Immune checkpoint inhibitors bring new success, new adverse events to cancer treatment

Immune checkpoint inhibitors (ICIs) are transforming cancer treatment and outcomes. Their novel mechanism of action is bringing dramatic improvements in patient outcomes and equally dramatic immunotherapy-related adverse events (irAEs) that differ from conventional drug-related AEs.

“The application of immunotherapy is evolving,” said Jennifer D. Possick, MD, Associate Professor of Pulmonary & Critical Care Medicine, Yale University School of Medicine and Director, Winchester Center for Lung Disease, Yale-New Haven Hospital. “Real-world applications and real-world populations differ significantly from uses and populations in the original clinical trials. We must be prepared to constantly adapt our assumptions and our approach.”

Dr. Possick opened the symposium, Immune Checkpoint Inhibitors: Updates on an Evolving Landscape, with the latest data on ICI-related pneumonitis, the most common and most deadly pulmonary irAEs. Other presentations provided updates on nonpneumonitis airway irAEs and nonpulmonary irAEs. The entire session is available on demand to registered CHEST 2021 attendees until October 1, 2022.

Variability is the hallmark of ICI-related pneumonitis, Dr. Possick said. Presentations are highly heterogeneous and pathophysiology seems variable.

ICI-associated pneumonitis occurs in 3% to 5% of patients treated with a single IC. The incidence doubles in consecutive or combination therapy using more than one ICI or an ICI plus another modality such as chemotherapy, radiotherapy, or EGFR therapy.

Patients with non-small cell lung cancer have a higher incidence of ICI-associated pneumonitis and more severe and fatal cases. Comorbid conditions may increase the risk for irAEs and understanding risk factors is a work in progress.

Dyspnea is the most common symptom of ICI-related pneumonitis, but the presentation can include multiple symptoms and a third of patients will also have another irAE. CAT scans are the imaging modality of choice as radiographs can miss about 25% of ICI-related pneumonitis.

Treatment guidelines are based on the degree of toxicity. According to the presenters, in general, patients with radiography changes who are asymptomatic should be monitored closely but ICI treatment delay is likely not needed.

In addition, the presenters recommend that clinicians hold ICI therapy and start corticosteroids in 2 days to 1 week if there is no improvement in patients with mild/moderate symptoms.

If patients have moderate-severe symptoms with impaired activities of daily living, they recommend discontinuing ICI treatment and escalating corticosteroid dosing, as well as adding infliximab if patients do not improve within 48 to 72 hours. Single-center experience suggests that tocilizumab may also be effective, but more study is needed.

ICI-mediated sarcoidosis and airway inflammatory conditions can be just as deadly as ICI pneumonitis, if less common.

“These nonpneumonitis irAEs are rare in ICI treatment, but the prognosis is very different from similar, non-ICI related conditions,” said Ajay Sheshadri, MD, MSCI, Associate Professor of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center.

“Many of these patients had response to ICI therapy and many did very well without steroids or other sarcoidosis treatment. ICI therapy may sometimes be safe in patients who develop sarcoidosis, but we need to consider the risk-benefit analysis individually for each patient. Histology is critical to distinguish sarcoidosis from cancer progression, infection, and other etiologies.”

There are few reports of airway inflammation after ICI therapy, Dr. Sheshadri said. Patients with COPD may respond better to ICIs than other patients. Exacerbations of asthma and other airway diseases following ICI therapy have been reported but are rare.

ICI effectively removes self-tolerance, leading to autoimmune-like events that can affect any organ. Nonpulmonary irAEs are common, occurring in up to 20% of patients in ICI monotherapy and 50% in combination therapy. Between 0.3% and 1.3% of these irAEs are fatal.

“Emergency medicine staff, intensivists, subspecialists, and primary care providers are largely inexperienced with patients who have been given ICIs in clinical practice,” warned Munish Luthra, MD, FCCP, Assistant Professor Pulmonary, Allergy, Critical Care & Sleep Medicine, Emory University School of Medicine. “Myocarditis is the most fatal irAE, at 40%, followed by endocrine and colitis at 2% to 5%, and most fatalities occur early, in the first 3 months of treatment.”

ICIs can induce a spectrum of cardiotoxicity, including myocarditis, arrhythmias, pericardial effusion, and conduction disturbances. Cardiotoxicity most often presents as decompensated heart failure, cardiogenic shock, coronary artery disease, and sudden death. Endomyocardial biopsy remains the gold standard diagnostic for myocarditis, but myocardial edema and late gadolinium enhancement on cardiovascular magnetic resonance imaging is noninvasive.

Gastrointestinal toxicities include diarrhea, colitis, enterocolitis, and hepatitis, Dr. Luthra continued, and are more common with anti-CTLA-4 (ipilimumab) treatment than anti-PD-1 or PD-L1 agents. High-grade colitis and hepatitis require the most aggressive intervention. These irAEs may need a GI consult and endoscopy for diagnosis.

About 1% of ICI patients show neurotoxicity, either inflammatory or peripheral neuromuscular autoimmune disorders. These toxicities are usually fatal.

“Intensivists should be aware of these fatal complications to implement early interventions to reduce morbidity and mortality,” Dr. Luthra advised.