Immunotherapy Treatments Only Just Emerging in Esophageal, Gastric Cancers

Geoffrey Ku, MD

As part of our coverage of ASCO’s 2017 Gastrointestinal Cancers Symposium held January 19th to the 21st in San Francisco, today we are speaking with Dr. Geoffrey Ku, MD, a medical oncologist with Memorial Sloan Kettering Cancer Center specializing in gastrointestinal malignancies. At this year’s meeting, Dr. Ku will be participating in an education session on advances in systemic therapy for esophageal and gastric cancer.

-Interview by Leah Lawrence

Cancer Network: Dr. Ku, your portion of the session will focus on immunotherapy. Immunotherapy is still somewhat new to the cancer scene, and is most commonly discussed in relation to melanoma, kidney, or lung cancers. How does research into immunotherapy for gastric and esophageal cancers compare with the progress in these other solid tumors?

Dr. Ku: Thanks for the question and I really appreciate the opportunity to discuss this. A part of the excitement is that while immunotherapy is certainly new the recognition is that in many different cancers it really is the most exciting development in last 20 or 30 years.

As you know, the premise is that we are giving drugs that essentially stimulate the immune system so that the immune system is able to recognize and attack cancer cells. These drugs were initially developed in melanoma, but over the space of 5 to 6 years there are now FDA-approved indications in many other common cancers including lung as well as bladder cancer. I would say that in esophageal and gastric cancer development of these drugs lags a little behind lung cancer, but there are certainly phase III studies that are ongoing.

In fact, at the Gastrointestinal Cancers Symposium there will be the results of a phase III study of one of these drugs that will be presented. At this point, we only have little bits of information, but the press release does suggest that it is a positive study that found clear benefit for one of the immune drugs versus placebo. That really is a milestone development in esophageal/gastric cancer.

Cancer Network: Do any specific types of gastric or esophageal cancers or subgroup of patients appear to benefit more from immunotherapy approaches?

Dr. Ku: That is certainly more than $64,000 question. It is the $640 million question. I think it is clear not only in esophageal/gastric cancer, but in other cancers that do respond to immune treatment that there are subgroups of patients who appear to derive more benefit than others. Certainly we think that one of the most helpful biomarkers, at this point, is a protein called PD-L1. PD-L1 is a target for many of these immune drugs. In esophageal/gastric cancer it is found about 40% of time. When it is present, it significantly increases the chance of shrinkage and response to these immune treatments. That is potentially one way to help select patients. Part of challenge of using PD-L1 is that even when it is not present there still are some patients who can benefit.

That is one important biomarker, but at the same time, we also know that, in general, the immune system is better able to recognize cancer cells that appear very abnormal. The more mutations that a cancer cell has the more likely it is to be recognized by the immune system. This remains an area of active development, but we are all trying to figure out how we can best figure out how abnormal cancer cells looks like, how many mutations they have.

Certainly, the thought is that markers like PD-L1, markers like the amount of mutations that are found in the cancer cells may allow us to fine tune who is and is not likely to benefit from these medications because while they are active, the reality is that they really only do benefit a minority of patients. They can have significant side effects, which involve inflammation of essentially any part of the body. That is what happens when the immune system becomes super activated.

Cancer Network: Among the different immunotherapeutic approaches, research of immune checkpoint inhibitors have shown the most promise, what trials have looked into these drugs in gastrointestinal cancers and what have the results shown so far?

Dr. Ku: There are a number of drugs that are all relatively similar. They all work by blocking a pathway known as PD-1/PD-L1. This is a pathway that we think helps to lower the immune system. We think that it is one way that cancer cells are able to evade the immune system after the immune system initially recognizes them. There are four or five different drugs that are being looked at and they are all antibodies. They are proteins that block this pathway. Representative drugs include pembrolizumab, nivolumab, and avelumab.

At this point in time, there are probably anywhere from five to seven, potentially even more, complementary phase III studies that are ongoing. As I mentioned, the one study that will be presented in about 10 days at the Gastrointestinal Cancers Symposium involves a drug called nivolumab, which blocks a protein called PD-1. In a study of about 450 patients-it was done mostly in East Asia-nivolumab helped patients live longer than patients who received placebo. Certainly, nivolumab is a leading contender, but pembrolizumab, which is a very similar drug, is also currently being looked at in multiple phase III studies, some of which are complete and potentially for which we will have results over the next 1 or 2 years.

Cancer Network: Looking to the future, what areas are yet to be explored and what clinical trials are the most eagerly awaited in this area?

Dr. Ku: There are really many phase III studies that are ongoing. These are studies all in the advanced setting. Patients who have cancer that has spread in the first place, or cancer that recurred after a combination of surgery, chemotherapy, or radiation. There are studies in the first-line setting, meaning patients who have not received any previous treatment. There are studies in the second-line setting, meaning for patients for whom the cancer has grown on one treatment. They are either looking at these immune drugs on their own or they are comparing them to standard chemotherapy. Any number of these phase III studies have results that are eagerly awaited.

In terms of looking to the future, it is a combination of some of the things that we discussed. The one thing I would emphasize is that despite the promise and the excitement of these drugs, it is a relative minority of patients that benefit. Approximately only 15% of all patients benefit from these immune treatments. Part of the goal as we move forward is trying to identify biomarkers or tests that can help us to figure out who falls into the 15% of patients.

Careful patient identification to select patients who are most appropriate for the treatments so that we minimize exposing patients who are not likely to benefit from these treatments is definitely a priority. At the same time, the second generation studies, which are already slowly beginning, are beginning to look at combination strategies with the premise that potentially two drugs are better than one, or two ways of activating the immune system is better than one. This is an approach that is born out in other cancers, including melanoma and lung cancer, but the idea now is to begin to look at two drugs that activate the immune system or a combination of immunotherapy with chemotherapy, or even combining these drugs with radiation. There is some thought that if we treat a tumor with radiation and we are able to kill the tumor cells and the contents of the tumor cells are released, an immune system that is already activated is better able to recognize them.

These are all new strategies that are slowly underway. To the degree that immunotherapy has transformed the treatment of many other cancers, it is on the verge of transforming esophageal and stomach cancer. With the second-generation studies, we will see in the next 5 to10 years an improvement or an increase in the number of patients who will benefit and also an increased ability to better identify patients who will benefit.

Cancer Network: I want to thank you again for speaking with us today and providing this update in immunotherapy in esophageal and gastric cancers.

Dr. Ku: You’re very welcome.