On April 29, 2025 D3 Bio, a clinical-stage biotechnology company pioneering precision oncology therapies, reported the simultaneous publication of landmark clinical data on its lead investigational drug D3S-001 in Nature Medicine and oral presentation of updated results at the 2025 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, D3 Bio, APR 29, 2025, View Source [SID1234652334]). These data affirm D3S-001’s differentiated mechanism of action, favorable safety profile and compelling efficacy in patients with KRAS G12C mutation–addicted cancers, including patients previously treated with first-generation KRAS G12C inhibitors.

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Promising Efficacy in G12Ci-Naïve and Resistant Patients

In a Phase 1a/1b clinical study (NCT05410145), D3S-001 demonstrated an overall objective response rate (ORR) of 73.5% in KRAS G12C inhibitor-naïve patients across multiple tumor types, including:

66.7% in non–small cell lung cancer (NSCLC)
88.9% in colorectal cancer (CRC)
75.0% in pancreatic ductal adenocarcinoma (PDAC)
Additionally, in 20 patients with NSCLC who had previously been treated with and progressed on first-generation G12C inhibitors, including sotorasib and adagrasib, D3S-001 achieved a 30.0% overall response rate (ORR) and 80.0% disease control rate (DCR), providing direct clinical evidence of its ability to overcome acquired resistance to first-generation G12Ci therapies.

"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. "We believe it is a truly new-generation KRAS G12C inhibitor with the potential to overcome the limitations of the first-generation inhibitors and become a cornerstone therapy for KRAS G12C-driven cancers."

AACR 2025 Data Highlights the Activity of D3S-001 in Overcoming Resistance in Patients with NSCLC Who Have Progressed on First-Generation G12C Inhibitors

At AACR (Free AACR Whitepaper) 2025, D3 Bio shared updated results from a Phase 2 expansion cohort of NSCLC patients who had previously been treated with FDA-approved or other experimental G12C inhibitors. The compound demonstrates encouraging clinical benefits in this patient population. The data include:

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, with 6 achieving partial response (a 43% response rate in the ctDNA-positive population)
Responses were observed in patients with KRAS G12C amplification, a known resistance mechanism to first-generation inhibitors, consistent with previous preclinical observations
The results support D3S-001’s unique ability to overcome molecular resistance in a population with urgent unmet medical needs.

"The clinical data, published at Nature Medicine and presented at AACR (Free AACR Whitepaper), 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, Professor of Clinical Oncology at the Chinese University of Hong Kong, and a global thought leader in targeted therapy for lung cancer. "Its potential to induce compelling responses in these challenging cases offers hope for a patient population with limited treatment options."

"At D3 Bio, we believe that solid science, combined with strong collaboration with global thought leaders, is the foundation for driving the field forward," said George Chen, MD, Founder, Chairman, and CEO of D3 Bio. "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. The continued clinical advancement of D3S-001 reflects not only the innovation behind its design, but also the strength of these collaborations to bring meaningful therapies to patients worldwide."

About D3S-001

D3S-001 is a next-generation KRAS G12C inhibitor designed to achieve rapid and complete KRAS G12C target engagement. In preclinical investigations, D3S-001 has demonstrated high covalent potency, complete engagement of KRAS G12C at clinically relevant doses and CNS penetration properties. D3S-001 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. Key publications:

D3S-001, a KRAS G12C Inhibitor with Rapid Target Engagement Kinetics, Overcomes Nucleotide Cycling, and Demonstrates Robust Preclinical and Clinical Activities. Cancer Discov (2024) 14 (9): 1675–1698.
D3S-001 in advanced solid tumors with KRAS G12C mutations. Nature Medicine (View Source)