Transcript:Philip A. Philip, MD: Locally-advanced pancreatic cancer, in the older days, when we talked about it and we did clinical trials, we included it with metastatic disease. If I want to step back and talk about the percentage of patients who we see with locally-advanced disease, these are one-third of the patients. So, we see more patients with metastatic disease, but we certainly see a good number of patients who have locally-advanced unresectable pancreatic cancer. These patients tend to have a bit of a different natural history. They can have disease that is localized through the pancreas. It’s not resectable, but it can stay there for a while; it can grow there and not metastasize. Although, in most patients, all of us would agree that it ultimately metastasizes. But there are patients where the disease stays very much in the pancreas and grows there.

Patients with locally-advanced unresectable disease can also live a bit longer than patients who have metastatic disease. Sometimes they can live much longer because the disease is only staying there. Traditionally, in this country especially, radiation therapy has been a major treatment strategy. Patients with newly-diagnosed locally-advanced pancreatic cancer, they went to the radiation doctor; we gave them radiation, and we also added chemoradiotherapy. But increasingly, it has been demonstrated that chemoradiotherapy doesn’t really necessarily prolong their life that much, because they have systemic disease. They are still going to be having liver metastases, lung metastases, and peritoneal metastases. They need systemic treatment. Now we have combination therapies that we use in metastatic disease: FOLFIRINOX/gemcitabine/nab-paclitaxel. We’re bringing in those combinations to locally-advanced unresectable disease in order to see whether that will be something which we can move their survival even forward, as we did in metastatic disease.

Although we don’t believe that it’s going to prolong survival necessarily in those patients when we treat them up front with radiotherapy, we made improvements with the radiotherapy itself. We have, for example, SBRT, the stereotactic body radiation treatment. We have better delivery of even the standard radiotherapy. We think that now while we’re using better systemic treatments to clear disease elsewhere in the body, we may go back and try to also treat that area in the pancreas with more effective treatment that’s also less toxic.

Collectively, good systemic therapy with better systemic treatments, better than Gemzar alone, plus better radiotherapy, might be the way to go forward with locally-advanced unresectable disease. It’s an important segment of pancreatic cancer because it represents one-third of the patients—so we have to be more active in that disease. If you open the website where you look at clinical trials, like clinicaltrials.gov, you see plenty of trials in metastatic disease. You see very few trials in locally-advanced unresectable disease, which is okay, because we’re looking at systemic treatments. But now we start to think of strategies where we bring those systemic treatments to really integrate them with radiotherapy to make it work better.

Tanios Bekaii-Saab, MD: The future of treatment in metastatic pancreas cancer, and the landscape that is emerging, continues to look relatively promising. And I think the way we have to think about pancreas cancer now is more like breaking it down into different groups. I think the biggest priority should be in looking at, specifically, the BRCA1, BRCA2, PALB2, and germline/somatic mutations. We should essentially explore the role of PARP inhibitors—such as olaparib, rucaparib and others—perhaps either as maintenance strategies or combined to 5-FU/MM-398 combinations. There’s a lot of preclinical rationale for combining the topoisomerase inhibitors with the PARP inhibitors. There are also some preclinical data that suggest that the liposomal or PEGylated formulations of irinotecan may actually play better with the PARP inhibitors than a free drug. So, these are interesting areas.

There are also studies that are looking at gemcitabine/cisplatin plus PARP inhibition that look at the same patient population and, hopefully, hold promise by itself. But the maintenance strategies with these PARP inhibitors following chemotherapy, specifically platinum-driven chemotherapy, should be explored. Unfortunately, right now, it’s just limited to those germline-mutated patients. But I think it should be expanded beyond that. Then, there’s this other group of what we call BRCAness that’s been established in ovarian cancer and other cancers that also is making its ways to being looked at in pancreas cancer. These may not respond as well as the germline mutations, the somatic BRCA mutations, or PALB2 mutations, but they actually seem to derive some additional benefit from PARP inhibition.

In fact, at ASCO, there’s a study called RUCAPANC that looked at rucaparib in pancreas cancer that was, unfortunately, stopped earlier because they didn’t see these early responses. Of the last 4 patients from the original 19 patients, 3 out of the 4 had a PR or a CR, and some of these responses have gone beyond, in fact, a year for one of the stable diseases. So, there is a lot of activity with this particular agent. Unfortunately, the study was stopped too early, but the program continues to move into the space of pancreas cancer. Olaparib is the same. The other study of interest is the study with PEGPH20 selecting for HA expression, or hyaluronic acid expression. Those with high expression would enter into this phase III study, which started accruing patients in the last couple of months. We’re combining PEGPH20 with gemcitabine/Abraxane versus gemcitabine/Abraxane alone. There are a number of other agents that are still in the very early stages of development; epigenetic modulators, HDAC (histone deacetylase) inhibitors, and others that are still worth exploring.

Although it’s been very disappointing to see the PD-1s not showing much activity, and algenpantucel-L and CRS-207/GVAX essentially failing, I think the question of immune therapy should be revisited at some point in the near future once we have better strategies that essentially break down the barrier a lot better, improve circulation around the tumor, and bring those beneficial immune cells more proximally to the tumor. Right now, I think most of the immune therapy strategies are proving to be futile without that aspect.

Transcript Edited for Clarity