At the 2026 ASCO Annual Meeting, Heinz-Josef Lenz, MD, from the University of Southern California Norris Comprehensive Cancer Center, presented interim results from the phase 2 randomized CRDF-004 trial evaluating onvansertib plus standard-of-care chemotherapy and bevacizumab in first-line RAS-mutated metastatic colorectal cancer.
Patients with RAS-mutated metastatic colorectal cancer have limited treatment options. Chemotherapy combined with bevacizumab has been a standard first-line treatment approach, but outcomes remain suboptimal. Onvansertib is a highly selective, oral, small-molecule inhibitor of PLK1 that blocks mitotic progression, DNA repair, and tumor cell adaptation to hypoxia.
Study Design
CRDF-004 was a dose-finding phase 2 randomized trial in first-line RAS-mutated metastatic colorectal cancer.
Eligible patients had unresectable first-line metastatic colorectal cancer with KRAS or NRAS mutations, no BRAF V600 mutation, no MSI-H/dMMR disease, and no prior bevacizumab.
A total of 110 patients were randomized across six treatment arms:
- FOLFIRI plus bevacizumab
- FOLFOX plus bevacizumab
- Onvansertib 20 mg plus FOLFIRI and bevacizumab
- Onvansertib 20 mg plus FOLFOX and bevacizumab
- Onvansertib 30 mg plus FOLFIRI and bevacizumab
- Onvansertib 30 mg plus FOLFOX and bevacizumab
The primary endpoint was objective response rate, assessed by blinded independent central review. Secondary endpoints included duration of response and progression-free survival. Results were presented in the intent-to-treat population.
Results
At the March 18, 2026 data cutoff, baseline characteristics were generally balanced across treatment arms. Onvansertib 30 mg plus FOLFIRI and bevacizumab showed a higher objective response rate than FOLFIRI plus bevacizumab. The confirmed objective response rate by blinded independent central review was:
- 42.1% with FOLFIRI plus bevacizumab
- 44.4% with onvansertib 20 mg plus FOLFIRI and bevacizumab
- 72.2% with onvansertib 30 mg plus FOLFIRI and bevacizumab
The onvansertib 30 mg plus FOLFIRI and bevacizumab arm also showed greater depth of response, with several patients achieving deep tumor shrinkage over time.
Progression-free survival also favored onvansertib-containing treatment. In the analysis comparing onvansertib 20 mg and 30 mg plus FOLFIRI and bevacizumab versus standard-of-care chemotherapy and bevacizumab, the hazard ratio for progression-free survival was 0.44 by blinded independent central review and 0.53 by investigator assessment.
In the analysis focused on onvansertib 30 mg plus FOLFIRI and bevacizumab versus FOLFIRI plus bevacizumab, median progression-free survival was not reached with onvansertib 30 mg plus FOLFIRI and bevacizumab. The progression-free survival hazard ratio was 0.55 by blinded independent central review and 0.57 by investigator assessment.
Across baseline subgroups, objective response rate by blinded independent central review generally favored onvansertib 30 mg plus FOLFIRI and bevacizumab compared with FOLFIRI plus bevacizumab.
Safety
Onvansertib showed no unexpected, overlapping, or new toxicities when added to FOLFIRI plus bevacizumab or FOLFOX plus bevacizumab. The safety profile of onvansertib in combination with FOLFIRI and bevacizumab was consistent with the known profiles of the individual agents. Grade 3 or higher adverse events shown in the presentation included decreased neutrophil count, anemia, platelet count decreased, and white blood cell count decreased.
Conclusion
Interim data from the phase 2 CRDF-004 trial showed that onvansertib 30 mg plus FOLFIRI and bevacizumab improved objective response rate and progression-free survival compared with standard-of-care therapy in first-line RAS-mutated metastatic colorectal cancer.
The safety profile of onvansertib in combination with FOLFIRI and bevacizumab was consistent with the known profiles of the individual agents, with no new safety signals identified. These findings confirm prior phase 2 activity observed with onvansertib in metastatic colorectal cancer and support the planned phase 3 evaluation of onvansertib 30 mg plus FOLFIRI and bevacizumab in this setting.
The full abstract is available on the official ASCO website.
You can also read about SWOG S2001 at ASCO 2026 on OncoDaily.
