San Diego-based biotech Cardiff Oncology announced a positive clinical update from its ongoing randomized Phase II CRDF-001 trial evaluating onvansertib in patients with RAS-mutated metastatic colorectal cancer (mCRC). Onvansertib is an oral, selective inhibitor of Polo-like Kinase 1 (PLK1), a protein often overexpressed in various cancers that regulates critical stages of mitosis. The data suggests that the addition of onvansertib to standard-of-care chemotherapy may overcome resistance mechanisms in patients who have not previously received bevacizumab in the first-line setting.

Trial specifics

The CRDF-001 trial is a randomized Phase II study designed to evaluate the efficacy and safety of onvansertib when combined with standard-of-care (SoC) FOLFIRI plus bevacizumab. The study specifically enrolled patients with RAS-mutated mCRC who are in the second-line setting. Patients were randomized to receive either the onvansertib combination or SoC alone. The primary endpoint of the trial is the objective response rate (ORR), with secondary endpoints including progression-free survival (PFS) and safety.

Initial results from the trial highlighted a significant difference in clinical activity based on prior bevacizumab exposure. In patients who were bevacizumab-naive in the first-line setting, the onvansertib combination achieved a confirmed ORR of 50% (4 out of 8 patients), compared to 0% (0 out of 6 patients) in the SoC control arm. Furthermore, the median PFS for these bevacizumab-naive patients reached 14.9 months in the onvansertib arm versus 5.6 months in the control arm. In contrast, patients who had received prior bevacizumab treatment did not show a comparable benefit, suggesting that the timing of PLK1 inhibition is critical to its therapeutic impact.

Cardiff Oncology noted that onvansertib was generally well-tolerated, with a safety profile consistent with previous studies. The company intends to focus future development on this bevacizumab-naive patient population. Fereydoun Firouz, Chief Executive Officer of Cardiff Oncology, stated in the press release that the data “provides a clear path forward for onvansertib in the first-line setting, where the unmet need remains high for RAS-mutated patients.”

Research context

Onvansertib functions by inhibiting PLK1, a master regulator of the cell cycle. By blocking PLK1, the drug induces mitotic arrest and subsequent apoptosis in rapidly dividing cancer cells. This mechanism is particularly relevant in RAS-mutated cancers, where the RAS signaling pathway often drives uncontrolled cell proliferation and survival. Onvansertib has received Fast Track designation from the US FDA for the treatment of RAS-mutated mCRC; however, the asset remains unapproved globally.

Colorectal cancer is the third most common cancer diagnosed in both men and women worldwide, with a high mortality rate when diagnosed at the metastatic stage. Approximately 50% of mCRC patients harbor RAS mutations, which are traditionally associated with a poorer prognosis and limited response to certain EGFR-targeted therapies like cetuximab (Erbitux). The current SoC for these patients typically involves fluoropyrimidine-based chemotherapy combinations (such as FOLFIRI or FOLFOX) paired with bevacizumab (Avastin), a VEGF inhibitor.

The competitive landscape for RAS-mutated mCRC is evolving rapidly, with several companies targeting the cell cycle or specific RAS isoforms. Amgen and Mirati Therapeutics (now part of Bristol Myers Squibb) have successfully brought KRAS G12C inhibitors, sotorasib (Lumakras) and adagrasib (Krazati), to market for specific mutations. However, these target only a small subset (approximately 3%) of mCRC patients.

Broader PLK1 inhibition or pan-RAS approaches are being explored by other firms. Boehringer Ingelheim is developing BI 1701963, a pan-KRAS inhibitor, currently in Phase 1/2 trials. Additionally, Takeda Pharmaceutical Company is investigating various oncology assets that target similar mitotic pathways. Cardiff Oncology’s focus on combining PLK1 inhibition with SoC chemotherapy represents a distinct strategy aimed at a larger segment of the RAS-mutated mCRC population compared to mutation-specific inhibitors.