ASCO26: Revolution's 'grand slam' data in pancreatic cancer

Revolution Medicines' pan-RAS(on) inhibitor daraxonrasib has delivered a big result in pancreatic cancer, with a doubling in overall survival compared to chemotherapy in the highly anticipated RASolute 302 trial.

There is a desperate need for improved therapies for pancreatic cancer, a notoriously aggressive and hard-to-treat disease, which in around 90% of cases has a mutation in the KRAS oncogene.

RASolute 302 looked at second-line therapy with daraxonrasib after standard first-line chemo, comparing it to investigator's choice of chemo in relapsed/refractory patients. According to lead investigator Brian Wolpin of the Dana-Farber Cancer Institute, second-line chemo "really does not work as well as we would like" with a median overall survival (OS) of only six to seven months.

The results speak for themselves, with a median OS of 13.2 months with Revolution's drug, compared to 6.7 months with investigator's choice of second-line chemo, in all-comer patients with metastatic pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer.

"I've heard this study described as a home run a lot," said Julie Gralow, who is chief medical officer and executive vice president of ASCO. " I would actually say it's a grand slam. It is much more than a home run."

Progression-free survival was also doubled to 7.2 months from 3.6 months with the pan-RAS(on) inhibitor, according to the results, which have also just been published in the New England Journal of Medicine (NEJM). Importantly, the side effects observed with Revolution's drug were manageable and caused fewer discontinuations than chemo (1.2% versus 11.2%).

"These results will change how scientists, clinicians, and patients think about treatment for pancreatic cancer, and support a new paradigm where RAS(ON) inhibition enters standard of care for patients with previously treated metastatic pancreatic adenocarcinoma," said Wolpin.

Revolution had already teased that daraxonrasib had improved OS in the study, but the scale of the improvement topped expectations and bodes well for the ongoing FDA review of the drug, which has a national priority review that could deliver a verdict in as little as one or two months once filed.

According to a STAT report, the company is hoping to finalise its marketing application next month and has already started shipping the drug to physicians and their patients under an early access programme agreed with the US regulator.

The pan-RAS category is pretty crowded, with more than a dozen drug candidates in clinical testing, but Revolution seems to have a healthy lead with other trials underway in PDAC as well as non-small cell lung cancer (NSCLC).

Those include the RASolute 303 trial in first-line PDAC, RASolute 304 in adjuvant treatment of PDAC treatable with surgery, and RASolve 301 looking at first-, second-, and third-line treatment of metastatic NSCLC.

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