First-in-human study of ZG19018, targeting KRAS G12C, as monotherapy in patients with advanced solid tumors.

e15127 Background: ZG19018 tablet is a selective KRAS G12C inhibitor that inhibits the activation of KRAS G12C and multiple downstream signaling pathways. It showed very promising anti-tumor effects in preclinical studies. Here we report the preliminary results from a phase 1 dose escalation study that assessed the tolerability, safety, pharmacokinetics and efficacy of ZG19018 in patients (pts) with advanced solid tumors. Methods: This is an open-label, multi-center study in pts with KRAS G12C mutated solid tumors and progressed following prior standard therapies. The study consisted of a rapid dose-escalation phase for the low-dose groups (50 mg qd and 150 mg qd, orally) and a standard 3+3 design phase for the high-dose groups (300 mg qd, 300 mg bid and 450 mg bid, orally). The first treatment cycle (21 days) was defined as the dose-limiting toxicity (DLT) assessment period. Patients could continue to receive ZG19018 until one of the treatment discontinuation criteria was met. Tumor response was assessed by the investigator per RECIST1.1 criteria. Pharmacokinetics profiles were also assessed in all pts. Results: As of January 31st, 2023, 14 pts (8 males and 6 females) completed the DLT assessments, with a median age of 65 years. Of them, 11 (78.6%) were non-small cell lung cancer (NSCLC) pts, 2 (14.3%) with colorectal cancer (CRC), and 1 (7.1%) with cervical cancer (CESC); 12 pts (85.7%) had received ≥ 1 line of stand therapies and 2 pts (14.3%) had received ≥ 3 lines. The dose group of 450 mg bid was determined as the maximally administered dose, where 2 pts experienced a DLT (grade 3 γ-GGT elevation and grade 3 ALT elevation, respectively), therefore an additional dose group of 400 mg bid has been added and is currently undergoing. Treatment-related adverse events (TRAEs) occurred in 13 pts (92.9%), most frequent in nausea (42.9%), diarrhea (42.9%), vomiting (35.7%), AST elevation (35.7%), γ-GGT elevation (35.7%), ALT elevation (28.6%), hypertriglyceridemia (28.6%), blood creatine phosphokinase MB elevation (21.4%) and ALP elevation (21.4%). No SAE was reported. In 12 pts evaluated for the best overall responses, 2 (16.7%) had PR (1 NSCLC, 1 CRC), 6 (50%) had SD (4 NSCLC, 1 CRC，1 CESC) and 4 (33.3%) had PD (4 NSCLC). The maximum drug exposure of ZG19018 is 8 months in 1 patient with colorectal cancer who is SD and remaining in the study. The C max and AUC 0-t increased from 50 mg qd to 450 mg bid approximately in dose proportion. Conclusions: ZG19018 is tolerable and demonstrates a good safety under the dose level of 450 mg bid. It also demonstrates preliminary antitumor effects in pts with solid tumors, with reasonable PK profiles. Clinical trial information: ChiCTR20220296 .