Introduction: Chemotherapy in combination with targeted agents are standard-of-care options for first and second-line treatment of metastatic colorectal cancer (mCRC) patients. Second-line treatment of KRAS-mutated mCRC confers a dismal patient outcome with response rates of 4% to FOLFIRI (5-fluorouracil (5FU), leucovorin, irinotecan) + bevacizumab and median progression-free survival of 5.5 months (Tournigand et al., JCO 2004). PLK1 is a serine/threonine kinase, master regulator of mitosis and its overexpression is associated with poorer outcomes in CRC (Weichert et al., World J. Gastroenterol. 2005). Onvansertib is an oral and highly selective PLK1 inhibitor with demonstrated efficacy as a single agent and synergistically with irinotecan and 5-FU in CRC preclinical models. Onvansertib was granted Fast Track Designation by the Food and Drug Administration for its clinical development program and is currently being investigated in combination with FOLFIRI + bevacizumab in a phase 1b/2 clinical study for second line treatment of patients with KRAS-mutated mCRC (NCT03829410). Preliminary results indicate that onvansertib in combination with chemotherapy is safe and efficacious and that early changes in plasma KRAS mutant are predictive of clinical response (ESMO 2020, Poster #2969).

Method: An expanded access program (EAP) was initiated to provide access to onvansertib for treatment of patients who do not meet eligibility criteria for enrollment in the clinical trial, and provides an opportunity to collect safety and efficacy data outside of the clinical study. Patients must be at least 18 years old, have confirmed metastatic and unresectable CRC with a KRAS mutation and have failed or progressed on standard of care systemic therapy. Patients are treated with onvansertib (15 mg/m2, Days 1 to 5 of a 14-day cycle) in combination with FOLFIRI + bevacizumab (Day 1 of each cycle). Patients are being monitored for safety, efficacy by radiographic scans, and for changes in KRAS mutant allelic frequency (MAF) in circulating tumor DNA (ctDNA) by liquid biopsy.

Result: The EAP was activated on June 9th 2020. As of November 12th 2020, 19 patients have been treated at 11 clinical sites across the United States. Changes in KRAS MAF after two cycles of therapy was evaluated in 17 patients. Thirteen patients had a KRAS mutation detected in ctDNA at baseline and 8 patients showed a decrease of >50% in KRAS MAF after the first two cycles. Clinical outcomes including efficacy and its correlation with changes in KRAS MAF will be presented at the AACR Annual meeting.

Conclusions: The EAP provides a path for patients who may benefit clinically, but are not eligible for the ongoing clinical trial, to gain access to onvansertib treatment.

Citation Format: Manish R. Sharma, Daniel Isaac, Ryan Ramaekers, Maya Ridinger, Mark Erlander, Lawrence Mendelsohn. Expanded access program of the PLK1 inhibitor onvansertib for treatment of patients with KRAS-mutant metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 425.