Phase I study of D-1553 to assess safety and efficacy in patients with non-small cell lung cancer (NSCLC) harboring KRAS(G12C) mutation.

Abstract Background: KRASG12C mutation acts as an oncogenic driver and occurs in ~15% of NSCLC. D-1553 is a novel and potent small molecule inhibitor of KRASG12C. Here we present the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of D-1553 in KRASG12C mutated NSCLC. Methods: Key inclusion criteria: KRASG12C identified by molecular testing, and after progression of standard therapy. Oral daily (QD) doses of 600, 800 and 1200 mg, and twice daily (BID) doses of 400 and 600 mg were assessed in dose escalation part; 600 mg BID was assessed in dose expansion part. Endpoints included safety, PK parameters, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and duration of response (DOR), evaluated by RECIST 1.1. Efficacy results included 6 NSCLC pts from dose escalation part of another Phase I study of D-1553 [NCT04585035] with similar inclusion/exclusion criteria as this study. Results: As of Dec 27, 2021, 16 pts with NSCLC (15 [93.8%] male, median age 61 [range: 30-74]) were enrolled in dose escalation part and 8 pts were evaluated in dose expansion part. D-1553 was well absorbed, with a median time to reach tmax in 1-4 hours. The Cmax and AUC of each dose group tested (400 mg and 600 mg, BID) increased linearly as the dose increased. However, the changes of Cmax and AUC in 600, 800 and 1200 mg (QD) group were not dose-dependent. No DLTs had been reported in dose escalation part. 15 pts (93.8%) had treatment-related adverse events (TRAEs), most of which were grade 1-2. The most frequently reported TRAEs (frequency ≥ 15%) were elevated alanine aminotransferase, aspartate aminotransferase and conjugated bilirubin, rash, anemia, asthenia, decreased appetite, hyperuricemia, and increased γ-glutamyltransferase. Among the 28 pts (including 14 pts from dose escalation, 8 pts from dose expansion, and 6 pts with NSCLC from another D-1553 study) evaluable for tumor response, 12 pts had partial response (PR), and 14 had stable disease (SD). ORR and DCR were 42.9% (12/28) and 92.9% (26/28), respectively. Among the 11 pts in 600 mg BID group, 6 pts had PR, and 3 had SD. ORR and DCR were 54.5% (6/11,) and 81.8% (9/11), respectively. Most of the patients with PR or SD were continuing on study at the time of the data cut-off. Conclusion: D-1553 is well tolerated with no DLTs at studied doses. Early results demonstrate significant anti-tumor activity of single-agent D-1553 in pts with KRASG12C mutated NSCLC. This study is ongoing. More results will be presented at the meeting. Citation Format: Hong Jian, Zhenbo Song, Yiping Zhang, Kunyan Li, Nong Yang, Melissa Moore, Pingli Wang, Yanqiu Zhao, Yi Gong, Craig Underhill, Sang-We Kim, Cheng-Ta Yang, Ziyong Xiang, Zhe Shi, Ling Zhang, Yaolin Wang, Shun Lu. Phase I study of D-1553 to assess safety and efficacy in patients with non-small cell lung cancer (NSCLC) 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 CT505.