Deciphera’s early ripretinib filing last month has proved not to be enough to ward off a challenge from Blueprint Medicines. The latter’s similarly super-targeted small-molecule cancer drug avapritinib yesterday scored US approval, over a month before its Valentine’s Day action date.
Both are chasing a relatively rare cancer type, gastrointestinal stromal tumours (GISTs), but are going about this in different ways. While Blueprint is starting with a very precise biomarker-driven strategy, carving out a tiny niche, Deciphera is initially pursuing a fourth-line, all-comers label.
Given how small avapritinib’s initial patient population must be, how precisely targeted Blueprint’s approach is, and how overwhelming the supporting data were, it is perhaps not surprising that the FDA acted with such alacrity. The drug, branded Ayvakit, is now approved for treating GISTs driven by the PDGFRα exon 18 mutation, including D842V mutations.
Avapritinib and ripretinib are inhibitors of mutated Kit and PDGFRα kinases, both of which often play a role in GISTs. Some 80% of front-line disease is thought to be driven by Kit, for instance, while PDGFRα involvement accounts for 2-14%, of which the most common is the exon 18 D842V substitution.
The first-line standard treatment for GISTs is Novartis’s Bcr-Abl tyrosine kinase inhibitor Gleevec, while Pfizer’s Sutent and Bayer/Amgen’s Stivarga can be used second and third line respectively.
Now patients can be given avapritinib as early as first line, as long as they carry the relevant PDGFRα mutation. Blueprint’s supporting trial, Navigator, showed an 84% overall remission rate in GIST subjects with the exon 18 mutation, and 89% for those specifically with the D842V type.
While pricing will be key, the initial market seems vanishingly small. At Gleevec’s peak, for instance, GISTs made up only $450m or so of an annual revenue figure of some $4.5bn, and Blueprint will initially have only a small, genetically defined slice of the GIST market.
|Avapritinib vs ripretinib in gastrointestinal stromal tumours (GISTs)|
|4th-line GIST*||2nd-line GIST||PDGFRα exon 18/D842V mut GIST|
|Avapritinib (Ayvakit), Blueprint|
|Status||Phase III||Study start delayed||Approved|
|Data||Vs Stivarga, topline data Q2 2020||vs Sutent||ORR 84-49%|
|Status||Filed Dec 2019||Phase III||–|
|Data||PFS 6.3m vs 1.0m for placebo||vs Sutent, ends 2021||–|
|Source: company filings; *strictly, Voyager enrolled subjects at 4th line or greater, while Invictus is a 3rd and 4th-line study.|
But Blueprint and Deciphera have clear expansion plans. In the former’s case, the Voyager study, head to head against Stivarga, will support avapritinib in fourth-line GISTs, while Compass-2L will in future investigate the drug against Sutent in the second-line setting.
For its part Deciphera has filed ripretinib for fourth-line GISTs on the back of the Invictus trial, and has an expected mid-2020 PDUFA date, while a second-line study, Intrigue, pits the project versus Sutent.
Mastocytosis, a disease 90-95% driven by active mutant Kit (typically D816V), is an important second indication for both projects, but here avapritinib disappointed, with a fatal bleed taking the shine off data presented at Ash.
Sellside consensus compiled by EvaluatePharma sees GISTs contributing $627m to ripretinib’s 2024 revenues, versus a figure of $392m for avapritinib. However, Leerink analysts yesterday upgraded Blueprint, arguing that avapritinib could be priced at $22,400 per patient per month, and generate peak global revenues of $1.2bn in Kit-mutant GISTs and $59m in PDGFRα-mutated disease.
A final scientific curiosity is that the rival tyrosine kinase inhibitors work slightly differently. Avapritinib is a typical inhibitor of mutant Kit & PDGFRα kinase, albeit optimised for D816V and other loop mutants; ripretinib is meant to bind to the kinase’s “switch pocket”, preventing it from being locked in its “on” state, and reducing the scope for mutation-based escape mechanisms.
How much of a difference this makes has yet to play out. For now Blueprint has an early lead.
This story has been updated to correct the expected PDUFA date for ripretinib.