Revolution Medicines’ experimental drug staved off cancer progression for seven and a half months in second-line metastatic pancreatic cancer patients with a variety of cancer-driving RAS mutations.
The new data, shared in a company presentation on Monday morning, also showed that the drug kept cancer progression at bay for a median of 8.1 months in second-line patients with any KRAS mutation found at codon 12 in the Phase 1 trial. Those mutations, which are described collectively as G12X, account for about 85% of pancreatic cancers.
According to Revolution, the single-arm study results represent a substantial improvement over the 2 to 3.5 months median progression-free survival reported in other studies for second-line chemotherapies, which are currently some of the few treatment options for pancreatic cancer patients.
The drug, known as RMC-6236, marks a potential breakthrough in tackling cancers driven by RAS mutations, which are behind about one-third of all human cancers and over 90% of pancreatic cancers. There are two KRAS inhibitors approved for a mutation called G12C in lung and colorectal cancer. But only 1% of pancreatic cancer patients have that mutation.
Revolution’s RAS inhibitor is meant to cover the range of RAS mutations that drive cancers. The company, which is a key player among a host of companies developing the next iterations of RAS inhibitors, now plans to start a pivotal Phase 3 study later this year for its treatment in second-line pancreatic cancer.
The approved inhibitors — Bristol Myers Squibb’s Krazati and Amgen’s Lumakras — tackle the “off” state of the mutated protein. But Revolution is developing a suite of RAS inhibitors that specifically go after the “on” state of the protein — the state that actually drives the cancer. Researchers hope that these inhibitors could be more effective treatments.
“Pancreatic cancer is really ideal for a treatment paradigm shift to targeting RAS with a broadly active RAS inhibitor,” Brian Wolpin, an oncologist at the Dana-Farber Cancer Institute and an investigator on the clinical trial, said during Revolution’s investor call Monday morning.
Pancreatic cancer is a deadly and hard-to-treat disease, and patients with metastatic disease usually survive less than a year, he added.
The company reported results on 127 patients with advanced or metastatic pancreatic ductal adenocarcinoma, the vast majority of whom had received one or two previous cancer treatments. At 20-plus weeks, 16 of 61 patients with RAS mutations saw their tumors shrink by at least 30% — good for a response rate of 26%.
In more advanced patients who previously received at least two treatment regimens, the median progression-free survival was 4.2 months.
The most common side effects were rash, which almost 90% of patients experienced, followed by diarrhea, nausea and mouth inflammation. “All common issues reported to date are believed to have been on-target and associated with inhibition of wild type RAS in normal tissue,” Revolution chief medical officer Wei Lin said during the call.
Three patients had grade 3 or higher cases of low platelet counts, one had a grade 3+ case of low white blood cell count and one had an irregular heart rhythm on an electrocardiogram. No patients discontinued treatment, though 28% either saw dose interruption or reduction.
Revolution’s Phase 3 RASolute 302 study will compare RMC-6236 to standard chemotherapy across 460 previously treated metastatic pancreatic cancer patients. The late-stage study’s primary analysis will only include patients with G12X mutations.
“Limiting the primary analysis to this population is designed to increase the probability of success,” said Lin.
A secondary analysis includes the “all-comer” population, which keeps the potential for a broad label that doesn’t require biomarker testing for specific mutations, according to Lin.