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No benefit from adding napabucasin to FOLFIRI in patients with previously treated metastatic colorectal cancer

The phase III CanStem303C study of the investigational agent napabucasin failed to reach its primary endpoints in patients with previously treated metastatic colorectal cancer. When given in combination with FOLFIRI, with or without bevacizumab, napabucasin failed to induce a significant overall survival benefit in the general study population and in patients whose tumour was positive for the phosphorylated signal transducer and activator of transcription 3 (pSTAT3) biomarker.

Napabucasin is an investigational, orally administered reactive oxygen species generator, bioactivated by the antioxidant enzyme NQO1. NQO1 is expressed at higher levels in colorectal cancer (CRC) cells than in healthy cells. The expression of phosphorylated STAT3 (pSTAT3) in tumour cells and cells of the tumour microenvironment may serve as a biomarker for NQO1 expression and possibly for tumours that are more sensitive to napabucasin. In the phase III CO.23 study, that enrolled patients with advanced CRC refractory to all available standard therapies, median overall survival (OS) was significantly longer for napabucasin than for placebo in an exploratory subgroup analysis of patients with tumours positive for pSTAT3. Furthermore, in a phase Ib/II study, napabucasin plus FOLFIRI with or without bevacizumab generated an ORR of 28%, including one complete response. Based on these data, the phase III CanStem303C trial was designed to compare the efficacy and safety of napabucasin plus FOLFIRI versus FOLFIRI alone in patients with previously treated mCRC and to assess the ability of pSTAT3 to predict the clinical activity of napabucasin.

CanStem303C study design

CanStem303C was a multi-centre, open-label, randomised phase III study of patients (≥18 years) with histologically confirmed mCRC who failed first-line fluoropyrimidine plus oxaliplatin with or without bevacizumab treatment. Patients were randomised (1:1) to FOLFIRI (IV infusion on day 1 of each 14-day cycle, at least two hours after first daily dose of napabucasin) + napabucasin 240 mg oral, twice daily or FOLFIRI alone. Bevacizumab could be used in either arm at investigator discretion. The general study population included 1,253 patients (N=624 napabucasin; N= 629 control) of whom 44% were biomarker-positive (N=275 napabucasin; N= 272 control). Primary endpoints of the study were overall survival (OS) in the general study population (all randomised patients) and in the subgroup of pSTAT3+ patients (biomarker-positive).

No overall survival benefit

After a median follow-up of 25.1 months, the median OS did not significantly differ between the napabucasin plus FOLFIRI and FOLFIRI alone arms (median OS of 14.3 vs. 13.8 months respectively, nominal one-sided p= 0.36). Also in the biomarker-positive tumour subgroup, the median OS was highly comparable between both treatment arms (13.2 months for napabucasin + FOLFIRI and 12.1 months for FOLFIRI alone, nominal one-sided p= 0.38). As such, these results do not support the findings of an earlier exploratory analysis that suggested a survival benefit for napabucasin-treated patients with colorectal tumours positive for pSTAT3. In contrast, in the FOLFIRI alone arm, median OS was significantly shorter in the subgroup of patients who were biomarker-positive vs. biomarker-negative (median OS 12.1 and 18.5 months, respectively, HR[95%CI]: 1.518[1.212-1.902], nominal two-sided p= 0.0002), supporting earlier studies that found pSTAT3 expression to be associated with poor prognosis in mCRC. No statistically significant differences between treatment arms were found in terms of progression-free survival, disease control rate or objective response rate in either the general study population or the biomarker-positive subgroup.

Any-grade treatment-emergent adverse events (TEAEs) were reported in 98.1% and 95.2% of patients in the general study population in the napabucasin and control arm (napabucasin; control), respectively. The most common (≥30% of patients) TEAEs were diarrhoea (84.6%, 53.9%), nausea (60.5%, 50.5%), vomiting (41.2%, 29.3%), and abdominal pain (41.0%, 25.2%). Grade ≥3 TEAEs were reported in 73.8% and 66.7% of patients in the general study population (napabucasin; control), the most common (≥10% of patients) of which were diarrhoea (21.2%, 7.0%), decreased neutrophil count (13.7%, 19.2%), and neutropenia (13.3%, 15.2%). The safety profile in the biomarker-positive population was consistent with that in the general study population. Dose modifications were necessary in 86.4% of patients in the napabucasin arm and in 78.4% in the FOLFIRI alone arm.


In CanStem303C, the addition of napabucasin to FOLFIRI with or without bevacizumab did not improve the survival of patients with previously treated mCRC, irrespective of pSTAT3 status. In the control arm, pSTAT3+ patients had shorter OS than pSTAT3- patients, supporting earlier studies that found pSTAT3 expression to be associated with poor prognosis in mCRC. Overall, treatment with napabucasin was associated with acceptable tolerability when combined with FOLFIRI, although the proportion of patients requiring dose modification was greater for napabucasin plus FOLFIRI than for FOLFIRI alone. No new safety signals emerged following combination treatment with napabucasin plus FOLFIRI.


Shah MA, et al. FOLFIRI ± napabucasin in patients with previously treated metastatic colorectal cancer (mCRC): overall survival results from the phase 3 CanStem303C study. Presented at 2021 ESMO World Congress on Gastrointestinal Cancer; Abstract O-7.

Speaker Manish A. Shah

Manish A. Shah

Manish A. Shah, MD, Weill Cornell Medicine, New York, USA


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