Sotorasib

Revolution Medicines headquarters in Redwood City, California. Credit: Tada Images via Shutterstock. Revolution Medicine plans to kickstart a Phase III trial following positive data from a first-in-human study of its investigational KRAS inhibitor RMC-6236 in pancreatic cancer patients. In an investor deck released yesterday [15 July], the company outlined updated data from the Phase I trial (NCT05379985) that outlined responses from 127 patients with pancreatic ductal carcinoma (PDAC) who received between a dose of RMC-6236 ranging from 160mg to 300mg. Median progression-free survival was 8.1 months in patients with the KRAS G12X mutation, and 7.6 months in those who broadly have RAS-mutant tumours. Among participants who had at least three prior treatment regimens, the median progression-free survival was 4.2 months. Out of the 127 participants, 96% suffered from side effects. The most common were rashes, diarrhoea, nausea, and mouth sores. Those adverse events were deemed severe or medically significant in 28% of patients. The company had previously presented early Phase I data, which covered 40 evaluable patients, at the European Society of Medical Oncology 2023 meeting in October. See Also: MHRA approves Pierre Fabre’s vibegron to treat OAB Rusan Pharma’s API Plant in Ankleshwar Receives US FDA GMP Approval The Redwood City, California-based company now plans on initiating a Phase III RASolute 302 trial in metastatic PDAC patients. The study will compare the 300mg dose of RMC-6236 to the investigator’s choice of standard chemotherapy among patients previously treated with two lines of therapy. According to Revolution, primary endpoint data is expected in 2026 and 2027. KRAS is a gene that provides instructions for making a protein called K-Ras, which is part of the RAS/MAPK pathway. It is the most frequently mutated oncogene, meaning KRAS has been a target investigated by cancer scientists for decades. There are currently only two approved KRAS inhibitors, Bristol Myers Squibb ’s (BMS) Krazati (adagrasib) and Amgen ’s Lumakras (sotorasib), both of which are KRAS G12C inhibitors indicated to treat NSCLC. Their US Food and Drug Administration (FDA) approvals were a breakthrough for the scientific community, with GlobalData forecasting sales of $1.63bn for Krazati and $787m for Lumakras in 2030. GlobalData is the parent company of Pharmaceutical Technology. In its 1Q earnings released in May, the company outlined plans to release data in H2 2024 to support the initiation of two pivotal studies in pancreatic cancer and NSCLC. Though KRAS G12C is a prominent mutation seen in lung cancer, certain malignancies such as pancreatic cancer most commonly have the G12D mutation in the KRAS gene. Therefore, there is a need for KRAS inhibitors that can treat other cancer types. GMC-6236 is part of the emerging innovation being seen in the KRAS space. Instead of targeting a specific mutation such as G12C, the drug is a multi-selective non-covalent inhibitor designed to treat patients with cancers driven by a wide range of common RAS mutations. Other companies advancing KRAS inhibitors include GenFleet Therapeutics, which is investigating the Phase III asset GFH925 , a KRAS G12C inhibitor for the treatment of patients with refractory metastatic colorectal cancer (CRC).

Dive Brief:An experimental cancer drug developed by Revolution Medicines shrank pancreatic tumors in about one-quarter of participants who had been followed for at least five months after treatment in an early-stage study.The update, which Revolution Medicines shared with investors Monday, is the latest cut of data from the trial, which has tested the companys targeted therapy RMC-6236 in people with lung or pancreatic tumors that are driven to growth by mutations in a cancer gene known as RAS.Among study participants who previously received one or more prior drug regimens for their cancer and have a KRAS G12X mutation, treatment with RMC-6236 led to a median progression-free survival of 8.1 months. Revolution claims this is higher than typically seen with other regimens and is advancing its drug into a Phase 3 pancreatic cancer trial later this year.Dive Insight:Revolution Medicines is one of a handful of biotechnology and pharmaceutical firms looking to exploit drug research advances that have made RAS mutations easier to target. Mutations in the gene are frequently a trigger for cancers of the lungs, pancreas or colon.Pancreatic cancer, which is considered among the hardest tumor types to treat, is particularly dependent on RAS mutations, according to Revolution Medicines. Currently, however, standard treatment is chemotherapy-based regimens that have limited effectiveness.RMC-6236 is designed to inhibit RAS signaling by binding to the mutant protein in its on state. The companys first-in-human study, which has enrolled nearly 400 patients with RAS-driven solid tumors, has so far evaluated nine different doses of the drug. Results were last presented in October.Mondays data are from 127 study participants with pancreatic ductal carcinoma who received between 160 milligram and 300 milligram doses of RMC-6236. Nearly all experienced side effects, most commonly rash, diarrhea, mouth sores and vomiting. Those adverse events were considered severe or medically significant in 22% of participants and in 28% required dose modification.Median progression-free survival, a measure of how long treatment staves off disease progression or death, was a median of 8.1 months in people who specifically have the KRAS G12X mutation, and 7.6 months in those who broadly have RAS mutant tumors, including those with KRAS G12X changes. According to Revolution Medicines, the benchmark median progression-free survival for chemotherapy regimens in this setting ranges from 2 months to 3.5 months.Among participants who had at least three prior treatment regimens, the median progression-free survival was 4.2 months.Revolution Medicines said it plans to advance the 300 milligram dose of RMC-6236 into a Phase 3 study comparing it to investigators choice of standard chemo among previously treated people with pancreatic cancer. The company anticipates starting the study in the second half of the year, with progression-free survival data coming in the first half of 2026.Along with Revolution Medicines, a range of other companies are advancing RAS inhibitors in solid tumors, including BridgeBio Oncology Therapeutics, Frontier Medicines and Eli Lilly. Two drugs specifically targeted to KRAS mutations, Amgens Lumakras and Bristol Myers Squibbs Krazati, are currently approved for lung cancer.Revolution Medicines recently absorbed EQRx via an all-stock deal, swelling its cash balance to $1.7 billion as of March 31. Shares in the company fell in early Monday morning trading before bouncing back to trade up by more than 2%. '