Lumakras is the next test of FDA’s hardening stance

The US withdrawal of Takeda’s tyrosine kinase inhibitor Exkivity on Monday was just the latest example of the FDA’s accelerated approval clampdown. 

The news should be another warning to companies that have taken advantage of this fast track, but whose products have later shown to have toxicity or lacklustre efficacy – or both. A look at other recent withdrawals suggests that the FDA is taking a particularly hard stance in uses where other options are available.

The next test case will be Amgen’s Lumakras. The KRAS inhibitor gained accelerated approval in 2021 in second-line G12C-mutated non-small cell lung cancer, and on Thursday an FDA adcom is set to discuss an application for its full approval. 

Despite excitement around KRAS inhibition, things do not look rosy. At last year’s ESMO meeting results from the confirmatory Codebreak-200 trial disappointed, alongside concerns about liver injury. 

And briefing documents released on Tuesday raised questions about whether Codebreak-200 could be considered adequate and well controlled, given “systemic bias” in the trial.

Post-marketing pact

The FDA’s tough stance might seem reasonable: in seeking accelerated approvals, companies make a commitment to confirm promising early findings with a more rigorous trial. 

But, in practice, confirmatory results have sometimes been slow to emerge. One of the most egregious examples comes outside oncology, with Sarepta’s Duchenne muscular dystrophy therapy Exondys 51, which gained accelerated approval in 2016, but whose confirmatory trial didn’t start until 2020.

In the cancer arena, a live issue involves Oncopeptides’ Pepaxto, which the FDA is trying to get pulled after it failed the confirmatory Ocean trial. 

The current situation has been years in the making. The agency only really started cracking down on accelerated approvals in earnest in 2021, when it convened an advisory committee meeting to discuss “dangling” approvals of PD-(L)1 inhibitors.

Several checkpoint blockers were pulled in various indications in the wake of this meeting. Another class to be hit en masse was PI3K inhibitors, with withdrawals for Zydelig, Ukoniq and Copiktra. 

But perhaps Exkivity has more in common with GSK’s Blenrep. Both products failed confirmatory trials, and both were also linked with toxicity: QTc prolongation and torsades de pointes for the Takeda product, and ocular toxicity for the GSK antibody-drug conjugate.

Both were also not the only option in their niche: Exkivity was marketed for NSCLC with EGFR exon 20 insertion mutations, the same use as Johnson & Johnson’s bispecific Rybrevant. And Blenrep targeted BCMA, where there are plenty of alternatives, including Bristol Myers Squibb’s Abecma, and J&J’s Carvykti and Tecvayli.

The competitive landscape might work in Amgen and Lumakras’s favour: there is only one other approved KRAS G12C inhibitor, Mirati’s Krazati, and this also only has an accelerated nod. Data from the Krystal-12, Mirati’s confirmatory second-line NSCLC trial, are due next year.

Notable US oncology drug withdrawals

Source: OncologyPipeline.