Avapritinib/NAVIGATOR trial

Background

NAVIGATOR, phase I open-label dose-escalation/expansion trial. 43 patients with advanced GIST harboring PDGFRA exon 18 mutations, including 38 with the PDGFRA D842V mutation that confers intrinsic resistance to imatinib and other approved TKIs. Avapritinib is a selective KIT/PDGFRA inhibitor designed to target this mutation.

Interventions and follow up

Treatment: avapritinib 300-400mg PO daily until progression or unacceptable toxicity
Primary endpoint: Overall response rate (ORR) by central radiology review
mFollow up: 27.5mo (long-term analysis)

Results

ORR (PDGFRA exon 18): 84% (CR 7%, PR 77%)
PDGFRA D842V subgroup ORR: 90% (CR 8%, PR 82%)
mDOR: not reached; ~70% of responders in ongoing response at 12mo

Adverse events

Hematologic: anemia (grade 3-4 ~26%)
Neurocognitive: cognitive effects (memory impairment, confusion) and rare intracranial bleeding were dose-limiting and require monitoring
Constitutional / other: fatigue, nausea, periorbital and peripheral edema common

Conclusions

Avapritinib produced deep, durable responses in advanced GIST with PDGFRA exon 18 (including D842V) mutations, a population without effective standard TKI therapy.

Key Limitations

Single-arm phase I with no comparator and small numbers; ORR/DOR endpoints without randomized PFS or OS; neurocognitive toxicity and intracranial bleeding are clinically important and dose-related; benefit is confined to PDGFRA exon 18 tumors. In unselected, heavily pretreated GIST (VOYAGER), avapritinib did not outperform regorafenib.

Clinical Context

FDA approved avapritinib (2020) for unresectable/metastatic PDGFRA exon 18-mutant GIST, including D842V; EMA approval is restricted to D842V. ESMO and ASCO recommend avapritinib as preferred therapy for PDGFRA D842V-mutant GIST, which is otherwise refractory to imatinib. It is not indicated for KIT-mutant GIST in routine practice.

References