Phase 1 study of TT-00973-MS, a highly selective and potent AXL inhibitor, in patients with advanced solid tumors.

Abstract

3106 Background: AXL is a member of the TAM family activated by the high-affinity ligand Gas6. The Gas6/AXL signaling pathway plays a critical role in drug resistance, tumor proliferation, metastasis, invasion, epithelial-mesenchymal transition and immune regulation, implicating AXL as an important target in cancer treatment. TT-00973-MS is a highly selective and potent AXL inhibitor which exhibited significant anti-tumor activities in both SK-OV-3 and H1299 derived CDX model with AXL over-expression. Here is first time to present the first-in-human study of TT-00973-MS. Methods: Dose escalation is performed using“3+3”design. Adverse events (AE) are evaluated per CTCAE v5.0 criteria. Tumor responses are evaluated per RECIST 1.1. Pts receive TT-00973-MS once daily continuously for 28-day cycles. The primary endpoint is to evaluate dose limiting toxicity (DLT) and identify the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D). Results: As of the data cut-off date on December 24, 2024, 18 pts have received TT-00973-MS treatment in 2 mg (n = 1), 5 mg (n = 3), 10 mg (n = 3), 17 mg (n = 7), 25 mg (n = 4) at QD dose levels. Median age was 56.5 (37∼69), 8 (44.4%) were males, all had ECOG PS ≤1. 66.6% of pts had Stage III/IV disease. 50% had ≥3 prior lines of systemic therapies. 66.7% had prior immunotherapies. One DLT was observed in a subject at 17 mg QD dose level (Grade 3 peripheral motor nerve disorder). The MTD was not reached. Treatment-related AEs (TRAEs) were reported in all pts, grade 3 in 6 (33.3%), and no grade 4 or 5. The most common TRAE (≥30%) included increased blood lactate dehydrogenase (83.3%), increased aspartate aminotransferase (72.2%), increased alanine aminotransferase (66.7%), hypercholesterolaemia (55.6%), hypoalbuminaemia (38.9%), hypertriglyceridemia (33.3%) and proteinuria (33.3%). Fourteen pts were efficacy evaluable. Two confirmed partial remission (PR) were achieved in pts with renal pelvis cancer (n = 1) and ovarian cancer (n = 1). TT-00973-MS is slowly eliminated from body, with a half-life of about 55 h. After multiple dosing (QD), steady state was reached within 15 days, and the mean accumulation factor of AUC 0-24h was approximately 6. Preliminary PK analysis showed a linear increase on exposure. Plasma levels of soluble AXL (sAXL) increased to approximately 1.7 times (range: 0.9∼2.8) the baseline levels at C1D28. Conclusions: The preliminary findings from this phase I study demonstratedthat the AXL inhibitor TT-00973-MS monotherapy exhibits a well-tolerable safety profile, promising pharmacodynamic activity, with early signs of efficacy in pts with heavily pre-treated advanced solid tumors. Further studies are warranted to comprehensively evaluate the efficacy and safety of TT-00973-MS in large patient populations and specific tumor types. Clinical trial information: NCT05673538 .