Assessment of KL590586, an Advanced Selective RET Inhibitor, in Patients with RET-Altered Solid Tumors

KL590586 is a powerful next-generation RET inhibitor that can overcome resistance mutations and treat brain metastases.

Researchers aimed to present preliminary data on the safety, pharmacokinetics(PK), and efficacy of KL590586, a next-generation selective RET inhibitor, in RET-altered advanced tumor patients (pts).

The study involved dose escalation (Bayesian Optimal Interval design) and expansion. The primary endpoint was establishing the maximum tolerated dose (MTD) and the Recommended Phase II Dose. Secondary endpoints included safety, PK, objective response rate (ORR), disease control rate (DCR), and duration of response (DoR) following the RECIST 1.1 criteria.

For about 87 pts with RET-altered tumors, 6 different dose levels (ranging from 10 to 120 mg QD) were administered. No dose-limiting toxicities (DLTs) were observed, and MTD was not determined. Treatment-related adverse events (TRAEs) occurred in 93.1% of pts, with the majority (74.7%) being mild to moderate (grade 1-2). These reversible events, affecting more than 25% of pts, included increased AST (50.6%), increased ALT (48.3%), elevated creatinine (33.3%), raised bilirubin (32.2%), constipation (32.2%), and headache (31%). Grade ≥3 TRAEs were seen in 24.1% of pts, with the most common ones (occurring in >2% of pts) being increased ALP (2.3%), increased GGT (2.3%), and ileus (2.3%).

Treatment-related adverse events(TRAEs) led to dose reduction in 4.6% of pts and treatment discontinuation in 6.9%. Hypertension, QT interval prolongation, platelets decrease, and lymphocytes decrease (leading to 1st gen SRI dose delays and modifications frequently) were rare (<5%) and low-grade. The exposure increased dose-dependently, and the mean half-life was 34.1-99.8 hours. Clinical responses were observed from 40mg onwards. 69 pts treated at the 40-120mg doses (57 NSCLC, 10 MTC, 1 pancreatic cancer, 1 ovarian cancer) were evaluable for efficacy analysis, and the ORR was 64% (NSCLC, MTC, and pancreatic cancer). Most pts (58/69) remained on treatment, with the longest treatment duration exceeding 11 months. The ORR in pretreated pts (median prior treatment: 2, range 1-9, 28% previously treated with anti-PD1/PD-L1 therapy), ORR was 63% (20/32,1CR), with a DCR of 91% and a median duration of response (DoR) that was not reached. Nine pts had previously received first-generation SRI treatment 7, experiencing tumor shrinkage ranging from -10% to -69%, resulting in 3 partial responses (PR) and 4 stable diseases (SD). Among 11 pts with brain metastases (without radiotherapy), 4 out of 5 with measurable brain disease achieved significant shrinkage, including rates of 100%, 100%, 80%, and 47%. The overall DCR for CNS (central nervous system) lesions was 100%.

In treatment-naïve NSCLC pts, the ORR was 76% (19/25,1CR), with a DCR of 92% and a median DoR that was not reached. Among 4 pts with brain metastases (without radiotherapy), 3 experienced complete or partial disappearance of their baseline brain lesions.

The study found KL590586 was well-tolerated and effective in RET-altered tumors, including those resistant to first-generation selective RET inhibitors and with brain metastases. 

Source: https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.16_suppl.3007#:~.

Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT05265091 

Qing Zhou, Yi-Long Wu, Xiangqian Zheng, Dapeng Li, Dingzhi Huang, Xingya Li, Anwen Liu, Xia Song, Shanghua Jing, Mingxia Wang, Xicheng Wang, Yongzhong Luo, Yong Song, Yanjun Mi, Jianying Zhou, Yun Fan, Haichuan Su, Tao Huang, Weiwei Ouyang, and Junyou Ge. DOI: 10.1200/JCO.2023.41.16_suppl.3007 Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) 3007-3007.