Key result
Third-generation EGFR-TKIs are linked to a ~1% incidence of severe cardiovascular toxicity and LVEF decline.
Why the study?
Cardiovascular toxicity during treatment with osimertinib is reported, but evidence for other third-generation EGFR-TKIs and their cardiovascular effects remains limited and uncertain.
Cohort (n=26)
No
Treatment with third-generation EGFR-TKIs for NSCLC may be associated with clinically meaningful cardiotoxicity, primarily presenting as heart failure and QTc interval prolongation.
May support cardiac monitoring in NSCLC on third-generation EGFR-TKIs; leaves open need for prospective validation of long-term risk.
Cardiovascular toxicity has been reported during treatment with osimertinib, but evidence for other third-generation EGFR tyrosine kinase inhibitors remains limited. Whether similar cardiovascular abnormalities occur during treatment with different agents in this class remains uncertain. We investigated the incidence, clinical phenotypes, and short-term outcomes of CTR-CVT in a real-world Chinese cohort receiving multiple third-generation EGFR-TKIs. This retrospective single-center cohort study screened 745 consecutive patients with NSCLC treated with third-generation EGFR-TKIs between January 2020 and June 2025. Twenty-six patients with complete paired baseline and follow-up cardiac assessments were included in the final analysis. Cancer therapy-related cardiovascular toxicity (CTR-CVT) was graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and serial changes in cardiac functional parameters were analyzed. CTR-CVT was documented in 8 of 745 screened patients (1.1%) during the study period, all graded as Grade 3 per CTCAE version 5.0. CTR-CVT presented as heart failure with reduced ejection fraction ( n = 5) and QTc interval prolongation ( n = 7), with concurrent occurrence in 4 patients. CTR-CVT occurred in two agents included: osimertinib (3/17) and furmonertinib (5/5). Among the 26 included patients with complete cardiac assessments, left ventricular ejection fraction (LVEF) decreased significantly from 63.2% to 57.0% ( P = 0.014), along with an increase in left ventricular end-diastolic diameter ( P = 0.048). The CTR-CVT group showed significant intra-group declines in LVEF and prolongation of QTc interval (both P < 0.01), while no significant changes were observed in the non-CTR-CVT group. Most patients achieved cardiac improvement during follow-up; patients with heart failure received standardized heart failure pharmacotherapy. In this real-world cohort, CTR-CVT occurred among patients receiving third-generation EGFR-TKI therapy. However, the small sample size, non-standardized cardiac surveillance, frequent concomitant systemic therapy, and residual confounding preclude causal attribution to individual agents or class-effect confirmation; larger multicenter prospective studies with standardized monitoring and comparator groups are warranted.
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Zhou et al. (2026) conducted a cohort in EGFR-mutant non-small cell lung cancer (n=26). Third-generation EGFR-TKIs (osimertinib, almonertinib, furmonertinib) was evaluated on Composite of cancer therapy-related cardiovascular toxicity (heart failure and/or QTc interval prolongation). Third-generation EGFR-TKI exposure was associated with a 1.1% incidence of severe cardiovascular toxicity among 745 screened patients, and a significant decrease in LVEF (P=0.014) in monitored cases.
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