442P - 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 tumor 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 February 13, 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 tumor shrinkage. Median progression-free survival (PFS) and duration of response (DOR) were not reached. In pts previously treated with C/V, 18-month (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%), anemia (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 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

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; Research grant/Funding (self): Ono Pharmaceutical. M.I. Hu: Advisory/Consultancy: Blueprint Medicines; Advisory/Consultancy: Eli Lilly & Co; Advisory/Consultancy: Loxo Oncology; Advisory/Consultancy: Veracyte. V. Subbiah: Research grant/Funding (institution): Roche/Genentech, Bayer, GlaxoSmithKline; Research grant/Funding (institution): Nanocarrier, Vegenics, Celgene; Research grant/Funding (institution): Northwest Biotherapeutics, Berghealth; Research grant/Funding (institution): Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, AbbVie; Research grant/Funding (institution): Alfa-sigma, Agensys; Research grant/Funding (institution): Boston Biomedical, Idera Pharma; Research grant/Funding (institution): Inhibrx, Exelixis; Research grant/Funding (institution): Blueprint Medicines; Research grant/Funding (institution): Altum, Dragonfly Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Loxo Oncology; Research grant/Funding (institution): Takeda, National Comprehensive Cancer Network, NCI-CTEP; Research grant/Funding (institution): UT MD Anderson Cancer Center, Turning Point Therapeutics; Research grant/Funding (institution): Boston Pharmaceuticals; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: ASCO, ESMO, Pharmamar; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Incyte; Advisory/Consultancy, Travel/Accommodation/Expenses: Helsinn; Advisory/Consultancy: Eli Lilly, R-Pharma US; Advisory/Consultancy: QED Pharma; Advisory/Consultancy, Research grant/Funding (institution): MedImmune; Advisory/Consultancy, Other relationship: Medscape. L. Wirth: Advisory/Consultancy: Bayer; Advisory/Consultancy: Blueprint Medicine; Advisory/Consultancy: Cue Biopharma; Advisory/Consultancy: Eisai; Advisory/Consultancy: Exelexis; Advisory/Consultancy: Genentech; Advisory/Consultancy: Lilly; Advisory/Consultancy: Loxo Oncology; Advisory/Consultancy: Merck; Advisory/Consultancy: Rakuten Medical. M. Schuler: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Roche; Advisory/Consultancy: Takeda; Advisory/Consultancy: MorphoSys; Honoraria (self): MSD; Honoraria (self): Roche Pharma AG; Licensing/Royalties, Institution has Patents, Royalties, Other Intellectual Property of Highly sensitive method for mutation detection by PCR: West German Cancer Center Essen, University Hospital Essen. A.S. Mansfield: Honoraria (institution): AbbVie; Honoraria (institution): AstraZeneca; Honoraria (institution): BMS; Honoraria (institution): Genentech/Roche; Travel/Accommodation/Expenses: Roche; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Verily; Non-remunerated activity/ies: Mesothelioma Applied Research Foundation. M.S. Brose: Honoraria (self), Advisory/Consultancy: Bayer; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self): Raffo; Honoraria (self), Research grant/Funding (self): Exelixis; Advisory/Consultancy: Loxo; Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (self): Lilly; Research grant/Funding (self): Blueprint Medicines Corporation. G. Curigliano: Advisory/Consultancy, Speaker Bureau/Expert testimony, Company Comment on Phase I-II studies: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Seattle Genetics; Advisory/Consultancy, Speaker Bureau/Expert testimony: Nanostring; Speaker Bureau/Expert testimony, Non-remunerated activity/ies, Writing engagement, Company Comment on Phase I-II studies: Novartis; Speaker Bureau/Expert testimony, Non-remunerated activity/ies, Writing engagement, Company Comment on Phase I-II studies: BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony, Company Comment on Phase I-II studies: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Foundation Medicine; Advisory/Consultancy, Speaker Bureau/Expert testimony: Samsung; Advisory/Consultancy, Speaker Bureau/Expert testimony: Celltrion; Advisory/Consultancy, Scientific Affairs Group: Ellipsis; Speaker Bureau/Expert testimony: MSD; Advisory/Consultancy: Mylan; Non-remunerated activity/ies, Company Comment on Phase I-II studies: Sanofi Phase I-II studies; Non-remunerated activity/ies, Company Comment on Phase I-II studies: Celgene; Non-remunerated activity/ies, Company Comment on Phase I-II studies: Servier; Non-remunerated activity/ies, Company Comment on Phase I-II studies: Orion, AstraZeneca, Seattle Genetics; Non-remunerated activity/ies, Company Comment on Phase I-II studies: AbbVie, Tesaro, Merck Serono; Non-remunerated activity/ies, Company Comment on Phase I-II studies: Merck Sharp Dome, Jassen Cilag, Philogen; Non-remunerated activity/ies, Company Comment on Phase I-II studies: Bayer, Medivation, MedImmune. 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. I. Matos: Research grant/Funding (self), ESMO Research Fellowship sponsored by Roche: Roche. D. Adkins: Honoraria (self): Lilly; Honoraria (self): Pfizer; Honoraria (self): Celgene; Honoraria (self): Merck; Honoraria (self): Cue; Honoraria (self): Aduro; Honoraria (self): Kura; Honoraria (self): Oncolys; Honoraria (self): Enzychyme; Honoraria (self): Matrix; Honoraria (self): Celldex. C.S. Baik: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Calgene Inc.; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Genentech Inc.; Research grant/Funding (institution): Loxo Oncology; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Spectrum Pharmaceuticals; Research grant/Funding (institution): BluePrint Medicines; Research grant/Funding (institution): Daiichi Sankyo Inc.; Research grant/Funding (institution): Rain Therapeutics; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): TP Therapeutics; Research grant/Funding (institution): Lilly Oncology. G. Lopes: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Boehringer Ingelheim; Travel/Accommodation/Expenses: E.R. Squibb Sons, LLC; 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), Spouse/Financial dependant, Honoraria: from Pfizer to an immediate family member: Pfizer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen; Honoraria (self), Travel/Accommodation/Expenses: Bayer; Advisory/Consultancy, Travel/Accommodation/Expenses, Spouse/Financial dependant, Consulting/advisory role to an immediate family member: Eisai; Advisory/Consultancy: Novartis; Advisory/Consultancy: Surface Oncology; Speaker Bureau/Expert testimony: MSD Oncology; Travel/Accommodation/Expenses: MiNA Therapeutics. H. Zhang: Shareholder/Stockholder/Stock options, Full/Part-time employment: Blueprint Medicines Corporation. C.D. Turner: Shareholder/Stockholder/Stock options, Full/Part-time employment: Celldex; Shareholder/Stockholder/Stock options, Full/Part-time employment: Blueprint Medicines Corporation. M.H. Taylor: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony: Eisai; Advisory/Consultancy, Travel/Accommodation/Expenses: Array BioPharma; Advisory/Consultancy, Travel/Accommodation/Expenses: Loxo; Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Advisory/Consultancy, Travel/Accommodation/Expenses: ArQule; Advisory/Consultancy, Travel/Accommodation/Expenses: Blueprint Medicines; Advisory/Consultancy: Novartis; Advisory/Consultancy: Sanofi/Genzyme; Speaker Bureau/Expert testimony: Merck; Research grant/Funding (institution): Abreos Biosciences; Research grant/Funding (institution): Arch Oncology; Travel/Accommodation/Expenses: Sanofi; Travel/Accommodation/Expenses: Novartis pharma SAS; Travel/Accommodation/Expenses: Eisai Europe Ltd. C-C. Lin: Advisory/Consultancy: Blueprint Medicines; Advisory/Consultancy: Boehringer-Ingelheim; Honoraria (self), Advisory/Consultancy: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Novartis; Advisory/Consultancy: Takeda; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Roche; Travel/Accommodation/Expenses: BeiGene; Travel/Accommodation/Expenses: Eli Lilly. All other authors have declared no conflicts of interest.