Entrectinib-related myocarditis in a young female patient with metastatic non-small cell lung cancer

Background

Targeted therapy, including tyrosine kinase inhibitors, is revolutionising cancer treatment, increasing overall survival of previously poor-prognosis tumours. We report a case of entrectinib-induced myocarditis, a rare event in which early diagnosis and management are crucial so that cancer treatment can be safely continued. This case highlights the need to be aware of cardiovascular disease occurrence in patients with cancer and the need for multidisciplinary team work between cardiology and oncology for better outcomes. Recommendations on screening, management and follow-up of cardiotoxicity as well as cancer treatment medication adjustment are sparse, shedding light on the crucial need for prospective studies on the cardio-oncology field.

Case presentation

A 51-year-old woman with a recent diagnosis of stage IV non-small cell lung cancer (NSCLC) initiated treatment with entrectinib 600 mg orally once daily. Two weeks after, she was referred to the emergency department for observation from an outpatient cancer centre due to sudden onset of pressure-like chest pain that irradiated to the interscapular region and dyspnoea. She had no known cardiovascular risk factors. The pain appeared at rest while she was in bed, was not aggravated by movement nor inspiration and was associated with shortness of breath and a feeling of being unwell. Before admission to the emergency department, she self-medicated with non-steroidal anti-inflammatory drugs, which seemed to alleviate the pain. Review of systems was negative for orthopnoea, peripheral oedema, dizziness or palpitations. On clinical examination, she was hypotensive with a blood pressure of 86/54 mm Hg, heart rate of 75 bpm, respiratory rate of 18 breaths/min and oxygen saturation of 94% on room air. She was afebrile with a temperature of 37.4°C. Physical examination was unremarkable.

Investigations

At the time of admission to the emergency department, the patient had already undergone extensive investigations. Two months earlier, she presented with a 2-week history of off balance, left lower limb weakness and neglect and neck pain radiating down the right arm. She underwent a head MRI that revealed two brain masses: one in the right superior parietal lobule measuring 20 mm with significant oedema and minimal midline shift to the left and another one in the medial right orbital frontal gyrus measuring 12.5 mm with significant oedema and mild mass effect. There was also a punctate focus of enhancement in the left superior cerebellar hemisphere. She also underwent a cervical spine MRI that sowed multiple spinal bony lesions with compromise of the exiting right C5 nerve root. A fluorodeoxyglucose-positron emission tomography (PET)/CT identified a right pulmonary lower lobe mass likely corresponding to the primary lesion, alongside with bilateral pulmonary metastases; right-sided lymphangitis carcinomatosis; multiple thoracic, right supraclavicular and abdominal nodes; and liver, brain and skeletal metastases. The PET/CT staging was therefore T4N3M1c. Biopsy and immunocytochemistry of a supraclavicular lymph node confirmed this to be an adenocarcinoma, cytokeratin 7 and thyroid transcription factor-1 positive and epidermal growth factor receptor wild type with a ROS1 fusion present. Given the patient’s neurological symptoms, she was started on dexamethasone 4 mg twice daily and naproxen 500 mg twice daily. After a month on therapy, her symptoms improved significantly, and the non-steroidal anti-inflammatory drug was stopped and the corticosteroid weaned down. Due to the presence of the ROS1 fusion, treatment with entrectinib was started.

The patient presented to the emergency department 2 months after the appearance of the neurological symptoms and 2 weeks after starting treatment with entrectinib. Her ECG showed normal sinus rhythm (figure 1). Laboratory evaluation revealed elevated C reactive protein (CRP) and cardiac troponin (table 1).

A repeat troponin showed an upward trend, with a peak of 179 ng/L. Chest X-ray showed a right parahilar opacity extending to the right cardiac border and a small effusion in the left costophrenic angle (figure 2). To exclude a pulmonary thromboembolism, the patient underwent a CT pulmonary angiogram (CTPA), which was normal. Transthoracic echocardiogram showed a non-dilated left ventricle (LV) with mildly impaired LV systolic function (Simpson’s biplane LV ejection fraction (LVEF) 48%) and reduced average global longitudinal strain (15.4%) (figure 3). At this point, differential diagnosis included non-ST-elevation myocardial infarction and myocarditis; however, the former was less likely given the absence of coronary calcium on CTPA image review. The patient underwent a cardiac MRI 4 days after presentation. The MRI scan revealed normal biventricular size with preserved biventricular systolic function. There was mild interstitial expansion/oedema (high normal native T1 at 1354–1363 ms using MOLLI at 3T, reference values: 1220–1360 ms, and borderline/mildly elevated T2 at 43–45 ms at 3T, reference: 36–43 ms) (figure 4). Inversion recovery T1-weighted images after gadolinium administration showed a small patch of subepicardial late enhancement on the basal inferolateral segment (figure 5). Both autoimmune and viral serological screening were negative. A likely diagnosis of drug-induced myocarditis was therefore considered.

Treatment

Entrectinib was withheld after patient’s admission to the emergency department. Cardioprotective therapy with an angiotensin-converting enzyme inhibitor (ACEi) (ramipril 1.25 mg daily) and a beta-blocker (BB) (bisoprolol 1.25 mg daily) was started. Given the favourable clinical (no further recurrence of chest pain), laboratory (downward trend of cardiac troponin and CRP) and imaging evolution (preserved LV systolic function on cardiac MRI), no specific myocarditis-directed treatment was started. Following multidisciplinary team (MDT) discussion, including both the cardio-oncology and oncology teams in charge of the patient, a decision was made to re-start entrectinib at a reduced dose of 400 mg daily.

Outcome and follow-up

The patient has been established on low doses of ramipril and bisoprolol, and cardiac function has normalised—subsequent MRI scans have shown a resolution in myocardial oedema. The patient continues on reduced dose of entrectinib with a good oncological response.