NAVIGATOR

NAVIGATOR was the first-in-human phase 1 study of avapritinib, a kinase inhibitor designed to bind the active conformation of KIT and PDGFRA and so to inhibit the D842V mutation that imatinib, sunitinib and regorafenib cannot. It enrolled patients with unresectable gastrointestinal stromal tumour in dose-escalation and expansion cohorts, including a cohort with PDGFRA D842V mutations and cohorts of KIT-mutant disease after prior kinase inhibitors.

In PDGFRA D842V-mutant GIST the response rate was very high and responses lasted for years, a transformation for a group with essentially no prior effective therapy, and avapritinib was approved in the United States in January 2020 for that indication. Activity in later-line KIT-mutant disease was more modest, and the confirmatory VOYAGER trial did not show superiority over regorafenib in that setting. Cognitive side effects and intracranial haemorrhage at higher doses were the notable toxicities.