Novel pSTAT3 Inhibitor Fails To Prolong OS in Advanced Colorectal Cancer

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Preclinical studies demonstrated that napabucasin — a first-in-class cancer stemness inhibitor that blocks STAT3 — may prevent self-renewal and induce cancer stem cell death.
Preclinical studies demonstrated that napabucasin — a first-in-class cancer stemness inhibitor that blocks STAT3 — may prevent self-renewal and induce cancer stem cell death.

Napabucasin failed to improve overall survival (OS) among patients with advanced colorectal cancer compared with placebo, according to a study published in The Lancet Gastroenterology and Hepatology.1

Colorectal cancer stem cells that express phosphorylated STAT3 (pSTAT3) have been associated with poor prognosis. Preclinical studies demonstrated that napabucasin — a first-in-class cancer stemness inhibitor that blocks STAT3 — may prevent self-renewal and induce cancer stem cell death.

For this double-blind phase 3 study (ClinicalTrials.gov Identifier: NCT01830621), which eventually halted patient accrual because of futility, 282 patients with advanced colorectal cancer who failed all available standard therapies were randomly assigned to receive napabucasin 480 mg or placebo twice daily.

The median follow-up was 19.4 months, during which 258 patients died. No significant differences in overall survival (OS) were observed in the napabucasin vs placebo group (4.4 months vs 4.8 months; adjusted hazard ratio [aHR], 1.13; 95% CI, 0.88-1.46; P = .34).

For the 55 patients with confirmed pSTAT3-positive tumors, there was a significant prolongation of OS, with median OS of 5.1 months in the napabucasin arm vs 3.0 months in the placebo arm (HR, 0.41; 95% CI, 0.23-0.73; P = .0025).

Patients who received napabucasin experienced higher incidence of treatment-related diarrhea, nausea, and anorexia compared with patients in the placebo arm. The most frequently reported grade 3 or worse treatment-related adverse events included abdominal pain, diarrhea, fatigue, and dehydration.

The authors concluded that “napabucasin might be an effective STAT3 inhibitor in patients with tumours positive for pSTAT3, and further investigation of napabucasin as monotherapy in advanced colorectal cancer is warranted in these patients.”

Reference

  1. Jonker DJ, Nott L, Yoshino T, et al. Napabucasin versus placebo in refractory advanced colorectal cancer: a randomised phase 3 trial. Lancet Gastroenterol Hepatol. 2018 Jan 31. doi: 10.1016/S2468-1253(18)30009-8 [Epub ahead of print]

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