Onvansertib in Combination with FOLFIRI and Bevacizumab in Second-line Treatment of KRAS-mutant Metastatic Colorectal Cancer: A Phase 1b Clinical Study.

PURPOSE:Onvansertib is a highly specific inhibitor of Polo-like kinase 1 (PLK1), with demonstrated safety in solid tumors. We evaluated, preclinically and clinically, the potential of onvansertib in combination with chemotherapy as a therapeutic option for KRAS-mutant colorectal cancer (CRC). PATIENTS AND METHODS:Preclinical activity of onvansertib was assessed: (1) in vitro in KRAS-wild type and -mutant isogenic CRC cells; and (2) in vivo, in combination with irinotecan, in a KRAS-mutant xenograft model. Clinically, a Phase Ib trial was conducted to investigate 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) in KRAS-mutant metastatic CRC patients who had prior oxaliplatin exposure. Safety, efficacy, and changes in circulating tumor DNA (ctDNA) were assessed. RESULTS:In preclinical models, onvansertib displayed superior activity in KRAS-mutant than wild-type isogenic CRC cells and demonstrated potent anti-tumor activity in combination with irinotecan in vivo. Eighteen patients enrolled in the Phase Ib study. Onvansertib recommended phase 2 dose was established at 15 mg/m2. Grade 3 and 4 adverse events (AE) represented 15% of all treatment-related AEs, with neutropenia being the most common. Partial responses were observed in 44% of patients with a median duration of response of 9.5 months. Early ctDNA dynamics were predictive of treatment efficacy. CONCLUSIONS:Onvansertib combined with FOLIFRI/bevacizumab exhibited manageable safety and promising efficacy in second-line treatment of KRAS-mutant metastatic CRC patients. Further exploration of this combination therapy is ongoing.