Blueprint eyes quick filing for GIST drug avapritinib

Avapritinib is an oral inhibitor of KIT and PDGFRA kinases, and is being developed for GIST and systemic mastocytosis (SM), two diseases that are linked to mutations in these enzymes.

New data from its phase 1 NAVIGATOR trial showed activity across all lines of therapy for patients with PDGFRα D842V-driven GIST, as well as in second-, third- and fourth-line for other GIST patients.

Blueprint’s chief executive Jeff Albers said on a conference call that the biotech is now hoping to file the drug in the US in the first half of next year for PDGFRA-driven GIST, as well as fourth-line, ‘all-comer’ GIST patients. There are currently no approved drugs for either of these indications.

That timeline would keep Blueprint in contention with Deciphera, which reported phase 1 results with its DCC-2618 candidate at the ESMO meeting last month.

However, the FDA recommended that Deciphera run a controlled phase 3 trial before filing, so it remains to be seen if the data in NAVIGATOR is compelling enough for the regulator to take a more lenient stance.

Albers said the company has started building the commercial operations it will need to start selling the drug, and also intends to accelerate trials of the drug as earlier-line treatment.

At the moment, Novartis’ multikinase inhibitor Glivec (imatinib) or an equivalent generic is the first-line treatment of choice for GIST, with Pfizer’s Sutent (sunitinib) and Bayer’s Stivarga (regorafenib) approved for second- and third-line use.

Michael Heinrich of Oregon Health and Sciences University, a lead NAVIGATOR investigator, ran through the trial results on the call, noting that avapritinib had an overall response rate (ORR) of 84%, made up of 9% complete responses and 75% partial responses in PDGFRA-driven GIST patients, with a 12-month duration of response (DoR) of 76%.

For the heavily pre-treated fourth-line or greater group who weren’t selected for PDGFRA mutations, the ORR was 20%, consisting of 1% complete and 19% partial responses, and a median DoR of 7.3 months. Heinrich said that compared favourably to the only option for these patients at the moment – namely retreatment with kinase inhibitor imatinib.

Blueprint is conducting a phase 3 trial called VOYAGER in third- and fourth-line GIST patients, but that isn’t due to read out until 2021. A phase 3 second-line trial called COMPASS-2L, which will compare avapritinib to Pfizer’s Sutent (sunitinib) – the typical second-line therapy – is now planned for the second half of 2019.

Meanwhile, Deciphera already has a phase 3 registration trial (INVICTUS) in fourth-line patients that should have results next May, and is also planning a head-to-head study (INTRIGUE) against Sutent due to start later this year.

Blueprint estimates there are around 30,000 patients in the US, Europe and Japan with PDGFRA-mutant GIST and SM.

As with all targeted medicines, the big challenge for Blueprint will be to try to encourage much more widespread genotyping to identify PDGFRA-mutant cancers if they are to move their drugs up the treatment pathway. DCC-2618 is a multikinase inhibitor and is not being developed for specific PDGFRA mutants.

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