Dr Spira on RMC-9805 in KRAS G12D–Mutated Pancreatic Ductal Adenocarcinoma

“Thirty-nine percent of patients had a 100% decrease in their KRAS G12D VAF [variant allele frequency] and 86% of patients had at least a 50% decline in that number. That tells us that patients who are responding [although] not [demonstrated] on imaging are also doing very well and that [contributes to] clinical benefit rate and, we hope, overall survival rate.”

Alexander I. Spira MD, PhD, FACP, FASCO, codirector, Virginia Cancer Specialists Research Institute; director, Thoracic and Phase I Program, clinical assistant professor, Johns Hopkins, discusses data from a phase 1 study (NCT06040541) of RMC-9805 in previously treated, advanced KRAS G12D–mutated solid tumors, including pancreatic ductal adenocarcinoma (PDAC).

RMC-9805 is a potent, orally bioavailable RAS(ON) G12D-selective covalent tricomplex inhibitor that is designed to directly inhibit RAS(ON) signaling. Among efficacy-evaluable patients with PDAC (n = 40), the overall response rate was 30% and the disease control rate was 80%. Additionally, among patients with PDAC who had circulating tumor DNA (ctDNA) data available at baseline (n = 28), 39% achieved a 100% decrease in KRAS G12D VAF and 86% experienced a decrease of greater than 50%, Spira explains.

The ctDNA findings indicate that patients who are responding but not displaying a response on imaging are benefiting from treatment with the agent, Spira says. Moreover, these findings provide an indication of response before overall and progression-free survival data are fully mature and can help inform larger, phase 3 study designs, Spira notes.

In terms of safety, no patients of any disease histology (n = 179) experienced treatment-related adverse effects (TRAEs) leading to treatment discontinuation and 3% had TRAEs leading to dose reduction. Any-grade TRAEs included nausea (30%), diarrhea (16%), vomiting (15%) increased alanine aminotransferase levels (7%), increased aspartate aminotransferase levels (6%), and rash (3%). Investigators concluded that the safety and clinical activity findings support the ongoing development of RMC-9805 as monotherapy and as a combination component.