San Diego-based Cardiff Oncology (Nasdaq: CRDF) reported that onvansertib, an oral PLK1 inhibitor, produced a confirmed objective response rate of 72.2% in first-line RAS-mutated metastatic colorectal cancer when combined with FOLFIRI/bevacizumab, compared with 42.1% for chemotherapy alone. The data were provided by Cardiff Oncology to the US FDA during an 'End-of-Phase II' meeting prior to agency clearance to begin a registrational Phase III trial.
RAS mutations — spanning KRAS and NRAS — are present in roughly 50–55% of mCRC cases, and outside of the narrow KRAS G12C subgroup (less than 4% of colorectal cancers, addressed by Bristol Myers Squibb's Krazati (adagrasib) in combination with Eli Lilly's Erbitux (cetuximab) in previously treated patients), no therapy is specifically approved for this population in the first-line setting. Bevacizumab-based chemotherapy doublets remain the de facto standard.
Onvansertib targets PLK1, a serine/threonine kinase involved in mitotic progression whose activity is upregulated in RAS-driven tumors, offering a mechanistic rationale for combining it with irinotecan-based regimens. Cardiff has indicated a global Phase III trial will follow the completed FDA alignment; the design — onvansertib 30 mg plus FOLFIRI/bevacizumab versus FOLFIRI/bevacizumab alone in first-line RAS-mutated mCRC — was presented at the 2026 ASCO Annual Meeting, with further details on trial plans expected in the coming months.
The CRDF-004 trial is a randomized, controlled, dose-finding Phase II study enrolling patients with first-line KRAS- or NRAS-mutated mCRC across six arms, designed to select the dose and regimen for a registrational program. In the intent-to-treat population, the 30 mg onvansertib plus FOLFIRI/bevacizumab arm achieved a confirmed ORR of 72.2% (13 of 18 patients) versus 42.1% (8 of 19) for FOLFIRI/bevacizumab alone, a roughly 30 percentage point difference. Median progression-free survival has not been reached in either the 20 mg or 30 mg onvansertib plus FOLFIRI/bevacizumab arms, while it has been reached in both standard-of-care comparator arms; PFS hazard ratios were 0.55 (95% CI: 0.15–2.09) by blinded independent central review and 0.57 (95% CI: 0.20–1.65) by investigator assessment. Four patients remain on treatment beyond 15 months, including two beyond 20 months. No meaningful efficacy signal emerged in the onvansertib plus FOLFOX/bevacizumab arms relative to FOLFOX/bevacizumab alone. Safety was consistent with the known profile of each component: grade 3 or higher events were infrequent, neutropenia was the most common treatment-emergent adverse event across both onvansertib and control arms, and no additive or unexpected toxicities were observed.
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