Insights From: Tony Saab, MD, Mayo Clinic; Davendra Sohal, MD, MPH, Cleveland Clinic
Tanios Bekaii-Saab, MD: Exciting times for pancreas cancer, I think there’s a lot of activity ongoing with a number of agents that are in phase III, a number of them actually moving into phase II, and then eventually to phase III. Immune therapy as we know is one of the most exciting fields in oncology. It has significant limitations though when it comes to pancreas cancer. Pancreas cancers tends to be this very cold tumor, very protective of its environment, full of immunosuppressive elements. Just excludes all these good cells, puts them outside.
So PD-1 [programmed cell death protein 1] inhibitors have not had any success except in that small subset of MSI [microsatellite instability]-high patients. For 99.5% of the patients, there does not seem to be much of a benefit from PD-1 inhibitors. There’s a study that reported on gemcitabine/nab-paclitaxel, and nivolumab. The study was not randomized but just looking historically at the results, it doesn’t seem to move the needle one bit. So I don’t think that’s the way to go for us.
Now, here’s the good news. That doesn’t mean immune therapy is dead in pancreas cancer, it’s just we have to be more intelligent, smarter about how we target the cancer cells. So one of the worst elements in pancreas cancer are those macrophages. Those tumor-associated macrophages that are just bad. They exclude good cells. I essentially induce a lot of bad stuff into the cancer cells.
So if we can shift the balance, the good macrophages that are outside, the bad macrophages that are inside, and there are strategies like CSF1R [colony stimulating factor 1 receptor] inhibitors and others that shift the balance. They enhance the good. They suppress the bad. Guess what happens then? Then PD-1 inhibitors may become active. And we have a study that suggested the combination of the 2 can induce responses.
So we see that. There are a lot of other ways to manipulate the immune system and these are underway. So I’m hopeful that there will be a role for immune therapies in select patients, but I don’t think it’s PD-1 except if you have MSI-high.
A number of other strategies are being built towards the future. We talked about the stem cell inhibitor, napabucasin with gemcitabine/nab-paclitaxel. A large study, CanStem111P, which will complete early this quarter, and hopefully we’ll have some reporting out by the end of the year. This was based on very promising early phase Ib study with almost 50% to 60% response rate and some CRs [complete responses] in a disease where we rarely see that with napabucasin and chemotherapy.
So that’s an exciting study that we’re looking forward to the results. The other study is with PEGPH20 and gemcitabine/nab-paclitaxel versus standard in high hyaluronic acid patients. So selected for the target. This study was based on some results that sound promising from a phase II randomized study, although we had a big hiccup with a SWOG [Cancer Research Network] study with FOLFIRINOX [fluorouracil/irinotecan/oxaliplatin] that showed a detriment with PEGPH20. So I’m a little bit lukewarm about this, but ultimately the phase III study hopefully will show us results one way or the other. But that’s another potential option. And then we have this whole discussion around BRCA and DDR [DNA damage response] and what do we do.
What we’re looking forward to is a lot of good results coming through from phase III trials. The POLO study will report; we’ll understand about the role of PARP [poly ADP ribose polymerase] inhibitors as maintenance in BRCA. We’ll also learn more about whether the field is moving forward in this whole group of patients that may be eligible for PARP inhibitors, for FOLFIRINOX, and then moving forward with immune therapy. So a very complex landscape that’s forming around us, in a good way.
We also have a large effort that’s being led by Mike Pishvaian, MD, PhD, and by PANCAN [Pancreatic Cancer Action Network] as well that combined are trying to break down pancreas cancer into multiple buckets and target these different buckets at a time where we never thought we’d be able to do that pancreas cancer.
Very exciting time, and I think the light at the end of tunnel is starting to actually shine closer and closer.
Davendra Sohal, MD, MPH: The key areas of research at this time and to evolve over the next 3 to 5 years in pancreatic cancer are, in the resectable setting, the use of neoadjuvant therapies. In the metastatic setting, the use of frontline regimens followed by maintenance therapy, followed by sequencing, how best to achieve that. Just like colon cancer, how could we extract the maximum mileage out of the drugs we have for metastatic pancreatic cancer? Number 3 would be the role of genes, whether somatic genes to allow treatment delineation such as microsatellite instability, such as a BRCA-ness phenomenon. And then in the germline setting, how to incorporate genetic counseling and genetic testing for all patients with pancreatic cancer, despite limited resources, because that can make a significant difference for the patients as well as their family members. So those are the key areas of research that are ongoing and will hopefully lead to further progress.