Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of GEC255, a novel KRASG12C inhibitor, in advanced solid tumors.
Authors: Zhang Yan , Zhou Lin , Gong Youling , Huang Meijuan , Tang Min , Liu Yongmei , Yu Min , Xiu Weigang , Liang Xinjun , Liu Xinyu , Fu Xin-Yuan , Lu You 
Published: June 2023

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Background: The KRASG12C mutation occurs in 12-14% of NSCLC and in 3-5% of CRC patients and is recognized as an oncogenic driver mutation. Recently the discovery of a cryptic binding pocket within the effector region of the KRASG12C oncoprotein has led to the rapid clinical development of a new series of specific inhibitors. GEC255 is a novel small molecule which showed excellent target engagement ability and a favorable pharmacological profile. Methods: This is a phase 1, open-label, multicenter study (CTR20212486) to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of GEC255 in patients (pts) with advanced solid tumors bearing KRASG12C mutation. The primary endpoint is safety and key secondary endpoints include PK and ORR. Key inclusion criteria: KRASG12C mutation identified through digital PCR, measurable or evaluable disease, ECOG PS ≤1, and life expectancy > 3 months. Key exclusion criteria: previous administration of specific KRASG12C inhibitors, uncontrollable plasma cavity effusion. Phase 1a is an accelerated titration, dose-escalating study to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Phase 1b is a dose expansion study which will enroll pts with NSCLC, CRC, and other solid tumors harboring the KRASG12C mutation. GEC255 will be administered PO QD until disease progression, intolerance, or withdrawal of consent. Results: 16 NSCLC pts (15 men, 1 woman, median age 58 y) were enrolled in Phase 1 dose escalation for the first 4 dose cohorts followed with dose escalation in chosen doses. No dose-limiting toxicity was observed and MTD has not been identified yet. GEC255 showed the linear increase in AUC exposure and Cmax with increasing doses. Tmax was 2-4 hours in all dosing groups and Ctrough within the 24-hour period was higher than pERK IC90 even in low dose group. The half-life of GEC255 in 24h period is about 8-9h and there is no increase in AUC upon daily dosing for 28 consecutive days. Among the 16 pts, most pts (n = 13) had ≥1 prior lines of treatment (tx). A total of 15 patients had treatment-related adverse events and most AEs are G1 or G2 (93.3%); the most frequent AEs are diarrhea (56.3%), ALT increase (37.5%), rashes (25%), and anemia (25%). Tumor response was evaluated in 13 pts. 10 pts (76.9%) had objective response (complete or partial response) and 12 pts (92.3%) had disease control (objective response or stable disease). In 600mg dose group, the ORR was 83.3% and DCR was 100% (n = 6). 7 pts are continuing to receive GEC255. Conclusions: GEC255 has been well tolerated at the doses tested and has shown encouraging anticancer activity to advanced NSCLC patients with KRASG12C mutation pts. MTD has not been determined, and enrollment into the dose exploration is ongoing. ( http://www.chinadrugtrials.org.cn/index.html ). Clinical trial information: CTR20212486 .