Can a Simple Beta-Blocker Improve Immunotherapy Responses?

At the American Society of Clinical Oncology (ASCO) annual meeting, researchers reported on a trial in progress that hopes to prove that blocking the effects of adrenergic stress with propranolol, a commonly used beta-blocker, will improve immune checkpoint inhibitor efficacy in esophageal cancer patients.

In this exclusive MedPage Today video, Sarbajit Mukherjee, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, explained the history behind this phase II trial in progress.

Following is a transcript of his remarks:

We have seen that especially in upper GI [gastrointestinal] cancers like esophageal and gastric cancer, immunotherapy is effective. And when combined with chemotherapy in the metastatic setting, it improves response rate, progression-free survival, as well as overall survival. We have nivolumab [Opdivo] as well as pembrolizumab [Keytruda] that have shown activity in this setting.

Unfortunately, still many patients do not respond to immunotherapy. We try to select them by biomarkers like MSI [microsatellite instability], PD-L1, or tumor mutational burden, to identify who would benefit most from immunotherapy. However, they do not always predict good response. And, as I mentioned before, that unfortunately still a vast majority of our patients do not respond to immunotherapy.

So we have taken different initiatives to make immunotherapy more effective in different types of GI cancers. And the one that I’m going to talk about right now is a clinical trial that we are conducting in patients with esophageal adenocarcinoma.

So, esophageal cancer is a very difficult-to-treat cancer. And there are two major histologic types. One is squamous cell carcinoma and the other one is adenocarcinoma. In the Western world, we mostly see adenocarcinoma, whereas in Asia, squamous cell carcinoma is the predominant type. Unfortunately, esophageal adenocarcinoma often is diagnosed at a very later advanced stage when patients are not curable by surgery, chemo, or radiation. So in those advanced settings, or when patients already have stage IV or metastatic disease, we try to give them what we call palliative treatment, meaning the goal of the treatment is to improve the life expectancy, as well as quality of life.

So the current standard of care is a combination of chemotherapy and immunotherapy. Based on CheckMate 648, 649, as well as KEYNOTE-590 studies, we have seen activities of different immune checkpoint inhibitors in these settings. And that led to different FDA approvals. Also, the KEYNOTE-811 study showed activity of a combination of targeted therapy and immunotherapy in specific subtype or HER2-positive gastroesophageal cancers.

But, as I mentioned, that still we need to make progress and we want to see how that can happen. So one of our basic scientists, Dr. Elizabeth Repasky, found out that stress can lead to a poor immune response. And we showed that in mice models. And we used a cold stress model to show that if mice are kept in cold they are under tremendous stress and the stress is mediated via adrenergic pathway, the same pathway that is involved in fight-or-flight response. But that could dampen your immune system. And in mice we saw that the tumor grew faster.

But we also found that if we block the adrenergic stress with some commonly prescribed medications like beta-blockers, one of them being propranolol, which is commonly used to treat different medical conditions, we were able to reverse the stress and we were able to restore the immune system and the mice had a better outcome.

So we then tried it in a phase I clinical trial in melanoma patients where we treated patients with a combination of pembrolizumab, an immune checkpoint inhibitor, with propranolol. And we saw that the combination was not only tolerated very well, but they also had an amazing response rate of 78%. So based on that we wanted to explore similar combination in other cancers.

But before doing that, we looked at our esophageal cancer patients, and by doing a chart review, we found that those patients that are on beta-blocker had better disease control, as well as overall survival. So based on that hypothesis and our animal data, as well as our phase I clinical trial, we decided to conduct this phase II clinical trial in esophageal adenocarcinoma patients, patients who are already metastatic or locally advanced and not enabled to any curative treatment will be enrolled in the study.

Patients will undergo treatment with cytotoxic chemotherapy plus pembrolizumab, which is basically the standard of care. But in addition, we will also add propranolol and we are hoping to see an increase in the response rate compared to the historical control. But at the same time, our key secondary endpoints will include progression-free survival, as well as overall survival. At the same time, we will collect tissue samples and blood samples from patients to do appropriate biomarker analysis.

So we are presenting this as a trials-in-progress abstract at ASCO this year. So far we have enrolled two patients and our target enrollment is up to 40 patients, depending on how many patients become unavailable or lost to follow-up.