One of the amazing things about the immune checkpoint blockade revolution in oncology is the extent to which it has concealed a parallel explosion, namely the growth in targeted small-molecule kinase inhibitors.
Deciphera floated in September 2017 precisely on this promise. Since then its fortunes have waxed and waned, but now the company has a chance to prove itself, as the phase III Invictus study of its lead asset, the Kit-PDGFRα kinase inhibitor ripretinib, is set to read out mid-year; a positive hit could result in regulatory filing, Deciphera reckons.
The extent of some analysts’ bullishness is reflected in ripretinib’s consensus 2024 estimated sales forecast, which according to EvaluatePharma amounts to $700m. Deciphera itself is sufficiently confident of success to have already started building commercial infrastructure to support launch.
|NPV as % of market cap||229%|
|Event||Results of phase III Invictus study|
Still, investors need to remain cautious. Invictus tests ripretinib in all-comer fourth-line gastrointestinal stromal tumour (GIST) patients, which likely amounts to a fairly small population, and there are questions about whether the drug could have use beyond this niche.
Invictus enrolled 129 subjects, and compares ripretinib directly against placebo, with 15-month PFS set as the primary endpoint; remission rate and 15-month overall survival feature among the trial’s secondary measures.
Leerink analysts rate Deciphera “underperform” despite expecting a hit in Invictus. They reckon ripretinib might not be used beyond the 90% of GIST patients with Kit-positive disease, and have negative expectations for the project’s use in PDGFRα-positive GISTs and advanced systemic mastocytosis; the project is also being studied in gliomas and other solid tumours.
In fairness, the baseline in fourth-line GISTs is pretty low. The latest cut of an uncontrolled study of ripretinib in all-comer GIST patients was declared successful having shown overall remission of just 9% in subjects who had failed three or more prior lines of therapy, and a median progression-free survival of 24 weeks. The vast majority of the 111 subjects in this late-line cohort had Kit-driven GISTs, so it is not entirely clear why the response to the Kit-targeted therapy was not higher.
The Blueprint issue
Leerink also says ripretinib is expected to enter the market behind Blueprint’s avapritinib, a rival Kit-PDGFRα inhibitor.
Still, this is no dead cert; avapritinib’s 2020 filing, for advanced systemic mastocytosis, is subject to FDA discussions. And in GISTs, in contrast to Deciphera, Blueprint is employing a biomarker-driven strategy from the outset, focusing on Kit-positive patients.
But the rival companies make for an interesting comparison, both having been created to capitalise on the promise of next-generation kinase inhibition (Vantage point – Life for kinase inhibitors in an immuno-oncology world, January 19, 2017).
Treatment of GISTs was revolutionised by Novartis’s Bcr-Abl tyrosine kinase inhibitor Gleevec, which is approved for first-line GISTs as well as chronic myelogenous leukaemia. Pfizer’s Sutent and Bayer’s Stivarga are second and third-line GIST therapies.
Deciphera has long argued that ripretinib is no ordinary kinase inhibitor, binding to its target kinase’s “switch pocket” and preventing the enzyme from being locked in its “on” state; this could enable it to control all mutant forms of Kit-PDGFRα kinase and reduce the scope for mutation-based escape mechanisms.
A separate Deciphera pivotal trial, Intrigue, testing ripretinib in second-line GISTs, was initiated last December. In the second-line setting a remission rate of around 20% among all-comers is expected.
The low expectations for Invictus reflect the lack of options for fourth-line subjects. All Deciphera has to do with ripentinib now is beat placebo. Convincing the US FDA that a broad label is warranted could be trickier.