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FDA workshop focuses on cancer immunotherapy-associated myocarditis, other CV toxicities
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On Dec. 1, the FDA held the Assessment of Cardiovascular Toxicities in Immuno-oncology Trials public workshop, with collaboration and support from the American Association for Cancer Research, the American College of Cardiology, the American Heart Association and the American Society of Clinical Oncology. This workshop brought together cardiologists, oncologists, immunologists and other specialists to better understand the new syndrome of myocarditis and other CV and metabolic toxicities associated with cancer immunotherapies.
Concerns of toxicity
Several immune checkpoint inhibitors have been approved in the United States and, thus, transformed the treatment of several types of cancers. However, some of the toxicities associated with these therapies, such as immune-related CV toxicities, may be life-threatening or fatal. Therefore, there is an urgent need to identify, prevent and mitigate these CV adverse reactions.
One group of presenters combined to set the stage for the big questions concerning immuno-oncology and combination immunotherapies. Marc Theoret, MD (FDA), provided an overview of the immuno-oncology approvals by the FDA. Andrew Lichtman, MD, PhD (Harvard), and James Gulley, MD, PhD (National Cancer Institute), summarized advancements in immunology and how immune checkpoints, which normally serve as “breaks” in the immune system, can be targeted by antibodies to harness the immune system against the fight for cancer. Next, Jeffrey Sosman, MD (Northwestern), discussed clinical data on immune checkpoint inhibitors that have revolutionized treatment for melanoma, lung cancer and other cancer types and, in some cases, have introduced cancer survivorship as a new theme in oncology. Doug Johnson, MD (Vanderbilt), and Michael Atkins, MD (Georgetown), then discussed the adverse effects of these therapies and how the immune system, activated by immune checkpoint inhibitors, can cause autoimmune disorders. Paul “PJ” Utz, MD (Stanford), Kevan Herold, MD (Yale), and Andy Mammen, MD, PhD (NIH), provided examples of rheumatologic, endocrine, musculoskeletal and neurologic autoimmune toxicities associated with these therapies.
The workshop then changed focus and addressed the growing number of reports of myocarditis seen after treatment with immune checkpoint inhibitors. Dr. Moslehi discussed the current state of knowledge with immune checkpoint inhibitor-associated myocarditis. Examples were provided of fatal and fulminant myocarditis after immune checkpoint inhibitor treatment and the growing reports of cardiac adverse events after treatment with immune checkpoint inhibitors in the literature. Other experts including Kirk Knowlton, MD (Intermountain Healthcare), JoAnn Lindenfeld, MD (Vanderbilt), Susan Gilchrist, MD (MD Anderson), Bonnie Ky, MD (Penn Medicine), and Mariell Jessup, MD (Leducq Foundation), provided a cardiology perspective on the pathophysiology and clinical presentation of myocarditis. Drs. Moslehi and Lichtman then summarized potentially basic and pathophysiology of immune checkpoint inhibitor-mediated myocarditis.
Strategies discussed
Detecting cardiotoxicity from oncology drugs has become a focus of many cardio-oncology specialists, and several experts discussed topics including how to screen for cardiotoxicity, how to adjudicate CV events in immuno-oncology trials and which imaging modalities should be used to diagnose CV toxicities.
Julia Beaver, MD (new director of the Division of Oncology Products at the FDA), gave a keynote speech, in which she described an overarching effort of the agency to modernize eligibility criteria for oncology clinical trials, including those involving cancer immunotherapies.
In the last session, Sean Khozin, MD, MPH (FDA), and Robert Miller, MD (Cancer LinQ), suggested several strategies of how “big data” can be collected in a smart manner in learning more about the CV toxicities associated with immune checkpoint inhibitors.
Perhaps the highlight of the day session was a patient perspective. John DeWolf, a patient of Ana Barac, MD (Medstar Health), articulated the potential successes as well the pitfalls of immunotherapy. Diagnosed with stomach cancer, DeWolf sought aggressive therapy involving immune checkpoint inhibitors in combination with a tyrosine kinase inhibitor and had a good response. However, he then presented with HF and pulmonary edema. It was unclear which therapy was the culprit for his presentation or whether either therapt played any role at all. Given the option of no treatment, he chose to fight on. As quoted in The Washington Post, which covered the FDA meeting, DeWolf told his doctors, “Bring it on. If there is a chance this is going to fix me, I’m taking it, and if I die in the process, that’s fine.”
Overall, all of the speakers agreed that immune checkpoint inhibitors have already transformed oncology care but that the medical community must better understand these rare but fulminant cases of myocarditis.
- For more information:
- Javid J. Moslehi, MD, is assistant professor of medicine and director of the cardio-oncology program at Vanderbilt University Medical Center. He can be reached at javid.moslehi@vanderbilt.edu.
- Laleh Amiri-Kordestani, MD, is team leader of the breast cancer group and cardio-oncology liaison at the FDA. She can be reached at laleh.amirikordestani@fda.hhs.gov.
Disclosures: Moslehi reports no relevant financial disclosures. Amiri-Kordestani is an employee of the FDA.