BBI608/FOLFIRI ± Bevacizumab in Advanced Colorectal Cancer

BBI608 (napabucasin) is an oral first-in-class cancer stemness inhibitor that blocks STAT3-mediated transcription of cancer stemness genes as well as the β-catenin pathway. Potent anti–cancer stem-cell (CSC) activity was observed in vitro and in vivo, in monotherapy and combination therapy. In phase 1 studies, BBI608 was generally well-tolerated with encouraging signs of antitumor activity.1 Hubbard and colleagues presented the results of a phase 1b open-label, multicenter study in patients with advanced colorectal cancer (CRC) that was undertaken to confirm the recommended phase 2 dose of BBI608 in combination with FOLFIRI with or without bevacizumab (BEV). The primary clinical objectives of the study were to determine the safety, tolerability, and preliminary antitumor activity of BBI608 in combination with FOLFIRI ± BEV.2

BBI608 240 mg twice daily was administered orally in 28-day cycles in combination with a standard FOLFIRI regimen with or without BEV 5 mg/kg, administered biweekly until progression of disease, unacceptable toxicity, or other discontinuation criteria were met. A total of 18 heavily pretreated patients with advanced CRC (metastatic, unresectable, or recurrent disease) and an average of ≥3 prior lines of therapy, of which 10 (56%) patients had previously progressed on FOLFIRI, were enrolled. Of the 17 patients evaluable for response, 8 received BBI608 plus FOLFIRI and 9 received BBI608 plus FOLFIRI with BEV. The most common adverse events included grade 1/2 diarrhea, abdominal pain, nausea, vomiting, and anorexia. No dose-limiting toxicity or new adverse events were seen, and the safety profile was similar to that observed with each regimen individually. Grade 3 adverse events related to protocol therapy included diarrhea in 3 patients, fatigue in 2, and dehydration in 1. All events resolved after dose reduction and/or start of antidiarrheal medications, and no significant pharmacokinetic interactions were observed.

Disease control (partial response [PR]+ stable disease [SD]) was observed in 16 (94%) of 17 evaluable patients, with 2 PR (per RECIST 1.1 criteria: 44% and 33% regression) and 14 SD (of which 13 [93%] had tumor regression <25%). Importantly, 90% of patients who had failed prior FOLFIRI treatment achieved PR or SD. In the evaluable patients, median progression-free survival was 5.54 months. Of 17 evaluable patients, 10 (59%) had prolonged SD >24 weeks. The authors concluded that BBI608 240 mg twice daily can be safely combined with FOLFIRI with and without BEV, with no new adverse events and no evidence of pharmacokinetic interaction. In addition, this combination demonstrates encouraging antitumor activity in 94% of heavily pretreated CRC patients, with prolonged disease control in >50% of patients, even in those with prior progression on FOLFIRI-based therapy. These results serve as further proof of principle of the value of a CSC inhibitor as part of a therapeutic regimen for advanced CRC, and warrant further development of BBI608 in combination with FOLFIRI ± BEV in patients with advanced CRC.



  1. Hubbard JM, et al. ASCO 2015. Abstract 3616.
  2. Hubbard JM, et al. ASCO 2016 Gastrointestinal Cancers Symposium. Abstract 569.