115MO - Long-term efficacy, tolerability and overall survival in patients (pts) with unresectable or metastatic (U/M) PDGFRA D842V-mutant gastrointestinal stromal tumour (GIST) treated with avapritinib: NAVIGATOR phase I trial update

Background

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.

Methods

In the NAVIGATOR study (NCT02508532), 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.

Results

As of March 9, 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 Tumors 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 achieved, with 2 (12%) CR and 12 (71%) PR. The most common adverse events (AEs, any grade) in ≥10% of pts with PDGFRA D842V-mutant GIST treated at 300/400 mg were nausea (74%), anemia (68%), diarrhea (66%), fatigue (58%), memory impairment (47%), periorbital edema (45%), decreased appetite (39%), increased lacrimation (34%), and vomiting, abdominal pain, hypokalemia, increased blood bilirubin and peripheral edema (all 32%). A total of 21% of pts discontinued treatment due to drug-related AEs. There were no treatment-related deaths.

Conclusions

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.

Clinical trial identification

NCT02508532.

Editorial acknowledgement

Medical writing support was provided by Cristina Tomas, PhD, and editorial support by Sinead Stewart, both of Paragon, Knutsford, UK, supported by Blueprint Medicines Corporation.

Legal entity responsible for the study

Blueprint Medicines Corporation.

Funding

Blueprint Medicines Corporation.

Disclosure

Y-K. Kang: Honoraria (self): ALX Oncology; Zymeworks; Amgen; Novartis; Macrogenics; Daehwa; Surface Oncology; BMS. R.L. Jones: Research grant/Funding (self): MSD; Honoraria (self): Adaptimmune; Athenex; Blueprint Medicines Corporation; Clinigen; Clinigen, Eisai; Epizyme; Daichii; Deciphera; Helsinn; Immunedesign; Lilly; Merck; PharmaMar; Tracon; UptoDate. M. von Mehren: Non-remunerated activity/ies: Blueprint Medicines Corporation; Non-remunerated activity/ies: Arog Pharmaceuticals; Non-remunerated activity/ies: Deciphera Pharmaceuticals. 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. S. George: Advisory/Consultancy, Research grant/Funding (self): Blueprint Medicines Corporation; 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. M.C. Heinrich: Research grant/Funding (self): Blueprint Medicines Corporation; Honoraria (self): MolecularMD; Honoraria (self): Novartis; Honoraria (self): Deciphera Pharmaceuticals. P. Schöffski: Honoraria (self): Deciphera Pharmaceuticals; Non-remunerated activity/ies: Exelixis; Non-remunerated activity/ies: Plexxikon; Non-remunerated activity/ies: Eisai; Non-remunerated activity/ies: Loxo; Non-remunerated activity/ies: Lilly; Non-remunerated activity/ies: Blueprint Medicines Corporation; Non-remunerated activity/ies: Ellipses Pharma; Non-remunerated activity/ies: Merck; Non-remunerated activity/ies: Servier; Non-remunerated activity/ies: Genmab; Non-remunerated activity/ies: Adaptimmune; Non-remunerated activity/ies: Intellisphere; Non-remunerated activity/ies: Transgene; Research grant/Funding (self): MSD; Research grant/Funding (self): Ipsen. 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. P.A. Cassier: Honoraria (self): Blueprint Medicines Corporation; Non-remunerated activity/ies: AbbVie; Non-remunerated activity/ies: Bayer; Non-remunerated activity/ies: BMS; Non-remunerated activity/ies: Merck; Non-remunerated activity/ies: Serono; Non-remunerated activity/ies: MSD; Non-remunerated activity/ies: Novartis; Non-remunerated activity/ies: Roche/Genentech; Non-remunerated activity/ies: GSK; Non-remunerated activity/ies: Janssen; Non-remunerated activity/ies: Lilly. P. Rutkowski: Honoraria (self): Blueprint Medicines Corporation; Honoraria (self): Novartis; Honoraria (self): BMS; Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer. W.D. Tap: Honoraria (self): 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. 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): Janssen. H. Shi: Full/Part-time employment: Blueprint Medicines Corporation. M. Roche: Honoraria (self): Epizyme; Shareholder/Stockholder/Stock options, Full/Part-time employment: Blueprint Medicines Corporation. S. Bauer: Research grant/Funding (self): Incyte; Research grant/Funding (self): Novartis; Honoraria (self), Research grant/Funding (self): Blueprint Medicines Corporation; Honoraria (self): Deciphera Pharmaceuticals; Honoraria (self): Bayer; Honoraria (self): Exelixis; Honoraria (self): Novartis; Honoraria (self): PharmaMar; Honoraria (self): ADC Therapeutics; Honoraria (self): Nanobiotix; Honoraria (self): Lilly; Honoraria (self): Daiichi-Sankyo; Honoraria (self): Plexxiko; Honoraria (self): Exelixis; Honoraria (self): Janssen. All other authors have declared no conflicts of interest.