Avapritinib Active Against Unresectable PDGFRA D842V-Mutant GIST

Avapritinib had a manageable safety profile and demonstrated activity in patients with PDGFRA D842V-mutant gastrointestinal stromal tumor (GIST), according to results from the phase 1 NAVIGATOR clinical trial (Lancet Oncol. 2020 Jul. Epub ahead of print).

“Targeting of KIT and PDGFRA with imatinib revolutionised treatment in [GIST]; however, PDGFRA [D842V]-mutated GIST is highly resistant to tyrosine kinase inhibitors,” wrote Michael Heinrich, MD, VA Portland Health Care System and Oregon Health & Science University Knight Cancer Institute, and co-investigators on what led to the NAVIGATOR study.

The researchers aimed to assess the safety, tolerability, and anti-tumor activity of avapritinib, a novel KIT and PDGFRA inhibitor that potently inhibits PDGFRA D842V, in patients with advanced GIST, including those with KIT and PDGFRA D842V-mutant GIST.

In this 2-part, open-label, dose-escalation study which took place between October 2015 and November 2018, a total of 46 patients with unresectable GIST were enrolled in the dose-escalation part, 20 of whom had PDGFRA D842V-mutations. An additional 36 patients with PDGFRA D842V-mutations were enrolled in the dose-expansion portion.

Oral avapritinib was administered once daily, starting at 30 mg and with increasing dosages until the maximum tolerated dose was reached or recommended phase 2 dose was determined.

The primary end points were the maximum tolerated dose, recommended phase 2 dose, and safety in the dose-escalation part of the study. The overall response and safety were the primary end points in the dose-expansion part.

The maximum tolerated dose was determined to be 400 mg while the recommended phase 2 dose was 300 mg.

Anemia was the most common treatment-related grade 3-4 adverse event in the safety population.

In the PDFGRA D842V-mutant population (n = 56), there was an 88% overall response rate (n = 49). Of  the 49 patients who responded to treatment, 5 had complete responses and 44 had partial responses.

“Avapritinib has a manageable safety profile and has preliminary antitumour activity in patients with advanced PDGFRA D842V-mutant GIST,” Dr Heinrich et al concluded.—Kaitlyn Manasterski