Publications

Sudden cardiac death (SCD) is a major cause of mortality in patients with nonischemic cardiomyopathy (NICM). Identifying patients who are at highest risk for SCD is an ongoing challenge. At present, guidelines recommend the use of an implantable cardioverter-defibrillator (ICD) in patients with NICM with a reduced left ventricular ejection fraction (LVEF) and heart failure (HF) symptoms. Some recent data, however, suggest that ICDs may not increase longevity in this population. Conversely, community-based studies have demonstrated that many at-risk individuals who may benefit from ICD therapy remain unprotected. Current recommendations for ICD implantation are continually debated, justifying comprehensive individualized risk assessment. Various promising techniques for further risk stratification are under evaluation, including cardiac magnetic resonance imaging, electrocardiographic assessment of electrical instability, and genetic testing. However, none of these strategies has been fully adapted into guidelines. Hence, clinical risk stratification practice today depends on LVEF and HF symptoms, which have poor sensitivity and specificity for predicting SCD risk.

Sudden cardiac death (SCD) is a major public health issue in the United States and worldwide. It is estimated to affect between 1 and 1.5 million patients worldwide annually, with the global burden expected to rise due to the concomitant rise in coronary artery disease in the developing world. Although arrhythmic causes of SCD such as ventricular tachycardia and ventricular fibrillation are common and well-studied, non-arrhythmic causes are also important, with diverse etiologies from ischemia-related structural heart disease to non-ischemic heart diseases, non-atherosclerotic coronary pathologies, and inflammatory states. Recent research has also found that risk factors and/or demographics predispose certain individuals to a higher risk of non-arrhythmia-related SCD. This review discusses the epidemiology, mechanisms, etiologies, and management of non-arrhythmic SCD.

BACKGROUND

VEGF promotes an immunosuppressive microenvironment and contributes to immune checkpoint inhibitor resistance in cancer. We aimed to assess the activity of the VEGF receptor tyrosine-kinase inhibitor axitinib plus the anti-PD-1 immune checkpoint inhibitor pembrolizumab in patients with sarcoma.

METHODS

This single-centre, single-arm, phase 2 trial was undertaken at a tertiary care academic medical centre in Miami, FL, USA, and participants were recruited from all over the USA and internationally. Patients were eligible if they were aged 16 years or older, and had histologically confirmed advanced or metastatic sarcomas, including alveolar soft-part sarcoma (ASPS); measurable disease with one site amenable to repeated biopsies; an ECOG performance status of 0-1; and progressive disease after previous treatment with at least one line of systemic therapy (unless no standard treatment existed or the patient declined therapy). The first five patients were enrolled in a lead-in cohort and were given axitinib 5 mg orally twice daily and pembrolizumab 200 mg intravenously for 30 min on day 8 and every 3 weeks for cycles of 6 weeks for up to 2 years. Thereafter, patients received escalating doses of axitinib (2-10 mg) plus flat dose pembrolizumab according to the schedule above. The primary endpoint was 3-month progression-free survival. All patients were evaluable for survival and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02636725, and is closed to accrual.

FINDINGS

Between April 19, 2016, and Feb 7, 2018, of 36 patients assessed for eligibility, 33 (92%) were enrolled and given study treatment (intention-to-treat population and safety population), 12 (36%) of whom had ASPS. With a median follow-up of 14·7 months (IQR 10·1-19·1), 3-month progression-free survival for all evaluable patients was 65·6% (95% CI 46·6-79·3). For patients with ASPS, 3-month progression-free survival was 72·7% (95% CI 37·1-90·3). The most common grade 3 or 4 treatment-related adverse events included hypertension (five [15%] of 33 patients), autoimmune toxicities (five [15%]), nausea or vomiting (two [6%]), and seizures (two [6%]). Serious treatment-related adverse events occurred in seven (21%) patients, including autoimmune colitis, transaminitis, pneumothorax, haemoptysis, seizures, and hypertriglyceridemia. There were no treatment-related deaths.

INTERPRETATION

Axitinib plus pembrolizumab has manageable toxicity and preliminary activity in patients with advanced sarcomas, particularly patients with ASPS, warranting further investigation in randomised controlled trials.

FUNDING

Merck, Pfizer, American Cancer Society, and Sylvester Comprehensive Cancer Center.