VOYAGER

Background

Phase III VOYAGER, randomized open-label, N=476 (avapritinib n=240, regorafenib n=236), unresectable/metastatic GIST after ≥2 prior TKIs (imatinib + ≥1 other). 78 sites, 19 countries, 2018–2019. Avapritinib (BLU-285): selective KIT/PDGFRA inhibitor vs approved multi-kinase comparator regorafenib in ≥3rd-line GIST. NCT03465722.

Interventions and follow up

Arm A: Avapritinib 300 mg PO once daily continuously
Arm B: Regorafenib 160 mg PO once daily, 3 wk on / 1 wk off (28-day cycles); both until progression or intolerance
Primary endpoint: PFS by central radiologic review per modified RECIST 1.1
mFollow up: ~12 mo

Results

mPFS (primary): 4.2 mo (avapritinib) vs 5.6 mo (regorafenib); HR 1.25, 95% CI 0.99–1.57, P=.055 — not met
ORR: 17.1% vs 7.2%
PDGFRA D842V subgroup: avapritinib superior (mPFS not reached vs 4.5 mo)

Adverse events

Avapritinib: cognitive effects (intracranial bleeding, memory impairment, confusional state) ~12%; periorbital edema 63%; nausea 58%; anemia 52%
Regorafenib: hand-foot skin reaction 57%; fatigue 46%; hypertension 38%; diarrhea 43%
Discontinuation: 15% vs 15%

Conclusions

Avapritinib did not meet superior PFS vs regorafenib in molecularly unselected ≥3rd-line GIST (HR 1.25, P=.055); mPFS shorter despite higher ORR. Benefit concentrated in PDGFRA D842V-mutant GIST; regorafenib preferred for KIT-mutant GIST in 3rd line.

Key Limitations

Molecularly unselected population diluted any signal; primary endpoint negative; cross-arm comparison confounded by enriched D842V activity in approved indication.

Clinical Context

Avapritinib FDA/EMA-approved only for PDGFRA D842V-mutant GIST. Regorafenib remains standard 3rd-line per ESMO; ripretinib 4th-line. VOYAGER did not expand avapritinib's role beyond D842V.

References