Long QT syndrome after using EGFR-TKIs in older patients with advanced non-small cell lung cancer

ABSTRACT

Background

Long QT syndrome (LQTS) has been reported in older patients with advanced non-small cell lung cancer (NSCLC) following the use of osimertinib, the third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). However, there have not been analytic epidemiology studies on this topic. We aimed to compare the risk of LQTS between osimertinib and first/second-generation EGFR-TKIs in older patients with advanced NSCLC.

Research design and methods

This retrospective observational study used the 2006–2019 Surveillance, Epidemiology, and End Results (SEER)-Medicare data and included older patients with advanced NSCLC who were treated with either osimertinib or first/second-generation EGFR-TKIs during 2007–2017. Inverse probability of treatment weighting (IPTW) was used to balance the two groups with propensity scores estimated based on the patients’ socioeconomic and clinical characteristics. Crude incidence rate (IR) and adjusted hazard ratio (HR) of the primary outcome, incident LQTS, were estimated.

Results

A total of 545 and 1,135 patients were included in the osimertinib and first/second-generation EGFR-TKI groups, which increased to 1,614 and 1,659, respectively, after IPTW. The osimertinib group had a higher IR of LQTS (2.62 per 100 person-years, 95% CI 2.03–3.38) compared to the first/second-generation EGFR-TKI group (1.33 per 100 person-years, 95% CI 0.92–1.92). After adjusting for covariates, the osimertinib group had a higher risk of LQTS than the first/second-generation EGFR-TKI group, with an HR of 1.94 (95% CI 1.23–3.08). The increased LQTS risk in the osimertinib group was even higher in females, whites and patients aged ≥ 75.

Conclusions

Given the elevated risk of LQTS associated with osimertinib user, close monitoring for cardiac rhythm irregularities of high-risk patients following initiation of EGFR-TKI is recommended.

Plain Language Summary

Long QT syndrome (LQTS) indicates a disorder of heart beats with prolonged QT intervals. There have been reports of LQTS in older patients with advanced non-small cell lung cancer (NSCLC) who were treated with osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). We conducted a retrospective study using Surveillance, Epidemiology, and End Results (SEER)-Medicare database, including older patients aged ≥ 65 with advanced NSCLC who were treated with EGFR-TKIs. Our results show higher incidence of LQTS after using osimertinib than first/second-generation EGFR-TKIs. After adjusting for patients’ characteristics that might have affected the incidence of LQTS, the risk of LQTS was significantly higher in osimertinib users than in earlier generation EGFR-TKI users. Females, whites, and patients aged ≥ 75 had an even higher risk of LQTS when treated with osimertinib. Close monitoring for cardiac rhythm irregularities in high-risk patients after osimertinib initiation is recommended.

KEYWORDS:

• Non-small cell lung cancer
• epidermal growth factor receptor tyrosine kinase inhibitors
• osimertinib
• Long QT syndrome
• cardio-oncology
• pharmacoepidemiologic study

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Study conception and design: Chanhyun Park, Joo-Young Byun; Data collection: Chanhyun Park; Data analysis: Joo-Young Byun; Interpretation of results: Chanhyun Park, Joo-Young Byun, Sola Han, Aiham Qdaisat; Draft manuscript preparation: Chanhyun Park, Joo-Young Byun; Review and revise manuscript: Chanhyun Park, Joo-Young Byun, Sola Han, Aiham Qdaisat; All authors reviewed the results and approved the final version of the manuscript.

Data availability statement

The authors used the 2006–2019 Surveillance, Epidemiology, and End Results (SEER)-Medicare data. The SEER-Medicare data is project specific and can be accessed with approved application.

Acknowledgments

This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the National Cancer Institute; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER-Medicare database.

The collection of cancer incidence data used in this study was supported by the California Department of Public Health pursuant to California Health and Safety Code Section 103885; Centers for Disease Control and Prevention’s (CDC) National Program of Cancer Registries, under cooperative agreement 1NU58DP007156; the National Cancer Institute’s Surveillance, Epidemiology and End Results Program under contract HHSN261201800032I awarded to the University of California, San Francisco, contract HHSN261201800015I awarded to the University of Southern California, and contract HHSN261201800009I awarded to the Public Health Institute. The ideas and opinions expressed herein are those of the author(s) and do not necessarily reflect the opinions of the State of California, Department of Public Health, the National Cancer Institute, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14740338.2023.2294924.

Additional information

Funding

This paper was partially supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: HI19C1328). The funders of this study had no role in the design of the study, analysis, interpretation, writing of the manuscript, or decision to submit the results.