Early Data Supports Avapritinib for Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GIST) are sarcomas that can occur anywhere in the gastrointestinal tract and are most often driven by activating mutations in the genes encoding the receptor tyrosine kinases KIT or PDGFRA. Although the type II (inactive state–binding) tyrosine kinase inhibitor (TKI) imatinib is effective for many GISTs, there is no currently approved drug that shows appreciable activity in the 5 to 6 percent of GISTs that harbor PDGFRA^D842V mutations, which bias the kinase toward existing in the active state. Heinrich, Jones, von Mehren, and colleagues conducted a phase I clinical trial of the KIT- and PDGFRA-targeting type II (active state–binding) TKI avapritinib in patients with unresectable GISTs. Forty-six patients who had KIT- or PDGFRA-mutant tumors were enrolled in the dose-escalation part of the study, and 36 patients who specifically had PDGFRA^D842V-mutant tumors were enrolled in the dose-expansion part of the study. Encouraging results were attained in patients who had PDGFRA^D842V-mutant tumors (including 20 patients from the dose-escalation part and all 36 patients from the dose-expansion part), among whom 9% had complete responses, 79% had partial responses, 13% had stable disease, and 0% had progressive disease as their best response. After a median follow-up period of 15.9 months, median progression-free survival and median overall survival could not be determined because more than half of patients remained progression-free and surviving. However, available data indicated that the overall survival rates were 100% at 6 months, 91% at 12 months, and 81% at 24 months. With regard to safety and tolerability, as assessed in all 82 patients, most experienced at least one treatment-emergent adverse event, most commonly nausea. There were no treatment-related deaths, but two categories of adverse events—cognitive effects such as memory impairment and intracranial bleeding—were deemed to be of special interest. In summary, this trial demonstrates that avapritinib has a manageable safety profile and shows promising early signs of efficacy in patients with PDGFRA^D842V-mutant GISTs, who currently have no approved treatment options available.

Heinrich MC, Jones RL, von Mehren M, Schöffski P, Serrano C, Kang, YK, et al. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol 2020;21:935–46.

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