Revolution Medicines has been on a roll this spring, delivering a string of clinical wins that have bolstered confidence in its platform, which broadly targets the RAS mutations behind some of the deadliest cancers.
Its RAS(ON) inhibitor pill, daraxonrasib, nearly doubled survival in previously treated patients with metastatic disease, while a second drug, zoldonrasib, showed early promise in hard-to-treat KRAS-driven lung cancer, shrinking tumors in more than half of patients.
The company’s stock prices shot up about 40% after the daraxonrasib results, helping to push its value to a heady $29 billion and crowning it as a top acquisition target.
But this new wave of clinical data did more than just establish Revolution as biotech’s toast of the town. It also provided additional validation that RAS mutations, including KRAS, are no longer the undruggable target they once were, and that second-generation products are building on the base provided by the two approved KRAS-inhibiting drugs, Lumakras and Krazati. The results give the company even more confidence in its clinical portfolio moving forward, said Dr. Alan Sandler, chief development officer at Revolution Medicines.
At the same time, Revolution’s success has raised questions about whether new options can overcome persistent challenges that have limited KRAS drugs — patients who don’t respond to treatment or develop drug resistance, and whether the approach will see similar success in other challenging tumor types like colorectal cancer.
“RAS impacts about 50% of all cancers. It's over 90% in pancreatic cancer, 50% of colon and about 30% of non-small cell lung cancer,” Sandler said. “So, those are the three big ticket items we're looking at.”
A grim diagnosis
Daraxonrasib’s phase 3 results in pancreatic cancer marked what Sandler called a “landmark change” for a disease commonly detected at a late stage with particularly grim survival statistics.
The investigational drug targets multiple RAS variants and earlier-stage data show that when used alone, tumors shrank or disappeared in nearly half of patients, and 71% avoided disease progression at six months. The effect of the drug was even more pronounced in people who got it on top of chemotherapy, with 58% of patients seeing a tumor response, and 84% becoming free of disease progression. This marks a major leap over traditional chemotherapy alone, where tumor response hovers between 23% and 43%, and progression-free survival at six months is between 40% and 50%.
Daraxonrasib also has fewer side effects compared with chemotherapy. However, patients have reported unpleasant effects, including former Senator Ben Sasse, who said he experienced bloody skin rashes, but that his tumors shrank by 76% while taking the drug. The drug was already accepted into the FDA’s national priority voucher pilot program, and these recent trial results could position it for a speedy market entry.
Overcoming KRAS mutations
Now that Revolution’s RAS approach has seen some success, Revolution is moving daraxonrasib into earlier lines of therapy and tumor types while testing combination approaches, which are broadly gaining favor in oncology, Sandler said.
“Single agents definitely have an impact, and we've shown that, but you typically will get even more of an impact and improved efficacy in combination,” he said.
The company is also working to overcome drug resistance with a new catalytic RAS agent that takes its current approach a step further.
“What this one does is these mutations, like many mutations in cancer, are preferentially in the on position, that's how they drive the tumor to grow. But by catalyzing a particular GTPase enzyme, it actually turns it into the off state,” Sandler said. “So, in its simplest form, turning off a mutation that drives cancer.”
Rising competition
Revolution will remain focused on research, Sandler said, but the company is facing plenty of competition in the RAS space, including from Erasca, which announced early results from its own RAS-targeting pill on Monday. The company showcased results demonstrating that 40% of pancreatic cancer patients saw their tumors shrink when taking the drug, as did 62% of those with advanced non-small cell lung cancer.
But Erasca is also staring down potential legal action from Revolution, which is alleging that its drug, ERAS-0015, may infringe on a Revolution patent and misappropriate its trade secrets. Erasca plans to contest the allegations, which it says are unfounded.
Some Big Pharmas are also working on second-generation products. Amgen has a pan-KRAS inhibitor, AMG 410, and Roche is advancing a KRAS G12C-targeting option, divarasib, in non-small cell lung cancer. Merck & Co.’s calderasib, a KRAS G12C inhibitor, is also being tested in multiple phase 3 trials, as is Eli Lilly’s phase 3 G12C drug, olomorasib. Lilly is also in the early stages with another KRAS G12D inhibitor and a pan-KRAS inhibitor.
For now, Revolution appears to be leading the pack.
“We like to think that we're the leaders, or certainly one of the leaders in the RAS space,” Sandler said. “And we're going to continue to develop, from a clinical perspective, the drugs that are already in the clinic, moving them from later stage into earlier stage … while continuing to look for new ways to impact the RAS pathway.”
