Abstract 4559
Background
BLU667, an investigational agent, is a potent and selective inhibitor of oncogenic rearranged during transfection (RET) alterations and predicted resistance mutations. Up to 90% of advanced medullary thyroid cancer (MTC) is characterized by single nucleotide variants and short insertions/deletions in the RET gene. In NSCLC, 1-2% of patients (pts) harbor rearrangements resulting in RET fusions. In the first-in-human ARROW study (NCT03037385), BLU-667 has demonstrated significant clinical activity in RET-altered NSCLC and MTC and has been well tolerated. Previous data has shown that early declines in circulating tumor DNA (ctDNA) may predict for treatment outcome. We investigated the change in ctDNA levels from baseline following treatment with BLU-667 and whether early changes in ctDNA during treatment were associated with clinical responses and outcomes.
Methods
Blood was collected at baseline and prespecified time points during treatment. Plasma from 111 pts with locally documented RET-altered MTC and NSCLC were profiled with the Personal Genome Diagnostics PlasmaSELECT™ R64 sequencing panel.
Results
RET fusions were detected at baseline in 45/63 (71%) pts with NSCLC and RET mutations in 35/48 (73%) pts with MTC. Baseline ctDNA mutant allele fraction (MAF; MTC) or unique fusion reads (NSCLC) correlated with the sum of target lesions (p<0.01). BLU-667 led to rapid RET ctDNA declines in almost all pts and across all doses (60-600 mg QD, 100-200 mg BID). Eighty-one percent of pts with NSCLC and detectable ctDNA at baseline had undetectable RET ctDNA after 8 weeks of treatment. Clearance of RET fusions in NSCLC was observed for multiple fusion partners including CCDC6 and KIF5B. Forty-one percent of pts with MTC harboring somatic RET mutations also had undetectable RET ctDNA after 8 weeks. The correlation between changes in ctDNA levels and clinical outcomes are currently not mature and will be reported at the meeting.
Conclusions
Treatment with BLU-667 led to a robust and rapid decline in ctDNA in almost all patients regardless of treatment dose or tumor diagnosis and in NSCLC irrespective of fusion partner studied.
Clinical trial identification
NCT03037385.
Editorial acknowledgement
Legal entity responsible for the study
Blueprint Medicines Corporation.
Funding
Blueprint Medicines Corporation.
Disclosure
G. Curigliano: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Seattle Genetics; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer. V. Subbiah: Advisory / Consultancy: MedImmune; Research grant / Funding (institution): Novartis (Inst), GlaxoSmithKline (Inst), NanoCarrier (Inst), Northwest Biotherapeutics (Inst), Genentech (Inst), Roche (Inst), Berg Pharma (Inst), Bayer AG (Inst), Incyte (Inst), Fujifilm (Inst), PharmaMar (Inst), D3 Oncology Solutions (Inst), Pfizer (Ins; Travel / Accommodation / Expenses: PharmaMar, Bayer AG. J.F. Gainor: Honoraria (self): Merck, Incyte, ARIAD Pharmaceuticals, Novartis, Pfizer; Advisory / Consultancy: Genentech, Bristol-Myers Squibb, Theravance, Loxo, Takeda, Array BioPharma, Amgen, Merck, Agios, Regeneron, Oncorus, Jounce Therapeutics; Research grant / Funding (institution): Merck (Inst), Novartis (Inst), Genentech (Inst), Bristol-Myers Squibb (Inst), Adaptimmune (Inst), AstraZeneca (Inst), ARIAD Pharmaceuticals (Inst), Jounce Therapeutics (Inst), Blueprint Medicines (Inst), Moderna Therapeutics (Inst), Tesaro (Inst), Alexo T. D.H. Lee: Honoraria (self): AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, CJ Healthcare, Eli Lilly, Janssen, Merck, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm and ST Cube; Advisory / Consultancy: Ministry of Food and Drug Safety, Korea, Health Insurance Review and Assessment Service, Korea, National Evidence-based Collaborating Agency, Korea, and National Cancer Control Planning Board, Korea. M.H. Taylor: Honoraria (self), Advisory / Consultancy: BMS, Eisai Inc, Array Biopharma, Bayer, LOXO, Blueprint, Arqule, Novartis; Speaker Bureau / Expert testimony: BMS, Eisai Inc; Research grant / Funding (institution): BioAtla; Travel / Accommodation / Expenses: BMS, Eisai Inc, Array Biopharma, Bayer, Loxo, Blueprint. V. Zhu: Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca, Roche-Foundation Medicine, Roche/Genentech, Takeda; Advisory / Consultancy, Shareholder / Stockholder / Stock options: TP Therapeutics. R.C. Doebele: Honoraria (self): Pfizer, AstraZeneca, ARIAD Pharmaceuticals, Guardant Health, Takeda Pharmaceuticals, Spectrum Pharmaceuticals, Trovagene; Advisory / Consultancy: Pfizer, OncoMed Pharmaceuticals, Trovagene, Ignyta, GreenPeptide, AstraZeneca; Research grant / Funding (institution): Ignyta (Inst); Travel / Accommodation / Expenses: Ignyta, ARIAD Pharmaceuticals, Guardant Health; Shareholder / Stockholder / Stock options: Rain Therapeutics; Licensing / Royalties: Other Intellectual Property: Licensing fees from Abbott Molecular for patent PCT/US2013/057495, licensing fees from Ignyta for biologic materials (Inst). G. Lopes: Advisory / Consultancy: Pfizer; Research grant / Funding (self): AstraZeneca; Research grant / Funding (institution): Merck Sharp & Dohme (Inst); EMD Serono (Inst), AstraZeneca (Inst), AstraZeneca, Blueprint Medicines (Inst), Tesaro (Inst), Bavarian Nordic (Inst), Novartis (Inst), G1 Therapeutics (Inst). E. Garralda: Research grant / Funding (self), Research grant / Funding (institution): Novartis; Travel / Accommodation / Expenses: BMS, Menarini, Glycotope; Licensing / Royalties: MSD. S.M. Gadgeel: Advisory / Consultancy: Pfizer, Genentech, ARIAD Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, AbbVie; Speaker Bureau / Expert testimony: AstraZeneca; Research grant / Funding (self), Research grant / Funding (institution): Merck; Research grant / Funding (institution): Pfizer (Inst), Merck, Genentech (Inst), Blueprint Medicines (Inst), ARIAD Pharmaceuticals (Inst), Takeda (Inst); Travel / Accommodation / Expenses: ARIAD Pharmaceuticals, Takeda. C.D. Turner: Full / Part-time employment: Blueprint Medicines Corporation. M. Palmer: Full / Part-time employment: Blueprint Medicines Corporation. S. Miller: Full / Part-time employment: Blueprint Medicines Corporation. All other authors have declared no conflicts of interest.
Resources from the same session
4596 - A Phase 2, Open-Label, Randomized, Multicenter Trial of Encorafenib + Binimetinib Evaluating a Standard-dose and a High-dose Regimen in Patients With BRAFV600-Mutant Melanoma Brain Metastasis (MBM) (POLARIS)
Presenter: Michael Davies
Session: Poster Display session 3
Resources:
Abstract
1891 - Continuation of annual screening mammograms and breast-cancer mortality in women over 70
Presenter: Xabier Garcia De Albeniz
Session: Poster Display session 3
Resources:
Abstract
5587 - Introducing standardized medical procedure and dynamic decision support program in precision oncology for the community of practice
Presenter: Istvan Petak
Session: Poster Display session 3
Resources:
Abstract
4757 - Effectively using primary care givers in oncology care through capacity building, task sharing and techno-mentoring.
Presenter: Dinesh Pendharkar
Session: Poster Display session 3
Resources:
Abstract
4497 - A single institution review of capecitabine related acute admissions and cost analysis
Presenter: Gemma Dart
Session: Poster Display session 3
Resources:
Abstract
2187 - Health status of middle-aged and older cancer survivors in China: results from the China Health and Retirement Longitudinal Study (CHARLS)
Presenter: Jiarui Li
Session: Poster Display session 3
Resources:
Abstract
5101 - Crossed looks on lung cancer perception and knowledge from general public and physicians in France: results of a two-fold survey
Presenter: Céline Mascaux
Session: Poster Display session 3
Resources:
Abstract
4354 - Knowledge and perception of clinical trials (CTs) and attitude towards participation among Polish oncological patients - A pilot survey
Presenter: Artur Kotowski
Session: Poster Display session 3
Resources:
Abstract
3499 - Achieving best possible cancer treatment outcomes in care pathways through benchmarking; ABC-Benchmarking
Presenter: Anke Wind
Session: Poster Display session 3
Resources:
Abstract
2270 - Impact of 10-day Fulbright Specialist Program (FSP) and Project Pink Blue (PPB) Education Sessions on Medical Oncology knowledge among Doctors that treat cancer in Nigeria
Presenter: Mike Martin
Session: Poster Display session 3
Resources:
Abstract