Pralsetinib (selective RET inhibitor) drives 92% ORR in pretreated RET fusion+ thyroid cancer; 68% ORR in RET-altered MTC

Pralsetinib is an oral, potent, selective RET tyrosine kinase inhibitor evaluated in the Phase 1/2 ARROW study (NCT03037385) in advanced/metastatic RET-altered thyroid cancer and medullary thyroid cancer (MTC). At the May 20, 2024 data lock, ORR was 91.7% in the 10-20% of RET-altered thyroid cancer with prior systemic therapy (MDP n=24; 16.7% CR; median DoR not reached; EP n=28 with median PFS not reached) and 68.2% in RET-altered MTC overall (MDP n=132; 9.1% CR; median DoR 39.6 mo; EP n=145 with median PFS 37.2 mo and OS not reached), with MTC ORR 56.7% post-cabozantinib/vandetanib (MDP n=60; median DoR 21.7 mo; median PFS 24.9 mo) and 79.0% in treatment-naïve MTC (MDP n=62; median DoR not reached; median PFS 55.3 mo). Grade ≥3 TRAEs occurred in 68% (TC) and 67% (MTC) with common TRAEs including transaminase elevations, cytopenias, and anemia; two TRAE-related deaths were reported (liver injury in TC; pneumonia in MTC)—efficacy compares favorably to older multikinase inhibitors in MTC (vandetanib/cabozantinib PFS benefit vs placebo in the ~11–19 mo range in pivotal trials), but toxicity remains substantial and “cleaner” selective RET inhibition benchmarks exist (e.g., selpercatinib in RET-activated thyroid cancer shows high response rates with long durability in long-term follow-up).