Immunotherapy—especially PD‑1 and PD‑L1 checkpoint inhibitors—has revolutionized cancer care. But as these therapies have become standard in treatment plans across dozens of malignancies, so too has the inevitability of encountering their darker side: immune‑related adverse events, or irAEs.
At ASCO this year, an excellent session focused on the rare but severe end of that toxicity spectrum. And while colitis, dermatitis, or pneumonitis are often top of mind, the real killers are the ones we see less often—but must learn to recognize and treat early: myocarditis, myositis, and myasthenia-like neurologic syndromes, including encephalitis.
Thanks to Drs. Douglas Johnson, Joe Elia‑Salam, John Probasco, and Sandrine Aspeslah for their excellent ASCO 2025 educational presentation. Their work helps us not only understand these toxicities but prevent the worst outcomes. These “triple‑M” syndromes are low in incidence but high in stakes. When they hit, they hit hard.
🔥 Not If, But When
Most practicing oncologists have given PD‑1 or PD‑L1 therapy thousands of times by now. The sheer volume means that over time, the question becomes less about “if” we’ll see severe irAEs—and more about “when.”
Many of us have stories. I remember a patient on the brink of finishing her two year trial protocol—ready to ring the bell—when she suddenly developed dyspnea and hypoxia prior to her last dose! A CT revealed bilateral infiltrates. She spent weeks in the ICU with steroid-refractory pneumonitis. While she eventually recovered over months with chronic O2 outpatient requirement (and remains in sustained remission), her experience was a stark reminder: immune toxicities don’t always follow a predictable timeline.
📈 Most irAEs Are Manageable. These Are Not.
While skin rash or thyroiditis can be handled in clinic, triple‑M syndromes are another beast. What’s striking is that:
- Myocarditis carries a 20–30% fatality rate
- Myositis and myasthenic syndromes share similar risk
- Encephalitis can be fatal in up to 15–20% of cases
- Even pneumonitis, depending on severity, has a 10–20% fatality
- Type 1 diabetes, hepatitis, and endocrinopathies each bring a measurable—albeit much lower—fatal risk
Perhaps more concerning is the variability in onset. While most irAEs manifest within the first 12 weeks of therapy, these severe events can appear several months after the last dose.
🧬 Recognizing Risk: The Thymoma Connection
Some patients are more vulnerable than others. Data presented at ASCO highlighted thymoma as a key risk factor for severe immune‑mediated myotoxicity—including myocarditis and myositis.
Why? Thymomas are associated with T‑cell dysregulation and autoimmunity. So if your patient has a history of thymoma, even if remote, your index of suspicion for triple‑M syndromes should be high.
🛑 Recognizing Myocarditis
Often subtle at first—fatigue, mild chest discomfort, shortness of breath—ICI myocarditis can progress rapidly. A delay in diagnosis could be deadly.
What to do:
- Labs: Troponin T more so than troponin I, CK, LDH, AST/ALT, BNP
- EKG: Look for arrhythmias, ST elevations, AV block
- Imaging: Echo, cardiac MRI
- Consult: Cardiology early, possibly muscle biopsy for confirmation
What’s new: emerging data show that troponin T often rises earlier and persists longer than troponin I. That could be a valuable marker in early detection.
Historically, patients with confirmed ICI myocarditis had a 60–70% mortality rate. But recent combination regimens using antithymocyte globulin (ATG) and ruxolitinib have brought this down to around less than 5%. That’s a massive shift—and it underscores the need for aggressive early treatment.
🧠 Encephalitis and Neurologic Syndromes
Ok… doesn’t start M… but still a very serious adverse effect! Neurologic irAEs are underrecognized and often underdiagnosed. Memory changes, confusion, personality shifts—these may be chalked up to age, stress, or even depression. But immune-mediated encephalitis is a medical emergency.
What to look for:
- New or rapidly evolving neuropsychiatric symptoms
- Seizures, confusion, visual changes, imbalance
- MRI brain, EEG, lumbar puncture, autoimmune encephalitis panel
Treatment includes:
- High-dose IV steroids
- IVIG or plasmapheresis
- Second-line: rituximab, tocilizumab, or ruxolitinib in steroid-refractory cases
- Neurology consultation early is essential
About 70% respond to first-line therapy. Second-line success is closer to 50%. The takeaway? Early recognition is the strongest predictor of survival and functional recovery.
🧠 Myositis and Myasthenia-Like Syndromes
These can present subtly—ptosis, weakness, shortness of breath—or as full-blown respiratory failure from diaphragmatic weakness.
One of my patients, receiving triple therapy (BRAF, MEK, and PD‑1), suddenly became profoundly weak. His wife said she had to “drag his body across the floor” as he couldn’t walk and had exertional dyspnea. Fortunately, he was admitted promptly, received high-dose steroids, IVIG, and slowly recovered over months.
Labs to order: CK, troponins, AST/ALT, LDH, acetylcholine receptor antibodies
Get pulmonary and neurology involved early
📚 So, What Should We Be Doing?
- Maintain a high index of suspicion for atypical symptoms—particularly in the first 3 months of therapy, but also long after.
- Use appropriate labs and imaging early—don’t wait for patients to decompensate.
- Get your specialists involved fast—cardiology, neurology, pulmonology, rheumatology.
- Treat aggressively—don’t be afraid to pull the trigger on high-dose steroids, IVIG, plasmapheresis, or even ATG/ruxolitinib for myocarditis and 2nd line rituximab for encephalitis.
- Educate your teams—these are rare events, but your nurses, APPs, and residents need to know what they look like. These are the immune-related emergencies every oncology provider should know.
Immunotherapy is here to stay. But with great power comes great responsibility. And as we give more of these agents, we will inevitably encounter more severe irAEs.
About the author
Dr. Sajeve Thomas is a distinguished medical professional and a compassionate guide in the field of oncology. With over a decade of dedicated experience as a board-certified medical oncologist/internal medicine specialist, Dr. Thomas has become a trusted expert in the treatment of melanoma, sarcoma, and gastrointestinal conditions. He brings a wealth of expertise to the complex and challenging world of oncology.
Disclosures:
Dr. Thomas serves as a speaker for Bristol Myers Squibb (BMS), Merck, Ipsen, Natera, Immunocore, Pfizer, and SpringWorks. He also receives industry grants in support of numerous clinical trials.