Onvansertib Combo Improves Outcomes in First-Line RAS-Mutated mCRC

New data from a randomized phase 2 clinical trial suggest that adding the targeted therapy onvansertib to standard first-line treatment may improve outcomes for patients with RAS-mutated metastatic colorectal cancer (mCRC), according to a news release from Cardiff Oncology, which shared updates from the CRDF-004 trial. The study showed dose-dependent improvements in tumor response and disease control when onvansertib was combined with FOLFIRI and Avastin (bevacizumab), a commonly used chemotherapy and anti-angiogenic regimen.

For patients with RAS-mutated mCRC, a subtype that does not benefit from certain targeted therapies, these findings point toward a potential new option.

“These data demonstrate promising enhanced benefits of onvansertib when combined with FOLFIRI and Avastin in RAS-mutated mCRC,” said Mani Mohindru, interim CEO. “We observed a consistent, dose-dependent treatment benefit across multiple measures of efficacy, including achieving statistical significance for progression-free survival compared to standard of care even with relatively small patient numbers.”

Trial results show improved response and disease control

In the intent-to-treat population, patients who received onvansertib in combination with FOLFIRI and Avastin experienced higher objective response rates compared with those treated with standard-of-care regimens alone. The benefit appeared dose-dependent, with the strongest results seen at the 30-milligram dose of onvansertib.

At this higher dose, nearly three-quarters of patients experienced confirmed tumor shrinkage, compared with just over 40% of patients receiving standard therapy. This represented a meaningful improvement in response for a first-line metastatic setting.

Trends also favored the onvansertib combination in progression-free survival, a measure of how long patients live without their cancer growing or spreading.

“The 30-miligram onvansertib [combination] arm outperformed both standard of care arms with no significant additive toxicity, supporting findings from our previous phase 2 trial in second-line RAS-mutated mCRC,” Mohindru emphasized in the news release. “While we continue to review data from the ongoing trial, our plan is to rapidly move forward with the onvansertib 30 mg dose in combination with FOLFIRI and Avastin and we believe confirmatory data from a registrational trial has the potential to make this regimen a new standard of care for first-line treatment of RAS-mutated mCRC.”

Why RAS-mutated mCRC is challenging

Colorectal cancer is one of the most common cancers worldwide, and many patients are diagnosed after the disease has spread. Mutations in KRAS or NRAS occur in a large proportion of cases and limit the effectiveness of certain targeted therapies, leaving chemotherapy-based regimens as the mainstay of treatment.

Although combinations such as FOLFIRI or FOLFOX with Avastin are widely used, long-term disease control remains difficult. New approaches that can deepen responses and delay progression without significantly increasing toxicity are urgently needed.

How the CRDF-004 study was designed

The CRDF-004 trial was a randomized, dose-finding phase 2 study designed to evaluate onvansertib added to standard first-line chemotherapy. Patients received either FOLFIRI or FOLFOX, each combined with Avastin, with or without onvansertib.

Two oral doses of onvansertib — 20 milligrams and 30 milligrams — were tested to identify the most effective dose with acceptable safety. Key endpoints included objective response rate, progression-free survival, duration of response and safety.

The study enrolled patients with previously untreated, first-line metastatic colorectal cancer harboring KRAS or NRAS mutations. Participants were included in an intent-to-treat analysis, meaning outcomes were assessed for all patients as originally assigned, reflecting real-world treatment scenarios.

Additional findings highlight dose-dependent benefit

Beyond response rates, additional data showed encouraging trends in disease control. Median progression-free survival had not yet been reached for patients receiving the 30-milligram dose of onvansertib, suggesting more durable benefit compared with standard therapy. The risk of disease progression or death was lower in the higher-dose onvansertib group than in patients receiving standard care alone.

Six months into treatment, more than 90% of patients treated with the 30-milligram onvansertib combination remained progression-free, compared with fewer patients in the standard therapy arms. These findings support the selection of the higher dose for future trials.

Importantly, onvansertib remained generally well tolerated. Serious side effects were infrequent, and no unexpected safety concerns emerged. Low white blood cell counts were the most common severe side effect, consistent with chemotherapy expectations.

Based on these findings, Cardiff Oncology plans to move forward with a registrational trial comparing onvansertib plus FOLFIRI and Avastin with current standard regimens. Final data and detailed trial plans are expected in the first half of 2026, following discussions with the U.S. Food and Drug Administration.

Additional studies are needed before onvansertib becomes widely available.

“There is a clear need for improved first-line treatment options for patients with mCRC, especially the half of those with RAS-mutated disease,” said Dr. J. Randolph Hecht, professor of clinical medicine at the David Geffen School of Medicine at UCLA, said in the release. “Unfortunately, first-line treatment for these patients hasn’t improved significantly for more than two decades. Onvansertib has a novel mechanism of action and these preliminary responses and progression-free survival results in combination with FOLFIRI and Avastin are encouraging enough to test in a large phase 3 trial. If such a trial were positive, it could become a new standard of care for these patients.”

Editor's note: This article is for informational purposes only and is not a substitute for professional medical advice, as your own experience will be unique. Use this article to guide discussions with your oncologist. Content was generated with AI and reviewed by a human editor.

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