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Kang YK , George S , Jones RL , Rutkowski P , Shen L , Mir O , Patel S , Zhou Y , von Mehren M , Hohenberger P , Villalobos V , Brahmi M , Tap WD , Trent J , Pantaleo MA , Schöffski P , He K , Hew P , Newberry K , Roche M , Heinrich MC , Bauer S
Avapritinib Versus Regorafenib in Locally Advanced Unresectable or Metastatic GI Stromal Tumor: A Randomized, Open-Label Phase III Study
J Clin Oncol. 2021 Aug 3 :Jco2100217
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PURPOSE: Primary or secondary mutations in KIT or platelet-derived growth factor receptor alpha (PDGFRA) underlie tyrosine kinase inhibitor resistance in most GI stromal tumors (GISTs). Avapritinib selectively and potently inhibits KIT- and PDGFRA-mutant kinases. In the phase I NAVIGATOR study (NCT02508532), avapritinib showed clinical activity against PDGFRA D842V-mutant and later-line KIT-mutant GIST. VOYAGER (NCT03465722), a phase III study, evaluated efficacy and safety of avapritinib versus regorafenib as third-line or later treatment in patients with unresectable or metastatic GIST. PATIENTS AND METHODS: VOYAGER 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). Primary end point was progression-free survival (PFS) by central radiology per RECIST version 1.1 modified for GIST. Secondary end points included objective response rate, overall survival, safety, disease control rate, and duration of response. Regorafenib to avapritinib crossover was permitted upon centrally confirmed disease progression. RESULTS: Four hundred seventy-six patients were randomly assigned (avapritinib, n = 240; regorafenib, n = 236). Median PFS was not statistically different between avapritinib and regorafenib (hazard ratio, 1.25; 95% CI, 0.99 to 1.57; 4.2 v 5.6 months; P = .055). Overall survival data were immature at cutoff. Objective response rates were 17.1% and 7.2%, with durations of responses of 7.6 and 9.4 months for avapritinib and regorafenib; disease control rates were 41.7% (95% CI, 35.4 to 48.2) and 46.2% (95% CI, 39.7 to 52.8). Treatment-related adverse events (any grade, grade ≥ 3) were similar for avapritinib (92.5% and 55.2%) and regorafenib (96.2% and 57.7%). CONCLUSION: Primary end point was not met. There was no significant difference in median PFS between avapritinib and regorafenib in patients with molecularly unselected, late-line GIST.
1527-7755 Kang, Yoon-Koo Orcid: 0000-0003-0783-6583 George, Suzanne Orcid: 0000-0002-1284-8493 Jones, Robin L Orcid: 0000-0003-4173-3844 Rutkowski, Piotr Shen, Lin Orcid: 0000-0002-8798-4756 Mir, Olivier Orcid: 0000-0002-6761-4002 Patel, Shreyaskumar Zhou, Yongjian von Mehren, Margaret Orcid: 0000-0001-6158-890x Hohenberger, Peter Villalobos, Victor Orcid: 0000-0002-8722-284x Brahmi, Mehdi Orcid: 0000-0001-9904-166x Tap, William D Orcid: 0000-0001-7779-2796 Trent, Jonathan Orcid: 0000-0001-6169-5238 Pantaleo, Maria A Schöffski, Patrick Orcid: 0000-0001-5980-030x He, Kevin Hew, Paggy Newberry, Kate Roche, Maria Heinrich, Michael C Orcid: 0000-0003-3790-0478 Bauer, Sebastian Orcid: 0000-0001-5949-8120 Journal Article United States J Clin Oncol. 2021 Aug 3:JCO2100217. doi: 10.1200/JCO.21.00217.