Avapritinib (ava) is a potent and selective inhibitor of activated KIT and PDGFRA, which has shown broad activity against GIST in pts in the Phase 1 NAVIGATOR study (NCT02508532), particularly in those with PDGFRα D842 mutations. We investigated whether baseline ctDNA levels and changes in ctDNA during treatment were associated with response.
Plasma ctDNA was sequenced at baseline and 2 mos after the start of treatment. Pts (n = 20) in dose-escalation were profiled using the Sysmex OncoBEAM™ PDGFRA assay; Pts (n = 12) in dose-expansion were sequenced with a custom Personal Genome Diagnostics PlasmaSELECT™ 60 panel.
As of 11 Jan 2018, response rate was 73% and stable disease rate was 23% per mRECIST v1.1 (modified for GIST). Median progression free survival (PFS) was not reached; estimated 12 mo PFS rate was 78%. Baseline ctDNA mutation allele fraction (MAF) correlated with target lesion size (p < 0.002). Lower than median baseline ctDNA MAF identified a group of pts with 100% PFS after a median follow up time of 16 mo (1.8 to 26.6 mo). Ava led to detectable ctDNA declines (median 5.2 fold) in all pts except those near the quantification limit (which changed minimally). Despite this, larger declines, or falling below the limit of quantification (BLQ), did not correlate with greater shrinkage or longer PFS. Instead, declines were barely quantifiable in pts with low baseline ctDNA approaching limit of detection, while larger declines were driven by high baseline MAF. Therefore, pts with the smallest declines in ctDNA had low baseline ctDNA and were least likely to progress.
Large ctDNA declines have been speculated to be a predictor of treatment response. We show in PDGFRα D842 mutant GIST low baseline ctDNA correlates with prolonged PFS yet ctDNA minimally declines due to detection limits. Surprisingly, large fold declines, even falling below the limit of detection, was not predictive of improved outcomes. Our data suggest that although highly effective targeted therapy achieves rapid declines in ctDNA, baseline ctDNA levels may be more prognostic and that declines in ctDNA levels, even to BLQ, may be falsely reassuring in this population.
Clinical trial identification
Legal entity responsible for the study
Blueprint Medicines Corporation.
Blueprint Medicines Corporation.
Samantha Clark, BSc, from iMed Comms an Ashfield Company, part of UDG Healthcare plc, provided copy editing support funded by Blueprint Medicines.
S. George: Fees from advisory board membership: Deciphera Pharmaceuticals, Blueprint Medicine; Fees for consulting: AstraZeneca. S. Bauer: Grants and personal fees: Novartis; Personal fees: PharmaMar, Lilly, Deciphera; Grants and personal fees: Blueprint Medicines; Grants: Incyte. R.L. Jones: Fees from consulting: Adaptimmune, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immunedesign, Lilly, Merck, PharmaMar. C. Serrano: Personal fees: Deciphera Pharmaceuticals for advisory board role; Research grants: Bayer Healthcare, Deciphera Pharmaceuticals, Pfizer. M. von Mehren: Personal fees for advisory board roles: Decipera, Blueprint. Y-K. Kang: Personal fees: BMS, Ono, Blueprint, Daehwa, LSK Biopharma, Novartis, Roche for advisory board participation. P. Schöffski: Consulting or advisory role (institutional support): 6th Element Capital, Adaptimmune, Amcure, AstraZeneca, Bayer, Blueprint Medicines, BMS, Boehringer Ingelheim, Cristal Therapeutics, Daiichi Sankyo, Eisai, Eli Lilly, Epizyme, Genzyme, Ipsen, Loxo Oncology, Medpace, Nektar, Philogen, Piqur Therapeutics, Plexxikon; Research funding (institutional support): Bayer, Blueprint Medicines, Cobiores nv, Exelixis, GSK, Novartis, Plexxikon; Travel, accommodation, expenses (institutional support): 6th Element Capital, Adaptimmune, Amcure, AstraZeneca, Bayer, Blueprint Medicines, BMS, Boehringer Ingelheim, Cristal Therapeutics, Daiichi Sankyo, Eisai, Eli Lilly, Epizyme, Genzyme, GSK, Ipsen, Loxo Oncology, Medpace, Nektar, Novartis, PharmaMar, Philogen. P. Cassier: Personal fees: Amgen, Blueprint Medicines, Novartis, Roche/Genentech for honoraria; Non-financial support from Amgen, Bristol-Myers Squibb, Novartis and Roche for travel accomodation and expenses; Research grants from Abbvie, AstraZeneca, Bayer, Blueprint Medicines, Bristol-Myers Squibb, Celgene, Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Plexxikon, Roche/Genentech, Taiho Pharmaceutical, Toray Industries, Transgene. O. Mir: Consultancy for Amgen, AstraZeneca, Bayer, Blueprint, Bristol Myers-Squibb, Eli-Lilly, Incyte, Ipsen, Lundbeck, MSD, Novartis, Pfizer, Roche, Servier, Vifor; Speakers bureau for Eli-Lilly, Roche, Servier; Stock ownership: Amplitude Surgical, Transgene. W.D. Tap: Personal fees: Adaptimmune, Blueprint Medicine, Daiichi Sankyo, Eli Lilly, EMD Serono, Esai, Immune Design, Janssen, Loxo, Novartis for Advisory Board participation and consulting. S.P. Chawla: Personal fees: Amgen, Epizyme, Five Prime, Immune design, Janssen, Novartis, PharmaMar, Prachi Pharmaceuticals for advisory and consulting roles; Reserach grants: Amgen, Bayer, Blueprint Medicine, BMS, Cba Pharma, Five Prime, Immune Design, Janssen, Karyopharm, Pharmaron UK, Novartis; Stock ownership: ADI Pharma, Cellestia, Counterpoint Biomedica, Uptick Health. P. Rutkowski: Advisory board: Novartis, Amgen, MSD, Roche, BMS, Bayer and Blueprint Medicine; Honoraria for lectures: Novartis, Pfizer, MSD, BMS, Roche. H. Shi, O. Schmidt-Kittler: Employment and stock ownership with Blueprint Medical. B. Mar: Employment at Blueprint Medical. M. Heinrich: Personal fees: Bayer, Blueprint Medicines, Deciphera, MolecularMD, Novartis for consulting; Personal fees: Novartis for expert testimony; Research funding: Blueprint Medicines, Deciphera; Equity interest: MolecularMD. All other authors have declared no conflicts of interest.