D3S-001 in advanced solid tumors with KRAS^G12C mutations: a phase 1 trial.

Area of Science:

• Oncology
• Pharmacology
• Clinical Trials

Background:

• KRAS-G12C mutations are key drivers in various advanced solid tumors.
• Existing KRAS-G12C inhibitors (G12Ci) face challenges like growth factor-induced nucleotide exchange.
• D3S-001 is a next-generation G12Ci designed for enhanced target engagement.

Purpose of the Study:

• To evaluate the safety and tolerability of D3S-001 in a Phase 1a dose-escalation study.
• To determine the maximum tolerated dose (MTD) of D3S-001.
• To assess the preliminary efficacy, including objective response rate (ORR), in patients with KRAS-G12C mutated tumors.

Main Methods:

• Phase 1a dose-escalation study in 42 patients with advanced solid tumors harboring KRAS-G12C mutation.
• Phase 1b expansion cohort in 20 patients with KRAS-G12C mutated non-small-cell lung cancer (NSCLC) pretreated with G12Ci.
• Assessment of safety, pharmacokinetics, MTD, ORR, and disease control rate (DCR).

Main Results:

• D3S-001 exhibited dose-dependent pharmacokinetics with no dose-limiting toxicities or MTD reached.
• Grade 3 treatment-related adverse events were low (16.7% in G12Ci-naive, 10.0% in G12Ci-pretreated).
• Confirmed ORR was 73.5% in the G12Ci-naive population (NSCLC, colorectal, pancreatic cancer) and 30.0% in pretreated NSCLC patients.

Conclusions:

• D3S-001 monotherapy is safe and well-tolerated in patients with KRAS-G12C mutated solid tumors.
• The drug demonstrates significant antitumor activity, with high ORR in treatment-naive patients.
• A dose of 600 mg was selected for further investigation; Phase 1b expansion is ongoing.