Landmark pancreatic cancer drug shows potential against lung cancer too

Just one week after the landmark US approval of a game-changing drug for advanced pancreatic cancer, the same therapy is showing promise against the world’s biggest cancer killer: lung cancer.

In a small clinical trial of the drug daraxonrasib (Rasonque), tumours shrank in more than 30% of participants with the most common form of lung cancer, non-small cell lung cancer. Each participant had a tumour-promoting mutation in a member of the RAS family of proteins, and had previously tried other therapies.

“We consider the results incredibly promising,” says Kathryn Arbour, a thoracic oncologist at the Memorial Sloan Kettering Cancer Center in New York City, and an author of the study, which was published today in the New England Journal of Medicine¹. “These are exciting times.”

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A larger study in which participants with non-small-cell lung cancer are randomly assigned to receive either daraxonrasib or standard chemotherapy is underway. Regulators such as the US Food and Drug Administration (FDA) are likely to require results from that trial before approving the drug as a lung cancer treatment.

That larger trial will also give researchers a better understanding of how long the effects of daraxonrasib last before tumours develop resistance to it. In the smaller trial, some participants’ tumours began to grow again after initially responding to treatment. “We’re really just now learning about the resistance mechanisms,” says Arbour.

Wrangling RAS

RAS proteins are mutated in some of the deadliest cancers, including many pancreatic, lung and colorectal tumours. These proteins were once considered ‘undruggable’ because it was difficult to design compounds that could bind to and inhibit them.

But over the past decade, researchers have developed creative approaches to gumming up RAS proteins. Daraxonrasib — which was developed by Revolution Medicines in Redwood City, California — does this by acting as a ‘molecular glue’ that first binds to a common cellular protein called cyclophilin A. The resulting complex forms a surface that can bind to both normal and mutant RAS molecules, preventing them from interacting with their usual protein partners.

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A previous study found that this approach is remarkably effective in pancreatic cancers bearing RAS mutations²: in a trial of 500 people with advanced pancreatic cancer, daraxonrasib nearly doubled the average survival time to 13.2 months, compared with 6.7 months for standard chemotherapy. Those data prompted the FDA to approve the drug on 26 August, more than six months earlier than expected.

“Of course, everyone is now asking the question: what next?” says Channing Der, a cancer researcher at the University of North Carolina at Chapel Hill. “Will this be extended to other cancers?”