Monica Mariniello ^1* Giulia Arrivi ² Laura Tufano ³ Antonio Lauletta ³ Mirella Moro ¹ Giacomo Tini ⁴ Matteo Garibaldi ^3,5 Raffaele Giusti ¹ Federica Mazzuca ²

• ¹ Unit of Medical Oncology, Sant'Andrea University Hospital, Rome, Italy
• ² Department of Clinical and Molecular Medicine, Oncology Unit, Sant' Andrea University Hospital, Sapienza University of Rome, Rome, Italy
• ³ Department of Neurosciences, Mental Health and Sensory Organs, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Lazio, Italy
• ⁴ Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Lazio, Italy
• ⁵ Neuromuscular Disease Centre, Sant'Andrea Hospital, Rome, Italy

Immunotherapy is increasingly used in advanced NSCLC, offering a significant anti-tumor response, but also causing rising immune-related adverse effects. The incidence of immune checkpoint inhibitor-induced myocarditis-myositis-myasthenia gravis is increasing and particularly concerning due to its high mortality rate. Prompt recognition, diagnosis and management are crucial. A 40-year-old patient, diagnosed with stage IV nononcogene addicted lung adenocarcinoma, treated with nivolumab-ipilimumab-chemotherapy as first-line, developed a rare myocarditis-myositis-myasthenia gravis overlap syndrome. Following the treatment, the patient presented with flu-like symptoms and chest pain, subsequently transferred to the cardiac intensive care unit. The physical examination revealed a visual acuity deficit, diplopia, ophthalmoparesis, ptosis, mydriasis, dysphagia, dyspnea, headache, nausea, dry mouth, asthenia, myalgia, and muscle weakness. Imaging and laboratory tests confirmed the triad, showing elevation of hs-cTnI and CK and positivity of anti-SAE1 and anti-PL-7 Abs. On ECG, ST segment elevation and RBBB. The echo showed hyperechogenicity of the inferolateral wall, pericardial detachment and thickening. The cardiac MRI demonstrated hypokinesia, edema, subepicardial LGE and pericardial effusion. Muscle biopsy revealing muscle fiber necrosis and regeneration with B and T lymphocytic endomysial inflammatory infiltrate and expression of MHC-I. Treatment with oral prednisone, pyridostigmine and IV Igs was started and due to poor clinical response followed by methylprednisolone. Despite stopping immunotherapy, the patient continued to benefit from it highlighted on subsequent reevaluation CT scans by partial disease response, as the patient was in complete remission, we decided to resume chemotherapy by omitting immunotherapy. At the radiological control following the four cycles of double CHT and during CHT maintenance, there was a further reduction of the disease. This report aims to raise awareness among physicians about these serious side effects. A multidisciplinary approach led to clinical improvement, early intervention, optimizing patient outcomes.