A phase 1 clinical trial to evaluate safety, tolerability, pharmacokinetics (PK) and efficacy of D-1553, a novel KRAS(G12C) inhibitor, in patients with advanced or metastatic solid tumor harboring KRAS(G12C) mutation.

Abstract Background: KRASG12C mutation is an oncogenic driver that occurs in approximately 15% of non-small cell lung cancer (NSCLC), 3% of colorectal cancer (CRC), and ~1% of several other solid tumors. D-1553 is a novel, potent and orally bioavailable KRASG12C inhibitor. Here we present the safety, tolerability and PK and preliminary efficacy of D-1553 from a phase I trial in patients (pts) with advanced or metastatic solid tumors harboring KRASG12C mutation. Method: Key inclusion criteria: KRASG12C identified by molecular testing, measurable disease, and refractory to or intolerant of standard therapy. D-1553 dose escalation included oral daily (QD) doses of 150, 300, 600, 800, and 1200 mg, and twice daily (BID) doses of 400, 600, and 800 mg. Primary endpoint: safety, tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary endpoints: PK parameters, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and duration of response (DOR), evaluated per RECIST 1.1. Results: As of Dec 27, 2021, 22 pts (12 [54.5%] male, median age 65 [range: 49-90]), including 14 pts with CRC, 6 pts with NSCLC, and 2 pts with other solid tumors, were enrolled. D-1553 was well absorbed, with a median time to reach maximum plasma concentration (Tmax) of 1-4 hours. The Cmax and AUC of each dose group (150-600 mg, QD; 400-600 mg, BID) increased linearly as the dose increased. However, the changes of Cmax and AUC in 600-1200 mg (QD), 600-800 mg (BID) groups were not in a dose-dependent manner. The most frequently reported treatment-related adverse events (TRAEs) (frequency ≥ 10%) were diarrhea, nausea, vomiting, headache, and lethargy, all grade ≤ 2. Thirteen pts (59.1%) had TRAEs: 11 pts (52.4%) had grade 2 or lower TRAEs; 2 (9.1%) had three grade ≥3 TRAEs (hypokalemia, hypertension, anaemia). No DLT has been reported. MTD was not reached. One pt (4.5%) discontinued the D-1553 therapy due to cerebral hemorrhage. This event was evaluated by investigator as unlikely related to the drug. Among 21 evaluable pts (including 14 CRC, 6 NSCLC, and 1 endometrial carcinoma (EC), confirmed ORR and DCR were 19.0% (4/21) and 85.7% (18/21), respectively. One pt with EC achieving PR had the best tumor burden reduction of 80%. Conclusion: In patients with KRASG12C mutated solid tumor, D-1553 is well tolerated with no DLTs at studied doses. The RP2D has been determined to be 600 mg BID. Preliminary efficacy results demonstrate promising clinical activity of single-agent D-1553 in pts with KRASG12C mutated solid tumor. This study is ongoing (NCT04585035) and more results will be presented at the meeting. Citation Format: Timothy Price, Jaspreet Grewal, Afaf Abed, Melissa Moore, Yu-Min Yeh, Shirish Gadgeel, Gary Richardson, Craig Underhill, Vinod Ganju, Keun-Wook Lee, Seok Jae Huh, Sang-We Kim, Chih-Hsin Yang, Yuh-Min Chen, Ziyong Xiang, Zhe Shi, Yaolin Wang, Ling Zhang, Michael Millward. A phase 1 clinical trial to evaluate safety, tolerability, pharmacokinetics (PK) and efficacy of D-1553, a novel KRASG12C inhibitor, in patients with advanced or metastatic solid tumor harboring KRASG12C mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT504.