Pharmacovigilance Analysis of Cardiac Toxicities Associated With Targeted Therapies for Metastatic NSCLC

Waliany, Sarah; Zhu, Han; Wakelee, Heather A.; Padda, Sukhmani K.; Das, Millie; Ramchandran, Kavitha; Myall, Nathaniel J.; Chen, Thomas; Witteles, Ronald; Neal, Joel W.

doi:10.1016/j.jtho.2021.07.030

Cited by 55 publications

(40 citation statements)

References 33 publications

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“…Furthermore, 15 cases were reported in Eudravigilance database ( 39 ). Both ALK and ROS1 inhibitors were associated with a higher risk of conduction disease and QT prolongation than other TKIs ( 56 ). It is important to monitor the heart rate and the blood pressure to prevent cardiac ADRs ( 57 ).…”

Section: Discussionmentioning

confidence: 99%

Safety profile of tyrosine kinase inhibitors used in non-small-cell lung cancer: An analysis from the Italian pharmacovigilance database

Sorbara¹,

Cicala²,

Santoro³

et al. 2022

Front. Oncol.

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IntroductionNon-small cell lung cancer (NSCLC) is often caused by molecular alterations that can be detected by predictive biomarkers including mutations or amplifications of several genes. Several tyrosine kinase inhibitors (TKIs) have been approved in Europe by the European Medicines Agency (EMA) for NSCLC. The aim of this study was to analyze the onset of adverse drug reactions (ADRs) related to TKIs in NSCLC through a spontaneous reporting system (SRS) database.MethodsAll ADR reports having as suspected drug afatinib (AFT), alectinib (ALEC), brigatinib (BRG), ceritinib (CER), crizotinib (CRIZ), erlotinib (ERL), gefitinib (GEF), lorlatinib (LORL), nintedanib (NTB), and osimertinib (OSI) recorded into the Report Reazioni Avverse dei Medicinali (RAM) system database for national data and into the Italian SRS database for Sicilian data and collected from 2006 to 2021 have been evaluated. A descriptive analysis of basal demographic and drug-related characteristics was performed. A case-by-case methodology was conducted paying particular attention to all serious ADR reports collected in Sicily, focusing on type of seriousness, age, sex, concomitant drugs, and comorbidities.ResultsOf the 3,048 Italian reports, most of ADRs were related to ERL (n = 1,448), followed by AFT (n = 435) and GEF (n = 366). ADR reports were slightly more frequent in females (52.2%) and in the age group >65 years (53.0%). A higher number of cases were related to skin disorders (n = 1,766; 57.9%), followed by gastrointestinal disorders (n = 1,024; 33.6%), general disorders and administration site conditions (n = 536; 17.6%), and infections (n = 483; 15.8%). The case-by-case assessment of Sicilian ADRs showed that 33 cases were serious (12.5%) and mainly involved ERL (n = 17; 51.5%), occurring in males with a higher onset of respiratory diseases (30.3%) such as respiratory failure, interstitial lung disease and dyspnea.DiscussionThe analysis of spontaneous ADR reports of TKIs confirmed, in general, well-known risks, which often include skin, gastrointestinal, general, liver, and respiratory diseases as well as infections. However, more attention should be paid to the occurrence of serious life-threatening ADRs including respiratory failure, interstitial lung disease, and cardiogenic shock, especially in young patients.

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Section: Discussionmentioning

confidence: 99%

Safety profile of tyrosine kinase inhibitors used in non-small-cell lung cancer: An analysis from the Italian pharmacovigilance database

Sorbara¹,

Cicala²,

Santoro³

et al. 2022

Front. Oncol.

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Section: Optimizing Treatment Sequencing In Egfr M...mentioning

confidence: 99%

“…Here, it is noteworthy that the benefits of this strategy should be weighed against its safety and tolerability profile, such as the higher incidence of diarrhea and rash with afatinib and prolonged QT interval with osimertinib. [93][94][95] A post-progression analysis of the LUX-Lung 3, 6, and 7 trials identified 37 patients who received osimertinib as subsequent therapy, including 10 patients in second line. 76 In these 37 patients, first-line treatment with afatinib resulted in a median PFS of 21.9 months, and the median duration of subsequent osimertinib therapy was 20.2 months.…”

Section: Optimizing Treatment Sequencing In Egfr Mutation-positive Nsclcmentioning

confidence: 99%

Optimizing Patient Outcomes Through Sequential EGFR TKI Treatment in Asian Patients With EGFR Mutation-Positive NSCLC

Liu

Zhou

Xia

2022

Clin Med Insights Oncol

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Patients from Asia with non-small-cell lung cancer (NSCLC) often have mutations in the epidermal growth factor receptor ( EGFR) gene. While an increasing number of EGFR tyrosine kinase inhibitors (TKIs) are now available for patients with EGFR mutation-positive NSCLC, most patients inevitably develop resistance to the treatment. Evidence from clinical studies suggests that treatment outcomes and resistance mechanisms vary depending on the choice of TKI therapy in the first-line setting. Hence, it is important to develop optimal treatment sequencing strategies that can provide maximum survival benefit for the patient. In this review we present clinical evidence in Asian patients with NSCLC for various EGFR TKIs, with the goal of supporting the optimization of treatment sequencing.

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“…Entrectinib, a relatively new tyrosine kinase inhibitor (TKI), has been reported to be effective as primary therapy for ROS1 fusion-positive NSCLC [ 3 ]. Although molecular targeted therapy is generally well tolerated, cardiovascular adverse events such as arrhythmia, heart failure, myocardial infarction, QTc prolongation, myocarditis, and pericarditis have been described in recent years [ 4 ]. Here, we report a patient with ROS1 fusion gene-positive lung cancer who developed drug-induced heart failure after receiving entrectinib.…”

Section: Introductionmentioning

confidence: 99%

Entrectinib-Induced Heart Failure in a Patient With Metastatic Lung Adenocarcinoma: A Case Report

Otsu¹,

Kata²,

Takayasu³

et al. 2022

Cureus

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Entrectinib is a recently approved multikinase inhibitor to treat advanced c-ros oncogene1 (ROS1) positive non-small cell lung cancer (NSCLC). Although molecular targeted therapy is generally well tolerated, cardiovascular adverse events have been described in recent years. We report a case of NSCLC with ROS1 rearrangement where the patient developed drug-induced heart failure after receiving entrectinib.A 74-year-old non-smoker female patient was diagnosed with stage IVB lung adenocarcinoma with ROS-1 positive and right breast cancer stage I. We started on entrectinib as the first-line therapy for lung cancer. Five days after, she developed oral dysesthesia and blood creatinine increased. These findings gradually worsened, so we temporarily discontinued entrectinib. After withholding the drug for 14 days, these findings improved, and we resumed entrectinib at a reduced dose. On day 19 of the reduced entrectinib dose, she presented to the outpatient with shortness of breath and bilateral lower extremity edema, accompanied by respiratory failure. Laboratory evaluation revealed elevated N-terminal pro-brain natriuretic peptide (NTpro BNP), troponin I, creatine kinase (CK), and C reactive protein (CRP), and transthoracic echocardiogram showed congestive heart failure (CHF) with a preserved ejection fraction (HFpEF). She did not complain of chest pain and fever, so we did not consider ischemic heart disease and viral myocarditis in the initial evaluation. There was no other causative cause of CHF. Therefore, we suspected entrectinib-related heart failure. Her symptoms improved and she recovered her cardiac function to baseline within a week of discontinuation of entrectinib and standard heart failure treatment. She developed heart failure after a onestep dose reduction and was prone to cardiotoxicity due to entrectinib. Considering that she could be treated with crizotinib, we decided discontinuation of entrectinib permanently. This case report highlights the potential cardiotoxicity of entrectinib and suggests the need for close monitoring of the cardiac functions of patients receiving entrectinib.

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Pharmacovigilance Analysis of Cardiac Toxicities Associated With Targeted Therapies for Metastatic NSCLC

Cited by 55 publications

References 33 publications

Safety profile of tyrosine kinase inhibitors used in non-small-cell lung cancer: An analysis from the Italian pharmacovigilance database

Safety profile of tyrosine kinase inhibitors used in non-small-cell lung cancer: An analysis from the Italian pharmacovigilance database

Optimizing Patient Outcomes Through Sequential EGFR TKI Treatment in Asian Patients With EGFR Mutation-Positive NSCLC

Entrectinib-Induced Heart Failure in a Patient With Metastatic Lung Adenocarcinoma: A Case Report

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