D3S-001 Receives

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

D3S-001 (Elisrasib) received FDA breakthrough therapy and orphan drug designations for KRAS G12C-mutated NSCLC and CRC, highlighting its potential in addressing unmet needs. Phase 1/2 study data showed a 73.5% ORR in KRAS G12C inhibitor-naive patients, with notable efficacy across multiple tumor types.

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.

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.

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