Incidence of cardiac toxicities in patients with advanced non-small cell lung cancer treated with osimertinib: A combined analysis of two phase III randomized controlled trials

Abstract

Background: Osimertinib is an oral, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). In both EGFR-TKI sensitizing and EGFR T790M resistance mutations in advanced non-small-cell lung cancer (NSCLC), osimertinib has shown to improve survival. Nevertheless, cardiac toxicities remain a safety concern. We undertook a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the incidence of cardiac toxicities. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through March 2018 were queried. Phase III RCTs that mentioned cardiac failure (CF), decrease in ejection fraction (EF) and ECG QT prolongation as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) and absolute risk difference (RD) with 95% confidence interval (CI). A fixed effects model was applied. Results: 971 patients with advanced NSCLC from two phase III RCTs were included. Studies compared osimertinib vs carboplatin/cisplatin+ pemetrexed and osimertinib vs gefitinib/erlotinib. The I2 statistic for heterogeneity was 0, and the heterogeneity X2 (Cochran's Q) was 1 (P=0.787), suggesting homogeneity among RCTs. The CF incidence was 21 (3.763%) in the osimertinib group vs 6 (1.453%) in control group. The RR for CF was 2.719 (95% CI: 1.094 - 6.755, P=0.031) and RD was 0.026 (95% CI: 0.006 - 0.046, P=0.012). The decrease in EF was noted in 16 (2.867%) in study arm vs 5 (1.211%) in control arm. The RR for decrease in EF was 2.502 (95% CI: 0.927 -6.753, P=0.070) and RD was 0.019 (95% CI: - 0.001 - 0.037, P=0.037). The QT prolongation was reported in 35 (6.272%) vs 12 (2.906%) in control group with the RR of 2.623 (95% CI: 1.374 -5.007, P=0.003) and RD of 0.04 (95% CI: - 0.017 - 0.071, P=0.002). Conclusions: Chemotherapy-induced cardiotoxicity, a major cause of morbidity and mortality, is one of the most feared complications and affects patients' quality of life and adds financial burden. Our study showed that osimertinib notably increased the risk of cardiac toxicities with a RR of 2.71 for CF and 2.62 for QT prolongation. Prompt monitoring and early intervention is warranted.