Cardiac safety of afatinib: a review of data from clinical trials

Ewer, Michael S.; Patel, Kushal; O'Brien, Dennis E.; Lorence, Robert M.

doi:10.1186/s40959-015-0006-7

Cited by 18 publications

(13 citation statements)

References 29 publications

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“… 16 , 20 However, there is inconclusive evidence or no clear association for an effect on LVEF with other HER2-targeting therapies, such as lapatinib, sunitinib, and afatinib. 16 , 21 - 24 Similar to the osimertinib data presented here, an analysis of cardiac failure with afatinib, a treatment for patients with EGFRm metastatic NSCLC, reported low rates of protocol-defined cardiac failure and clinically significant LVEF reductions, comparable to those seen with the control treatment arms. The authors concluded that afatinib was not associated with cardiac failure or clinically significant LVEF reductions in the clinical trial program; therefore, no evidence of direct or primary cardiac or cardiovascular toxicity was found.…”

Section: Discussionsupporting

confidence: 62%

“…The authors concluded that afatinib was not associated with cardiac failure or clinically significant LVEF reductions in the clinical trial program; therefore, no evidence of direct or primary cardiac or cardiovascular toxicity was found. 24 …”

Section: Discussionmentioning

confidence: 99%

“… 16 , 20 Similarly, mixed results were seen in studies with other drugs such as lapatinib, sunitinib, and afatinib. 21 - 24 The reasons for these inconsistencies are unknown, although HER2-targeting therapies may not cause direct cardiotoxicity but instead inhibit antioxidant systems that maintain normal heart function, particularly during oxidative stress conditions as induced by anthracyclines. 25 Conversely, a possible cardioprotective effect of small-molecule HER2 inhibitors may be implicated.…”

Section: Introductionmentioning

confidence: 99%

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Cardiac Safety of Osimertinib: A Review of Data

Ewer

Tekumalla

Walding

et al. 2021

JCO

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PURPOSE Osimertinib is a third-generation, CNS-active, irreversible, oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits both EGFR-TKI-sensitizing and T790M resistance mutations. We assess the cardiac failure risk in patients receiving osimertinib by evaluating the available data. METHODS Post hoc analyses of cardiac data from (1) studies in patients with advanced non–small-cell lung cancer, FLAURA (osimertinib, n = 279; comparator EGFR-TKI, n = 277) and AURA3 (osimertinib, n = 279; chemotherapy, n = 140), and (2) a pooled data set of patients treated with osimertinib 80 mg from across the clinical trial program (n = 1,142), including cardiac failure-related adverse events and left ventricular ejection fraction (LVEF) reductions. An LVEF pharmacokinetic or pharmacodynamic analysis of the pooled data set was performed. The sponsor's global safety database was analyzed for cardiac failure-related adverse events, and a literature search was conducted. RESULTS Decreases in LVEF from a baseline of ≥ 10 percentage points to an absolute value of < 50% following osimertinib treatment were observed in 8 (3.1%) and 14 (5.5%) patients in FLAURA and AURA3, respectively, and in 35 (3.9%) patients in the pooled population. Most events were asymptomatic and resolved without treatment of the event or osimertinib discontinuation. The pharmacokinetic or pharmacodynamic analysis did not indicate a relationship between exposure to osimertinib and decreases in LVEF from baseline. The database and literature search showed no specific trend or pattern that was suggestive of a safety issue in patients receiving osimertinib. CONCLUSION These data do not suggest a causal relationship between osimertinib and cardiac failure. However, because of LVEF decreases that were observed in patients with cardiac risk factors before osimertinib treatment, cardiac monitoring, including an assessment of LVEF at baseline and during osimertinib treatment, is advised.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cardiac Safety of Osimertinib: A Review of Data

Ewer

Tekumalla

Walding

et al. 2021

JCO

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“…34,35 However, there is no evidence of cardiac dysfunction from afatinib clinical trials to date, and there were no heart failure AEs reported in patients with ERBB2 mutation-positive NSCLC treated with afatinib in this NPU program. 36 The NPU program provides a large pool of patients who have received afatinib in "real life" conditions in clinical practice. However, missing information is an inherent limitation in this type of analysis.…”

Section: Discussionmentioning

confidence: 99%

Activity of Afatinib in Heavily Pretreated Patients With ERBB2 Mutation–Positive Advanced NSCLC: Findings From a Global Named Patient Use Program

Peters

Curioni-Fontecedro

Nechushtan

et al. 2018

Journal of Thoracic Oncology

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“…Inhibition of the HER2 receptor raised concerns about the cardiological safety of afatinib. Analysis of data from clinical studies, LUX-Lung 3 (229 patients treated with afatinib), LUX-Lung 1 (390 patients treated with afatinib) and 49 other studies (3865 patients treated with afatinib), was designed to determine the risk of heart failure [44]. It appeared that the occurrence of events in clinical randomized studies for 100 patient-years (events/100 patient-years) was similar for afatinib and a placebo (2.40 vs. 2.23), as well as for afatinib and chemotherapy (2.28 vs. 2.92); similar frequency was seen in other studies without randomization (2.88).…”

Section: Afatinibmentioning

confidence: 99%

Cardiovascular Complications of Systemic Therapy in Non-Small-Cell Lung Cancer

Zaborowska-Szmit

Krzakowski

Kowalski

et al. 2020

JCM

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Cardiovascular diseases may determine therapy outcomes of non-small-cell lung cancer (NSCLC). The evidence for how iatrogenic cardiovascular complications contribute to ceasing anticancer treatment, decreasing the quality of life or even premature death, is unclear. Older patients and smokers are at risk of atherosclerosis and arterial thromboembolic events (TE), such as myocardial infarction or stroke. Venous TE can be observed in up to 15% of NSCLC patients, but the risk increases three to five times in ALK (anaplastic lymphoma kinase)-rearranged NSCLC. ALK inhibitors are associated with electrophysiological disorders. Cytotoxic agents and anti-VEGF inhibitors mainly cause vascular complications, including venous or arterial TE. Cardiac dysfunction and arrhythmias seem to be less frequent. Chemotherapy is often administered in two-drug regimens. Clinical events can be triggered by different mechanisms. Among epidermal growth factor inhibitors, erlotinib and gefitinib can lead to coronary artery events; however, afatinib and osimertinib can be associated with the development of heart failure. During anti-PD1/anti-PDL1 therapy, myocarditis is possible, which must be differentiated from acute coronary syndrome and heart failure. Awareness of all possible cardiovascular complications in NSCLC encourages vigilance in early diagnostics and treatment.

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Cardiac safety of afatinib: a review of data from clinical trials

Cited by 18 publications

References 29 publications

Cardiac Safety of Osimertinib: A Review of Data

Cardiac Safety of Osimertinib: A Review of Data

Activity of Afatinib in Heavily Pretreated Patients With ERBB2 Mutation–Positive Advanced NSCLC: Findings From a Global Named Patient Use Program

Cardiovascular Complications of Systemic Therapy in Non-Small-Cell Lung Cancer

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