Efficacy and safety profile of pimicotinib (ABSK021) in tenosynovial giant cell tumor (TGCT): Phase 1b update.
Authors: Yao Lu , Zhou Yong , Li Binghao , Xie Xianbiao , Du Xinhui , Yuan Ting , Chen Bo , Zou Qingping , Guo Qiuxiang , Liang Pan , Wang Chen , Shan Boyao , Tong Zhichao , Dong Yang , Weitao Yao , Shen Jingnan , Ye Zhaoming , Tu Chongqi , Niu Xiaohui 
Published: June 2023

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Background: TGCT is a rare type of locally aggressive neoplasm that is mainly caused by overexpression of colony-stimulating factor 1 (CSF1) gene. Pimicotinib is an oral, highly potent, and selective small-molecule antagonist of CSF-1R with minimum inhibition of c-Kit and PDGFR, and has been granted Breakthrough Therapy Designation for TGCT by FDA in Jan 2023. Here, we report the updates from 50 mg QD cohort as well as the preliminary data from 25 mg QD cohort in TGCT pts. Methods: The study (NCT04192344) is to evaluate the safety and preliminary antitumor activity of Pimicotinib at 50 mg QD and 25 mg QD in TGCT pts not amenable to surgical resection. Results: As of December 31, 2022, 49 TGCT pts were enrolled, including 37 pts treated with 50 mg QD and 12 pts with 25 mg QD. Median age was 39 y (range: 19-76) and 40.8% were male. The tumor location was mainly in knee (53.1%), hip (18.4%) or ankle (12.2%). Thirty-one pts received at least one prior surgery, and 1 pt received prior exploratory systemic therapy (Anlotinib). Median treatment duration was 7.9 mos (range: 0.4-12.5), and 89.8% remained on treatment. The ORR was 77.4% (24/31, including 2 CR) in 50 mg QD and 40% (4/10, including 1 CR) in 25 mg QD by IRC based on RECIST 1.1. Most responses were achieved within 25 wks and median DOR in both cohorts was not reached. Average improvement of flexion range of knee at wk 13 from baseline was 30.2 degrees (n = 13, range: 2, 105) in 50 mg QD and 4.8 degrees (n = 5, range: -12, 24) in 25 mg QD. Proportion of responders based on BPI-30 at wk 25 was 66.7% (16/24) in 50 mg QD and 60% (3/5) in 25 mg QD, along with a similar trend of stiffness. Most TEAEs were Gr 1 or 2. Four Gr 3/4 TEAEs were reported (2 drug-related), including 1 Gr 3 serious TEAE. Most common TEAEs (≥20%) include LDH increase (75.5%), CPK increase (67.3%), α-HBDH increase (63.3%), AST increase (42.9%), amylase increase (26.5%), ALT increase (24.5%), pruritus (20.4%) and rash (20.4%). No hair color changes or serious liver injuries were reported. CPK and transaminase elevations were asymptomatic, on-target and quickly recovered after drug interruptions. nder steady-state, 50 mg QD resulted in ~ 2-fold higher Cmax and Ctrough compared to 25 mg QD, in sync with findings from escalation phase. Significant PD changes were observed in both cohorts, such as increase in plasma CSF-1 levels, decrease in non-classical monocytes and C-terminal telopeptide(CTx). Changes from baselines in both CSF-1 and CTx showed a correlation with pimocetinib plasma concentrations. Conclusions: Pimicotinib has demonstrated a significant antitumor activity, favorable safety, and PK profiles at both 50 mg QD and 25 mg QD with no apparent hepatotoxicity. The changes in PD biomarkers indicate significant CSF-1R inhibition in TGCT pts. Updated data from 50 mg QD cohort showed higher ORR and continuous improvement over a longer treatment time, which supports the further evaluation of Pimicotinib in a phase 3 study. Clinical trial information: NCT04192344 .