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Revolution Medicines’ daraxonrasib is a certain approval for patients with metastatic pancreatic cancer and tumor progression following chemotherapy. The only gating factor seems to be the speed at which the company can submit the drug to the Food and Drug Administration. Once that happens, daraxonrasib will be cleared quickly and become the new standard of care in the second-line setting.
After the drug’s standing ovation during the ASCO plenary session, the talk shifted to how (and when) the use of daraxonrasib might be expanded to patients with newly diagnosed, metastatic pancreatic cancer.
A speedier-than-expected approval in the first-line setting would benefit more patients. Sales of the drug would grow faster, boosting Revolution and its valuation. It could also impact the way competing drugs for pancreatic cancer, including other RAS inhibitors, are developed.
By showing a near-doubling of overall survival already in the second-line setting, daraxonrasib is an example of a “transformative therapy” that makes conducting future, randomized clinical trials more challenging logistically and ethically, said Rick Pazdur, the former top cancer drug regulator at the FDA, speaking at a STAT event held last Friday during the ASCO meeting.
STAT Plus: Practice-changing results reported for Revolution Medicines pancreatic cancer drug
“If you’re going to do a first-line trial, you have the potential of losing equipoise,” Pazdur said. “People are going to want the drug. Let’s face it, if you have a fatal disease like pancreatic cancer and you are going to die from that disease, you do not want to go on the [control] arm.”
Pazdur was referring to “clinical equipoise,” or the principle of genuine uncertainty that provides the ethical basis for randomizing patients to different treatment arms in a clinical trial.
Earlier this year, Revolution started a large, randomized Phase 3 study in first-line, or newly diagnosed, metastatic pancreatic cancer. Participants are being randomized to one of three arms: daraxonrasib alone, daraxonrasib with chemotherapy, or chemotherapy alone. The primary endpoints are progression-free survival and overall survival.
Pazdur’s point: It might be difficult, if not unethical, for Revolution to enroll this study because patients with pancreatic cancer, now knowing the survival benefit of daraxonrasib in their disease, will balk at the one-third odds of receiving only chemotherapy.
Even if Revolution manages to fully enroll the study, a loss of equipoise might imperil the analysis. More participants randomized to the chemotherapy control arm might drop out early or never receive treatment at all in order to seek daraxonrasib outside the study. Or, physicians may be quick to diagnose tumor progression in all study participants, even before progression can be confirmed, because they know patients will then be eligible to cross over and receive daraxonrasib.
This has happened before, Pazdur noted, specifically mentioning a randomized Phase 3 study of Amgen’s Lumakras, the KRAS inhibitor for non-small cell lung cancer.
No one wants the loss of equipoise in a clinical trial to be the reason daraxonrasib can’t reach the broadest possible swath of pancreatic cancer patients. Pazdur, you won’t be surprised to learn, has a proposed solution.
He called it “reverse accelerated approval.”
“I love that term,” he said Friday. It would work thusly:
Revolution could enroll patients with newly diagnosed pancreatic cancer and randomize them into the three arms. But instead of waiting for tumor progression or death, analyze the study for tumor response, which could be done much more quickly. If one or both of the daraxonrasib arms shows better tumor shrinkage than chemotherapy alone, you could approve the drug for newly diagnosed patients.
In order to confirm the drug’s long-term benefit, Pazdur explained, Revolution, with the support of regulators, would compare the overall survival of patients in the study treated with daraxonrasib to the survival of similar patients in an external control arm.
“I would expect they would win on this,” Pazdur said. “This would be a very patient-centric approach.”
A precedent also exists. Pfizer used a similar (but not exactly the same) approach to win accelerated and later full approval for Braftovi, its BRAF inhibitor for newly diagnosed metastatic colon cancer.
Pazdur no longer works at the FDA, so his proposal, while logical and persuasive, may never see the light of day.
Revolution CEO: ‘Very open’ but cautious on what it would take to move daraxonrasib to the frontline
Mark Goldsmith, CEO of Revolution Medicines, right, at a STAT event last week.Megan Bearder Photography
Revolution CEO Mark Goldsmith also spoke at STAT’s ASCO event last Friday night. I asked him onstage about efforts to accelerate the potential approval of daraxonrasib for newly diagnosed patients.
“We’d love to do that,” he told me. “Clearly we’re very open to this, but ultimately this requires the regulatory apparatus to have that flexibility.”
“Are you having these discussions with the FDA right now?” I asked.
“I’m not going to comment on that,” he replied. In April, Revolution presented updated results from an early, single-arm study of newly diagnosed pancreatic cancer patients that showed daraxonrasib achieving a 47% and 58% overall response rate when used alone and in combination with chemotherapy, respectively.
“We know [daraxonrasib] is highly active in the first line,” Goldsmith said, referencing these results. “But what do we need to show to convince the decision-makers? That’s something that we just have to learn. We have a terrific relationship with the folks at the FDA. They will have every interest in trying to serve patients as we do. We’ll keep working on this.”
He added, “In the meantime, we just have to run the Phase 3 trial that we’ve designed. It’s a properly designed trial. It will enroll quite quickly, and we’ll continue to generate data.”
Goldsmith spoke at our event before Pazdur took the stage, and Goldsmith had to leave for another company event before Pazdur spoke.
You can read more about my chat with Goldsmith at our event here. And here is video footage of the panel with Pazdur at the event.
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