Avapritinib in Patients With Advanced Gastrointestinal Stromal Tumors Following at Least 3 Prior Lines of Therapy


Background

Most gastrointestinal stromal tumors (GIST) driven by KIT or platelet‐derived growth factor receptor A (PDGFRA) mutations develop resistance to available tyrosine kinase inhibitor (TKI) treatments. NAVIGATOR is a two‐part, single arm, dose escalation/expansion study designed to evaluate safety and antineoplastic activity of avapritinib, a selective, potent inhibitor of KIT and PDGFRA, in patients with unresectable or metastatic GIST.

Patients and Methods

Eligible patients were ≥18 years with histologically/cytologically confirmed unresectable GIST and Eastern Cooperative Oncology Group performance status ≤2, and initiated avapritinib at 300 mg or 400 mg once daily. Primary endpoints were safety in patients who initiated avapritinib at 300 mg or 400 mg once daily and overall response rate (ORR) in patients in the safety population with ≥3 previous lines of TKI therapy.

Results

As of November 16, 2018, in the safety population (N = 204), most common adverse events (AEs) were nausea (131 [64%]), fatigue (113 [55%]), anemia (102 [50%]), cognitive effects (84 [41%]), and periorbital edema (83 [41%]); 17 (8%) patients discontinued due to treatment‐related AEs, most frequently confusion, encephalopathy, and fatigue. ORR in response‐evaluable patients with GIST harboring KIT or non‐D842V PDGFRA mutations and with ≥3 prior therapies (n = 103) was 17% (95% CI 10–25). Median duration of response was 10.2 months (95% CI 7.2–10.2), and median progression‐free survival was 3.7 months (95% CI 2.8–4.6).

Conclusion

Avapritinib has manageable toxicity with meaningful clinical activity as fourth‐line or later treatment in some patients with GIST with KIT or PDGFRA mutations.

Implications for practice

In the NAVIGATOR trial, avapritinib, an inhibitor of KIT and platelet‐derived growth factor receptor A (PDGFRA) tyrosine kinases, provided durable responses in a proportion of patients with advanced gastrointestinal stromal tumors (GIST) who had received ≥3 prior therapies. Avapritinib had a tolerable safety profile, with cognitive adverse events manageable with dose interruptions and modification in most cases. These findings indicate that avapritinib can elicit durable treatment responses in some patients with heavily pre‐treated GIST, for whom limited treatment options exist.



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