First-Line Onvansertib Plus Bevacizumab and Chemo Yields Responses in RAS-Mutated mCRC

Onvansertib (PCM-075; NMS-1286937) produced early signals of efficacy with a tolerable safety profile when combined with standard-of-care (SOC) bevacizumab (Avastin) plus chemotherapy in patients with previously untreated RAS-mutated metastatic colorectal cancer (mCRC), according to findings from the ongoing phase 2 CRDF-004 trial (NCT06106308).¹

At a data cutoff of July 8, 2025, across the intent-to-treat population (n = 110), among patients who received onvansertib at 30 mg (n = 37), the confirmed objective response rate (ORR) was 49% compared with 30% among patients in the control arm who received SOC alone (n = 37). Furthermore, this rate was 42% among patients who received onvansertib at 20 mg (n = 36). The confirmed ORRs at 6 months in these respective arms were 46%, 22%, and 33%.

Early progression-free survival (PFS) data also demonstrated a trend favoring treatment with onvansertib at 30 mg plus SOC vs the control therapy, although the median PFS has not been reached. At a median follow-up of 6 months, a separation of the PFS curves was also observed in both onvansertib arms compared with the control arm.

Dose-dependent responses favoring the 30-mg dose were observed for all end points, including ORR, depth of response, and early tumor shrinkage.

Additionally, a safety analysis conducted in 104 safety-evaluable patients showed that the onvansertib regimens were well tolerated, and no unexpected or major adverse effects (AEs) were observed. The rate of grade 3 or higher AEs was low. The most common treatment-emergent AE associated with onvansertib was neutropenia.

“We are highly encouraged by the 19% improvement in confirmed ORR, as well as the shorter time to response and deeper tumor regression observed in our trial with onvansertib combined with SOC compared to SOC alone,” Roger Sidhu, MD, chief medical officer of Cardiff Oncology, stated in a news release. “The totality of the data we are releasing today strengthens the initial findings from our December 2024 data release in a significantly larger patient population, compares favorably to [data from] previous practice-changing phase 3 trials, and demonstrates that onvansertib could be a novel therapy for the treatment of [patients with] first-line RAS-mutated mCRC.”

CRDF-004 enrolled patients with histologically confirmed mCRC who had a documented NRAS or KRAS mutation.² Patients were not permitted to have received prior systemic therapy in the metastatic setting and needed to have an ECOG performance status of 0 or 1, as well as acceptable organ function.

Patients were randomly assigned to 1 of 6 arms, where they received onvansertib at 20 mg plus SOC bevacizumab plus FOLFOX (leucovorin, fluorouracil, and oxaliplatin) or FOLFIRI (leucovorin, fluorouracil, and irinotecan), onvansertib at 30 mg plus the SOC regimen, or the SOC regimen alone. Onvansertib was administered on days 1 to 5 and days 15 to 19 of each 28-day treatment cycle. The SOC regimen was administered on days 1 and 15 of each cycle.

ORR serves as the primary end point. Secondary end points include PFS, duration of response, disease control rate, overall survival, and safety. Additional prespecified end points are early tumor shrinkage and depth of response.¹ 

“We are highly encouraged by the strength of our data, which achieve the key objectives we set for the trial and positions us to engage in discussions with the FDA as we advance toward our registrational CRDF-005 trial,” Mark Erlander, chief executive officer of Cardiff Oncology, concluded in the news release. “Looking ahead, we are optimistic about onvansertib’s potential to redefine the first-line treatment for RAS-mutated mCRC and will provide an update on our first-line mCRC program by [the first quarter of] 2026.”

References

1. Cardiff Oncology announces positive data from ongoing randomized phase 2 first-line RAS-mutated mCRC clinical trial (CRDF-004). News release. Cardiff Oncology, Inc. July 29, 2025. Accessed July 30, 2025. https://investors.cardiffoncology.com/news-releases/news-release-details/cardiff-oncology-announces-positive-data-ongoing-randomized
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 April 29, 2025. Accessed July 30, 2025. https://clinicaltrials.gov/study/NCT06106308