(P 429) SINGLE-ARM, OPEN-LABEL PHASE II TRIAL OF XL092 (ZANZALINTINIB) IN PATIENTS WITH ADVANCED LEIOMYOSARCOMA: TRIAL IN PROGRESS

Objective: Advanced leiomyosarcoma (LMS) has limited effective systemic treatment options in the metastatic setting. Approved subsequent line agents such as trabectedin and pazopanib have demonstrated short-term improvements in progression-free survival (PFS). Other tyrosine kinase inhibitors (TKIs) targeting Vascular Endothelial Growth Factor Receptor (VEGFR), have shown activity in LMS. Their broader use is often limited by toxicity and the emergence of resistance. New active and tolerable agents are needed. XL092 is a next-generation, orally available, multi-targeted TKI that inhibits VEGFR2, MET, and TAM family kinases (e.g. AXL, and MER)—pathways implicated in LMS tumor growth. XL092 has a relatively short half-life (~21 hours), allowing for daily dosing and potentially more flexible management of side effects. Early clinical data report a favorable safety profile, with most common grade ≥3 treatment related adverse events being hypertension (13%), diarrhea (4%), fatigue (4%). This Phase II trial aims to assess the antitumor activity and tolerability of XL092 in patients with advanced LMS.

Methods: This is a single-center, phase II study of XL092 monotherapy in patients with advanced or metastatic LMS. Eligible patients must have histologically confirmed LMS, measurable disease per RECIST 1.1, and ≥2 prior lines of systemic therapy (≥ 2 previous TKIs allowed). XL092 is dosed at 100 mg orally once daily in 14-day cycles until progression or unacceptable toxicity. Dose reduction to 60 mg and 40 mg is allowed. The primary endpoint is 6-month PFS. Secondary endpoints include ORR, median PFS, OS, duration of response (DOR), and safety.

Results: Enrollment is ongoing. The first patient was screened in September 2024. As of June 2025, 12 have enrolled. A total of 29 patients will be enrolled to ensure 26 evaluable for primary analysis.

Conclusion: This trial will evaluate the clinical activity and tolerability of XL092 in heavily pretreated LMS. A 6-month PFS of ≥50% would strongly support further investigation of XL092 in this population. Protocol is being amended to include a second cohort of translocation-associated sarcomas