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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., Competing Interests: Yoon-Koo KangConsulting or Advisory Role: DAEHWA Pharmaceutical, Bristol Myers Squibb, Zymeworks, ALX Oncology, Amgen, Novartis, Macrogenics, Surface Oncology, Blueprint Medicines Suzanne GeorgeStock and Other Ownership Interests: Abbott LaboratoriesConsulting or Advisory Role: Blueprint Medicines, Deciphera, Bayer, Lilly, UpToDate, Research to Practice, MORE Health, Daiichi, KayotheraResearch Funding: Blueprint Medicines, Deciphera, Daiichi Sankyo RD Novare, Merck, Eisai, SpringWorks TherapeuticsPatents, Royalties, Other Intellectual Property: UptoDateExpert Testimony: BayerOther Relationship: Research to Practice, WCG Robin L. JonesConsulting or Advisory Role: Lilly, Immune Design, Merck Serono, Adaptimmune, Daiichi Sankyo, Eisai, Morphotek, TRACON Pharma, Immodulon Therapeutics, Deciphera, PharmaMar, Blueprint Medicines, Clinigen Group, Epizyme, Boehringer Ingelheim, Bayer, Karma Oncology, UpToDateResearch Funding: GlaxoSmithKlineTravel, Accommodations, Expenses: PharmaMar Piotr RutkowskiHonoraria: Bristol Myers Squibb, MSD, Novartis, Roche, Lilly, Pfizer, Pierre Fabre, Sanofi, MerckConsulting or Advisory Role: Novartis, Blueprint Medicines, Bristol Myers Squibb, Pierre Fabre, MSD, AmgenSpeakers' Bureau: Pfizer, Novartis, LillyResearch Funding: Novartis, Roche, Bristol Myers SquibbTravel, Accommodations, Expenses: Orphan Europe, Pierre Fabre Olivier MirStock and Other Ownership Interests: Transgene, Amplitude Surgical, IpsenHonoraria: RocheConsulting or Advisory Role: Lilly, Pfizer, Roche, Lundbeck, JanssenSpeakers' Bureau: Lilly, Roche, PfizerResearch Funding: Ipsen, AstraZeneca, Blueprint MedicinesTravel, Accommodations, Expenses: Roche, Pfizer Shreyaskumar PatelConsulting or Advisory Role: Novartis, Immune Design, MaxiVax, Epizyme, Janssen, Lilly, Daiichi Sankyo, Bayer, Dova Pharmaceuticals, DecipheraResearch Funding: Blueprint Medicines, Hutchinson Med Pharma Margaret von MehrenConsulting or Advisory Role: Deciphera, ExelixisResearch Funding: ArQule, Novartis, Blueprint Medicines, Deciphera, Gradalis, Springworks Therapeutics, Lilly, Arog, Genmab, ASCOTravel, Accommodations, Expenses: Deciphera Pharmaceuticals, NCCNOther Relationship: NCCN Peter HohenbergerHonoraria: Roche, AstraZeneca, GlaxoSmithKline, BLUMedicine, NovartisConsulting or Advisory Role: Nanobiotix, PfizerResearch Funding: Novartis, Siemens Healthcare DiagnosticsTravel, Accommodations, Expenses: PharmaMar Victor VillalobosEmployment: Janssen OncologyConsulting or Advisory Role: Janssen, Lilly, Novartis, AbbVie, Ignyta, Agios, Epizyme, Blueprint Medicines, Springworks Therapeutics, NanoCarrier, Daiichi SankyoTravel, Accommodations, Expenses: Lilly, Janssen, Xencor, GenMab, Epizyme Mehdi BrahmiExpert Testimony: BayerTravel, Accommodations, Expenses: PharmaMar, Mundipharma William D. TapLeadership: Certis Oncology Solutions, Atropos, Innova TherapeuticsStock and Other Ownership Interests: Certis Oncology Solutions, AtroposConsulting or Advisory Role: EMD Serono, Lilly, Daiichi Sankyo, Blueprint Medicines, Agios, NanoCarrier, Deciphera, C4 Therapeutics, Mundipharma, Adcendo, Ayala Pharmaceuticals, Kowa Pharmaceutical, Servier, AbMaxBioResearch Funding: Novartis, Lilly, Plexxikon, Daiichi Sankyo, TRACON Pharma, Blueprint Medicines, Immune Design, BioAtla, DecipheraPatents, Royalties, Other Intellectual Property: Companion Diagnostic for CDK4 inhibitors—14/854,329, Enigma and CDH18 as companion Diagnostics for CDK4 inhibition—SKI2016-021-03 Jonathan TrentConsulting or Advisory Role: Novartis, Lilly, Janssen, Blueprint Medicines, Deciphera, Daiichi Sankyo, Epizyme, Agios, C4 Therapeutics, Bayer Patrick SchöffskiHonoraria: Deciphera, Blueprint Medicines, Boehringer IngelheimConsulting or Advisory Role: Blueprint Medicines, Ellipses Pharma, Adaptimmune, Intellisphere, Transgene, Deciphera, Exelixis, Boehringer Ingelheim, Medscape, Guided Clarity, Ysios Capital, Studiecentrum voor KernenergieResearch Funding: CoBioRes NV, Eisai, G1 Therapeutics, Novartis, PharmaMarTravel, Accommodations, Expenses: MSD, Ipsen, Boehringer Ingelheim Kevin HeEmployment: Blueprint Medicines, AgiosStock and Other Ownership Interests: Blueprint Medicines, Agios, Incyte Paggy HewEmployment: Blueprint MedicinesStock and Other Ownership Interests: Blueprint MedicinesTravel, Accommodations, Expenses: Blueprint Medicines Kate NewberryEmployment: Blueprint MedicinesStock and Other Ownership Interests: Blueprint Medicines Maria RocheEmployment: Blueprint Medicines, EpizymeStock and Other Ownership Interests: Blueprint Medicines, Epizyme Michael C. HeinrichStock and Other Ownership Interests: MolecularMDHonoraria: NovartisConsulting or Advisory Role: MolecularMD, Novartis, Blueprint Medicines, Deciphera, Theseus PharmaceuticalsPatents, Royalties, Other Intellectual Property: Patent on treatment of GIST-licensed to NovartisExpert Testimony: Novartis Sebastian BauerHonoraria: Novartis, Pfizer, Bayer, Pharmamar, GlaxoSmithKlineConsulting or Advisory Role: Blueprint Medicines, Bayer, Lilly, Deciphera, Nanobiotix, Daiichi Sankyo, Exelixis, Janssen-Cilag, ADC Therapeutics, Mundipharma, GlaxoSmithKlineResearch Funding: Blueprint Medicines, Novartis, IncyteTravel, Accommodations, Expenses: PharmamarNo other potential conflicts of interest were reported.