Onvansertib Exhibits Encouraging Responses in RAS-Mutant Metastatic CRC

Both dose cohorts of onvansertib showed an early separation of progression-free survival (PFS) curves vs the control arm after a median follow-up of 6 months.

The addition of onvansertib (PCM-075) to chemotherapy and bevacizumab (Avastin) in the first-line setting improved response rates vs standard-of-care (SOC) bevacizumab/chemotherapy in patients with RAS-mutant metastatic colorectal cancer (CRC), according to a news release from the drug’s developer, Cardiff Oncology, Inc.¹

Efficacy data from the phase 2 CRDF-004 trial (NCT06106308) revealed that the as of the data cutoff date of July 8, 2025, the confirmed objective response rate (ORR) per blinded independent central review (BICR) among patients treated with 20 mg (n = 36) or 30 mg of onvansertib (n =37) was 42% and 49% vs 30% in those treated with SOC alone (n = 37). The respective 6-month confirmed ORR rates were 33%, 46%, and 22%, and the unconfirmed ORR was 50%, 59%, and 43%.

According to the news release, both dose cohorts showed an early separation of progression-free survival (PFS) curves vs the control arm after a median follow-up of 6 months. Median PFS was not reached in either arm, but a dose dependent effect favored the 30 mg cohort.

“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. Furthermore, early PFS data show a trend favoring the 30 mg dose of onvansertib vs control,” Roger Sidhu, MD, chief medical officer of Cardiff Oncology, said in the news release.¹ “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 previous practice-changing phase 3 trials, and demonstrates that onvansertib could be a novel therapy for the treatment of first-line RAS-mutated [metastatic] CRC.”

Patients with KRAS- or NRAS-mutant metastatic CRC were randomly assigned 1:1:1 to receive 20 mg or 30 mg of onvansertib plus chemotherapy/bevacizumab, or chemotherapy/bevacizumab alone. Onvansertib was given on days 1 to 5 and 15 to 19 of 28-day cycles.² Chemotherapy consisted of either leucovorin (folinic acid), fluorouracil, and oxaliplatin (FOLFOX) or leucovorin, fluorouracil, and irinotecan (FOLFIRI); regimens were given on days 1 and 15 of 28-day cycles.

The primary end point of the trial was ORR per BICR. Secondary end points included PFS, duration of response, disease control rate, overall survival, and safety.

In a safety analysis assessing 104 patients treated in the study, investigators found that the onvansertib combination was well-tolerated with no major or unexpected toxicities observed. Grade 3 or higher adverse effects (AEs) were considered infrequent, and neutropenia was the most common treatment-emergent AE observed with onvansertib.

Patients eligible for enrollment had histologically confirmed KRAS- or NRAS-mutant metastatic CRC, no previous systemic therapy for metastatic disease, an ECOG performance score of 0 or 1, and acceptable organ function.

Those excluded from trial participation included those with concomitant KRAS or NRAS and BRAF V600 mutations or microsatellite instability–high/deficient mismatch repair disease; prior treatment with VEGF inhibition; oxaliplatin treatment within 12 months before random assignment; and a known dihydropyrimidine dehydrogenase (DPD) deficiency. Patients with uncontrolled intercurrent illness, those with untreated or symptomatic brain metastases, and those treated with anticancer chemotherapy or a biologic therapy within 28 days of first study dose were also ineligible for enrollment on the trial.

“We are highly encouraged by the strength of our data, which achieves 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, stated in the news release.¹ “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 [metastatic] CRC 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://tinyurl.com/rvzhw797
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://tinyurl.com/4szac4a2