Onvansertib Triplet Improves Efficacy in First-Line RAS-Mutated mCRC

Onvansertib combined with standard-of-care chemotherapy and bevacizumab (Avastin) regimens improved outcomes in patients with treatment-naive RAS-mutated metastatic colorectal cancer (CRC), according to a press release from the developer, Cardiff Oncology.¹

The findings potentially address a significant unmet need in the RAS-mutated population, which accounts for approximately half of all metastatic CRC cases and has seen limited therapeutic advancement in the first line setting for more than 2 decades. Results came from the randomized phase 2 CRDF-004 trial (NCT06106308) trial, which evaluated 2 separate doses of onvansertib in combination with bevacizumab and either leucovorin, fluorouracil, and irinotecan (FOLFIRI) or leucovorin, fluorouracil, and oxaliplatin (FOLFOX) in patients with first-line KRAS- or RAS-mutated metastatic CRC.²

“These data demonstrate promising enhanced benefits of onvansertib when combined with FOLFIRI/bevacizumab in [patients with] RAS-mutated metastatic CRC,” stated Mani Mohindru, PhD, interim chief executive officer, in the press release.¹ “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/bevacizumab 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 metastatic CRC.”

Clinical Efficacy

In an intent-to-treat analysis with a data cut-off of January 22, 2026, onvansertib at 30 mg plus FOLFIRI and bevacizumab achieved a confirmed overall response rate (ORR) of 72.2%. This represented a substantial improvement over the 43.2% ORR observed in the combined standard of care arms—FOLFIRI plus bevacizumab and FOLFOX plus bevacizumab—and the 42.1% ORR in the FOLFIRI plus bevacizumab control arm alone. When onvansertib was administered at 20 mg in combination with FOLFIRI and bevacizumab, the ORR was 44.4%.

Additionally, the 30-mg onvansertib plus FOLFIRI and bevacizumab arm achieved statistical significance for progression-free survival (PFS) compared with standard of care, demonstrating a hazard ratio of 0.37 (95% CI, 0.13-1.02; P = .048). While the median PFS had not yet been reached for the onvansertib arms at the time of the analysis, the standard of care regimens demonstrated a median PFS of 10.97 months (95% CI, 6.53-15.44). The 6-month PFS rate was 94.1% (95% CI, 83.6%-100.0%) with 30 mg onvansertib plus FOLFIRI and bevacizumab, 88.1% (95% CI, 73.9%-100.0%) with 20 mg ovansertib plus FOLFIRI and bevacizumab, 79.5% (95% CI, 61.1%-100.0%) with FOLFIRI and bevacizumab, and 88.8% (95% CI, 77.4%-100.0%) with standard of care.

“There is a clear need for improved first-line treatment options for patients with metastatic CRC, especially the half of those with RAS-mutated disease,” added J. Randolph Hecht, MD, professor of Clinical Medicine at the David Geffen School of Medicine at UCLA, in the 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 phase 3 trial. If such a trial were positive, it could become a new standard of care for these patients.”

Trial Breakdown

Participants were [randomly assigned] to receive 20 mg of onvansertib plus standard of care, 30 mg of onvansertib plus standard of care, or standard of care alone. In the experimental arms, onvansertib was administered orally as a capsule once daily on days 1 through 5 and days 15 through 19 of each 28-day cycle.²

Eligibility criteria required patients to have histologically confirmed metastatic CRC with a documented KRAS or NRAS mutation and unresectable disease. Patients must have been treatment-naive in the metastatic setting and possessed an ECOG performance status of 0 or 1. The primary end point of the trial was ORR per RECIST v1.1, with secondary endpoints including PFS, duration of response, and safety.

Safety and Tolerability

The addition of onvansertib to standard chemotherapy did not result in major or unexpected toxicities or significant additive adverse effects (AEs). Neutropenia was identified as the most common treatment-emergent AE across the treatment arms, though investigators characterized it as manageable.

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 February 18, 2026. https://tinyurl.com/27axc7pz
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 February 18, 2026. https://tinyurl.com/3222nz3f