Clinical efficacy and tolerability of the selective RET inhibitor soxataltinib (SY-5007) in advanced RET fusion–positive non–small cell lung cancer (NSCLC): Primary findings from a confirmatory phase III trial.

8639 Background: Oncogenic RET gene fusions represent a clinically validated molecular driver occurring in approximately 1–2% of all NSCLC cases, establishing a critical need for targeted therapeutic strategies. Soxataltinib is a novel, orally bioavailable, and highly selective small-molecule inhibitor of RET kinase. Its anti-tumor potency and safety have been previously reported in a phase I/II study. Here we confirmed its clinical value in a pivotal phase III study. Methods: This multicenter, single-arm Phase III clinical trial was designed to evaluate the efficacy and safety of Soxataltinib in patients with RET fusion–positive NSCLC who were previously untreated for advanced disease. The primary endpoint was the confirmed Objective Response Rate (ORR), as determined by Blinded Independent Central Review (BICR) per RECIST v1.1. The secondary endpoints included investigator-assessed ORR, Disease Control Rate (DCR), Duration of Response (DOR), Progression-Free Survival (PFS), Overall Survival (OS), and safety. Results: At the data cutoff (April 10, 2025), the Per-Protocol Population (PPP) comprised 95 patients, 61 of whom were Key efficacy population (KEP) for statistical hypothesis. Soxataltinib demonstrated profound anti-tumor efficacy. The primary endpoint was met. The BICR-confirmed ORR was 90.0% (95%CI: 79.5, 96.2) for KEP and 87.4% (95%CI: 79.0, 93.3) for PPP. The overall DCR was 96.7% (95%CI: 88.5, 99.6) for KEP and 93.7% (95%CI: 86.8, 97.6) for PPP. The median PFS and DOR had not yet been reached, with an estimated 15-month PFS rate of 68.9% (95%CI: 54.3, 79.7) and 65.0% (95%CI: 51.5, 75.6) and 12-month DOR rate of 73.8% (95%CI: 58.2, 84.4) and 69.1% (95%CI: 53.8, 80.1), respectively for KEP and PPP. The OS data remained immature. The safety analysis population comprised 96 patients who received at least one dose of Soxataltinib. The most common Grade ≥3 treatment-emergent adverse events (TEAEs) were hypertension (22.9%), diarrhea (16.7%), Aspartate aminotransferase increased (6.3%), Alanine aminotransferase increased (5.2%), and hyponatraemia (5.2%). These events were predominantly manageable. None of the patients permanently discontinued treatment due to a treatment-related adverse event. No patient died due to TEAE that was definitely related, probably related, or possibly related to Soxataltinib. Conclusions: The primary analysis of this Phase III trial confirmed Soxataltinib as a highly effective and well-tolerated therapeutic agent for patients with RET fusion–positive NSCLC in the first-line setting. This observed high response rates and durable disease control benefit underscored its potential as a best-in-class RET inhibitor. The adverse event profile was predictable and manageable, supporting its feasibility for long-term administration. Clinical trial information: NCT06031558 .