D3 Bio's investigational drug D3S-001 has demonstrated remarkable efficacy in patients with KRAS G12C mutation-driven cancers, according to landmark clinical data published in Nature Medicine and presented at the 2025 American Association for Cancer Research (AACR) Annual Meeting.
The clinical-stage biotechnology company reported that D3S-001, a next-generation KRAS G12C inhibitor, achieved an overall objective response rate (ORR) of 73.5% in KRAS G12C inhibitor-naïve patients across multiple tumor types in a Phase 1a/1b clinical study (NCT05410145).
Impressive Response Rates Across Multiple Cancer Types
The study revealed particularly strong efficacy across several difficult-to-treat cancers:
- 66.7% response rate in non-small cell lung cancer (NSCLC)
- 88.9% response rate in colorectal cancer (CRC)
- 75.0% response rate in pancreatic ductal adenocarcinoma (PDAC)
Perhaps most significantly, D3S-001 demonstrated efficacy in patients who had previously progressed on first-generation KRAS G12C inhibitors such as sotorasib and adagrasib. In 20 NSCLC patients with acquired resistance to these therapies, D3S-001 achieved a 30.0% overall response rate and an 80.0% disease control rate.
"These findings demonstrate that D3S-001 fulfills the defining qualities of a next-generation KRAS G12C inhibitor: fast and complete target engagement, favorable safety, consistent and promising efficacy across all tumor types, brain penetration, and ability to overcome first-generation resistance," said Byoung Chul Cho, MD, PhD, lead and co-supervisory author and Professor and Head of Yonsei Cancer Center, Yonsei University College of Medicine.
Overcoming Resistance Mechanisms
At AACR 2025, D3 Bio presented updated results from a Phase 2 expansion cohort specifically examining NSCLC patients previously treated with FDA-approved or experimental G12C inhibitors. The data revealed:
- 60% of patients experienced tumor shrinkage
- 30% achieved partial responses
- 80% disease control rate
- 11 of 14 ctDNA-positive patients achieved >90% G12C MAF reduction
- 43% response rate in the ctDNA-positive population
- Responses in patients with KRAS G12C amplification, a known resistance mechanism
These results are particularly significant given the limited treatment options for patients who develop resistance to first-generation KRAS G12C inhibitors.
Mechanism of Action and Development Status
D3S-001 is designed to achieve rapid and complete KRAS G12C target engagement. In preclinical studies, it demonstrated high covalent potency, complete engagement of KRAS G12C at clinically relevant doses, and CNS penetration properties.
"The clinical data validates D3S-001 as a promising treatment for patients with KRAS G12C-driven tumors, both naïve and refractory to first-generation inhibitors," said Tony Mok, MD, co-supervisory author of the Nature Medicine paper and Professor of Clinical Oncology at the Chinese University of Hong Kong.
The drug is currently in a Phase II global clinical trial in patients with advanced solid tumors harboring KRAS G12C mutations, including NSCLC, CRC, and other tumor types.
Clinical Significance and Unmet Need
KRAS mutations occur in approximately 25% of all cancers, with the G12C mutation being particularly common in NSCLC (13%), colorectal cancer (3%), and pancreatic cancer (2%). First-generation KRAS G12C inhibitors have shown clinical benefit, but resistance often develops, creating a significant unmet need.
George Chen, MD, Founder, Chairman, and CEO of D3 Bio, emphasized the importance of the findings: "Our Cancer Discovery paper reported the new mechanism and properties of D3S-001 in preclinical settings, and now we are excited to witness the nearly seamless translation of these important features into the clinic."
Future Directions
The promising results across multiple tumor types, including those resistant to first-generation therapies, position D3S-001 as a potential cornerstone therapy for KRAS G12C-driven cancers. The drug's ability to penetrate the blood-brain barrier also suggests potential efficacy against brain metastases, a common complication in advanced cancer.
As the Phase II trial progresses, researchers will continue to evaluate D3S-001's efficacy, safety profile, and ability to overcome various resistance mechanisms. The development of D3S-001 represents an important advance in precision oncology, potentially offering new hope to patients with limited treatment options.
