First-in-human phase 1 study of pimicotinib (ABSK021), a CSF-1R inhibitor, in patients with advanced solid tumors.
Authors: Falchook Gerald Steven , Liang Yan , Harvey R. Donald , Fu Siqing , Weitao Yao , Qin Yan-ru , Zhang Xiaojing , Henry Jason Timothy , Zou Qingping , Shan Boyao , Liang Pan , Wang Chen , Li Wenjia , Pamuklar Zehra Nurgul , Pei Yi , Chang Zhiwei , Wang Jiaqiang , Piha-Paul Sarina A. , Bhave Manali A. , Yin Yongmei 
Published: June 2023

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Background: Colony-stimulating factor 1 (CSF-1) pathway is involved in the development of various types of cancer. Pimicotinib is an orally available, selective, potent small molecule CSF-1R inhibitor with significant pre-clinical anti-tumor activity. Here we present the results of the phase 1 trial. Methods: The escalation part employed a 3+3 design with a starting dose of 25 mg QD (28-day/ cycle) to determine the maximum tolerated dose (MTD) and the recommended dose for expansion (RDE). Additional pts with selected tumor types including pancreatic carcinoma, triple-negative breast cancer, lung cancer, and sarcoma were treated at RDE in the expansion part for further evaluation. Tenosynovial giant cell tumor (TGCT) cohorts were analyzed and reported separately. Results: As of December 31, 2022, 74 pts received at least one dose of pimicotinib at 25 mg (n=6), 50 mg (n=58), 75 mg (n=8), or 100 mg (n=2) QD. respectively. Median age was 59 y; 68.9% were female; 47.3% were white, 33.8% were Asian and 18.9% were African American. 74.3% were ECOG PS 1; 85.1% had metastasis; 67.6% had ≥3 lines of prior systemic anti-tumor therapies. Median duration of treatment was 49.5 days (range 4-377). Treatment-related adverse events (TRAEs), Grade ≥3 TRAEs, and serious TRAEs occurred in 74.3%, 21.6%, and 4.1% of pts, respectively. The most common TRAEs (≥20%) were serum enzyme elevations, including CPK, AST and LDH, which were all believed to be pimicotinib MOA related, with CPK increase (14.9%) being the only Grade ≥3 TRAE reported in ≥10% of pts. 3 pts (4.1%) reported serious TRAEs of ascites, blood bilirubin increase, and vaginal hemorrhage. After single and multiple dosing, pimicotinib plasma exposure increased slightly less than dose proportion. The rapid oral absorption (median tmax of 0.87 - 1.52 hrs) with moderate terminal t1/2 (mean t1/2 ranges: 43.6 - 63.5 hrs) suggested sustained drug exposure was achieved with a once daily dosing schedule. No dose adjustment was needed based on tested covariates including weight, age and race. Pimicotinib treatment led to a more than 85% reduction of non-classical monocytes (NCM) across all dose levels. Plasma CSF-1 levels were significantly increased from 25mg QD to 50mg QD and reached a plateau at 50mg QD, with ~40-fold maximal induction. Reduced CD163+ macrophages in skin and tumor tissues were seen at 50mg QD. All tested doses showed adequate inhibition of NCM, and CSF-1 change showed a positive correlation with plasma pimicotinib concentration. The MTD and RDE were determined as 75 mg QD and 50 mg QD. Conclusions: Tolerable safety profile and favorable PK/PD properties supported pimicotinib to be further evaluated in advanced solid tumors, including combinations. Clinical trial information: NCT04192344 .