Next-generation KRASG12C inhibitor monotherapy convenient, shows promising antitumour activity

A multinational phase I study led by the Chinese University of Hong Kong (CUHK) reports an overall objective response rate (ORR) of >70 percent in advanced solid KRAS^G12C-mutant tumours treated with D3S-001, a next-generation KRAS^G12C inhibitor developed in mainland China.

D3S-001 is a next-generation GDP-bound KRAS^G12C inhibitor designed to enhance target engagement efficiency and overcome growth factor–induced nucleotide exchange that first-generation KRAS^G12C inhibitors, such as adagrasib and sotorasib, are susceptible to. [Cell Rep 2022;39:110993; Cancer Discov 2020;10:1129-1139] In preclinical profiling, D3S-001 demonstrated improved covalent potency over adagrasib and sotorasib, achieving complete target inhibition at single-digit nanomolar concentrations, implying a potency of two orders of magnitude greater than that of sotorasib and adagrasib. [Cancer Discov 2024;14:1675-1698]

The phase Ia study included 42 patients (median age, 64.0 years; male, 76.2 percent; Asian, 88.1 percent) with advanced solid tumours (non-small-cell lung cancer [NSCLC], n=25; colorectal cancer [CRC], n=13; pancreatic ductal adenocarcinoma [PDAC], n=4) harbouring KRAS^G12C mutation. Overall, 42.9 percent of patients had received ≥3 prior lines of systemic therapy, while 14.3 percent had been treated with a KRAS^G12C inhibitor. D3S-001 monotherapy’s safety and tolerability were the primary endpoint, while ORR, duration of response (DoR), disease control rate (DCR), and progression-free survival (PFS) were among the secondary endpoints. [Nat Med 2025;doi:10.1038/s41591-025-03688-6]

No dose-limiting toxicities (DLTs) were observed over D3S-001's studied dose range of 50–900 mg of D3S-001, and the maximum tolerated dose (MTD) was not reached. Treatment-related adverse events (TRAEs) of any grade occurred in 78.6 percent of patients. The most frequent TRAEs of any grade were nausea (45.2 percent), diarrhoea (31.0 percent), increased amylase level (19.0 percent), hypertriglyceridaemia (19.0 percent), vomiting (19.0 percent), and increased lipase level (16.7 percent). Grade 3 TRAEs were reported in 16.7 percent of patients and included hypertriglyceridaemia, hyperkalaemia, nausea, abnormal hepatic function, and increased lipase, alanine aminotransferase and aspartate aminotransferase levels. No grade 4 or 5 TRAEs were reported, while serious TRAEs occurred in 7.1 percent of patients.

The confirmed ORR in 34 evaluable patients was 73.5 percent and the DCR was 97.1 percent. Among KRAS^G12C inhibitor–naïve patients, the confirmed ORR was 66.7 and 88.9 percent in those with NSCLC (n=21) and CRC (n=9), respectively. The confirmed ORR in PDAC patients, all of whom were KRAS^G12C inhibitor–naïve, was 75.0 percent. Among all KRAS^G12C inhibitor–naïve patients, the estimated 6-month PFS rate was 68.6 percent, while the estimated 6-month DoR rate among responders was 78.4 percent.

Twenty patients with KRAS^G12C inhibitor–pretreated NSCLC, of whom 80.0 percent had received anti–PD-1 or anti–PD-L1 therapy ≥12 weeks before enrollment, were included in the phase 1b dose-expansion study and received D3S-001 at the selected phase II dose of 600 mg QD. Tumour shrinkage and partial response were observed in 60.0 and 30.0 percent of patients, respectively; the DCR was 80.0 percent.

“The study findings suggest D3S-001 is superior to first-generation KRAS inhibitors, especially in CRC, where it can achieve a high remission rate when used alone, without the need for combination with anti-EGFR antibodies, overcoming the limitations of existing KRAS inhibitors,” said one of the study authors, Dr Herbert Loong of the Department of Clinical Oncology, CUHK. “For NSCLC patients with disease progression after treatment with KRAS inhibitors, D3S-001 still offered a 30 percent remission rate, addressing the issue of drug resistance. Moreover, it has only mild side effects and is given once daily, making it safe and convenient for long-term use.”