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Onvansertib in Combination with FOLFIRI and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal
Daniel H Ahn1, Afsaneh Barzi2, Maya Ridinger3
1Division of Medical Oncology, Mayo Clinic, Phoenix, Arizona.
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.
Patients And Methods:
Preclinical activity of onvansertib was assessed (i) in vitro in KRAS wild-type and -mutant isogenic colorectal cancer cells and (ii) 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 patients with KRAS-mutant metastatic colorectal cancer 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 colorectal cancer cells and demonstrated potent antitumor activity in combination with irinotecan in vivo. Eighteen patients enrolled in the phase Ib study. Onvansertib recommended phase II 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 patients with KRAS-mutant metastatic colorectal cancer. Further exploration of this combination therapy is ongoing. See related commentary by Stebbing and Bullock, p. 2005.
Insights
Onvansertib combined with chemotherapy shows promise for KRAS-mutant colorectal cancer. This combination therapy demonstrated manageable safety and encouraging efficacy in a Phase Ib trial.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Colorectal cancer (CRC) remains a significant health challenge, with KRAS mutations often predicting poor prognosis.
- Targeting polo-like kinase 1 (PLK1) with inhibitors like onvansertib offers a novel therapeutic strategy.
- Combination therapies are crucial for overcoming resistance and improving outcomes in metastatic CRC.
Purpose of the Study:
- To evaluate the preclinical and clinical efficacy of onvansertib in combination with chemotherapy for KRAS-mutant colorectal cancer.
- To determine the safety and tolerability of onvansertib plus FOLFIRI/bevacizumab in patients with previously treated metastatic CRC.
- To assess the predictive value of circulating tumor DNA (ctDNA) dynamics in response to treatment.
Main Methods:
- Preclinical assessment of onvansertib in KRAS wild-type and mutant colorectal cancer cell lines and xenograft models.
- A Phase Ib clinical trial involving patients with KRAS-mutant metastatic colorectal cancer receiving onvansertib with FOLFIRI/bevacizumab.
- Evaluation of safety, efficacy (response rates, duration of response), and ctDNA changes.
Main Results:
- Onvansertib showed superior preclinical activity in KRAS-mutant cells and potent antitumor effects in vivo with irinotecan.
- The recommended Phase II dose of onvansertib was determined to be 15 mg/m2.
- Partial responses were observed in 44% of patients, with a median response duration of 9.5 months; early ctDNA dynamics predicted efficacy.
Conclusions:
- Onvansertib in combination with FOLFIRI/bevacizumab demonstrates manageable safety and promising efficacy in the second-line treatment of KRAS-mutant metastatic colorectal cancer.
- This combination represents a potential therapeutic option for this patient population.
- Further clinical investigation of this onvansertib-based regimen is warranted.
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