Onvansertib in Combination with FOLFIRI and Bevacizumab in Second-line Treatment of KRAS-mutant Metastatic Colorectal Cancer: A Phase 1b Clinical Study
Mené sur 18 patients atteints d'un cancer colorectal de stade métastatique avec mutations au niveau du gène KRAS (durée médiane de suivi : 10 mois), cet essai de phase IB détermine la dose maximale tolérée de l'onvansertib (un inhibiteur de PLK1 dispensé par voie orale) en combinaison avec une chimiothérapie de deuxième ligne de type FOLFIRI avec bévacizumab puis évalue l'efficacité de cette combinaison du point de vue du taux de réponse
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.