EXPLORER: safety and efficacy of avapritinib in advanced systemic mastocytosis (phase 1)
The first study of avapritinib, a drug designed to hit the KIT D816V mutation that drives most mastocytosis, produced responses in three quarters of patients with advanced disease and set the dose for later trials.
Overview
Phase 1 dose-escalation and expansion study of 86 patients with advanced systemic mastocytosis treated with avapritinib, a selective inhibitor of KIT D816V.
The overall response rate in response-evaluable patients was 75 percent with deep and durable responses, falls in serum tryptase and KIT D816V allele burden, and a recommended dose of 200 mg daily; cognitive effects and intracranial bleeding (mainly with severe thrombocytopenia) were the notable toxicities. The results, with PATHFINDER, led to approval of avapritinib for advanced systemic mastocytosis in 2021.
- Overall response 75 percent in evaluable patients; complete remissions with full or partial haematological recovery in a substantial minority.
- Intracranial haemorrhage occurred mainly in patients with platelet counts below 50,000 per microlitre, prompting a platelet threshold for treatment.
Avapritinib is the most active drug in advanced systemic mastocytosis; platelet counts must be checked before and during treatment.
- Phase 1 without a comparator; response criteria changed between cohorts.
- Cognitive adverse effects are common and dose-related.
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