In a phase II trial reported in the Journal of Clinical Oncology, Ahn et al found the combination of the PLK1 inhibitor onvansertib with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab showed activity in the second-line treatment of KRAS-mutant metastatic colorectal cancer.
Study Details
In the U.S. multicenter trial, 53 patients who had received prior treatment with oxaliplatin/fluorouracil with or without bevacizumab, enrolled between December 2019 and October 2023, received onvansertib at 15 mg/m2 once daily on days 1 to 5 and 15 to 19 of a 28-day cycle plus FOLFIRI (irinotecan at 180 mg/m2, leucovorin at 400 mg/m2, and fluorouracil at 400 mg/m2 bolus and then 2,400 mg/m2 via 46-hour infusion) and bevacizumab at 5 mg/kg once daily on days 1 and 15. Treatment continued until disease progression or unacceptable toxicity. The primary outcome measure was objective response rate.
Key Findings
Among the 53 patients, objective responses were observed in 14 patients (26.4%, 95% confidence interval [CI] = 15.3%–40.3%), with a complete response in 1. The median duration of response was 11.7 months (95% CI = 9.4 months to not reached). Disease control was observed in 92.5% of patents. Median progression-free survival was 8.4 months (95% CI = 6.0–14.8 months).
In a post hoc analysis, 13 patients who had not previously received bevacizumab had a significantly better objective response rate (76.9% vs 10.0%, odds ratio = 30.0, P < .001) and median progression-free survival (14.9 months vs 6.6 months, hazard ratio = 0.16, P < .001). As stated by the investigators, “Our translational findings support that prior bevacizumab exposure contributes to onvansertib resistance.”
Grade 3 or 4 treatment-related adverse events occurred in 70% of patients, most commonly neutropenia (41%), hypertension (9.4%), nausea (7.5%), and diarrhea (7.5%). Adverse events led to treatment discontinuation in four patients (7.5%).
The investigators concluded: “Onvansertib in combination with FOLFIRI [plus] bevacizumab showed significant activity in the second-line treatment of patients with KRAS-mutant [metastatic colorectal cancer], particularly in patients with no prior bevacizumab treatment. These findings led to the evaluation of the combination in the first-line setting (ClinicalTrails.gov identifier NCT06106308).”
Heinz-Josef Lenz, MD, of the University of Southern California Norris Comprehensive Cancer Center, Los Angeles, is the corresponding author of the Journal of Clinical Oncology article.
Disclosure: The trial was supported by Cardiff Oncology. For full disclosures of the study authors, visit ascopubs.org.
