Daraxonrasib resistance traced to two tumor escape mechanisms

October 5, 2026 at 02:36 AM2 min

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Researchers have identified two distinct changes in pancreatic tumors that allow them to escape daraxonrasib, a KRAS-targeting pill that roughly doubles median survival in advanced disease. Biopsies from 66 patients showed the drug kills about half of cancer cells within two weeks, while surviving cells shift to a chemotherapy-sensitive form and some tumors overproduce the KRAS protein the drug blocks. The findings point to combination strategies that could extend the drug's benefit beyond its typical seven-month window.

Key Facts

Daraxonrasib was cleared in August after years with few meaningful treatment advances for pancreatic cancer.
In the phase 3 trial presented at the American Society of Clinical Oncology meeting, patients with previously treated metastatic disease who took daraxonrasib lived a median of 13.2 months, compared with 6.7 months for those on standard chemotherapy.
Biopsies from 66 patients showed the drug eliminates about half of cancer cells within two weeks.
Blood tests from 44 patients revealed many tumors began producing large amounts of KRAS, the protein daraxonrasib is designed to block.
Daraxonrasib targets KRAS, a protein driven by gene mutations found in about 90% of pancreatic cancers.

Resistance Mechanisms

Biopsies taken from 66 patients before, during and after treatment showed that daraxonrasib eliminates about half of the cancer cells within just two weeks. The surviving cells looked noticeably different, with the misshapen, irregular appearance of the original tumor cells giving way to cells that more closely resembled the kind that respond to chemotherapy. A separate set of blood tests from 44 patients revealed a second pattern: many tumors began producing large amounts of KRAS, the very protein daraxonrasib is designed to block, in effect overwhelming the drug by making more of its target.

Combination Strategies

The findings suggest two possible strategies for extending the drug's punch. One is combining multiple KRAS inhibitors so tumors that ramp up KRAS production are hit from more than one direction. The other is pairing daraxonrasib with chemotherapy, since the cells left behind after the initial response appear to be the type that chemo can attack. Studies are also underway testing daraxonrasib earlier in the course of the disease rather than only after chemotherapy has failed.