Pralsetinib (RET TKI) doubles PFS vs platinum SOC in 1L RET+ metastatic NSCLC—but infections jump

Pralsetinib is an oral, selective RET tyrosine kinase inhibitor evaluated in AcceleRET-Lung, a randomized, open-label Phase 3 trial in previously untreated RET fusion–positive advanced/metastatic NSCLC (NCT04222972). In the ITT population (n=223; pralsetinib n=110 vs platinum-based SOC n=113; baseline brain mets 15–16%), pralsetinib improved median PFS to 18.7 vs 9.0 months (HR 0.59, p=0.003), increased ORR to 65.5% vs 41.6% (p<0.001), and extended median DOR to 20.6 vs 9.7 months (p=0.004); OS was immature/impacted by crossover (median OS NR vs 39.8 months; HR 1.09, p=0.742). Grade ≥3 TRAEs included hypertension (11.1%), neutropenia (10.2%), and anemia (8.3%), but the differentiating safety signal was higher infections with pralsetinib (71.3% vs 51.9%), including pneumonia (19.4% vs 5.8%) and opportunistic infections (9.3% vs 1.0%), with 7.4% infection-related deaths vs 0 on SOC (study terminated early January 27, 2025).