Onvansertib Shows Promising Early Efficacy in First-Line KRAS-Mutated mCRC

Cardiff Oncology has reported positive initial data from its ongoing randomized phase 2 clinical trial, CRDF-004 (NCT05593328), evaluating the investigational polo-like kinase 1 (PLK1) inhibitor onvansertib in combination with standard-of-care (SOC) chemotherapy for patients with first-line KRAS- or NRAS-mutated metastatic colorectal cancer (mCRC).¹ The preliminary results suggest a notable improvement in objective response rates (ORR) when onvansertib is added to a backbone of FOLFIRI or FOLFOX with bevacizumab (Avastin), offering a potential new therapeutic avenue for a patient population with limited treatment options. The trial is a critical step in assessing the role of this targeted therapy in the frontline setting.

The data highlights a dose-dependent increase in ORR. In the control arm, which received SOC alone (FOLFIRI/FOLFOX plus bevacizumab), the ORR was 33% (n = 3/9). In contrast, the addition of onvansertib to the SOC regimen yielded higher response rates. The 20 mg dose cohort achieved a 50% ORR (n = 5/10), while the 30 mg dose cohort demonstrated an even more significant ORR of 64% (n = 7/11). Overall, the response rate for all onvansertib-treated patients was 57% (n = 12/21).

These early findings are particularly encouraging for a disease subset that historically exhibits poor response to traditional chemotherapy. The RAS mutation, present in approximately 50% of colorectal cancer cases, is a known driver of resistance to EGFR-targeted therapies, underscoring the need for novel treatment strategies.

“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 [progression-free survival (PFS)] data shows a trend favoring the 30mg dose of onvansertib vs control,” said Roger Sidhu, MD, chief medical officer of Cardiff Oncology, in a press 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 previous practice-changing phase 3 trials, and demonstrates that onvansertib could be a novel therapy for the treatment of first-line RAS-mutated mCRC.”

About Onvansertib

Onvansertib is a small-molecule inhibitor designed to selectively target PLK1, a serine/threonine kinase that plays a crucial role in cell cycle progression, particularly mitosis. By disrupting this pathway, onvansertib induces apoptosis in cancer cells. The rationale for combining a PLK1 inhibitor with chemotherapy is rooted in the synergistic potential to overcome resistance mechanisms and enhance the cytotoxic effects of conventional agents.

The favorable safety profile observed so far in the trial is also a key factor. Onvansertib has been generally well tolerated, with adverse events (AEs) being consistent with those typically associated with the FOLFIRI and bevacizumab regimen. This suggests that the addition of the PLK1 inhibitor does not significantly increase the toxicity burden for patients, an essential consideration for its integration into the frontline setting where maintaining quality of life is paramount. Grade 3 or higher AEs have been infrequent, and the most common treatment-emergent AE associated with onvansertib has been neutropenia.

About CDRF-004

CDRF-004 is a phase 2, randomized, open-label study investigating FOLFIRI and bevacizumab with or without onvansertib for second-line treatment of mCRC harboring a KRAS or NRAS mutation.² The study recruited patients across 27 sites in the US, and patients were required to have histologically confirmed disease, disease progression following oxaliplatin/fluoropyrimidine-based therapy with or without bevacizumab, not received prior treatment with irinotecan, and acceptable organ function. Patients with concomitant BRAF V600 or microsatellite instability-high or deficient mismatch repair disease, gastrointestinal disorders that would significantly impact absorption of an oral agent, or known hypersensitivity to irinotecan, fluoropyrimidine, or leucovorin were not eligible for enrollment. Further, patients could not have received more than 1 prior chemotherapy regimen in the metastatic setting, and a history of heart disease, current uncontrolled hypertension, or a history of arterial thrombotic or embolic events were exclusion criteria for bevacizumab.

The study’s primary end point is ORR, and secondary end points include PFS, incidence of AEs, disease control rate, duration of response, overall survival, and pharmacokinetics.

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. July 29, 2025. Accessed August 5, 2025. https://tinyurl.com/2k7pmdat

2. Study of Onvansertib in Combination With FOLFIRI and Bevacizumab Versus FOLFIRI and Bevacizumab for Second Line Treatment of Metastatic Colorectal Cancer in Participants With a Kirsten Rat Sarcoma Virus Gene (KRAS) or Neuroblastoma-RAS (NRAS) Mutation. ClinicalTrials.gov. Updated January 10, 2025. Accessed August 5, 2025. https://clinicaltrials.gov/study/NCT05593328