Sequencing Strategies: Metastatic Pancreatic Adenocarcinoma - Episode 8

Immunotherapy in MSI-High Pancreatic Tumors


Kenneth H. Yu, MD: Immunotherapy is an approach for treating cancer. It has gained a lot of interest and excitement in the last few years. Because immunotherapy has proven to be effective in other cancers, like melanoma and lung cancer, we are also interested in using that approach to treat pancreatic cancer. One of the important caveats is that cancers have to have mutations and need to make abnormal proteins that your immune system can recognize. In some tumor types, like melanoma, tumors make a lot of abnormal proteins. It makes it easier for the immune system to go after those kinds of tumors.

Unfortunately, for pancreatic cancer, many studies have shown that these tumors don’t make a lot of abnormal proteins. So, from the get-go, it’s a bit challenging to target pancreatic tumors with an immunotherapy approach. But we’re still very interested. There are also other sets of obstacles that I described, in terms of the tumor stroma. So, there are a number of obstacles in the stroma—whether it be the physical barrier or these myeloid cells that are trying to suppress the immune system or the T cells, themselves, which are not activated.

So, while we are very interested in using immunotherapy to target pancreatic cancer, it’s clear that there are a number of hurdles that remain in our way. We still need to do a lot of research to understand what those hurdles are, how to overcome them, and how to effectively treat pancreatic cancer with immunotherapy.

Fadi Braiteh, MD: In the year 2017, the FDA had approved a record number of anti-cancer agents. I believe more than 27 new agents have been approved, which is great for the field and for our patients. What was really landmark was the approval, by the FDA, of an anti-cancer agent being agnostic when it comes to the tissue. This was the approval of pembrolizumab in microsatellite instability-high malignancy, regardless of the tissue of origin—where the cancer originated. It’s great. It’s with a companion test in a specific patient population. Now, of course, this is probably led by colorectal cancers, etc. But there is a set of patients with MSI-high pancreatic adenocarcinoma. It may be that these are part of a Lynch syndrome? Remember, by definition, Lynch syndrome patients are MSI-high, or not. We don’t know. There were only 4 patients enrolled in that study, and 2 patients have had an objective response rate. Again, this remains a rare incidence in pancreatic adenocarcinoma. But, in my opinion, every solid tumor patient is a candidate to have the tissue tested for microsatellite instability, because MSI-high will result in 2 consequences.

First, if the patient is MSI-high and you’ve not considered testing him or her for Lynch syndrome, this meets the Bethesda criteria—in colorectal cancer, at least—to consider genetic counseling and testing for Lynch syndrome. And, more importantly, the patient would be a candidate for a checkpoint inhibitor. The only FDA-approved drug is pembrolizumab. But across community settings and university centers, we have clinical trials for MSI-high solid tumors—whether it is a single-agent checkpoint inhibitor or it is combined with other agents, such as cytotoxic, PARP inhibitors, or even some novel other checkpoint inhibitor, as well.

John L. Marshall, MD: We had a dramatic change in how we do drug development. For the first time ever, the FDA approved a drug based on a molecular target, microsatellite instability, regardless of what kind of cancer you had. This has never happened before. When this first happened, some of the pancreas cancer advocacy groups went as far as saying, “New drug approved for pancreas cancer.” But, we should pause. The reality is, most pancreas cancer is not MSI-high. Now, that doesn’t mean that we shouldn’t biopsy or try to figure that out. The reality is, a very low percentage will be MSI-high. And so, at least for today, pembrolizumab (Keytruda), or checkpoint inhibitors, really do not have much of a role for a majority of patients with pancreas cancer. A lot of clinical trials are looking at that—trying to combine or take other approaches. But for right now, I don’t think pembrolizumab will be routinely incorporated into treatment, simply because MSI-high is not very common in pancreas cancer.

Kenneth H. Yu, MD: As oncologists may know, pembrolizumab is approved for the treatment of microsatellite instability-high tumors. This includes tumors like pancreatic cancer. In our experience, where we’ve done genetic sequencing on hundreds of patients with pancreatic cancer, we understand that this subset of patients is very small. Less than 1% of patients with pancreatic cancer probably also have MSI-high status.

For patients who we identify as having MSI-high status, I think it is reasonable to use pembrolizumab to treat those patients. My own personal practice is not to use it as a frontline treatment. Usually, we’ll use effective cytotoxic chemotherapy, first. If the treatment is either not working or the patient is getting weary of the chemotherapy, we would consider using a drug like pembrolizumab.

For patients who don’t have this microsatellite instability-high status in the tumor, it’s clear that pembrolizumab is really ineffective. So, I would never use it for such a patient. Even in patients who have MSI-high tumors, my general approach is to try to enroll them into an immunotherapy study—whether it’s pembrolizumab or another checkpoint inhibitor, in combination with some other immunotherapy, or immunotherapeutic agent—which is still my preference. But in the absence of that, it’s certainly very reasonable to use pembrolizumab.

Transcript Edited for Clarity