Daraxonrasib Pill Nearly Doubles Survival in Late-Stage Pancreatic Cancer Trial

A once-daily pill called daraxonrasib roughly doubled median survival compared with standard chemotherapy in people with metastatic pancreatic cancer who had already been treated, according to results presented Sunday at the American Society of Clinical Oncology’s annual meeting in Chicago and published in the New England Journal of Medicine.

The trial, called RASolute 302, was a global, randomized, open-label phase 3 study of 500 patients: 248 assigned to the drug and 252 to investigator’s-choice chemotherapy, most often gemcitabine with nab-paclitaxel or liposomal irinotecan with fluorouracil and leucovorin. It was sponsored by Revolution Medicines, which makes the drug, and presented at the meeting’s plenary session by Brian Wolpin. All patients had been treated before; the median follow-up was 8.5 months.

In the main analysis, patients with a RAS G12 mutation lived a median of 13.2 months on daraxonrasib, against about 6.6 to 6.7 months on chemotherapy (the two outlets round it differently), a hazard ratio of 0.40 (95% confidence interval 0.30 to 0.54), meaning a 60 percent lower relative risk of death at any point. The broader group of all patients showed the same 13.2 versus 6.7 months. Median progression-free survival was 7.3 months versus 3.5 months. In absolute terms, ASCO Post reported that 53.3 percent of patients in the G12 group on the drug were alive at one year, compared with 18.7 percent on chemotherapy, or roughly one in five.

Tumors shrank in 33.2 percent of the G12 patients on the drug against 11.8 percent on chemotherapy, according to Consultant360’s account of the presentation. ASCO Post said the drug also delayed worsening pain, by a median of 9.2 months versus 3.8 months.

Side effects were different rather than absent. Treatment-related adverse events of grade 3 or worse occurred in 43.6 percent of patients on daraxonrasib and 57.5 percent on chemotherapy. The most common severe problems on the drug were rash and mouth sores, known as stomatitis. ASCO Post reported that rash led to dose reductions in 17.4 percent of patients and stomatitis in 6.6 percent, while only 1.2 percent stopped the drug because of side effects, against 11.2 percent on chemotherapy. Wolpin described a preventive approach using oral antibiotics and topical steroids.

Outside oncologists were enthusiastic. “These results are landscape-changing for metastatic pancreatic cancer patients with a KRAS mutation,” Rachna Shroff told Consultant360, and ASCO Post quoted her calling it a “gamechanger.” Julie Gralow, ASCO’s chief medical officer, called the findings a “grand slam.” Jennifer Knox, who discussed the study at the meeting, said she would have preferred to see the drug tested first-line but accepted the pragmatic second-line design because it gives a faster readout and is so positive.

There are limits. The trial was open-label, so patients and doctors knew who received the drug, and it enrolled only people with good performance status (ECOG 0 to 1), according to Consultant360. The drug is not yet approved. The data are to be submitted to the U.S. Food and Drug Administration, and the drug is also being studied as a first treatment for pancreatic cancer and in other RAS-driven cancers, ASCO Post reported.