This year’s meeting of the American Society of Clinical Oncology is abuzz with talk of RAS inhibitors, largely driven by Revolution Medicines’ barnburner pancreatic cancer data drop earlier this year. But even as competitors swirl, RevMed is confident that it can maintain the leadership position it has worked so hard to obtain.
“We’re very confident in our approach, and certainly we have a head start over many other companies at this particular time,” Alan Sandler, M.D., RevMed’s chief development officer, told Fierce in Chicago.
RevMed is using ASCO as a chance to shine a spotlight on the full data from the phase 3 RASolute 302 clinical trial of daraxonrasib, which enrolled 500 patients with previously treated metastatic pancreatic ductal adenocarcinoma. The results were also published in the New England Journal of Medicine today.
After previously revealing that daraxonrasib doubled overall survival compared to chemotherapy, from 6.6 months to 13.2 months, RevMed has now shared a similar result for progression-free survival. The RAS inhibitor posted an average PFS of 7.3 months, compared to 3.5 months in the chemotherapy arm.
Daraxonrasib’s safety profile, too, has been an open question. Now, RevMed is giving the answer. For patients given daraxonrasib, 43.6% of them had a treatment-related adverse event of grade 3 or worse, lower than the 57.5% rate in the chemotherapy arm. But the key difference is the kinds of side effects seen with daraxonrasib.
While chemotherapy often led to fatigue, anemia, nausea and neutropenia, the most common side effects in the daraxonrasib group were rash, diarrhea, mouth inflammation and also nausea.
“It’s certainly a different profile from chemotherapy, and we believe more favorable for patients,” Sandler told Fierce.
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One patient given daraxonrasib died during the study due to lung inflammation, which the investigators deemed to be treatment related. But, Sandler said, much remains unclear about what actually happened in this case.
The patient “had multiple pulmonary nodules going in” to the study, the exec explained, and was then treated for suspected pneumonia before ultimately moving to hospice care. The death was attributed to treatment out of an abundance of caution, Sandler added, but the company is “not sure what precisely happened.”
This death was the only one out of 250 patients who received daraxonrasib, Sandler pointed out, with the candidate’s newly shared quality-of-life data also proving its superior safety profile in his eyes.
“Not only are patients living longer, but they’re actually feeling better while they’re living longer,” Sandler said.
Ahead of the pack
RAS was long considered an undruggable target, with the first generation of inhibitors—Amgen’s Lumakras and Bristol Myers Squibb’s Krazati—showing limited efficacy because they targeted the “off” form of Ras, a group of proteins that handle important cell regulation duties.
By targeting the active, “on” form of Ras, RevMed has opened the floodgates for a sea of new inhibitors to surge through.
Many follow-on RAS inhibitors are likely to come from China, as the nation’s biopharma industry continues to surge thanks to its ability to quickly churn out molecules and push them into the clinic. But some of RevMed’s rivals come from inside America’s borders, and they are hardly upstart biotechs.
Gilead Sciences is one compatriot that has gotten into the RAS game, albeit still at an early stage. The pharma’s Chief Medical Officer Dietmar Berger, M.D., Ph.D., told Fierce at ASCO that he believes progress in the red-hot RAS world is still possible.
“There is an opportunity to innovate even further,” he said. In addition to compounds like daraxonrasib that work on a variety of RAS mutations, there are also RAS degraders, he explained, and Gilead has an eye on them all.
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Of course, RevMed is hardly slowing down itself when it comes to advancing the potential of RAS inhibition. The biotech, headquartered in Redwood City just down the road from Gilead’s Foster City HQ, endeavors to bring daraxonrasib into first-line pancreatic cancer and other RAS-dependent cancers while also forging ahead with next-gen molecules that combat the resistance that cancer can develop to the star molecule.
The key candidate here is the preclinical RM-055. RAS-dependent cancers can overcome inhibition by pumping out more and more RAS. RM-055 is designed to flip RAS from its active state to an inactive one, to counteract this proliferation. RevMed is also continuing to explore the intricacies of RAS biology, Sandler said.
“Our belief is that the RAS pathway, once mutated and activated in a cancer, always remains important,” he told Fierce. “Continuing to attack that is going to be key.”
It goes without saying that no matter what RevMed does next, it will have a large audience watching closely. Speculation has swirled about the potential for a Big Pharma to scoop up the RAS specialist, while others think RevMed has become too valuable for many companies to afford.
At the moment, though, RevMed remains keenly focused on its mission to bring daraxonrasib to the masses and continue developing new medicines that target RAS, which is overexpressed on more than 90% of pancreatic cancers, 60% of colorectal cancers and 30% of non-small cell lung cancers, Sandler said.
RevMed’s pipeline also includes another pancreatic cancer candidate called zoldonrasib, as well as the earlier solid tumor asset elironrasib. The biotech is also open to partnerships, like its ongoing pact with Summit Therapeutics, and expects many other potential partners to come knocking if daraxonrasib secures FDA approval.
“We’re working full steam ahead on building our global company and building it to be able to take care of cancer patients with RAS-driven cancers,” Sandler said. “About 30% of all cancers are RAS-driven, so that’s a huge potential impact.”
