The Cancer Stem-Cell Inhibitor BBI608 plus Paclitaxel in Advanced Pancreatic Cancer
Treatment options for patients with previously treated metastatic pancreatic cancer are urgently needed. Cancer stem cells (CSCs) and cells with cancer stemness properties are resistant to chemotherapy, and can initiate relapse and metastases following treatment with conventional therapies. Treatment with conventional therapies that target “bulk” non-CSCs can enrich the tumor population for CSCs. BBI608, a first-in-class cancer stemness inhibitor that works through inhibiting the Stat3 pathway, has shown potent synergistic antitumor activity with paclitaxel in vivo.1 In a phase 1b dose-escalation study in patients with advanced solid tumors, BBI608 plus weekly paclitaxel was well-tolerated and a recommended phase 2 dose of BBI608 480 mg twice daily was determined.2 In the presentation by Bekaii-Saab and colleagues, patients with heavily pretreated metastatic pancreatic adenocarcinoma were enrolled in a phase 1b/2 extension study to assess safety, tolerability, and preliminary anticancer activity of BBI608 administered with paclitaxel weekly.3 BBI608 was administered orally at a starting dose of 480 mg or 500 mg twice daily along with paclitaxel 80 mg/m2 intravenously weekly for 3 of every 4 weeks.
A total of 41 patients were enrolled in the study. Patients had received a median of 2 prior lines of treatment, including FOLFIRINOX (71%), gemcitabine/nab-paclitaxel (44%), or both (37%). Overall, prior therapy included gemcitabine in 90%, a thymidylate synthetase inhibitor (eg, 5-fluorouracil, capecitabine) in 80%, platinum in 76%, irinotecan in 73%, and taxane in 44%. Common treatment-related, grade 3 adverse events included diarrhea (N = 2; 4.9%), abdominal pain (N = 2; 4.9%), and nausea (N = 1; 2.4%), and were rapidly reversible.
For evaluable patients (N = 31), the overall objective response rate (partial response [PR] + complete response [CR]) was 6% and the DCR (stable disease + PR + CR) was 48%. In evaluable taxane-naïve patients (N = 19), the objective response rate was 11%, DCR was 63%, and 16% were progression-free at 24 weeks. The mean progression-free survival (mPFS) was 2.2 months and the mean overall survival (mOS) was 6 months in the overall cohort. For the taxane-naïve patients, mPFS was 3.9 months and mOS was 7.4 months. The authors concluded that BBI608 plus weekly paclitaxel was well-tolerated and demonstrated safety and promising antitumor activity in patients with refractory, heavily pretreated pancreatic cancer, particularly taxane-naïve patients. Durable disease control and prolonged overall survival in this pretreated population are notable, especially given the historically poor results in this setting.
- Li Y, et al. Proc Natl Acad Sci U S A. 2015;112:1839-1844.
- Hubbard JM, et al. ASCO 2015. Abstract 3616.
- Bekaii-Saab TS, et al. ASCO 2016 Gastrointestinal Cancers Symposium. Abstract 196.