Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Winson Y. Cheung, MD, MPH, University of Calgary and CancerControl Alberta; Manuel Hidalgo, MD, PhD, Harvard Medical School and Beth Israel Deaconess Medical Center; Ramesh K. Ramanathan, MD, Mayo Clinic; Tanios Bekaii-Saab, MD, FACP, Mayo Clinic; Thomas Seufferlein, MD, University of Ulm
Johanna C. Bendell, MD: Tony, tell us a little bit more. Manuel told us a bit about the STAT3 inhibitors. You’ve been very involved with this program. Can you tell us about that?
Tanios Bekaii-Saab, MD, FACP: There’s a group of agents that have been developed, but specifically in pancreas, there is an agent called BBI-608, which is at least presumed to be a stemness or stem cell inhibitor. But it’s primarily a STAT3 inhibitor.
Johanna C. Bendell, MD: Tell us, what in the world is a cancer stem cell?
Tanios Bekaii-Saab, MD, FACP: That’s a very elusive element. I’m not sure that we understand them, but they are supposed to be the hardiest, most stubborn cancer cells that essentially are chemotherapy-resistant, radio-resistant, resistant to anything. They’re actually the minority of the cells at the beginning, but there’s an interesting component, those cells that exhibit some stemness-like features. Essentially, when you push those with chemotherapy, they acquire stem cell features. And those, ultimately, become the bulk of cancer cells that, as we progress from one line to the other, end up essentially being the bulk of cancer. That’s why we end up with less, and less likelihood of hitting those. At least that’s one hypothesis, being able to effect cancer with further chemotherapy. In the beginning, we have a good response. Eventually, we’ll lose that response.
So, the whole concept of stem cells and some stemness is a bit more dynamic than the rigid way we thought about stem cells. We had stem cells and we had the rest of them. Now, we think we have stem cells, we have some that exhibit stemness-like features, and then we have the cells.
So, this agent, at least preclinically, was shown to block the stemness features and sensitize cancer cells through the effects of chemotherapy, specifically, taxanes and gemcitabine, but also to others. We had a phase Ib study that was presented multiple times. In the evaluable patients, there was about a 55% response rate. The waterfall plot looked very impressive. That led to a phase III study with gemcitabine/nab-paclitaxel plus or minus the BBI-608. It’s one of the largest studies, probably, in pancreas cancer. It included more than 1100 patients. It does have 2 stopping points, first, around 200 patients. So, the patients will be assessed as we go. But the study is really one of very few, unfortunately, in the field, phase III studies that are bringing some novel agents into pancreas cancer. Until, of course, we have the results of the study, this looks promising, like a lot of other agents that look very promising. But the ultimate test will be the results of the phase III study.
Johanna C. Bendell, MD: And, probably, the other large phase III study that’s ongoing right now is looking at hyaluronidase. Ramesh, tell us a little bit about this. The study has been plagued with some issues, but is now pushing forward.
Ramesh K. Ramanathan, MD: Hyaluronan (HA) in this important part of the stroma. In tumors which always express hyaluronan, just like HER2 in breast cancer, it’s a poor prognostic factor. But, there’s an agent, PEGPH20, that inhibits hyaluronan and degrades the stroma. And, in preclinical models with gemcitabine, pretreating with PEGPH20 improved survival in mice. It showed very impressive survival.
That led to a study, initially, with gemcitabine and PEGPH20. This was a randomized study that showed a benefit, which led to an industry sponsored study of gemcitabine/nab-paclitaxel plus or minus PEGPH20. That study has been presented recently. For the PEGPH20 arm, it did, overall, show improvement in the progression-free survival response rate. And, in the 30% to 40% of tumors which had hyaluronan, it also showed an improvement. That’s a phase III study—HALO 301. It’s the only biomarker-driven study, currently. All patients need to be HA-high by immunohistochemistry.
In parallel, SWOG did a study with FOLFIRINOX, assuming that PEGPH20 would work with any backbone. At interim analysis, there was no benefit. The study was closed prematurely. PEGPH20 with FOLFIRINOX did not show any improvement.
Johanna C. Bendell, MD: Now, for the subset of HA-high patients, have you divided that out yet?
Ramesh K. Ramanathan, MD: Not yet. It’s important to note that the PEGPH20 dosing was less. With FOLFIRINOX, PEGPH20 caused more toxicity. You are to use less, and it’s for an unselected population. There’s a lot to learn. There is a mechanistic effect here.
Johanna C. Bendell, MD: We also learned that for this particular drug, we need to give some low molecular weight heparin to those patients, as well.
Ramesh K. Ramanathan, MD: Correct, very importantly. This was not found in the phase I study: that in pancreatic cancer, it causes more thromboembolic events. Also, this drug causes musculoskeletal events where you had to give prophylactic steroids.