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3D Illustration of a pancreas with tumors iStock, libre de droit Jefferies analyst Kelly Shi in a Sunday note to investors said that both data drops for Revolution Medicines’ experimental RAS inhibitors are positive for the two promising assets in pancreatic ductal adenocarcinoma, which could be “synergistic” in the first-line setting based on preclinical combination data. Revolution Medicines on Friday posted a pair of readouts for its investigational RAS inhibitors, demonstrating strong survival outcomes and response rates in patients with advanced pancreatic ductal adenocarcinoma. According to a company presentation on Friday, these data will help advance its mission “to revolutionize patients with RAS-addicted cancers,” leading to better treatment outcomes in pancreatic ductal adenocarcinoma (PDAC), a highly aggressive and lethal type of pancreatic cancer. According to Revolution, more than 90% of PDAC tumors carry oncogenic RAS mutations. In a Friday late-breaking oral session at the 2024 Symposium on Molecular Targets and Cancer Therapeutics of the EORTC-NCI-AACR, Revolution revealed Phase I/Ib data for RMC-9805, an orally available RAS(ON) G12D-selective inhibitor. The biotech touted strong preliminary efficacy for RMC-9805, which elicited a 30% objective response rate and an 80% disease control rate. Revolution combined both confirmed and pending treatment responses in its outcome assessment. RMC-9805 also had an “encouraging safety profile,” the company said in its announcement. In the 99 patients who were treated with 1,200 mg of RMC-9805 daily, the most common treatment-related toxicities were gastrointestinal in nature, including nausea and diarrhea. There were no grade 4 or 5 adverse events, though four patients needed to have their doses lowered due to side effects. Revolution CEO Mark Goldsmith in a statement said that the company is “pleased” with these early data for RMC-9805, “which demonstrate encouraging initial safety, tolerability and antitumor activity.” These findings suggest that the candidate “has the potential to play a role in an emerging treatment paradigm” for PDAC patients, and further provide compelling evidence of Revolution’s approach to target RAS(ON) in RAS-addicted cancers. Also last week, the biotech revealed more data to back its RAS(ON) pipeline, announcing that its Phase I/Ib RMC-6236 showed “ durable antitumor activity ” in advanced PDAC patients, resulting in “encouraging” progression-free and overall survival outcomes. Unlike RMC-9805, RMC-6236 is a RAS(ON) multi-selective inhibitor. The study results— which were also presented at the EORTC-NCI-AACR meeting—primarily enrolled patients with KRAS G12X mutations, in whom RMC-6236 had landmark overall survival of 89% at six months. Objective response rate was 29%. RMC-6236 was generally well-tolerated at the tested dose levels of 160 mg to 300 mg, once-daily. The most common adverse events grade 3 and above were rashes, stomatitis and diarrhea. Toxicities necessitating dose adjustment were reported in 35% of patients. In a Sunday investor note, Jefferies analyst Kelly Shi said that both readouts “are straightforwardly positive” for Revolution and called both RMC-9806 and RMCM-6236 “promising assets” that could be “synergistic” in the first-line setting for PDAC. Both molecules have “complementary” mechanisms of action, Shi said, and Revolution is “committed” to studying the combo in first-line PDAC, though it has yet to reveal specific details for this program.

In an interview Friday, Revolution Medicines CEO Mark Goldsmith, who says he prefers to understate rather than exaggerate, floated a lofty goal: cure pancreatic cancer — or get close. “That’s our aim, and we don’t think that’s right around the corner, but we’re off to a very good start,” he told Endpoints News. It’s an ambitious vision, given that the five-year survival rate for pancreatic cancer is 13%, according to the American Cancer Society. Revolution is developing a suite of RAS inhibitors, and the company’s shares have more than doubled in the past 12 months because of excitement over their potential to treat solid tumors, particularly pancreatic cancer. The Redwood City, CA-based company reported results this week from early-stage trials of two of its experimental treatments in pancreatic cancer, where more than 90% of cases harbor RAS mutations. In a late-breaking presentation Friday, Revolution Medicines said that 12 of 40 previously treated pancreatic cancer patients who received a 1,200 mg daily dose of its KRAS G12D inhibitor, called RMC-9805, saw their tumors shrink at least 30%. (The company included confirmed responses as well as unconfirmed responses still on treatment.) That’s good for a 30% response rate, and the company said it would use a 1,200 mg dose in a Phase 2 trial for pancreatic cancer. The data, presented at what’s known as the Triple Meeting, were the first clinical results from RMC-9805. They’re from a broader Phase 1/1b study looking at the drug in patients with solid tumors harboring KRAS G12D mutations who had received a median of two previous treatments. The company, which informally goes by RevMed, said that 179 patients have been dosed with the drug. At the 1,200 mg daily dose, with which 99 patients have been treated, the most common side effects were nausea, diarrhea and vomiting and rash. It described those adverse events as low-grade and limited, though there was one grade 3 case of elevated liver enzymes. The company also has a multi-RAS inhibitor that can tackle a range of mutations in a Phase 3 trial. Known as RMC-6236, RevMed announced it dosed a first pancreatic cancer patient in that trial on Monday. The study will include a core population of pancreatic cancer patients with RAS G12X mutations, as well as other mutations. RevMed shared updated results from 127 patients in an earlier Phase 1/1b study of RMC-6236. In that study, overall survival rates were 14.5 months in both previously treated pancreatic cancer patients with any RAS mutation, as well as with those with a mutation at codon 12 (which is referred to as KRAS G12X). While the study didn’t have a control arm, Jefferies analyst Kelly Shi said the benchmark for survival in those patients with chemotherapy is about six to seven months. Grade 3 or greater side effects related to the drug were rash (which impacted 8% of patients), stomatitis and diarrhea, and 35% of patients required dose modifications because of side effects, but none dropped out because of that. Goldsmith said the two experimental compounds have “overlapping but also distinct profiles, and two overlapping but also distinct ranges of target.”