A phase 2 trial published in the Journal of Clinical Oncology reveals that onvansertib, when combined with FOLFIRI (folinic acid, fluorouracil, and irinotecan hydrochloride) and bevacizumab, demonstrates significant clinical activity in the second-line treatment of patients with KRAS-mutated metastatic colorectal cancer (CRC), particularly in those who have not previously received bevacizumab.
The multicenter, open-label, single-arm trial (NCT06106308) enrolled 53 patients with KRAS-mutated metastatic CRC. Patients received onvansertib (15 mg/m2 orally on days 1-5 and 15-19 of a 28-day cycle) in combination with FOLFIRI and bevacizumab (5 mg/kg intravenously on days 1 and 15). The primary endpoint was overall response rate (ORR) per RECIST v1.1 criteria. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), and reduction in KRAS-mutant allelic burden.
Efficacy Results
The investigator-assessed ORR for all patients treated with onvansertib at the recommended phase 2 dose was 26.4% (95% CI, 15.3%-40.3%), including one complete response and 13 partial responses. The median time to response was 86 days. A decrease in target lesion size from baseline was observed in 73.6% of patients. The disease control rate was 92.5%, the median duration of response (DOR) was 11.7 months (95% CI, 9.4-not reached), and median progression-free survival (PFS) was 8.4 months (95% CI, 6.0-14.8).
Impact of Prior Bevacizumab Exposure
A post hoc analysis revealed a significant difference in outcomes based on prior bevacizumab exposure. Patients who were bevacizumab-naive (n = 13) had an ORR of 76.9% (95% CI, 46.2%-95.0%) and a median PFS of 14.9 months (95% CI, 13.5-not reached). In contrast, patients previously treated with bevacizumab had an ORR of 10.0% (95% CI, 2.8%-23.7%) and a median PFS of 6.6 months (95% CI, 5.6-9.8).
Study Termination and Future Directions
The study was terminated early due to the significant results observed in the subgroup analysis of bevacizumab-naive patients. According to the study authors, "Patients with no prior exposure to bevacizumab showed marked increased efficacy with an ORR of 76.9% and a median PFS of 14.9 months, underscoring the unique sensitivity of this population to onvansertib. This exceptional response, alongside our translational studies showing onvansertib’s effect on the hypoxia pathway and angiogenesis, supports shifting onvansertib development to the frontline setting, where all patients are bevacizumab naïve."
Safety Profile
The most common treatment-emergent adverse events (AEs) of any grade were fatigue (73.6%), neutropenia (71.7%), nausea (62.3%), diarrhea (52.8%), and stomatitis (45.3%). Grade 3 or 4 AEs occurred in 62.3% and 7.5% of patients, respectively. There were 4 grade 4 AEs, including 3 cases of neutropenia and 1 of colonic perforation.
Ongoing Research
The open-label, multicenter, randomized phase 2 CRDF-004 study (NCT06106308) is currently evaluating onvansertib plus chemotherapy/bevacizumab as a first-line therapy versus chemotherapy/bevacizumab.
