D3 Bio Showcases Next-Generation KRAS G12C Inhibitor D3S-001 in Nature Medicine and AACR 2025 Presentation, Demonstrating Breakthrough Efficacy and Resistance Overcoming Potential
D3 Bio, a clinical-stage biotechnology company at the forefront of precision oncology innovation, has announced a major milestone in its pursuit of next-generation cancer therapies. The company revealed significant clinical findings for its lead investigational therapy, D3S-001, in two prestigious forums simultaneously: a peer-reviewed publication in Nature Medicine and an oral presentation at the 2025 American Association for Cancer Research (AACR) Annual Meeting.
The data presented and published represent a major step forward in the development of therapies targeting KRAS G12C, a common and challenging oncogenic driver mutation across several difficult-to-treat solid tumors. These findings not only demonstrate D3S-001’s differentiated mechanism of action and favorable safety profile but also underscore its best-in-class potential, particularly in patients who have developed resistance to existing KRAS G12C inhibitors.
Targeting KRAS G12C: A Persistent Challenge in Oncology
KRAS G12C mutations are found in a significant subset of patients with non–small cell lung cancer (NSCLC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and other solid tumors. While first-generation KRAS G12C inhibitors—such as sotorasib and adagrasib—have provided therapeutic options for these patients, their efficacy is often limited by resistance mechanisms that emerge during treatment.
D3 Bio’s investigational drug, D3S-001, is engineered to overcome these limitations by achieving more complete and sustained inhibition of the KRAS G12C protein, even in tumors that have developed resistance to earlier treatments. The clinical data now emerging from early-phase trials provide compelling evidence that D3S-001 could represent a transformative advance in this space.
Strong Phase 1 Results Show Compelling Efficacy and Safety
In the multicenter Phase 1a/1b study (NCT05410145), D3S-001 demonstrated a remarkable overall objective response rate (ORR) of 73.5% in KRAS G12C inhibitor–naïve patients, spanning multiple cancer types. Specifically, the drug achieved:
- 66.7% ORR in non–small cell lung cancer (NSCLC)
- 88.9% ORR in colorectal cancer (CRC)
- 75.0% ORR in pancreatic ductal adenocarcinoma (PDAC)
These results underscore the broad antitumor activity of D3S-001 across multiple KRAS G12C-driven malignancies, offering hope to patients who have not previously received targeted therapy for this mutation.
Notably, D3S-001 also demonstrated efficacy in patients who had previously been treated with first-generation KRAS G12C inhibitors and subsequently experienced disease progression. Among 20 such NSCLC patients, the therapy achieved a 30% ORR and an 80% disease control rate (DCR), highlighting its ability to overcome acquired resistance—one of the most significant unmet needs in KRAS-targeted therapy.
A Paradigm Shift: Redefining What a KRAS G12C Inhibitor Can Achieve
“These findings demonstrate that D3S-001 fulfills the defining qualities of a next-generation KRAS G12C inhibitor,” said Dr. Byoung Chul Cho, MD, PhD, Professor and Head of Yonsei Cancer Center at Yonsei University College of Medicine, and co-supervisory author of the Nature Medicine publication. “It offers fast and complete target engagement, has a favorable safety profile, demonstrates promising and consistent efficacy across tumor types, penetrates the brain, and crucially, it can overcome resistance seen with first-generation inhibitors.”
Dr. Cho added that the results position D3S-001 as more than an incremental improvement over existing therapies. Rather, it may be a foundational therapy that redefines the treatment landscape for patients with KRAS G12C-driven cancers.
AACR 2025 Presentation Reinforces Resistance-Overcoming Capabilities
At the 2025 AACR Annual Meeting, D3 Bio presented updated results from a Phase 2 expansion cohort focused on NSCLC patients who had previously received and progressed on first-generation KRAS G12C inhibitors. The data underscore D3S-001’s ability to provide meaningful clinical benefit even in this heavily pretreated and refractory population.
Key highlights from the AACR presentation include:
- 60% of patients experienced tumor shrinkage
- 30% achieved partial responses
- 80% disease control rate
- In patients with detectable circulating tumor DNA (ctDNA):
- 11 of 14 achieved >90% reduction in KRAS G12C mutant allele frequency (MAF)
- 6 of these 14 patients (43%) achieved partial responses
Importantly, the study also documented clinical responses in patients with KRAS G12C gene amplification—a known resistance mechanism that limits the effectiveness of first-generation inhibitors. This observation provides further support for D3S-001’s unique mechanism of action and its ability to address resistant tumor biology.
A Therapeutic Option for Both Naïve and Refractory Patients
Dr. Tony Mok, MD, Professor of Clinical Oncology at the Chinese University of Hong Kong and co-supervisory author of the Nature Medicine paper, highlighted the real-world implications of these findings. “The clinical data published in Nature Medicine and presented at AACR validate D3S-001 as a promising treatment option for patients with KRAS G12C–driven tumors—regardless of whether they are naïve or refractory to first-generation inhibitors,” said Dr. Mok. “Its ability to produce meaningful responses in patients who have few other treatment options brings hope to a group that has historically been underserved.”
Building on Scientific Collaboration and Innovation
The success of D3S-001 thus far is rooted not only in innovative drug design but also in D3 Bio’s collaborative approach to scientific research and clinical development. “At D3 Bio, we believe that solid science, combined with strong partnerships with global thought leaders, is the key to advancing the field,” said George Chen, MD, Founder, Chairman, and CEO of D3 Bio.
Dr. Chen noted that the preclinical foundation for D3S-001 was previously published in Cancer Discovery, where the compound’s novel mechanism and pharmacological advantages were described in detail. “Now we are thrilled to see how these attributes have translated nearly seamlessly into the clinic. The clinical progress of D3S-001 is a testament to the power of science and collaboration to deliver therapies that matter.”
As D3 Bio continues to advance D3S-001 through the clinic, the company is focused on expanding its development efforts, exploring additional tumor types, and potentially accelerating the drug’s path to regulatory approval. Plans are underway to initiate additional Phase 2 and Phase 3 trials, including global studies that could support registration in multiple territories.
With its demonstrated efficacy in both treatment-naïve and resistant populations, favorable safety profile, and evidence of central nervous system activity, D3S-001 is emerging as a frontrunner in the race to develop truly next-generation KRAS G12C inhibitors.
The dual spotlight on D3S-001—via publication in Nature Medicine and presentation at AACR 2025—marks a pivotal moment for D3 Bio and for the broader oncology community. With mounting clinical evidence supporting its efficacy and resistance-overcoming capabilities, D3S-001 may soon redefine the treatment paradigm for patients with KRAS G12C-mutated cancers.
As the company continues to push forward, patients and clinicians alike are watching closely, hopeful that D3S-001 could become a new standard of care in precision oncology.
