Activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients with advanced RET-altered thyroid cancers.

Abstract

6018 Background: RET alterations are targetable oncogenic drivers in ~90% of advanced medullary thyroid cancer (MTC) and 20% of papillary thyroid cancer (PTC), yet no selective RET inhibitors are approved. BLU-667 is an investigational highly potent and selective RET inhibitor targeting oncogenic RET alterations including those that confer resistance to multikinase inhibitors (MKIs). We provide an update on the expanded experience of BLU-667 in RET-altered thyroid cancer from the registration-enabling ARROW study (NCT03037385). Methods: ARROW is a global DE (30-600 mg daily [QD or BID]) and dose expansion (DX; 400 mg QD) study in pts with advanced solid tumors. Primary objectives are response rate (ORR; RECIST 1.1) and safety. Results: As of 19Dec2018, 60 pts with RET-mutated MTC (M918T [37], C634R/S/W [8], V804M [4], other/pending [11]) and 5 pts with RET-fusion+ PTC (NCOA4 [3], CCDC6 [2]) received BLU-667 (37 DE, 28 DX). 58% had prior MKI therapy. Among 49 response-evaluable MTC pts, ORR is 47% (95% CI: 33, 62; 2 complete and 21 partial responses (PR); 4 PR pending confirmation; 25 stable disease; 1 progressive disease). 96% (22/23) of responding pts continue treatment; 15 with response duration ≥ 6 months. 2/4 evaluable PTC pts had PR; all 5 enrolled PTC pts continue treatment at 8-11 months. Responses in MTC occur regardless of MKI resistance (prior cabozantinib/vandetanib: ORR 46% (12/26)) or RET genotype (PR in 2/3 evaluable pts with V804M). Disease control rate in MTC pts is 98%. Rapid plasma clearance of RET variants and marked reduction in CEA and calcitonin is observed. Treatment-related toxicity in MTC/PTC pts, generally low-grade and reversible (28% had grade 3 events, no grade 4/5 events, no events requiring discontinuation), includes decreased WBC (23%), increased AST (17%), increased ALT, blood creatinine, and phosphate, hypertension, and decreased neutrophils (all 15%). Conclusions: BLU-667 demonstrates potent, durable and broad antitumor activity and is well tolerated in MTC/PTC pts regardless of MKI resistance and may significantly improve outcomes for pts with RET-altered thyroid cancers. Enrollment of the expansion is ongoing with registrational intent. Clinical trial information: NCT03037385.