The PLK1 Inhibitor Onvansertib in Combination with FOLFIRI and Bevacizumab in Second-line Treatment of KRAS-mutant Metastatic Colorectal Cancer: A Single-Arm, Phase II Trial.
Purpose: This phase II study evaluated the efficacy and tolerability of onvansertib, a polo-like kinase 1 (PLK1) inhibitor, combined with FOLFIRI + bevacizumab for the second-line treatment of KRAS-mutant metastatic colorectal cancer (mCRC).  Patients and Methods: This multicenter, open-label, single-arm study enrolled KRAS-mutated mCRC patients previously treated with oxaliplatin and 5-fluorouracil with or without bevacizumab. Patients received onvansertib 15 mg/m2 (days 1-5 and 15-19 of a 28-day cycle) and FOLFIRI + bevacizumab (days 1 and 15). The primary endpoint was the objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), duration of response (DOR), and tolerability. Translational and preclinical studies were conducted in KRAS-mutant CRC.   Results: Among the 53 patients treated, the confirmed ORR was 26.4% (95% CI, 15.3 to 40.3). The median DOR was 11.7 months (95% CI, 9.4 to not reached). Grade 3/4 adverse events were reported in 62% of patients. A post hoc analysis revealed that patients with no prior bevacizumab treatment had a significantly higher ORR and longer PFS compared to patients with prior bevacizumab treatment: ORR of 76.9% versus 10.0% (odds ratio of 30.0, p<0.001) and median PFS of 14.9 months versus 6.6 months (hazard ratio of 0.16, p<0.001). Our translational findings support that prior bevacizumab exposure contributes to onvansertib resistance. Preclinically, we showed that onvansertib inhibited the hypoxia pathway and exhibited robust antitumor activity in combination with bevacizumab through the inhibition of angiogenesis.   Conclusion: Onvansertib combined with FOLFIRI + bevacizumab showed significant activity in the second-line treatment of KRAS-mutant mCRC patients, particularly in patients with no prior bevacizumab treatment. These findings led to the evaluation of the combination in the first line setting (ClinicalTrails.gov identifier: NCT06106308). Overall design: KRAS-mutant CRC cell lines were treated with DMSO or onvansertib at two doses for 20 h and then exposed to hypoxia or kept in normoxia for 4h. RNA-seq data were examined for hypoxia related genes specifically regulated by onvansertib.