PDGFRA D842V-mutant GIST is highly resistant to all kinase inhibitors approved in the European Union for U/M GIST. Avapritinib, a novel KIT/PDGFRA kinase inhibitor, potently inhibits PDGFRA D842V mutants.
In the NAVIGATOR study, adult pts with U/M PDGFRA D842V-mutant GIST (regardless of prior therapy) received oral, once-daily avapritinib (dose escalation, 30–600 mg; dose expansion, 300 [recommended phase II dose, RP2D]/400 mg [maximum tolerated dose]). Long-term efficacy and safety in pts with PDGFRA D842V-mutant GIST treated at 300/400 mg from both phases are reported.
As of 9 March 2020 data cut-off (median follow-up, 26 months [mo]), 38 pts with PDGFRA D842V-mutant GIST treated at 300/400 mg achieved an overall response rate (ORR, modified Response Evaluation Criteria in Solid Tumours version 1.1) of 95%, with 5 (13%) complete responses (CR), and 31 (82%) partial responses (PR); of the 5 TKI-naïve pts, 2 had a CR and 3 a PR. Median duration of response was 22 mo (95% confidence interval [CI] 14–not reached [NR]). Median progression-free survival (PFS) was 24 mo (95% CI 18–NR), and median overall survival (OS) was NR; PFS and OS rates at 36 mo were 34% and 71%, respectively. In pts with PDGFRA D842V-mutant GIST who received less than the 300 mg RP2D (n=17), an ORR of 82% was still achieved, with 2 (12%) CR and 12 (71%) PR. Most common adverse events (AEs, any grade) in ≥10% of pts with PDGFRA D842V-mutant GIST treated at 300/400 mg were nausea (74%), anaemia (68%), diarrhoea (66%), fatigue (58%), memory impairment (47%), periorbital oedema (45%), decreased appetite (39%), increased lacrimation (34%), and vomiting, abdominal pain, hypokalaemia, increased blood bilirubin and peripheral oedema (all 32%). A total of 21% of pts discontinued treatment due to drug-related AEs. There were no treatment-related deaths.
In pts with U/M PDGFRA D842V-mutant GIST, avapritinib has clinical activity with durable responses and a tolerable safety profile, with no additional safety signals to those found in the NAVIGATOR study overall GIST population.
NCT02508532.
Medical writing support was provided by Cristina Tomas, and editorial support was provided by Sinead Stewart, all of Paragon, Knutsford, UK, supported by Blueprint Medicines Corporation, Cambridge, MA according to Good Publication Practice guidelines.
Blueprint Medicines Corporation.
Blueprint Medicines Corporation.
R.L. Jones: Research grant/Funding (self): MSD; Honoraria (self): Adaptimmune; Honoraria (self): Athenex; Honoraria (self): Blueprint Medicines Corporation; Honoraria (self): Clinigen; Honoraria (self): Eisai; Honoraria (self): Epizyme; Honoraria (self): Daichii; Honoraria (self): Helsinn; Honoraria (self): Deciphera; Honoraria (self): Immunedesign; Honoraria (self): Lilly; Honoraria (self): Merck; Honoraria (self): Pharmamar; Honoraria (self): Tracon. C. Serrano: Advisory/Consultancy, Research grant/Funding (self): Deciphera Pharmaceuticals; Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: Bayer AG; Research grant/Funding (self), Travel/Accommodation/Expenses: Pfizer, Inc; Honoraria (self), Advisory/Consultancy: Blueprint Medicines Corporation; Travel/Accommodation/Expenses: PharmaMar; Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Lilly. M. von Mehren: Advisory/Consultancy: Blueprint Medicines Corporation; Advisory/Consultancy: Arog Pharmaceuticals. S. George: Advisory/Consultancy, Research grant/Funding (institution): Blueprint Medicines Corporation; Advisory/Consultancy, Research grant/Funding (self): Deciphera Pharmaceuticals; Research grant/Funding (self): Pfizer; Research grant/Funding (self): Bayer; Research grant/Funding (self): Ariad; Research grant/Funding (self): Novartis; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: AstraZeneca. M. Heinrich: Honoraria (self), Research grant/Funding (self): Blueprint Medicines Corporation; Honoraria (self): Molecular MD; Honoraria (self): Novartis; Honoraria (self), Research grant/Funding (self): Deciphera Pharmaceuticals. Y-K. Kang: Honoraria (self): ALX Oncology; Honoraria (self): Zymeworks; Honoraria (self): Amgen; Honoraria (self): Novartis; Honoraria (self): Macrogenics; Honoraria (self): Daehwa; Honoraria (self): Surface Oncology; Honoraria (self): BMS. P. Schoeffski: Honoraria (self), Advisory/Consultancy: Deciphera Pharmaceuticals; Honoraria (self): Exelixis; Advisory/Consultancy: Plexxikon; Advisory/Consultancy: Eisai; Advisory/Consultancy: Loxo; Advisory/Consultancy: Lilly; Advisory/Consultancy: Blueprint Medicines Corporation; Advisory/Consultancy: Ellipses Pharma; Advisory/Consultancy: Merck; Advisory/Consultancy: Servier; Advisory/Consultancy: Genmab; Advisory/Consultancy: Adaptimmune; Advisory/Consultancy: Intellisphere; Advisory/Consultancy: Transgene; Research grant/Funding (self): MSD; Research grant/Funding (self): Ipsen. P. Cassier: Honoraria (self): Blueprint Medicines Corporation; Advisory/Consultancy: Abbvie; Advisory/Consultancy: Bayer; Advisory/Consultancy: BMS; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: MSD; Advisory/Consultancy: Novartis; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: GSK; Advisory/Consultancy: Janssen; Advisory/Consultancy: Lilly; Advisory/Consultancy: Amgen; Advisory/Consultancy, Research grant/Funding (self): Novartis. O. Mir: Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Janssen; Advisory/Consultancy: Lundbeck; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Servier; Advisory/Consultancy: Vifor Pharma; Shareholder/Stockholder/Stock options: Amplitude Surgical; Shareholder/Stockholder/Stock options: Transgene; Shareholder/Stockholder/Stock options: Ipsen. S.P. Chawla: Research grant/Funding (self): Amgen; Research grant/Funding (self): Roche; Research grant/Funding (self): Threshold Pharmaceuticals; Research grant/Funding (self): GSK; Research grant/Funding (self): CytRx Corporation; Research grant/Funding (self): Ignyta; Research grant/Funding (self): Immune Design; Research grant/Funding (self): Tracon Pharma; Research grant/Funding (self): SARC; Research grant/Funding (self): Karyopharm Therapeutics; Research grant/Funding (self): Jansen. P. Rutkowski: Honoraria (self): Novartis; Honoraria (self): BMS; Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self): Blueprint Medicines Corporation. W.D. Tap: Honoraria (self), Advisory/Consultancy: Blueprint Medicines Corporation; Honoraria (self): Eli Lilly; Honoraria (self): EMD Serono; Honoraria (self): Eisai; Honoraria (self): Janssen; Honoraria (self): Immune Design; Honoraria (self): Daiichi Sankyo; Honoraria (self): Loxo; Honoraria (self): GSK; Honoraria (self): Agios Pharmaceuticals; Honoraria (self): NanoCarrier; Honoraria (self): Deciphera Pharmaceuticals; Advisory/Consultancy: Certis Oncology Solutions; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Atropos Therapeutics; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Daiichi Sankyo. T. Zhou: Shareholder/Stockholder/Stock options, Full/Part-time employment: Blueprint Medicines Corporation. M. Roche: Shareholder/Stockholder/Stock options, Full/Part-time employment: Blueprint Medicines Corporation. S. Bauer: Honoraria (self), Research grant/Funding (self): Blueprint Medicines Corporation; Research grant/Funding (self): Incyte; Research grant/Funding (self): Novartis; Honoraria (self): Deciphera Pharmaceuticals; Honoraria (self): Bayer; Honoraria (self): Exelixis; Honoraria (self): Novartis. All other authors have declared no conflicts of interest.