Targeting cancer stem cells in the BRIGHTER trial
Napabucasin, a novel oral agent that targets the STAT3 pathway, is the most advanced new drug in clinical development designed specifically to attack cancer stem cells (CSCs), a subset of the total cancer cell population that is believed to drive tumor recurrence and metastasis even after cytotoxic therapy. The investigational small molecule, also known as BBI608, is being evaluated in the phase III BRIGHTER trial as a second-line treatment for patients with gastric and gastroesophageal junction cancer who already have undergone platinum and fluoropyrimidine-based chemotherapy.
The study, which was launched in June 2014, is seeking to enroll 700 patients who experience clinical or radiologic disease progression during first-line treatment for unresectable or metastatic disease or ≥6 months after finishing therapy. By targeting STAT3, a transcription factor, napabucasin is believed to suppress stemness pathways including STAT3 and β-catenin.3 CSCs are important targets for anticancer therapy because of four key characteristics, according to a research summary by Boston Biomedical, the Cambridge, Massachusetts, biotechnology company that is developing the drug. These characteristics include stemness, the capacity to self-renew and differentiate into cancer cells; aberrant signaling pathways; resistance to standard therapies; and the ability to promote tumor recurrence and metastasis.
TARGETED ONCOLOGY: Please provide an overview of the BRIGHTER trial and how it has developed since last year?
SHAH: This is an important second-line study of chemotherapy with or without a novel STAT3 inhibitor, which works as a stem cell or a stemness inhibitor. Cancer stem cells are likely responsible for the development or recurrence and disease progression in patients with solid tumor malignancies, and for the first time we are now able to test agents that are really targeting the stemness phenotype. So the BRIGHTER study is a multicenter, multinational study and we are ahead of accrual with regard to meeting our endpoint. The total study is about 700 patients, and we are nearly half way there already.
TARGETED ONCOLOGY: What is the efficacy of BBI608 in gastric cancer?
SHAH: There has been a phase I/II study that has been reported, at least in an abstract form.3 What we see is that in the second- and third-line setting, we are seeing response rates that are quite favorable compared with Taxol alone on the order of 30% to 50%. There is hope that this is a new option that could be a positive.
TARGETED ONCOLOGY: Has there been any research as far as how this drug would fit in with current treatment options?
SHAH: With more options that will be available, we need to think carefully about how best to line the treatments up in a way that patients get the most benefit. The other thing is to manage toxicities and things like that. One of the emerging ideas is that not all gastric cancers are the same. There are subtypes of gastric cancer that may benefit more from by certain treatment. The main aspect is to identify which cancers would be best treated by a PD-1 inhibitor, which cancers would be best treated by a stem cell inhibitor and how to sequence accordingly.
TARGETED ONCOLOGY: Have any concerning toxicities surfaced in the BRIGHTER trial?
SHAH: The trial is ongoing and it’s being monitored by a data safety monitoring board. No signals have been raised according to that. We do know that there are side effects from the pills itself and I know that the company is working on a new formulation of the pill.
TARGETED ONCOLOGY: What’s next for the drug after the BRIGHTER trial?
SHAH: Boston Biomedical is a very progressive company and they are looking at other ways to improve on BBI608. One option is to combine that stemness inhibitor with another stem cell inhibitor that they have in their pipeline to see if we can have dual blockade, and another one is to actually combine BBI608 with some of the PD-1 and PD-L1 inhibitors as well.