A phase 1, first-in-human, open-label study evaluating the safety, tolerability, pharmacokinetics, and efficacy of RNK08954 in patients with advanced solid tumors with a KRAS G12D mutation.

729 Background: RNK08954 is a potent, oral and highly selective small molecule dual (On/OFF) non-covalent inhibitor of mutant KRAS G12D with unique pharmacologic properties that achieve high target exposure. RNK08954 given orally (PO) once daily demonstrated significant growth inhibition and tumor regressions in several xenograft models in vivo. Methods: This Phase 1 clinical study is designed to evaluate the safety, tolerability, PK/PD and antitumor activity of RNK08954. The Phase 1A (Dose Exploration) Enrolled 42 patients utilizing U-BOIN (Utility-based Bayesian Optimal Interval) design. Key eligibility criteria included patients (pts) with ECOG 0 or 1; advanced solid tumors with KRAS G12D mutations; documented evidence of disease progression; and adequate organ function. Patients with stable brain metastases were also eligible. RNK08954 was administered PO QD for 21-day cycles until disease progression (PD). A Safety Review Committee (SRC) overaw the study. The endpoints of the study were optimally biological dose (OBD), safety, PK and clinical activity per RECIST v1.1. Results: 42 pts were enrolled across 5 dose levels: 200 (n=1), 400 (n=3), 800 (n=10), 1000 (n=16), and 1200mg QD (n= 12). Pts presented with non-small cell lung cancer [NSCLC (n=14)]; PDAC (n=17), ovarian/endometrial cancers (n=3) and others (n=8). Most pts (98%) received at least one prior therapy. Treatment was generally well tolerated. Grade ≥ 3 treatment related adverse events (TRAE) included diarrhea (5%), vomiting (2%), decreased appetite (5%), decreased white blood cells (2%), and hypokalemia (5%). A total of 36 patients were evaluable for response. Objective response rate (ORR) and disease control rate (DCR) were 28% and 86% in all patients, and 15% and 85% in PDAC, respectively. Median duration on treatment was 3.5 months. Additional safety, efficacy and PK outcomes will be presented at the meeting. Conclusions: In pts with KRAS G12D mutation, the treatment with RNK08954 was well tolerated and demonstrated encouraging clinical activity, particularly in PDAC patients. The phase 1B is now enrolling patients in these indications. Clinical trial information: NCT06667544 .