A phase I study of KL590586, a next-generation selective RET inhibitor, in patients with RET-altered solid tumors.
Authors: Zhou Qing , Wu Yi-Long , Zheng Xiangqian , Li Dapeng , Huang Dingzhi , Li Xingya , Liu Anwen , Song Xia , Jing Shanghua , Wang Mingxia , Wang Xicheng , Luo Yongzhong , Song Yong , Mi Yanjun , Zhou Jianying , Fan Yun , Su Haichuan , Huang Tao , Ouyang Weiwei , Ge Junyou 
Published: June 2023

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Background: KL590586 (A400/EP0031) is a potent next-generation selective RET inhibitor (SRI) with activity against acquired resistance mutations to first-generation SRIs, and brain metastases (mets). Here we present preliminary data of the phase Ⅰ part from a phase I/II study (KL400-I/II-01, NCT05265091) in patients (pts) with RET-altered advanced tumors to define safety, pharmacokinetics (PK) and efficacy. Methods: The phase Ⅰ of KL400-I/Ⅱ-01 consisted of dose-escalation (Bayesian Optimal Interval design) and dose-expansion. Primary endpoints were to determine the maximum tolerated dose (MTD) and/or Recommended Phase II Dose. Secondary endpoints included safety, PK, objective response rate (ORR), disease control rate (DCR), and duration of response (DoR) as per RECIST 1.1. Results: As of Dec. 30, 2022, 87 pts with RET-altered tumors were treated at 6 doses levels (10 to 120 mg QD). No DLTs were observed, and MTD was not reached. Incidence of treatment-related adverse events (TRAEs, any grade) was 93.1% (81/87), most (74.7%) were grade 1-2, reversible and included (>25%): AST increase (50.6%), ALT increase (48.3%), creatinine increase (33.3%), bilirubin increase (32.2%), constipation (32.2%) and headache (31%). 24.1% of pts had grade ≥3 TRAEs, the most common (occurring in >2% of pts) were ALP increase (2.3%), GGT increase (2.3%), ileus (2.3%). TRAEs led to dose reduction or treatment discontinuation in 4.6% and 6.9% of pts, respectively. 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 found to be 34.1-99.8 h. Clinical responses were observed from 40mg onwards. 69 pts treated at the 40-120mg dose levels (57 NSCLC, 10 MTC, 1 pancreatic cancer, 1 ovarian cancer) were evaluable for efficacy analysis, ORR was 64% (NSCLC, MTC and pancreatic cancer). Most pts (58/69) remained on treatment, with the longest >11 months. The ORR in pts with systemic pretreated NSCLC (median prior treatment: 2, range 1-9, 28% pretreated with anti-PD1/PD-L1 therapy) was 63%(20/32, 1 CR), DCR 91% with median DoR not reached. 9 pts received prior 1st gen SRI, 7 with tumor shrinkage of -10% to -69%, with 3 PR and 4 SD. 11 pts with brain mets (without radiotherapy):4/5 with measurable brain disease had 100%, 100%, 80%, and 47% shrinkage. Overall CNS DCR was 100%.The ORR in treatment naïve NSCLC was 76% (19/25, 1 CR), DCR 92% and median DoR not reached. 3/4 pts with brain mets (without radiotherapy) had complete or partial disappearance of baseline brain lesions. Conclusions: KL590586 was well-tolerated, and associated with robust clinical activity in RET-altered tumors regardless of tumor type, including NSCLC pts with resistance to1st gen SRIs and with CNS mets. Pivotal studies are planned. Clinical trial information: NCT05265091 .