Findings from an open-label, randomised, multicentre phase III VOYAGER study indicate that avapritinib is not superior to regorafenib in terms of median progression-free survival (PFS) in third-line or later treatment of patients with molecularly unselected unresectable or metastatic gastrointestinal stromal tumour (GIST). However, avapritinib demonstrated a high overall response rate (ORR) and prolonged duration of response (DoR) in a subgroup of seven patients with PDGFRA D842V–mutated GIST. The safety profile of avapritinib in VOYAGER was consistent with previously reported. The study results are published by Prof. Sebastian Bauer of the Department of Medical Oncology, Sarcoma Centre, West German Cancer Centre, DKTK-Partner-Site, University of Duisburg-Essen in Essen, Germany and colleagues on 3 August 2021 in the Journal of Clinical Oncology.
Approximately 80% of GISTs are driven by activating oncogenic mutations in receptor kinase KIT and 5-10% by mutations in platelet-derived growth factor receptor alpha (PDGFRA). Activation loop mutations are detectable in approximately 44-67% of KIT-mutated GISTs after treatment with imatinib and are increased to approximately 82% after treatment with imatinib and sunitinib. In approximately 5-6% of patients with unresectable or metastatic GIST, primary activation loop mutations in PDGFRA amino acid 842, particularly D842V, confer primary resistance to imatinib and other tyrosine kinase inhibitors (TKIs).
Avapritinib is a potent, selective inhibitor of KIT and PDGFRA tyrosine kinases, with high potency for KIT D816V–mutated and PDGFRA D842V–mutated kinases. In a phase I NAVIGATOR study, avapritinib demonstrated the ORR of 21% as fourth-line or later therapy in patients with advanced molecularly unselected GIST and 88% in patients with advanced PDGFRA D842V–mutated GIST, regardless of previous therapy. Findings from NAVIGATOR formed the basis for US Food and Drug Administration and European Medicines Agency approvals of avapritinib for treatment of adult patients with unresectable or metastatic GIST harbouring a PDGFRA exon 18 mutation, including D842V mutations.
VOYAGER evaluated efficacy and safety of avapritinib versus regorafenib as third-line or later treatment in patients with molecularly unselected unresectable or metastatic GIST, previously treated with imatinib and one or two other TKIs. It is the first randomised study in late-line unresectable or metastatic GIST that uses an active comparator, regorafenib, as a control arm.
The study investigators randomly assigned patients 1:1 to avapritinib 300 mg once daily (4 weeks continuously) or regorafenib 160 mg once daily (3 weeks on and 1 week off). The study primary endpoint was PFS by central radiology per RECIST version 1.1 modified for GIST. Secondary endpoints included ORR, overall survival (OS), safety, disease control rate (DCR), and DoR. Regorafenib to avapritinib crossover was permitted upon centrally confirmed disease progression.
In total, 476 patients were randomly assigned, 240 to avapritinib and 236 to regorafenib arm. Median PFS was not statistically different between two arms, 4.2 months in avapritinib and 5.6 months in regorafenib arm (hazard ratio 1.25; 95% confidence interval [CI] 0.99 to 1.57; p = 0.055).
The OS data were immature at cut-off. The ORRs were 17.1% and 7.2%, with DoRs of 7.6 and 9.4 months for avapritinib and regorafenib; DCRs were 41.7% (95% CI 35.4 to 48.2) and 46.2% (95% CI 39.7 to 52.8), respectively.
Treatment-related adverse events of any grade and grade ≥3 were similar for avapritinib (92.5% and 55.2%) and regorafenib (96.2% and 57.7%).
The authors commented that avapritinib was not superior to regorafenib in their study in terms of median PFS in third-line or later treatment of patients with unresectable or metastatic GIST. Most patients enrolled had KIT-mutated tumours. Consistent with previous experience with avapritinib, response rates and PFS remained high and durable in 3% of patients with PDGFRA D842V–mutated tumours. VOYAGER findings do not suggest any change in later-line treatment paradigms for KIT-mutated GIST. However, avapritinib is the most active available compound for patients with PDGFRA D842V–mutated GIST.
The study was sponsored by Blueprint Medicines Corporation.
Reference
Kang Y-K, George S, Jones RL, et al. Avapritinib Versus Regorafenib in Locally Advanced Unresectable or Metastatic GI Stromal Tumor: A Randomized, Open-Label Phase III Study. JCO; Published online 3 August 2021. DOI: 10.1200/JCO.21.00217