A phase I/II study of first-in-human trial of JAB-21822 (KRAS G12C inhibitor) in advanced solid tumors.
Jian Li, Jun Zhao, Baoshan Cao, Jian Fang, Xiaoyan Li, Mengzhao Wang, Yi Ba, Xingya Li, Zhihua Li, Zhe LIU, Yongsheng Wang, Ying Cheng, Chunmei Bai, Lin Shen
Abstract
3089 Background: KRAS G12C mutation occurs in approximately 4% of non-small cell lung cancer (NSCLC), 1-2% of colorectal cancer (CRC) and other solid tumors in China. JAB-21822 (Jacobio, Beijing, PRC) is a highly selective, covalent oral inhibitor of KRAS G12C. Methods: NCT05009329 is an ongoing first-in-human, open label phase I/II study of JAB-21822 in patients with advanced solid tumors. The primary objective is to evaluate the safety and tolerability of JAB-21822. Other objectives include preliminary efficacy, pharmacokinetics, and biomarkers. Here we report the results from the dose escalation phase of the trial. Results: As of January 28th, 2022, 53 patients with a median age of 62 years (39-79) were enrolled in 5 different dose levels: 200mg QD, 400mg QD, 800mg QD, 400mg BID and 400mg TID. Most patients (55%) had ≥ 2 prior lines of therapy. No dosing-limiting toxicities were observed. Two treatment-related adverse events (TRAEs) were G4 neutropenia (1 in 400mg BID and 1 in 400mg TID). The most common TRAEs (≥ 10%) included anemia (24.5%), total bilirubin increase (20.8%), direct bilirubin increase (15.1%), proteinuria (13.2%) and indirect bilirubin increase (11.3%). Only Grade 1 and 2 TRAEs were observed in the QD cohorts. A total of 33 patients (22 NSCLC, 9 CRC and 2 pancreatic cancer) had at least 1 post-baseline tumor assessment; in the 800mg QD cohort, overall response rate (ORR) and disease control rate (DCR) were 50% (5/10) and 100% (10/10), respectively, including 4 non-confirmed partial response (PR); in the 400mg QD cohort had an ORR and DCR of 80% (4/5) and 100% (5/5) respectively, including 2 non-confirmed PR. Patients with NSCLC (400mg QD and 800mg QD), the ORR and DCR were 70% (7/10) and 100% (10/10), respectively, including 5 non-confirmed PR. With respect to the pharmacokinetics analysis, JAB-21822 was rapidly absorbed with an average T max of 2 hr and reached higher plasma exposures (C max and AUC 0-24h ) after a single dose and multiple doses at C1D8. Conclusions: JAB-21822 was well tolerated with impressive preliminary efficacy in patients with heavily treated solid tumors harboring KRAS G12C mutation. The study is enrolling patients in the expansion phase. Multiple JAB-21822-based combination trials are also ongoing. Clinical trial information: NCT05009329.