exclaim-02 trial, a phase 3 front-line study, failed to show a PFS benefit against platinum chemo, and was stopped for futility three months ago. Accordingly the group is moving to pull approvals worldwide. For doctors and patients this will be no huge loss – Exkivity had a notoriously toxic side-effect profile, carrying a warning of QTc prolongation and torsades de pointes – and it had largely been eclipsed by Johnson & Johnson’s EGFR x cMet bispecific MAb Rybrevant, whose position will thus be consolidated. Clinical discontinuations of NSCLC projects targeting the exon 20 insertion niche include Spectrum’s poziotinib and Rain Oncology’s tarloxotinib, though just last month Dizal’s sunvozertinib, a tyrosine kinase inhibitor claiming to have broad EGFR coverage, secured its first approval, in China. Selected projects targeting NSCLC exon 20 insertion (in EGFR unless stated)ProjectCompanyStatusRybrevant^J&JApproved in US & elsewhereSuvozheDizal PharmaceuticalsApproved in ChinaIvesaAllist PharmaceuticalsPh3*ZipalertinibOtsuka (bought back from Cullinan)Ph3 first-line settingYK-029ASuzhou PuhePh3 first-line settingPyrotinibJiangsu HengruiPh3 in HER2 exon 20 insertionsJMT101^^Shanghai JMT-BioPh2 Tagrisso comboPLB1004AvistonePh2FWD1509Shenzhen Forward PharmaceuticalPh1/2BLU-451Blueprint (ex Lengo)Ph1/2JS111Shanghai JunshiPh1/2STX-721Scorpion TherapeuticsPh1/2ORIC-114Oric PharmaceuticalsPh1 in various EGFR mutations**BAY2927088BayerPh1 in various EGFR mutations**TY-4028Tyk MedicinePreclinical (first trial cleared Jul 2023)ABSK112Abbisko/AllistPreclinicalExkivityTakeda/AriadWithdrawn in Oct 2023 after 2021 launchTarloxotinibRain OncologyDeprioritisedPoziotinibSpectrumDiscontinued after EGFR exon 20 failure and HER2 exon 20 CRLBDTX-189Black Diamond TherapeuticsDiscontinued in favour of BDTX-1535Notes: ^EGFR x cMET bispecific; ^^MAb (all others are TKIs); *approved in China for T790M NSCLC; **includes HER2 exon 20 insertion. Source: OncologyPipeline.