Zoldonrasib trial aims to extend survival in advanced pancreatic cancer
Developer also seeing benefits for PDAC patients treated with daraxonrasib
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Dosing has begun in a global clinical trial testing Revolution Medicines‘ RAS(ON) inhibitor candidate zoldonrasib as a first-line treatment for advanced pancreatic ductal carcinoma (PDAC) associated with the RAS G12D genetic mutation.
Called RASolute 305 (NCT07621718), the Phase 3 study is comparing zoldonrasib in combination with chemotherapy against chemo alone in an estimated 670 adults with PDAC, an aggressive form of pancreatic cancer. The trial is now recruiting participants ages 18 and older with a recent diagnosis of metastatic disease — meaning the cancer has spread to other parts of the body — at three sites in the U.S.
Revolution is testing whether its experimental oral therapy, when used alongside chemotherapy, can extend survival in people with metastatic PDAC.
The company also recently announced positive data for daraxonrasib, another of its investigational RAS-targeted therapies. In a Phase 3 trial involving previously treated people with PDAC with a range of RAS mutations, daraxonrasib more than doubled overall survival versus standard chemotherapy.
The developer has now launched another Phase 3 trial — this one dubbed RASolute 303 (NCT07491445) — to test daraxonrasib as a first-line therapy in this patient population. That study is recruiting approximately 900 participants at sites in the U.S. and Japan.
“Both RASolute 305 and RASolute 303 … reflect our broad commitment to studying RAS(ON) inhibitors with differentiated profiles across a range of unmet medical needs in pancreatic cancer,” Alan Sandler, MD, chief development officer of Revolution, said in a company press release announcing that the first participant has been dosed in RASolute 305.
Revolution is focused on developing targeted therapies for people with RAS-addicted cancers — cancers that rely on mutated RAS genes to survive and grow. These genes normally regulate cell growth and division, but mutations can cause them to be overactive, allowing for the uncontrolled cell growth that contributes to cancer development and progression.
Of all major cancers, PDAC is the most commonly RAS-driven one — about 90% of patients have tumors that harbor RAS gene mutations, according to Revolution.
Because it often does not cause major symptoms until it has progressed substantially, PDAC typically is already metastatic, meaning it has spread to other tissues, by the time it is diagnosed in most patients. This makes it especially difficult to treat, with a five-year survival rate of about 3%.
Developer testing both daraxonrasib and zoldonrasib in trials
Both daraxonrasib and zoldonrasib are daily oral RAS (ON) inhibitors that block RAS proteins in their activated state, helping halt cancer cell growth.
While daraxonrasib is multiselective, meaning it is designed to be effective across a broad range of RAS variants, zoldonrasib is mutation-specific, intended particularly for the G12D mutation. That mutation is the most common RAS mutation in PDAC patients. It is also “associated with particularly poor clinical outcomes,” Sandler noted.
Zoldonrasib has been tested in a Phase 1 trial (NCT06040541) that enrolled people with G12D-mutant solid tumors. Data from the subset of participants with previously treated PDAC showed that the therapy was well tolerated with promising signs of antitumor activity.
RASolute 305 will involve people with metastatic RAS G12D-associated PDAC who have not yet been treated. Participants will receive either zoldonrasib plus standard care chemotherapy or chemotherapy with a placebo. The chemotherapy regimen will be determined by the clinician and will include either modified FOLFIRINOX or gemcitabine plus nab-paclitaxel. FOLFIRINOX is a combination of cancer drugs.
The study’s main goals are to evaluate overall survival and progression-free survival, which is the time spent alive without cancer progression. Secondary endpoints include other measures of the treatment’s antitumor effects, as well as safety and tolerability, and patient-reported outcomes.
These unprecedented findings provide important clinical validation of RAS(ON) inhibition in pancreatic cancer and support its evaluation earlier in the treatment course.
According to the developer, the data to date suggest that these medications may extend survival for people with PDAC.
“These unprecedented findings provide important clinical validation of RAS(ON) inhibition in pancreatic cancer and support its evaluation earlier in the treatment course,” Sandler said.
Beyond pancreatic cancer, Revolution is also investigating both daraxonrasib and zoldonrasib for treating non-small cell lung cancer and other types of solid tumors.
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