Phase I/IIa study of DN022150, a novel selective noncovalent small molecule KRAS G12D inhibitor in patients with advanced KRAS G12D–mutant solid tumors.

Abstract

3007 Background: The KRAS G12D mutation is ranks among the most common RAS mutations across human cancers and is closely linked to poor clinical outcomes. DN022150 is a novel highly selective KRAS G12D inhibitor, that exerts potent antitumor effect by specifically binding to the switch-II pocket of the mutant KRAS G12D protein, this binding mechanism blocks the interaction of GDP and GTP with the mutant protein, thereby abrogating activation of the downstream of the RAS-MAPK signaling pathway. We report preliminary findings from the first-in-human study of DN022150 in patients with advanced KRAS G12D-mutant solid tumors. Methods: This Phase I/IIa study evaluates the safety, tolerability, pharmacokinetics (PK), and efficacy of DN022150 in patients with locally advanced or metastatic solid tumors harboring KRAS G12D mutations who have progressed following prior standard therapies. The study includes three sequential parts: dose escalation, dose expansion, and indication exploration. During dose escalation, patients receive fixed doses of DN022150. Based on integrated analysis of safety, tolerability, PK, and efficacy data from escalation phase, approximately 1-3 dose/frequency cohorts will be selected for the subsequent dose-expansion phase. The primary objective is to evaluate the safety, tolerability, and preliminary antitumor activity of DN022150 in patients with KRAS G12D-mutated advanced solid tumors. Results: As of January 22, 2026, a total of 56 patients were enrolled. Among them, 83.9% (47/56) had an ECOG PS of 1 and 66.1% (37/56) diagnosed with pancreatic cancer. Approximately 80% had received ≥2 prior lines of systemic therapy. Safety analysis included 49 participants (dose levels: 20-650 mg). Notably, no dose-limiting toxicities occurred across all dose levels. Grade ≥3 TEAEs were observed in 44.9% (22/49) of patients, with TRAEs in 30.6% (15/49). No grade 4-5 TRAEs were documented. TRAEs led to dose delays in 14.3% (7/49) of patients and treatment interruptions in 16.3% (8/49). The most common grade ≥3 TRAEs (≥5%) were neutropenia, anemia, and leukopenia. Tumor assessments were conducted every 8 weeks (±7 days). Among the 31 evaluable patients, treated at dose levels of 200 mg to 650 mg, an impressive 96.8% (30/31) achieved target lesion reduction at first post-baseline assessment, including 71% (22/31) with ≥20% reduction. ORR was 37.5% (3/8) at 450 mg and 31.3% (5/16) at 650 mg, with DCR of 87.5% (7/8) and 93.8% (15/16). Conclusions: DN022150 demonstrated favorable safety and tolerability profiles in patients with KRAS G12D-mutated advanced solid tumors, with no dose-limiting toxicities observed and manageable TRAEs. The agent showed potent antitumor activity, confirming its precise targeting of the KRAS G12D mutation. These results position DN022150 as a promising novel therapy for this molecularly defined population. Clinical trial information: CTR20242749.