How Immunotherapy for Esophageal Cancer is Making an Impact

Each year, esophageal cancer affects an estimated 500,000 people worldwide, including 17,000 in the U.S. When caught early, esophageal cancer can often be treated successfully, but the more it progresses, the worse a patient’s prognosis becomes. Once the disease has metastasized, or spread to other organs, only five percent of these patients live beyond five years.

Fortunately, checkpoint immunotherapy, which was first approved for cancer of the lowermost portion of the esophagus, the gastroesophageal junction, by the U.S. Food and Drug Administration (FDA) in 2017, has shown promise in treating patients with advanced disease. Since then, more potential benefits of immunotherapy for esophageal cancer patients have been revealed, and other novel immune-based approaches continue to be explored in clinical trials. As of April 2020, there were 164 active immunotherapy clinical trials for esophageal cancer patients.

To better understand the current immunotherapy landscape in esophageal cancer and how these immune-based approaches are starting to improve care for some patients, we spoke with Deirdre J. Cohen, MD, the director of the clinical trials office at NYU Langone Health’s Perlmutter Cancer Center. She is also a member of the American Society of Clinical Oncology (ASCO) and is the institutional principal investigator for the ECOG-ACRIN Cancer Research Group, a national cooperative oncology group that conducts clinical trials that are funded by the National Cancer Institute.

Arthur N. Brodsky, PhD:

Thank you for joining us today, Dr. Cohen!

In 2017, the PD-1-blocking checkpoint immunotherapy pembrolizumab was approved for patients with advanced, PD-L1-positive esophageal cancer who had received but not responded to two prior systemic treatments. Last year, this same drug received another FDA approval that allows patients with advanced, PD-L1-positive esophageal cancer to receive this treatment as a second-line therapy. What does this approval mean and how has it changed clinical care for esophageal cancer patients?

Deirdre J. Cohen, MD:

This approval brings another exciting tool into the armamentarium available to us to treat advanced esophageal cancer. Compared to chemotherapy, this treatment seems to have relatively fewer side effects, albeit there can be some rare and serious side effects. Overall though, it's much better tolerated.

What's also exciting about this approval is that, for those patients who do respond to pembrolizumab, typically those responses are very durable, which is something we don’t usually see with chemotherapy.

Arthur N. Brodsky, PhD:

That's great news, that it’s providing longer term relief for some patients. Now, this approval only covers patients whose tumors express the PD-L1 protein. Can you explain the significance of this biomarker and why it might be a good indicator of who is likely to respond to immunotherapy?

Deirdre J. Cohen, MD:

In terms of PD-L1 as a biomarker, it's certainly not a perfect biomarker, but it can be helpful. That’s because PD-L1 is the “key” that fits into the PD-1 “lock” on T cells and diminishes their activity. Unsurprisingly, those patients whose tumors express higher levels of PD-L1—which can be found on both tumor cells and some immune cells in the tumor microenvironment—tend to have better responses to immunotherapies that block the interaction between PD-1 and PD-L1. But that doesn’t mean that patients whose tumors don’t express PD-L1 can’t also benefit.

So, it's a start in terms of a clinically useful biomarker, but it is by no means the whole story. There is a lot of continued research going on that is trying to identify additional biomarkers that can improve our ability to predict who are the patients who are more likely to derive the most benefit from checkpoint immunotherapy.

Arthur N. Brodsky, PhD:

I’d like to go back to the side effects of immunotherapy, which you briefly touched on. What are some common immunotherapy side effects and how are they detected and managed?

Deirdre Cohen, MD:

In general, checkpoint immunotherapies, specifically those that target the PD-1/PD-L1 pathway, are very well tolerated. However, the main side effects that are concerning are autoimmune in nature, meaning the immune system attacks your own healthy cells, not just the cancer cells. This can cause side effects such as colitis (inflammation of the bowels), pneumonitis (inflammation of the lungs), and myocarditis (inflammation of the heart). Inflammation in these various organs can be quite serious and may require treatment with steroids as well as discontinuation of the treatment, at least temporarily.

The way we monitor for side effects is through physical exams, understanding patients' symptoms, and laboratory assessment. This information is also considered in the context of the patient’s overall health history. Another of the most common autoimmune side effects is the development of hypothyroidism, which we can follow and monitor with laboratory tests.

Arthur N. Brodsky, PhD:

Do we know anything about how the emergence of side effects in a patient may influence their potential response?

Deirdre Cohen, MD:

There are some data, mainly in other cancers like melanoma and lung cancer, where there seems to be a correlation between low-grade side effects and positive patient responses. There aren’t as much data in esophageal cancer regarding the correlation, if it exists there. At the same time, a lack of side effects doesn’t indicate a patient won’t respond to immunotherapy. If they’re feeling great on the treatment, it does not mean that they’re not responding to the treatment, in fact that is often a very good sign.

Arthur N. Brodsky, PhD:

So, despite the great benefits provided by checkpoint immunotherapy for patients with advanced esophageal cancer, they still only work in a small minority of patients. In other cancers, we've seen that combining these checkpoint immunotherapies with other types of treatments can improve patient response rates. Have there been combination strategies that have shown promise in esophageal cancer?

Deirdre Cohen, MD:

Yes. The most promising combination approaches involve the treatment of esophageal cancers that overexpress HER-2, a protein that is commonly overproduced in several cancer types. In a recent study, combining a HER-2-targeting antibody (trastuzumab) with PD-1 checkpoint immunotherapy and chemotherapy led to responses in more than 80 percent of patients treated. Even though the study was small, the results were very exciting and now there's a very large phase 3 study to see if this pans out in a bigger patient population.

Additionally, combining PD-1 inhibitors with agents that target tumor blood vessel growth—known as VEGF pathway inhibitors—is an interesting strategy and looks like it may be beneficial. Other promising studies are looking at checkpoint immunotherapy in combination with other molecular targeted drugs such as CDK inhibitors.

Arthur N. Brodsky, PhD:

Hopefully, some of these combinations will prove as useful in esophageal cancer as they have in other cancers. Like other relatively new treatment approaches, most cancer immunotherapy strategies are first evaluated in patients with advanced cancer. In some cancer types, however, immunotherapy has also demonstrated significant benefits when used earlier in the course of treatment, including in patients who don’t yet have advanced disease.

Are there trials that are currently exploring immunotherapy in these earlier settings for esophageal cancer patients?

Deirdre Cohen, MD:

As of yet, there haven’t been any definitive practice-changing studies, but they're ongoing. Some are looking at using immunotherapy combinations in the neoadjuvant setting, meaning before patients have surgery to remove their cancer. It’s also being looked at in the adjuvant or post-operative setting. Early data so far suggest that using immunotherapy in combination with chemotherapy, surgery, and radiation therapy after surgery is safe and potentially able to improve patient outcomes, so that's exciting.

Finally, it's being looked at in the peri-operative setting, meaning both before and after chemotherapy. So, we’re evaluating its benefits when it’s given before surgery, after surgery, and both before and after surgery, and with or without radiation therapy. Overall, there are a lot of promising, early signals, but the big studies are currently underway to validate the early findings.

Arthur N. Brodsky, PhD:

What is it about traditional treatments like chemotherapy and radiation therapy that makes them suitable combination partners for immunotherapy?

Deirdre Cohen, MD:

The premise is that chemotherapy and radiation therapy, by directly killing cancer cells, can increase the presentation of tumor antigens for the immune system to “see.” Once the immune system recognizes these tumor antigens, it can then launch an attack against the cancer cells that express them. Then, when the checkpoint immunotherapy is given, it prevents tumor-targeting T cells from being shut down, thereby enabling them to continue hunting down and eliminating tumor cells.

Arthur N. Brodsky, PhD:

Up until now, we’ve only been discussing checkpoint inhibitors, but there are other, newer types of immunotherapies that may also be able to help patients with esophageal cancer. In particular, cellular immunotherapies like CAR T cells have shown remarkable benefits in blood cancers. Are there efforts under way studying cell therapies for esophageal cancer patients?

Deirdre Cohen, MD:

Yes, there's been really exciting work done with cell-based therapies like CAR T cells, especially in blood cancers, and this approach is now being looked at in esophageal cancer. It's early days, for sure, but I think that there is immense promise as we learn more and more about how to use these cell-based therapies and manipulate immune responses against solid cancers, including cancers of the esophagus.

Arthur N. Brodsky, PhD:

Finally, none of these immunotherapies—or any modern treatment, really—would have been possible without clinical trials. How valuable are clinical trials, both for patients and the cancer immunotherapy field in general?

Deirdre Cohen, MD:

Clinical trials are very important in terms of being able to offer patients access to treatments that they might not otherwise receive. Trials also allow us to really understand whether new investigational medicines are truly safe and effective, without relying on anecdotal evidence. Without clinical trials we would have no way of knowing what works and wouldn't be able to advance the field and ultimately improve outcomes for cancer patients.

Arthur N. Brodsky, PhD:

Absolutely agree. Clinical trials are such a valuable resource for patients, and it’s a shame that more aren’t aware of the opportunities available to them through these studies.

Could you share your hopes and vision for the future of cancer immunotherapy in esophageal cancer?

Deirdre Cohen, MD:

My hope is that we better understand how to elicit an immune response from all of our patients. Because what's so exciting is that many of those folks who have responded have had such amazing and durable and life-changing responses. Moving forward, we just need to figure out how to flip the switch so that all our patients’ immune systems can be empowered to go after their cancers and keep them healthy.

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