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Napabucasin Linked With Objective Responses in Advanced CRC

Published: Monday, Feb 06, 2017

Johanna Bendell, MD

Johanna Bendell, MD

As many as one-third of patients with treatment-resistant colorectal cancer (CRC) attained objective responses with the stemness inhibitor napabucasin (BBI-608) plus FOLFIRI chemotherapy with or without bevacizumab (Avastin), according to evaluable results of a study presented at the 2017 Gastrointestinal (GI) Cancers Symposium.1

Disease-control rates (DCR) in various subgroups ranged as high as 93%, including patients with and without prior exposure to FOLFIRI and those with high and low expression levels of the p-STAT3 biomarker. The combination led to no new or unexpected adverse events (AEs).

“Encouraging signs of anti-cancer activity were observed in patients with advanced CRC who had failed prior standard chemotherapies, including patients refractory to FOLFIRI, suggesting napabucasin may sensitize chemo-refractory CRC to FOLFIRI plus or minus bevacizumab,” reported Johanna Bendell, MD, a medical oncologist at the Sarah Cannon Research Institute.

“Encouraging synergistic activity between napabucasin and FOLIRI was observed in patients with CRC regardless of p-STAT3 status. These results warrant further development of napabucasin in combination with FOLFIRI, with and without bevacizumab, in advanced CRC.”

Cancer stem cells, also known as stemness-high cancer cells, contribute fundamentally to treatment resistance, disease recurrence, and metastasis. The first-in-class stemness inhibitor napabucasin targets STAT3-driven gene expression to suppress cancer stemness.

Prior data of a phase III randomized placebo-controlled trial of napabucasin monotherapy showed a significant improvement in overall survival (OS) in patients with p-STAT3–positive tumors who were treated with napabucasin.2 Preclinical and early-phase studies previously suggested that napabucasin may sensitize heterogeneous cancer cells to chemotherapy and targeted agents.

Collectively, the evidence provided a rationale to evaluate napabucasin in combination with chemotherapy plus or minus bevacizumab in patients with advanced pretreated CRC. The phase Ib/II study presented at the GI meeting involved 63 patients with metastatic, unresectable, or recurrent CRC.

All patients received napabucasin at 240 mg BID and standard doses of FOLFIRI chemotherapy (5-FU at 400 mg/m2 bolus with 2400 mg/m2, irinotecan at 180 mg/m2, and leucovorin at 400 mg/m2 via infusion). Some patients also received bevacizumab at 5 mg. The trial’s primary objectives were safety and tolerability with the napabucasin/FOLIRI regimen with and without bevacizumab. Secondary outcomes included preliminary assessment of efficacy, pharmacokinetics, and pharmacodynamics.

Patients had a median age of 59, with equal distribution of men and women. Four patients received napabucasin combination therapy as their first systemic regimen for advanced disease, and 30 of the remaining 59 had received at least 2 prior regimens. All but 4 patients had good or excellent performance status (Karnofsky Performance Scale Index ≥80%). One-third of the patients had KRAS-positive tumors, and 33 had high p-STAT3 expression (52%).

Data on antitumor activity showed responses in patients with and without prior exposure to FOLFIRI and those with high or low p-STAT3 expression. By an intention-to-treat analysis, objective response rates were 29% for patients with no prior exposure to FOLFIRI, 21% for those previously treated with FOLFIRI, 24% for high p-STAT3 status, and 27% for low p-STAT3 status. The DCR for the same subgroups of patients were 82%, 72%, 79%, and 77%, respectively.

Analyses based on evaluable patients showed response rates of 23% in those who received prior FOLFIRI, 33% who did not receive FOLFIRI, 26% in patients with high p-STAT3 expression, and 32% in those with low p-STAT3 expression. DCRs in evaluable patients were 81% (prior FOLFIRI), 84% (high p-STAT3), 92% (low p-STAT3), and 93% (no FOLFIRI).

The most common AEs were grade 1/2 diarrhea, nausea, vomiting, and fatigue, all of which were rapidly reversible with supportive medications, Bendell and colleagues reported in a poster presentation. The most common grade 3/4 AE was grade 3 diarrhea in 14 patients (22.2%). No other grade 3/4 adverse events affected as many as 10% of patients, and no dose-limiting toxicities were observed.


  1. Bendell JC, O’Neil BH, Starodub A, et al. Cancer stemness inhibition and chemosensitization: Phase 1b/II study of cancer stemness inhibitor napabucasin (BBI-608) with FOLFIRI +/- bevacizumab (Bev) administered to colorectal cancer (CRC) patients (pts). J Clin Oncol. 2017;35 (suppl 4S; abstract 593).
  2. Jonker DJ, Nott L, Yoshino T, et al. A randomized phase III study of napabucasin [BBI608] (NAPA) vs placebo (PBO) in patients (pts) with pretreated advanced colorectal cancer (ACRC): the CCTG/AGITG CO.23 trial. Ann Oncol. 2016;27 (suppl_6; abstract 4540).

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