1913O - Results from the registrational phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET mutation-positive medullary thyroid cancer (RET+ MTC)

Background

Pralsetinib is a highly potent, selective RET inhibitor targeting oncogenic RET alterations. We provide the registrational data for pts with RET+ MTC from the ARROW study.

Methods

ARROW (75 sites in 11 countries; NCT03037385) consists of a phase I dose escalation to establish the recommended phase II dose (400 mg once daily [QD] orally), and phase II expansion cohorts defined by tumour type and/or RET alteration. Primary phase II objectives are overall response rate (ORR; blinded independent central review per RECIST v1.1) and safety. We report efficacy for response-evaluable pts (REP) with RET+ MTC and safety for all pts who initiated pralsetinib 400 mg QD, both as of data cut-off date 13 Feb 2020.

Results

In 79 REP with RET+ MTC (mutation: 61% M918T, 28% C634X, 4% V804X, 8% other), ORR was 65% (95% CI, 53–75; n=51/79, 5% complete response [CR]; 59% partial response [PR; 1 pending confirmation]). ORR for pts with prior cabozantinib and/or vandetanib (C/V) was 60% (95% CI, 46–74; n=32/53; 2% CR; 58% PR [1 pending]) and in treatment-naïve pts ORR was 74% (95% CI, 49–91; n=14/19; 5% CR; 68% PR; all confirmed). Disease control rate was 97% (95% CI, 91–100); 99% (78/79) of pts experienced tumour shrinkage. Median progression-free survival (PFS) and duration of response (DOR) were not reached. In pts previously treated with C/V 18-mo PFS was 71% (95% CI, 58–85), and 18-mo DOR was 90% (95% CI, 77–100). In treatment-naïve pts, 18-mo PFS was 85% (95% CI, 65–100) and 86% (12/14) of responses were ongoing at data cut-off (up to 15 mo). Responses occurred regardless of RET genotypes (somatic or germline), including 5 of 6 pts with V804X gatekeeper mutation. In the safety population (n=438), treatment-related adverse events (TRAEs) were primarily grade 1–2; most common any-grade TRAEs were increased aspartate aminotransferase (34%), anaemia (24%), increased alanine aminotransferase (23%), constipation (23%) and hypertension (22%). 4% of pts discontinued due to TRAEs.

Conclusions

Pralsetinib demonstrated potent and durable clinical activity in RET+ MTC regardless of prior treatment with approved multikinase inhibitors or RET-mutation and was well tolerated.

Clinical trial identification

NCT03037385.

Editorial acknowledgement

Medical writing support was provided by Miriam Cohen, PhD, 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.

Legal entity responsible for the study

Blueprint Medicines Corporation.

Funding

Blueprint Medicines Corporation.

Disclosure

M. Hu: Advisory/Consultancy: Blueprint Medicines Corporation; Advisory/Consultancy: Eli Lilly & Co; Advisory/Consultancy: Loxo Oncology; Advisory/Consultancy: Veracyte. V. Subbiah: Research grant/Funding (self): Roche/Genentech; Research grant/Funding (self): Novartis; Research grant/Funding (self): Bayer; Research grant/Funding (self): GSK; Research grant/Funding (self): Nanocarrier; Research grant/Funding (self): Vegenics; Research grant/Funding (self): Celgene; Research grant/Funding (self): Northwest Biotherapeutics; Research grant/Funding (self): Berghealth; Research grant/Funding (self): Incyte; Research grant/Funding (self): Fujifilm; Research grant/Funding (self): PharmaMar; Research grant/Funding (self): D3; Research grant/Funding (self): Pfizer; Research grant/Funding (self): Multivir; Research grant/Funding (self): Amgen; Research grant/Funding (self): AbbVie; Research grant/Funding (self): Alfa-sigma; Research grant/Funding (self): Agensys; Research grant/Funding (self): Boston Biomedical; Research grant/Funding (self): Idera Pharma; Research grant/Funding (self): Inhibrx; Research grant/Funding (self): Exelixis; Research grant/Funding (self): Blueprint Medicines Corporation; Research grant/Funding (self): Loxo Oncology; Research grant/Funding (self): MedImmune; Research grant/Funding (self): Altum; Research grant/Funding (self): Dragonfly Therapeutics; Research grant/Funding (self): Takeda; Research grant/Funding (self): National Comprehensive Cancer Network. L.J. Wirth: Advisory/Consultancy: Bayer; Advisory/Consultancy: Blueprint Medicines Corporation; Advisory/Consultancy: Cue Biopharma; Advisory/Consultancy: Eisai; Advisory/Consultancy: Exelixis; Advisory/Consultancy: Genentech; Advisory/Consultancy: Lilly; Advisory/Consultancy: Loxo Oncology; Advisory/Consultancy: Merck; Advisory/Consultancy: Rakuten Medical. M. Schuler: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Novartis; Advisory/Consultancy: Roche; Advisory/Consultancy: Takeda; Advisory/Consultancy: MorphoSys. A.S. Mansfield: Honoraria (institution): AbbVie; Honoraria (institution): AstraZeneca; Honoraria (institution): BMS; Honoraria (institution): Roche/Genentech; Travel/Accommodation/Expenses: Novartis; Research grant/Funding (institution): Verily Research; Non-remunerated activity/ies: Mesothelioma Applied Research Foundation. M.S. Brose: Honoraria (self), Research grant/Funding (institution): Exelixis; Advisory/Consultancy, Research grant/Funding (institution): Blueprint Medicines Corporation; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Honoraria (self), Advisory/Consultancy: Bayer; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self): Raffo; Advisory/Consultancy: Loxo. G. Curigliano: Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Seattle Genetics; Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Foundation Medicine; Advisory/Consultancy, Speaker Bureau/Expert testimony: NanoString; Advisory/Consultancy, Speaker Bureau/Expert testimony: Samsung; Advisory/Consultancy, Speaker Bureau/Expert testimony: Celltrion; Non-remunerated activity/ies: Ellipsis; Speaker Bureau/Expert testimony: BMS; Speaker Bureau/Expert testimony: MSD; Advisory/Consultancy: Mylan. S. Leboulleux: Advisory/Consultancy: Lilly; Advisory/Consultancy: Bayer; Speaker Bureau/Expert testimony: Eisai. V.W. Zhu: Honoraria (self): AstraZeneca; Honoraria (self): Roche/Foundation Medicine; Honoraria (self): Roche/Genentech; Honoraria (self): Takeda; Shareholder/Stockholder/Stock options: TP Therapeutics. B. Keam: Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy, Research grant/Funding (self): MSD Oncology; Advisory/Consultancy: ABL Bio; Advisory/Consultancy: Genexine; Advisory/Consultancy: Cellid; Advisory/Consultancy: Ono Pharmaceutical. I. Matos: Research grant/Funding (self): Roche. C-C. Lin: Advisory/Consultancy: Blueprint Medicines Corporation; Advisory/Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Novartis; Advisory/Consultancy: Takeda; Honoraria (self): BMS; Honoraria (self): Roche; Travel/Accommodation/Expenses: BeiGene; Travel/Accommodation/Expenses: Eli Lilly. D. Adkins: Advisory/Consultancy: Lilly; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Celgene; Advisory/Consultancy: Merck; Advisory/Consultancy: CUE; Advisory/Consultancy: Aduro; Advisory/Consultancy: KURA; Advisory/Consultancy: Oncolys; Advisory/Consultancy: Enzychyme; Advisory/Consultancy: Matrix; Advisory/Consultancy: Celldex. C.S. Baik: Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): Celgene; Research grant/Funding (self): Novartis; Research grant/Funding (self): MedImmune; Research grant/Funding (self): SWOG; Research grant/Funding (self): Genentech; Research grant/Funding (self): Loxo Oncology; Research grant/Funding (self): Pfizer; Research grant/Funding (self): Spectrum Pharmaceuticals; Research grant/Funding (self): Blueprint Medicines Corporation; Research grant/Funding (self): Daiichi Sankyo; Research grant/Funding (self): Rain Therapeutics; Research grant/Funding (self): AbbVie; Research grant/Funding (self): TP Therapeutics; Research grant/Funding (self): Lilly Oncology. G. Lopes: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Boehringer Ingelheim; Travel/Accommodation/Expenses: E R Squibb Sons; Research grant/Funding (institution), Travel/Accommodation/Expenses: Janssen; Research grant/Funding (institution): MSD; Research grant/Funding (institution): EMD Serono; Research grant/Funding (institution): Blueprint Medicines Corporation; Research grant/Funding (institution): Tesaro; Research grant/Funding (institution): Bavarian Nordic; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): G1 Therapeutics; Research grant/Funding (institution): Adaptimmune; Research grant/Funding (institution): BMS; Research grant/Funding (institution): GSK; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Rgenix; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Lilly. D. Sarker: Honoraria (self): Pfizer; Honoraria (self): Bayer; Advisory/Consultancy: Ipsen; Honoraria (self): Novartis; Advisory/Consultancy: Eisai; Advisory/Consultancy: Surface Oncology; Advisory/Consultancy: MSD Oncology. H. Zhang, C. Turner: Shareholder/Stockholder/Stock options, Full/Part-time employment: Blueprint Medicines Corporation. M. Taylor: Advisory/Consultancy, Speaker Bureau/Expert testimony: BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony: Eisai; Advisory/Consultancy: Array BioPharma; Advisory/Consultancy: Loxo Oncology; Advisory/Consultancy: Bayer; Advisory/Consultancy: ArQule; Advisory/Consultancy: Blueprint Medicines Corporation; Advisory/Consultancy: Novartis; Advisory/Consultancy: Sanofi/Genzyme; Speaker Bureau/Expert testimony: Merck. All other authors have declared no conflicts of interest.