Napabucasin versus placebo in refractory advanced colorectal cancer: a randomised phase 3 trial.

Background: Napabucasin is a first-in-class cancer stemness inhibitor that targets STAT3, which is a poor prognostic factor in colorectal cancer. This study aimed to test napabucasin in advanced colorectal cancer.

Methods: This study was a double-blind randomised phase 3 trial done at 68 centres in Canada, Australia, New Zealand, and Japan. Patients with advanced colorectal cancer with a good Eastern Cooperative Oncology Group (ECOG) performance status (0-1) for whom all available standard therapies had failed were eligible for the study. Patients were randomly assigned (1:1) to receive placebo or napabucasin through a web-based system with a permuted block method, after stratification by ECOG performance status, KRAS status, previous VEGF inhibitor treatment, and time from diagnosis of metastatic disease. Napabucasin 480 mg or matching placebo was taken orally every 12 h. All patients received best supportive care. The primary endpoint was overall survival assessed in an intention-to-treat analysis. This is the final analysis of this trial, which is registered at ClinicalTrials.gov, number NCT01830621.

Findings: Accrual began on April 15, 2013, and was stopped for futility on May 23, 2014, at which point 282 patients had undergone randomisation (138 assigned to the napabucasin group and 144 to the placebo group). Overall survival did not differ significantly between groups: median overall survival was 4·4 months (95% CI 3·7-4·9) in the napabucasin group and 4·8 months (4·0-5·3) in the placebo group (adjusted hazard ratio [HR] 1·13, 95% CI 0·88-1·46, p=0·34). The safety population included 136 patients in the napabucasin group and 144 patients in the placebo group. More patients who received napabucasin had any grade of treatment-related diarrhoea (108 [79%] of 136 patients), nausea (69 [51%]), and anorexia (52 [38%]) than did patients who received placebo (28 [19%] of 144 patients, 35 [24%], and 23 [16%], respectively). The most common severe (grade 3 or worse) treatment-related adverse events were abdominal pain (five [4%] patients receiving napabucasin vs five [3%] receiving placebo), diarrhoea (21 [15%] vs one [1%]), fatigue (14 [10%] vs eight [6%]), and dehydration (six [4%] vs one [1%]). 251 (89%) patients had data on pSTAT3 expression, of whom 55 (22%) had pSTAT3-positive tumours (29 in the napabucasin group, 26 in the placebo group). In a prespecified biomarker analysis of pSTAT3-positive patients, overall survival was longer in the napabucasin group than in the placebo group (median 5·1 months [95% CI 4·0-7·5] vs 3·0 months [1·7-4·1]; HR 0·41, 0·23-0·73, p=0·0025).

Interpretation: Although there was no difference in overall survival between groups in the overall unselected population, STAT3 might be an important target for the treatment of colorectal cancer with elevated pSTAT3 expression. Nevertheless, these results require validation.

Funding: Canadian Cancer Society Research Institute and Boston Biomedical.