Efficacy and safety of pralsetinib as first-line treatment of RET fusion–positive advanced or metastatic non–small cell lung cancer (NSCLC): The phase 3 AcceleRET-Lung study.

8504 Background: Pralsetinib, an oral tyrosine kinase inhibitor, selectively and potently targets oncogenic RET fusion and mutation proteins. Pralsetinib is FDA approved to treat adults with metastatic RET -altered NSCLC. We present efficacy and safety of pralsetinib vs standard of care (SOC) in first-line RET fusion-positive NSCLC from a randomized phase 3, open-label study, AcceleRET-Lung (NCT04222972). Methods: AcceleRET-Lung was conducted at 74 sites in 22 countries. Adults with RET fusion-positive advanced or metastatic NSCLC received pralsetinib 400 mg/d or platinum-based SOC therapy. Crossover to pralsetinib was optional upon progression. The primary end point was progression-free survival (PFS) per RECIST v1.1. Secondary end points included overall response rate (ORR), overall survival (OS), duration of response (DOR), and safety. Efficacy was evaluated in randomized patients (intent-to-treat population ITT). Safety was assessed in patients receiving ≥1 dose of study drug. Results: 223 ITT patients were randomized to pralsetinib (n=110) or SOC (n=113). Pralsetinib and SOC groups had similar baseline characteristics (median age: 62 and 63 y, respectively; female: 48% and 57%; median lesions: both 4; brain metastases: 15% and 16%). The study was terminated early per sponsor decision on January 27, 2025. ITT patients in the pralsetinib group had significantly greater median PFS vs SOC (18.7 vs 9.0 mo; P =0.003), ORR (65.5% vs 41.6%; P <0.001), and median DOR (20.6 vs 9.7 mo; P =0.004; Table). Safety was generally consistent with the known pralsetinib profile except for a higher rate of infection in the pralsetinib group vs SOC (71.3% vs 51.9%), including pneumonia (19.4% vs 5.8%), urinary tract infections (17.6% vs 7.7%), and opportunistic infections (9.3% vs 1.0%). There were 32 (30.0%) and 26 (25.0%) deaths in the pralsetinib and SOC groups, respectively, with 8 (7.4%) and 0 due to infection. Common grade ≥3 TRAEs in the pralsetinib vs SOC groups were hypertension (11.1% vs 0), neutropenia (10.2% vs 8.7%), anemia (8.3% vs 10.6%), and decreased neutrophil count (7.4% vs 4.8%). Conclusions: In a Phase 3 study, pralsetinib met the primary PFS end point and had a significantly greater and more durable ORR vs SOC, confirming the clinical utility of pralsetinib in RET fusion-positive NSCLC. Monitoring for infections with pralsetinib is warranted. Clinical trial information: (1) NCT04222972 ; (2) 2023-505035-12-00; (3) 2019-002463-10. Efficacy outcomes. Pralsetinib (n=110) SOC(n=113) Stratified hazard ratio/odds ratio (95% CI) P Value Duration of follow-up, mo, median (range) 20.5(0, 49.8) 16.0(0, 42.3) - - PFS, mo, median (95% CI) 18.7(11.1, 25.2) 9.0(7.1, 11.5) 0.59(0.42, 0.84) 0.003 ORR, % (95% CI) 65.5(55.8, 74.3) 41.6(32.4, 51.2) 2.81(1.61, 4.93) <0.001 OS, mo, median (95% CI) NR (29.6, NR) 39.8(39.8, NR) 1.09(0.65, 1.85) 0.742 DOR, mo, median (95% CI) 20.6(17.2, 31.8) 9.7(7.6, 15.9) 0.48(0.28, 0.80) 0.004