Tanios Bekaii-Saab, MD
The first-in-class stemness inhibitor napabucasin (BBI-608) is being studied in combination with gemcitabine and nab-paclitaxel in patients with metastatic pancreatic adenocarcinoma.
In results from the phase Ib/II study presented at the 19th World Congress on Gastrointestinal (GI) Cancer, this combination was shown to be safe and demonstrated encouraging signs of efficacy.
The combination is currently being evaluated in a phase III study (NCT02993731).
In an interview with OncLive
at the GI Congress, lead author Tanios Bekaii-Saab, MD, professor of Medicine, Mayo Clinic, discussed the promise of napabucasin in a disease that lacks treatment options.
OncLive: Please provide an overview of your study.
At this year’s World Congress on Gastrointestinal Cancer, we presented the results of one of our studies that is looking at an agent called napabucasin. It is a first-in-class agent in terms of its targets—which are thought to be very important in cancer stemness. So, the whole concept of cancer stem cells and stemness—we know it is one of the major bad drivers in cancer because it makes it tough for chemotherapy to work effectively by creating these mechanisms of resistance. These are super resistant cells. The stemness factor is equally interesting because it is under pressure and a lot of the cancer cells can revert back to that stemness effect and even back to cancer stem cells, which essentially makes it very difficult to kill. The agent essentially targets pathways that are very relevant to stem cells and stemness. And preclinically, it seemed very promising when combined with various chemotherapies including taxanes and gemcitabine.
So, with that rationale, we moved into this phase I/II study in pancreas cancer, combining napabucasin with gemcitabine and nab-paclitaxel. It enrolled about 66 patients total on the study. When we looked at the efficacy of combining napabucasin with gemcitabine and nab-paclitaxel, one of the most interesting findings was to see a response rate close to 55%. In a disease where you rarely see responses, the only example would be FOLFIRINOX in a highly-selected patient population, the response rate was 30% to 31%.
So, this was a very promising signal—and we had 2 complete responders, which you rarely see in this disease. There was a lot of interesting activity, particularly when we look at the maturing progression-free survival and overall survival—they again look higher than what would be expected for this combination.
Then, we looked at the safety—which was one of the primary endpoints of the study—and it appears that napabucasin does not add to the toxicities of the chemotherapy regimen itself. There are additional GI toxicities, primarily diarrhea, but these tend to resolve within 24 hours after stopping the drug and readjusting, or can be managed with supportive care. It is a learning curve, like with all of these new first-in-class agents, you tend to learn with the first patient or two. We learned in our experience that it is actually easy to manage and most of these patients actually do extremely well on this treatment.
What are the next steps?
The cumulative knowledge from this study essentially led to the development of the phase III study that is ongoing, CanStem 111P, which is essentially a standard-of-care arm of gemcitabine plus nab-paclitaxel plus napabucasin versus gemcitabine and nab-paclitaxel. Very straightforward—standard-of-care plus the experimental agent versus standard-of-care.
It is 1132 patients, so a very large study, probably one of the largest in pancreas cancer, but it includes 2 interim analyses at the 50% and 80% marks, where we are going to check for fatality or for significant activity. And, of course, we continue to monitor safety. We have about 10% of the sites accruing, and will have more to follow.
Will napabucasin be used strictly in combination with chemotherapy?
It is very interesting. As a single agent, most of these agents in this group are very challenging. The whole concept of cancer stem cells and stemness is not just an isolated event, it is an event that happens even more so under pressure—under the pressure of chemotherapy. In most diseases, we expect this agent to work best when combined with chemotherapy, not as a single agent. When given alone in a study in colorectal cancer, it was interesting to see that when they actually enriched for the biomarker, which was prespecified, that hazard ratio was 0.21. So, as a single agent, it seems to have activity in a subgroup of patients.