Revolution aims for Phase III trial with pan-RAS inhibitor

Revolution Medicines, headquartered in Redwood City, California, plans to embark on a Phase III trial following the promising results of a first-in-human study of its experimental KRAS inhibitor, RMC-6236, in patients suffering from pancreatic cancer.

The company disclosed new data from its Phase I trial (NCT05379985) on July 15, showcasing responses from 127 individuals with pancreatic ductal carcinoma (PDAC). Participants received doses of RMC-6236 ranging from 160mg to 300mg. The median progression-free survival was 8.1 months for patients with the KRAS G12X mutation and 7.6 months for those with RAS-mutant tumors. For those who had undergone at least three prior treatment regimens, the median progression-free survival was 4.2 months.

Adverse events were prevalent, affecting 96% of the 127 participants. The most commonly reported side effects included rashes, diarrhea, nausea, and mouth sores. Of those, 28% experienced severe or medically significant adverse events.

Earlier, the company introduced initial Phase I data, covering 40 evaluable patients, at the European Society of Medical Oncology 2023 meeting in October.

Revolution Medicines now aims to launch the Phase III RASolute 302 trial in patients with metastatic PDAC. This study will compare a 300mg dose of RMC-6236 to the standard chemotherapy chosen by investigators for patients who have previously undergone two lines of therapy. Primary endpoint data is anticipated between 2026 and 2027.

KRAS, a gene that provides instructions for making K-Ras protein, plays a crucial role in the RAS/MAPK pathway. It is the most frequently mutated oncogene and has been a focal point for cancer research for decades. Currently, there are only two approved KRAS inhibitors: Bristol Myers Squibb’s Krazati (adagrasib) and Amgen’s Lumakras (sotorasib). These medications target the KRAS G12C mutation and are primarily used to treat non-small cell lung cancer (NSCLC). Their approval by the US Food and Drug Administration (FDA) was a significant milestone, with GlobalData projecting Krazati sales of $1.63 billion and Lumakras sales of $787 million by 2030.

In its first-quarter earnings report released in May, Revolution Medicines shared plans to publish data in the second half of 2024, supporting the initiation of two pivotal studies in pancreatic cancer and NSCLC. While the KRAS G12C mutation is notably prevalent in lung cancer, pancreatic cancer often involves the G12D mutation in the KRAS gene. This underscores the necessity for KRAS inhibitors capable of treating various cancer types.

RMC-6236 represents a new wave of innovation in the KRAS inhibitor landscape. Unlike treatments targeting specific mutations like G12C, RMC-6236 is a multi-selective non-covalent inhibitor crafted to address cancers driven by a broad spectrum of common RAS mutations.

Other companies are also making strides with KRAS inhibitors. For instance, GenFleet Therapeutics is advancing its Phase III asset GFH925, a KRAS G12C inhibitor, for patients with refractory metastatic colorectal cancer (CRC).