In the second-line treatment of patients with metastatic colorectal cancer harbouring KRAS mutation, onvansertib combined with FOLIFRI/bevacizumab demonstrates promising clinical activity while having a manageable safety profile, according to the results of a phase Ib study.
Researchers assessed the preclinical activity of onvansertib (i) in vitro in KRAS wild-type and -mutant isogenic colorectal cancer cells and (ii) in vivo, in combination with irinotecan, in a KRAS-mutant xenograft model.
In the phase Ib trial, 18 patients with KRAS-mutant metastatic colorectal cancer who had prior oxaliplatin exposure were given onvansertib at doses 12, 15, and 18 mg/m2 (days 1–5 and 14–19 of a 28-day cycle) in combination with FOLFIRI/bevacizumab (days 1 and 15). Safety, efficacy, and changes in circulating tumour DNA (ctDNA) were evaluated.
In preclinical models, onvansertib showed a stronger effect against KRAS-mutant than wild-type isogenic colorectal cancer cells. Furthermore, combining onvansertib and irinotecan yielded potent antitumour activity in vivo.
The recommended phase II onvansertib dose was established at 15 mg/m2. Of the treatment-related adverse events (AEs) recorded, 15 percent were grade 3 and 4, with neutropenia being the most common.
A total of 44 percent of patients achieved partial responses, with a median duration of response of 9.5 months. Early ctDNA dynamics predicted treatment efficacy.