Onvansertib Combo Appears Efficacious in KRAS+ Metastatic Colorectal Cancer

The addition of onvansertib to folinic acid, fluorouracil, and irinotecan hydrochloride (FOLFIRI) and bevacizumab (Avastin) demonstrated efficacious clinical activity among patients with KRAS-mutated metastatic colorectal cancer (CRC) in the second-line setting, according to findings from a multicenter, open-label, single-arm phase 2 trial (NCT06106308) published in the Journal of Clinical Oncology.

For all patients treated with onvansertib at the recommended phase 2 dose, investigator-assessed overall response rate (ORR) was 26.4% (95% CI, 15.3%-40.3%), with one complete response and 13 partial responses; median time to response was 86 days. A decrease in target lesion size from baseline was observed in 39 patients (73.6%). 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).

The addition of onvansertib to fFOLFIRI and bevacizumab showed clinical activity among patients with KRAS-mutated metastatic colorectal cancer in the second-line setting

In a post hoc analysis, the trial authors evaluated how prior exposure to bevacizumab affected results in the study. They found that patients who were bevacizumab naïve (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) when compared with patients previously treated with bevacizumab who 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).

The authors terminated the study early because of the significant results found in the subgroup analysis, indicating that patients without previous exposure to bevacizumab had much higher clinical benefit on the trial’s regimen.

“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,” the authors of the study wrote. “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.”

The primary end point was ORR per RECIST v1.1 criteria in patients who received at least 1 cycle of treatment. The secondary end points were disease control rate, PFS, DOR, and reduction in KRAS-mutant allelic burden in liquid biopsies.

A total of 53 patients were enrolled in the trial. Treatment protocol was as follows: 15 mg/m2 of onvansertib administered orally once daily from days 1 to 5 and days 15 to 19 of a 28-day cycle; FOLFIRI consisting of 180 mg/m2 of irinotecan intravenously, 400 mg/m2 of leucovorin intravenously, 400 mg/m2 of fluorouracil bolus intravenously, and 2400 mg/m2 of intravenous fluorouracil continuously for 46 hours; and 5 mg/m2 of bevacizumab administered once daily on days 1 and 15 until unacceptably toxicity, disease progression, death, or withdrawal.

Patients were required to be 18 years or older; had to have histologically confirmed metastatic and unresectable CRC with KRAS mutations in exon 2, 3, or 4; had to have received 6 weeks or more of oxaliplatin and fluoropyrimidine with or without bevacizumab; needed to have progressed within 6 months of treatment or shown intolerance to oxaliplatin; had to have an ECOG performance status of 0 or 1; and had to have adequate organ function.

Patients were ineligible for participation if they had microsatellite instability–high disease or mismatch repair deficiency, more than 1 prior chemotherapy regimen for metastatic disease, untreated brain metastasis, and a BRAF V600mutation.

Regarding safety, 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%). AEs of grade 3 or 4, respectively, occurred in 62.3% and 7.5% of patients. There were 4 grade 4 AEs, 3 of which were neutropenia and 1 was colonic perforation.

The open-label, multicenter, randomized phase 2 CRDF-004 study (NCT06106308) is currently evaluating the viability of onvansertib plus chemotherapy/bevacizumab as a first-line therapy vs chemotherapy/bevacizumab.

Reference

Ahn DH, Ridinger M, Cannon TL, et al. Onvansertib in combination with chemotherapy and bevacizumab in second-line treatment of KRAS-mutant metastatic colorectal cancer: a single-arm, phase II Trial [published correction appears in J Clin Oncol. 2024 Nov 19:JCO2402458. doi: 10.1200/JCO-24-02458]. J Clin Oncol. Published online October 30, 2024. doi:10.1200/JCO-24-01266