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)

Abstract

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. 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. 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. 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.