Results from a phase I study of KL590586 in patients with advanced RET-mutant medullary thyroid cancer.

Abstract

6098 Background: RET mutations occur in 70% of medullary thyroid cancers (MTC). KL590586 (A400/EP0031) is a potent next-generation brain-penetrant selective RET inhibitor (SRI) with activity against acquired resistance mutations to first-generation SRIs (Zhou et al. 2023, Garralda et al. 2024). Here we present the preliminary safety and efficacy data of KL590586 in patients (pts) with advanced RET-mutant MTC from the phase I part of a phase I/II study completed in China (KL400-I/II-01, NCT05265091). Methods: The phase I part, comprising a dose-escalation phase and a dose-expansion phase, was conducted to evaluate the safety, pharmacokinetics, and efficacy of KL590586 in pts with RET-altered solid tumors. Eligible pts with advanced RET-mutant MTC were enrolled to receive KL590586 once a day (QD) until disease progression or unacceptable toxicity. Tumor assessments were performed every 8 weeks as per RECIST v1.1. Results: As of September 20, 2024, 27 advanced RET-mutant MTC pts without prior SRIs were enrolled and treated in the phase I part across 4 dose levels (20 to 90 mg QD). The median age was 49 years, and 66.7% of pts were male. Among these 27 pts, 8 were treatment-naïve, and 19 had received previous systemic treatment, with 84.2% of them treated with multikinase inhibitors (MKIs). The median follow-up was 19.0 months. Adverse events were reported for all pts. The most common adverse events considered treatment related (TRAEs, ≥ 35%) were increased ALT (77.8%), increased AST (70.4%), headache (48.1%), increased blood creatine phosphokinase (40.7%), increased blood lactate dehydrogenase (37.0%), and hyperuricaemia (37.0%), with grade ≥3 TRAEs occurring in 22.2% of pts. The most frequent grade ≥ 3 TRAEs (≥ 5%) were increased ALT (7.4%) and increased GGT (7.4%). No TRAEs led to treatment discontinuation or death. At data cut-off, the confirmed objective response rate (cORR) was 63.0% (17/27) and the disease control rate was 100% for overall population. The cORR was 56.3% (9/16) and 62.5% (5/8) in pts with prior MKI or treatment naïve, respectively. Median duration of response was not reached (95% CI, 7.4 to NE), with the longest duration still ongoing at 25.8 months. Similarly, median progression-free survival (PFS) was not reached, with the 24-month PFS rate of 77.8%. Conclusions: KL590586 was well tolerated in pts with advanced RET-mutant MTC, exhibiting a safety profile consistent with that previously reported in NSCLC (Zhou et al. 2023). In MTC pts with or without previous MKIs, KL590586 demonstrated robust clinical activity with durable responses. The findings support further investigation of KL590586 as a potential therapeutic alternative for this patient population. Phase II trials are evaluating KL590586/EP0031 in China and US/Europe/UAE. Clinical trial information: NCT05265091 .