436P Phase Ib/II study of the polo-like kinase 1 (PLK1) inhibitor, onvansertib, in combination with FOLFIRI and bevacizumab for second line treatment of KRAS-mutated metastatic colorectal cancer

Second-line treatment of KRAS-mutated metastatic colorectal cancer (mCRC) confers a dismal patient (pt) outcome with response rates of 4% to FOLFIRI (5-fluorouracil (5FU), leucovorin, irinotecan) + bevacizumab (bev) and median progression-free survival (PFS) of 5.5 months. PLK1 is a serine/threonine kinase, master regulator of mitosis. PLK1 inhibition has synthetic lethality with KRAS-mutated CRC tumor cells. Onvansertib is an oral and highly-selective PLK1 inhibitor with demonstrated efficacy as a single agent and synergistically with irinotecan in CRC preclinical models. This single-arm phase Ib/II study (NCT03829410) assesses the safety and preliminary efficacy of onvansertib in combination with FOLFIRI + bev in second line KRAS-mutated mCRC. Pts are treated with onvansertib (days 1-5) + FOLFIRI-bev (day 1) in a 14-day cycle. In the phase Ib, a standard 3 + 3 dose-escalation design is used to determine the maximum tolerated dose or recommended phase II dose. Secondary objectives are preliminary efficacy determined by radiographic scans every 8 weeks and reduction in KRAS mutant allelic burden evaluated by liquid biopsy. As of May 4, 2020, onvansertib 12 and 15 mg/m2 dose levels were cleared for safety. At dose level 18 mg/m2, 1 of 3 pts had a DLT (G4 neutropenia deemed to be associated with 5FU bolus) and 3 additional pts are enrolling. Most common all-causality adverse events (AEs) were fatigue, diarrhea, nausea and neutropenia. All grade 3/4 AEs resolved within 2.5 weeks and did not result in treatment discontinuation. Of the 9 pts evaluable for efficacy, 4 (44%) had partial response (PR) and 4 (44%) stable disease with 1 pt proceeded to curative surgery followed by no evidence of disease. Median PFS is >6 months to-date, with 6 of the 9 pts remaining on treatment. Decrease in plasma KRAS mutant during the first cycle of treatment was highly predictive of tumor regression. Preliminary results indicate that onvansertib is safe and efficacious in combination with chemotherapy in KRAS-mutated mCRC pts and early changes in plasma KRAS mutant are predictive of clinical response.