The Society for Immunotherapy of Cancer (SITC) has released new consensus recommendations on the recognition and clinical management of immune-related side effects from cancer immunotherapy.

The authors, members of the SITC Toxicity Management Working Group, noted that immunotherapy has become a pillar in the treatment of cancer, with clinical trials showing that checkpoint inhibitors can provide long-term benefit with generally manageable side effects. However, emerging patterns suggest that checkpoint inhibitors may cause unwanted side effects in a number of organ systems.

“We have, in a comprehensive fashion, organized thoughts on the proper screening, diagnosis, management, and handling of treatment interruptions or cessations with immune checkpoint inhibitors,” Igor Puzanov, MD, director of the Early Phase Clinical Trials Program and co-leader of the Cancer Center Support Grant Experimental Therapeutics Program at Roswell Park Cancer Institute in Buffalo, NY, told MedPage Today. “The recommendations provide an online reference point for practicing oncologists to find quick reference if they have a patient with a particular toxicity.”

New immunotherapy agents are being approved at a rapid pace, and patients have new treatment options, but “many of these agents have side effects we haven’t seen before. We’re seeing effects on the skin, lungs, gastrointestinal and endocrine systems, joints, heart and other organs, and some of these are only just beginning to be described,” he continued. “Clinicians need guidance on how to recognize early signs, how to treat adverse effects, and when to refer to a disease specialist.”

Puzanov is one of the four co-leaders of the multidisciplinary Working Group, which SITC convened to meet for a full-day workshop to develop the document to standardize the management of immune-related adverse events. Medical oncologists, surgeons, disease specialists, scientists, pharmacists, nurses, and others with relevant expertise met to develop guidance on managing adverse effects from immune checkpoint inhibitors.

The recommendations state that when caught early, most side effects from checkpoint inhibitors are mild to moderate and can be treated with drugs that temporarily suppress the immune system. “We focused on ensuring that clinicians recognize and know how to manage these emerging side effects so patients can continue to take advantage of the benefits of immunotherapy,” said Puzanov.

Serious and occasionally life-threatening immune-related adverse events have been reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by checkpoint inhibitor. Immunotherapy-related immune-related adverse events typically have a delayed onset and prolonged duration compared with adverse events from chemotherapy. Effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies, he said.

The recommendations follow an earlier effort by the European Society for Medical Oncology, which issued the first comprehensive Clinical Practice Guidelines for the management of toxicities from immunotherapy in May 2017. The SITC effort, however, is unique, Puzanov said, because it included representatives from pharmaceutical companies, who provided information derived from large databases of toxicities of immunotherapy.

“From the information in the databases, we also learned what we don’t have. We may ask about symptoms, but not recognize that fatigue or dyspnea may hide cardiac toxicity. A patient may actually have cardiomyopathy and be coded as [having] fatigue and dyspnea.” Puzanov noted that reports of fatal cardiac side effects from immune checkpoint inhibitors began appearing in the literature around 2016.

“Immune checkpoint inhibitors are coming to the community where practicing oncologists work. [Checkpoint inhibitors] have a different set of side effects than chemotherapy or targeted therapy. Physicians who treat cancer patients — hospitalists, emergency room physicians, and specialists — need to be aware of these side effects.”

For example, he noted, if a patient on chemotherapy develops shortness of breath and fever, the recommended treatment is antibiotics and supportive care. “If a patient on immunotherapy develops these symptoms, they could be due to cytokine storm, and the patient could develop pneumonitis. The patient may still develop pneumonia, but it may be pneumonitis. This can be confusing.”

Some side effects, like pneumonitis, come on early after immunotherapy, while others, like cardiac events, may come later. “Once we know the problem, we can properly treat the patient.”

Puzanov said he hopes clinicians will refer to the online consensus recommendations in real-time when they see patients: “If a patient presents with fever from immunotherapy, the clinician can look at the recommendations and decide whether this is an infection from the drug itself, and then start the patient on corticosteroids.”

The new recommendations are a “living document, and the plan is to update them accordingly as immune checkpoint inhibitors evolve and new drugs and combinations become available.

The next step for SITC is to issue a comprehensive handbook that provides more information on individual drugs and side effects with more references, he said, adding that SITC leaders will also be involved in the development of ASCO and NCCN guidelines.

“Immune checkpoint inhibitors are a whole new therapeutic ballgame,” said Puzanov. “They have changed the way we practice and treat cancer patients, but have also brought new challenges with novel toxicities. We need to conduct prospective trials with these agents to dig into the etiology of side effects. That will help us recognize which patients have the potential to develop toxicities at baseline when we give them immune checkpoint inhibitors.”