Onvansertib Triplet Shows Dose-Dependent Frontline Benefit in RAS-Mutant Metastatic CRC

Treatment with the oral PLK1 inhibitor onvansertib combined with standard-of-care (SOC) chemotherapy and bevacizumab (Avastin) yielded dose-dependent improvements in tumor response and progression-free survival (PFS) in first-line RAS-mutated metastatic colorectal cancer (mCRC), according to new interim data from the phase 2 CRDF-004 trial (NCT06106308).¹

The intent-to-treat analysis, with a data cut-off of January 22, 2026, evaluated 73 patients across several treatment arms. The most compelling results emerged from the cohort receiving 30 mg of onvansertib in combination with FOLFIRI and bevacizumab. In this group, the confirmed objective response rate (ORR) jumped to 72.2%, nearly doubling the 40% range observed in the SOC-only arms and the 20-mg onvansertib arm. These figures validate earlier findings and continue a favorable trend reported in August 2025.

Although the primary end point of ORR narrowly missed statistical significance (P =.051), the clinical signal was reinforced by PFS data. The study met statistical significance for PFS in the 30-mg onvansertib plus FOLFIRI/bevacizumab combination compared with SOC, with a hazard ratio of 0.37 (95% CI, 0.13-1.02; P =.048). The median PFS had not been reached at the time of analysis.

The trial also compared combinations with FOLFOX chemotherapy, showing that onvansertib provided a more robust benefit when paired with FOLFIRI rather than FOLFOX.

Regarding safety, onvansertib continued to be well tolerated in combination with both chemotherapies plus bevacizumab, with neutropenia being the most common manageable treatment-emergent adverse event across arms. No new or unexpected safety signals emerged.

“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 J. Randolph Hecht, MD, professor of Clinical Medicine at the David Geffen School of Medicine at the University of California Los Angeles, in a news release.¹ “Unfortunately, first-line treatment for these patients hasn’t improved significantly for more than [2] decades. Onvansertib has a novel mechanism of action and these preliminary responses and PFS results in combination with FOLFIRI/bevacizumab are encouraging enough to test in a large [p]hase 3 trial. If such a trial were positive, it could become a new [SOC] for these patients.”

Onvansertib was previously investigated in the second-line setting of RAS-mutated mCRC in the phase 2 ONSEMBLE study (NCT03829410). Accordingly, the agent holds a fast track designation from the FDA for second-line treatment of KRAS-mutant mCRC, awarded in May 2020.

Phase 2 Trial Design

The CRDF-004 trial was designed as a randomized, open-label, dose-finding study. Its primary objective was to identify the optimal dose of onvansertib (20 mg vs 30 mg) and the most effective chemotherapy backbone (FOLFIRI vs FOLFOX) to bring forward into registrational studies through evaluation of safety, efficacy, and pharmacokinetics.² The study’s primary end point is ORR; secondary end points include PFS, duration of response, and safety.

Eligible patients had previously untreated mCRC and harbored KRAS or NRAS mutations, a population that has historically seen limited progress in first-line targeted options beyond anti-VEGF therapy.

Next Steps in Development

Following these results, the sponsor has selected the 30-mg dose of onvansertib to advance in combination with FOLFIRI and bevacizumab for its registrational program. The company is currently finalizing the design of a registrational trial in consultation with the FDA. According to the sponsor, final data and registration plans will be revealed in early 2026.

“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/bev[acizumab] and we believe confirmatory data from a registrational trial ha[ve] the potential to make this regimen a new SOC for [first-line] treatment of RAS-mutated mCRC,” added Mani Mohindru, PhD, interim CEO of Cardiff Oncology, in the news release.¹

REFERENCES

1. Cardiff Oncology announces positive update from its randomized Phase 2 trial of onvansertib in first-line RAS-mutated mCRC. News release. Cardiff Oncology. January 27, 2026. Accessed January 29, 2026. https://tinyurl.com/35du92ca

2. Study of onvansertib in combination with FOLFIRI and bevacizumab or FOLFOX and bevacizumab versus FOLFIRI and bevacizumab or FOLFOX and bevacizumab for first-line treatment of metastatic colorectal cancer in adult participants with a KRAS or NRAS mutation. ClinicalTrials.gov. Updated January 12, 2026. Accessed January 29, 2026. https://clinicaltrials.gov/study/NCT06106308