Clinical activity and safety of RNK08954 in advanced non–small cell lung cancer (NSCLC) patients with <i>KRAS</i> G12D mutation (NCT06667544).

3006 Background: KRAS G12D is the most prevalent subtype of KRAS mutations across solid tumors. RNK08954 is a potent and selective KRAS G12D small molecule oral inhibitor. It inhibited proliferation of KRAS G12D-mutant cells and demonstrated significant tumor regressions in mouse xenograft models. Here we report the results of RNK08954 from Phase 1 first-in-human study. Methods: This ongoing multicenter open-label trial of RNK08954, comprises of: Phase 1a dose-escalation (U-BOIN design, 5 dose levels: 200, 400, 800, 1000 and 1200 mg RNK08954 single agent QD) and Phase 1b dose optimization and expansion cohorts (NSCLC, Pancreatic, and other tumor types). Key endpoints were determining the recommended doses for expansion (RDE), safety, tolerability, antitumor activity (objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression free survival (PFS)), pharmacokinetics and pharmacodynamics. Patients (pts) enrolled into the study had solid tumors not amenable to standard therapy; 0 or 1 ECOG PS; and KRAS G12D mutation. Results: At data cutoff (Jan 20, 2026), 106 pts were enrolled, with 47 pts presenting with NSCLC. The median age was 65 years, and 91.5% of pts had ECOG 1. Prior lines of therapy ranged between 1 and 3, with a median of 14 mo since NSCLC diagnosis. The ORR was 38.5% (15/39; 95% CI: 23.4, 55.4), DCR was 94.9% (37/39; 95% CI: 82.7%, 99.4%), median DoR was not reached (NR) at the time of analysis (Q1, Q3: 4.8, NR) and median PFS will be reported with mature data. ctDNA analysis demonstrated correlation with clinical benefits. RNK08954 demonstrated a near-dose dependent exposure across dose levels. Both 1000 and 1200 mg were chosen for RDE, and the recommended Phase 2 is considered as 1200 mg QD. Overall, treatment was tolerated, with diarrhea (78.7%), nausea (61.7%) and vomiting (55.3%) being the most frequent treatment related events (TRAEs) and were mainly Grade 1. Grade 3 TRAEs occurred in 23.4%, with diarrhea most frequent TRAEs (10.6%). No Grade 3 or higher transaminase elevation (ALT/AST) was observed, only one patient experienced Grade 3 neutropenia.There were no fatal events. Further updated results will be presented at the meeting. Conclusions: RNK08954 was well tolerated and displayed promising antitumor activity in pts with KRAS G12D-mutant NSCLC. The study supports further evaluation either as monotherapy or in combination with standard of care and/or novel agents. Clinical trial information: NCT06667544 .