D3S-001 Receives FDA Breakthrough Therapy, Orphan Drug Designations in Select KRAS G12C-Mutant Solid Tumors

The FDA has granted breakthrough therapy designation to D3S-001 for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non–small cell lung cancer (NSCLC) who have received prior chemotherapy and immunotherapy but have not been previously treated with a KRAS G12C inhibitor.1

D3S-001 has also been granted orphan drug designation (ODD) for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC).

Both regulatory decisions are supported by data from an ongoing phase 1/2 study (NCT05410145) evaluating D3S-001 in patients with advanced solid tumors displaying a KRAS G12C mutation.

Findings from the phase 1a/b portion of this trial, reported during the 2024 ESMO Congress and published in Nature Medicine, demonstrated an objective response rate (ORR) of 73.5% among KRAS G12C inhibitor–naive patients across tumor types (n = 25 of 34). By tumor type, the ORR was 66.7% in NSCLC (n = 14 of 21), 88.9% in CRC (n = 8 of 9), and 75.0% in pancreatic ductal adenocarcinoma (PDAC; n = 3 of 4).2,3

Updated results from a phase 2 expansion cohort of patients with NSCLC (n = 20) who had been previously treated with KRAS G12C inhibitors showed a partial response (PR) rate of 30.0% and disease control rate (DCR) of 80.0% with the monotherapy.2 Moreover, 60% of patients achieved tumor shrinkage. Among 14 patients with positive circulating tumor DNA, 11 achieved a greater than 90% G12C MAF reduction; the PR rate in this patient population was 43%. Notably, responses were observed in patients with KRAS G12C amplification, consistent with prior preclinical data.

"We are very pleased to receive both breakthrough therapy and orphan drug designations from the FDA for D3S-001, which highlights D3S-001's promising potential to address critical unmet needs in patients with KRAS G12C–mutated cancers," George Chen, founder and CEO of D3 Bio, stated in the news release.1 "These designations also recognize D3S-001's novel profile as a next-generation KRAS G12C inhibitor. We look forward to bringing this exciting new treatment to patients with support and collaboration from health authorities."

D3S-001 is a next-generation KRAS G12C inhibitor designed to potently, selectively, and covalently bind to the inactive RAS (Off) form of the G12C variant, thereby blocking the nucleotide cycling between the inactive and active states of the mutant protein and achieving more rapid and complete KRAS G12C target engagement.

In prior preclinical and clinical studies, D3S-001 demonstrated substantially improved covalent potency and more rapid and complete KRAS G12C target engagement at clinically relevant doses when compared with approved KRAS G12C inhibitors such as sotorasib and adagrasib.4 Moreover, the agent displayed central nervous system penetration and an ability to overcome limitations of nucleotide cycling and RTK activation in KRAS G12C-mediated cancers, resulting in robust activity.

Of note, D3S-001 previously received ODD for the treatment of patients with pancreatic cancer, as well as fast track designation for late-line NSCLC and CRC.

Phase 1/2 Study Overview

The phase 1 portion of the study comprised a dose-escalation study in patients with advanced solid tumors harboring KRAS G12C mutations (n = 42) and a phase 1b expansion cohort of patients with NSCLC whose disease progressed after prior exposure to KRAS G12C therapy (n = 20).3 The primary end points in phase 1 were safety and determination of the maximum tolerated dose. Secondary end points included pharmacokinetics, confirmed ORR, and DCR.

Additional results from phase 1 showed that D3S-001 demonstrated dose-dependent pharmacokinetics, and the maximum tolerated dose was not reached. D3S-001 at a dose of 600 mg was selected for further investigation based on pharmacokinetics.

Regarding safety, no dose-limiting toxicities or grade 4 or 5 treatment-related adverse effects (TRAEs) were observed. Grade 3 TRAEs were reported in 16.7% of patients in the KRAS G12C inhibitor–naive dose-escalation cohort and 10.0% of patients in the pretreated NSCLC expansion cohort.

The agent is currently under evaluation both as monotherapy and in combination regimens across tumor types in the ongoing phase 2 trial.1

References

1. D3 Bio, Inc. announces FDA breakthrough therapy designation and orphan drug designation for D3S-001 for the treatment of patients with KRAS G12C-mutated cancers. News Release. D3 Bio. August 28, 2025. Accessed August 28, 2025. https://www.prnewswire.com/news-releases/d3-bio-inc-announces-fda-breakthrough-therapy-designation-and-orphan-drug-designation-for-d3s-001-for-the-treatment-of-patients-with-kras-g12c-mutated-cancers-302540808.html
2. D3 Bio announces nature medicine publication and AACR 2025 presentation highlighting D3S-001 as a next-generation KRAS G12C inhibitor with best-in-class potential. News Release. D3 Bio. April 29, 2025. Accessed August 28, 2025. https://www.businesswire.com/news/home/20250429337560/en/D3-Bio-Announces-Nature-Medicine-Publication-and-AACR-2025-Presentation-Highlighting-D3S-001-as-a-Next-Generation-KRAS-G12C-Inhibitor-with-Best-in-Class-Potential
3. Cho BC, Lu S, Lee MA, et al. D3S-001 in advanced solid tumors with KRASG12C mutations: a phase 1 trial. Nat Med. 2025;31:2768–2777. doi:10.1038/s41591-025-03688-6
4. D3 Bio’s D3S-001 demonstrates significantly improved covalent potency in depleting cellular active KRAS in pre-clinical and clinical studies in KRAS G12C-mediated cancers. News Release. D3 Bio. November 25, 2024. Accessed August 28, 2025. https://www.businesswire.com/news/home/20241125088779/en/D3-Bios-D3S-001-Demonstrates-Significantly-Improved-Covalent-Potency-in-Depleting-Cellular-Active-KRAS-in-Pre-Clinical-and-Clinical-Studies-in-KRAS-G12C-Mediated-Cancers