Characterizing Cardiotoxicity of FDA-Approved Soft Tissue Sarcoma Targeted Therapies and Immune Checkpoint Inhibitors: A Systematic Review

Background: Soft tissue sarcomas (STS) are aggressive cancers that show increasing response to novel targeted-therapies and immune-checkpoint-inhibitors. Despite anecdotal reports of cardiovascular adverse events (AEs) and major adverse cardiovascular events (MACE) potentially hindering their utility, the true cardiotoxic profile of these novel-therapies in STS has been largely understudied. Methods: We assessed the incidence and severity of AEs and MACE of contemporary FDA-approved targeted and immune-based therapies for STS, using data from landmark clinical trials supporting FDA-approval. We also analyzed data from the FDA adverse-event-reporting-system-(FAERS) for FDA-approved STS targeted and immune-based therapies for comparative real-world validation. Results: Overall, 12 clinical trials supporting FDA-approval of STS targeted-therapies and immune-checkpoint-inhibitors, incorporating 1249 patients, were identified. These clinical trials revealed 751 AEs including, hypertension (382, 50.87%), atrial fibrillation (3, 0.40%), myocardial infarction (2, 0.27%), cardiac failure (congestive included) (9, 1.20%), and cardiac failure (heart failure included) (7, 0.93%). Compared to placebo, those treated saw higher MACE (OR: 3.27, p < 0.001). The FAERS data showed 489 reported AEs including hypertension (275, 56.24%), atrial fibrillation (31, 6.34%), myocardial infarction (15, 3.07%), and cardiac failure (congestive included) (30, 6.13%). Programmed death-ligand 1 (PD-L1) inhibitors had the highest probability of AEs (0.65, 1.17), followed by tyrosine kinase inhibitors (0.66, 0.11), tropomyosin receptor kinase inhibitors (0.25, 0.13), mammalian target of rapamycin inhibitors (0.21, 0.09), and enhancer of zeste homologue 2 inhibitors (0.11, 0.06). Proportions were calculated from the samples in clinical trials supporting FDA-approval and FAERS, respectively. Conclusions: In this investigation, contemporary FDA-approved therapies for STS are associated with increased risk of AEs