Abstract
<div>AbstractPurpose:<p>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 <i>KRAS</i>-mutant colorectal cancer.</p>Patients and Methods:<p>Preclinical activity of onvansertib was assessed (i) <i>in vitro</i> in <i>KRAS</i> wild-type and -mutant isogenic colorectal cancer cells and (ii) <i>in vivo</i>, in combination with irinotecan, in a <i>KRAS</i>-mutant xenograft model. Clinically, a phase Ib trial was conducted to investigate onvansertib at doses 12, 15, and 18 mg/m<sup>2</sup> (days 1–5 and 14–19 of a 28-day cycle) in combination with FOLFIRI/bevacizumab (days 1 and 15) in patients with <i>KRAS</i>-mutant metastatic colorectal cancer who had prior oxaliplatin exposure. Safety, efficacy, and changes in circulating tumor DNA (ctDNA) were assessed.</p>Results:<p>In preclinical models, onvansertib displayed superior activity in <i>KRAS</i>-mutant than wild-type isogenic colorectal cancer cells and demonstrated potent antitumor activity in combination with irinotecan <i>in vivo</i>. Eighteen patients enrolled in the phase Ib study. Onvansertib recommended phase II dose was established at 15 mg/m<sup>2</sup>. 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.</p>Conclusions:<p>Onvansertib combined with FOLIFRI/bevacizumab exhibited manageable safety and promising efficacy in second-line treatment of patients with <i>KRAS</i>-mutant metastatic colorectal cancer. Further exploration of this combination therapy is ongoing.</p><p><i><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-24-0251" target="_blank">See related commentary by Stebbing and Bullock, p. 2005</a></i></p></div>
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