D3S-001 is a next-generation KRAS-G12C inhibitor (G12Ci) designed to enhance target engagement efficiency and overcome growth factor-induced nucleotide exchange. D3S-001 was evaluated in a phase 1a dose-escalation study in patients with advanced solid tumors harboring KRASG12C mutation (N = 42) and a phase 1b expansion cohort of patients with non-small-cell lung cancer (NSCLC) whose disease progressed after prior G12Ci therapy (N = 20). The primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints included pharmacokinetics, confirmed objective response rate (ORR) and disease control rate. D3S-001 demonstrated dose-dependent pharmacokinetics and no dose-limiting toxicities, and the maximum tolerated dose was not reached. Grade 3 treatment-related adverse events were reported in seven patients (16.7%) in the G12Ci-naive dose-escalation cohort and two patients (10.0%) in the G12Ci-pretreated NSCLC expansion cohort. There were no grade 4 or 5 treatm

Abstract. Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting the active, GTP-bound (ON) form. T...

Targeting SRC overcomes G12Ci resistance in KRAS-G12C mutant cancers.

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KRASG12C inhibitor (G12Ci) has produced encouraging, albeit modest and transient, clinical benefit i

AbstractKRAS is one of the most frequently mutated oncogenes in human cancer (present in ∼25% of cancers). Recent approvals of covalent KRAS G12C inhibitors (KRAS G12Ci) have demonstrated that this on...

KRASG12C inhibitor (G12Ci) has produced encouraging, albeit modest and transient, clinical benefit i