Updated efficacy and safety of zurlectrectinib in adult patients (pts) with locally advanced or metastatic NTRK fusion–positive (NTRK+) solid tumors.

3112 Background: NTRK gene fusion is one of the most defined driving factors of carcinogenesis, which occurs in various adult tumor types. Zurlectrectinib, a highly selective next-generation TRK tyrosine kinase inhibitor, previously demonstrated encouraging efficacy and manageable toxicity in pts with NTRK+ tumors in a phase I/II clinical trial (NCT04685226). The pivotal phase II clinical trial (NCT05745623) is currently ongoing. Here we present the integrated results of adult pts from both trials. Methods: Pts with locally advanced or metastatic solid tumors, who failed from clinical standard of care or for whom there was currently no effective therapy, were enrolled in this study. The primary endpoint was confirmed objective response rate (ORR) per independent review committee (IRC). Tumor responses were assessed by IRC and investigators per RECSIT1.1 and RANO (BM) criteria. Treatment-emergent adverse events were evaluated and graded according to CTCAE v5.0. Results: As of 23 Nov 2024, a total of 229 adult pts were enrolled in the two trials. Forty-nine TRK inhibitor naïve adult pts were evaluable for efficacy representing 12 different solid tumor types. Among the efficacy population, the distribution of NTRK1, NTRK2 and NTRK3 fusions was 53.1%, 2.0% and 44.9% respectively. The median age was 51.0 years (range: 18-77). Pts had received a median of two prior lines of systemic therapies, with ECOG performance status between 0-1. Median follow-up was 11.7 months. The confirmed ORR by IRC was 83.7% (95% CI: 70.3, 92.7), 5 pts (10.2%) with complete response. Median duration of response (DOR) and median progression-free survival (PFS) by IRC were not reached. The DOR rate and PFS rate by IRC at 12 months was 92.0% and 90.5%, respectively. Two of the three pts (66.7%) who had brain metastasis at the baseline achieved intracerebral ORR, which is consistent with the good brain penetration and strong intracranial activity of zurlectrectinib. In the safety population of adults (N = 229), treatment-related adverse events (TRAEs) were predominantly grade 1 or 2. The most common TRAEs (≥20%) were anemia (28.4%), increased alanine transferase (27.9%) and increased aspartate transferase (25.8%). Grade ≥3 TRAEs (≥2%) were weight gain (3.5%) and dizziness (2.2%). No Serious TRAEs occurred in ≥2% pts. TRAEs led to dose interruption, reduction and discontinuation in 9.2%, 3.9% and 0.4% of safety population, respectively. Conclusions: In line with previously reported results, zurlectrectinib continued to demonstrate a deep and durable responses in adult pts with NTRK+ advanced solid tumors with or without brain metastasis. Zurlectrectinib was also well-tolerated and showed favorable safety profile in adult pts with various tumor types. Clinical trial information: NCT05745623 .