Osimertinib-induced cardiac failure with QT prolongation and torsade de pointes in a patient with advanced pulmonary adenocarcinoma

Abstract

Osimertinib-induced cardiotoxicity is a well-known but rare disorder. An 84-year-old woman was diagnosed with recurrence of lung adenocarcinoma showing an epidermal growth factor receptor mutation of exon 19 deletion, which was initially treated by curative-intent thoracic radiotherapy 4 years prior. She started taking osimertinib (80 mg/day). She had no history of heart disease and showed no signs of cardiac problems. However, 2 months later she presented with symptoms of cardiac failure and QT prolongation on electrocardiogram. Cardiac enzyme levels were not elevated and coronary computed tomography angiography showed no significant stenosis. On admission, sudden-onset torsade de pointes required electrocardioversion. Thus, drug-induced cardiac failure was strongly suspected and we stopped osimertinib therapy. Cardiac function and the electrocardiogram abnormality improved. To our knowledge, this is the third case of coincidence of cardiac failure and QT prolongation and the second case of sudden-onset torsade de pointes associated with osimertinib treatment. In our case, osimertinib-induced cardiac failure with QT prolongation was recovered by stopping the drug treatment. The potential for cardiotoxicity should be considered with osimertinib treatment.

Introduction

Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) used for treatment of non-small cell lung cancer harboring an EGFR mutation. Cardiotoxicity is an infrequent but important adverse event (AE) of chemotherapeutic agent treatment. For example, osimertinib can cause QT prolongation. Furthermore, according to a US retrospective clinical study from 2016 to 2018, osimertinib significantly increased the risk of cardiotoxicity including cardiac failure, atrial fibrillation, QT prolongation, myocardial infarction, and pericardial effusion compared with other EGFR-TKIs [1]. In that study, cardiac failure was the most common AE associated with osimertinib treatment, followed by QT prolongation. A Japanese single-center retrospective study of 123 patients treated with osimertinib monotherapy from 2014 to 2019 also reported that severe cardiac AEs (defined as Common Terminology Criteria for Adverse Events ≥ grade 3) occurred in six patients (4.9%), which involved one case of acute myocardial infarction, three cases of heart failure with reduced left ventricular ejection fraction (LVEF), and two cases of valvular heart disease [2]. In that study, grade 3 QTc prolongation (> 501 ms) was observed in two patients (1.6%) and one of them simultaneously presented with both heart failure and QT prolongation.

Herein, we report a rare case of osimertinib-induced cardiotoxicity in which congestive heart failure, QT prolongation, and torsade de pointes (TdP) occurred at the same time.

Case report

An 80-year-old Japanese woman (ex-smoker) with a smoking history of 20 packs per year was diagnosed with a lung adenocarcinoma harboring an EGFR exon 21 L858R point mutation. She underwent right upper lobectomy and lymphadenectomy (p-T2aN0M0, stage IB). However, 1 year later another lung tumor developed in her left lower lobe, which was also diagnosed as an adenocarcinoma harboring an EGFR exon 19 deletion (c-T1bN0M0, stage IA). She completed curative-intent stereotactic thoracic radiotherapy and her clinical course was stable for approximately 4 years afterwards. However, at 84 years of age a new consolidation emerged in her left lower lobe (Fig. 1a). Transbronchial biopsy histopathologically confirmed recurrence of the adenocarcinoma with an EGFR exon 19 deletion. She was started on osimertinib treatment (80 mg/day).

Fig. 1.

Chest computed tomography (CT) scans of the mediastinal window setting (a) before osimertinib treatment and (b) at admission (2 months after initiating osimertinib treatment)

She had no underlying cardiac diseases or remarkable cardiac events, except for a > 5 year history of stable hypertension. Sixteen months before initiation of osimertinib, transthoracic ultrasound cardiography (UCG) showed a left ventricular end-diastolic diameter of 47 mm and an LVEF of 65%. Just prior to initiation of osimertinib, her electrocardiogram (ECG) was normal (QTc, 467 ms; Fig. 2a), although we did not examine her UCG at that time. At 7 months prior to osimertinib treatment her N-terminal pro-brain natriuretic peptide (NT-proBNP) was 1292 pg/mL, while at 1 week prior her BNP was 399.1 pg/mL. Two months later, she presented with dyspnea and bilateral lower limb edema. In our emergency room she showed high blood pressure (150/96 mmHg), tachycardia (110 beats/min), tachypnea (33 breaths/min), and decreased oxygen saturation (92% on room air). Chest X-ray and computed tomography (Fig. 1b) revealed cardiomegaly, bilateral pleural effusion, and tumor shrinkage in the left lower lobe. We did not examine her ECG between initiation of osimertinib and the ER visit. However, ECG at admission showed QTc prolongation (524 ms) and poor R progression (Fig. 2). Transthoracic UCG showed a dilated and diffusely hypocontractile left ventricle (left ventricular end-diastolic diameter 56 mm, LVEF 35%). Creatine kinase MB isozyme and troponin T levels were normal, while NT-proBNP was elevated (7469 pg/mL). A coronary CT angiography scan was normal. Thus, we suspected osimertinib as the cause of heart failure and discontinued its use.

Fig. 2.

Electrocardiogram (a) before initiation of osimertinib (QTc 467 ms) and (b) after 2 months of osimertinib treatment (QTc 524 ms)

At admission, TdP with loss of consciousness occurred repeatedly (Fig. 3). An electrocardioversion successfully controlled the arrhythmia. Thereafter, no arrhythmic event was observed. We started furosemide intravenously on admission and changed to oral azosemide and spironolactone on the sixth hospital day. We also administered oral enalapril maleate and bisoprolol fumarate on the fourth hospital day. Her symptoms gradually improved and her ECG had returned to normal (QTc 464 ms) at discharge. She was discharged on the 24th hospital day. At 15 days, 4 months, and 8 months after osimertinib discontinuation, her LVEF was improved to 45%, 62%, and 51%, respectively, and her NT-proBNP was decreased to 3,435 pg/mL, 922 pg/mL, and 2,808 pg/mL, respectively. She did not receive any other chemotherapy and died of cancer progression and cachexia at home 15 months after osimertinib discontinuation.

Fig. 3.

Electrocardiogram on admission showing torsade de pointes

Discussion

This is a rare case in which osimertinib simultaneously induced congestive heart failure and QT prolongation. To our knowledge, only two cases of coincidence cardiac dysfunction and QT prolongation caused by osimertinib have been reported (Table 1). Unlike those cases, our patient received prior stereotactic thoracic radiotherapy and her heart was within the irradiation area. Radiation therapy can damage both cardiomyocytes and vasculature. This radiation-induced heart disease is often underestimated, because it can be asymptomatic. Nevertheless, it is important to recognize the risks for cardiac dysfunction.

Table 1.

Review of case reports of concomitant cardiotoxicity including cardiac failure and QT prolongation due to osimertinib

Authors (year)	Age, Sex	EGFR mt	Smoking status	Heart diseases	Prior treatment	Time to AE	Osimertinib response	Cardiac outcome
Kunimasa [2]	78 F	L858R	Never	HTN Aortic aneurysm	ND	3 months	PR	Improved
Bian [7]	85 M	L861Q + T790M	ND	ND	Gefitinib	0.5 months	ND	TdP, Improved
This case	84 F	del19	Ex	None	SRT	2 months	PR	TdP, Improved

AE adverse event, EGFR mt epidermal growth factor receptor mutation, F female, HTN hypertension, M male, ND not documented, PR partial response, SRT stereotactic thoracic radiotherapy, TdP torsade de pointes

The etiology of osimertinib-induced cardiotoxicity is unclear. However, it may be similar to trastuzumab, a monoclonal antibody against human EGFR2 (HER2). Osimertinib inhibits both EGFR and HER2. HER2 is expressed in multiple organ systems including cardiomyocyte membranes and plays an important role in myocyte survival, growth, and stress responses [3, 4]. Afatinib, a second-generation and irreversible EGFR inhibitor, also inhibits EGFR and HER2. However, according to the LUX-Lung 3 (n = 229), LUX-Lung 1 (n = 390), and 49 other (n = 3865) clinical studies, afatinib was not associated with increased risk of cardiac failure, AEs, or LVEF reductions [5]. To our knowledge, there is only one reported case of afatinib-induced cardiac failure [6]. Speculatively, these differences in the frequency of cardiotoxicity between osimertinib and afatinib may relate to differences in the HER2 response between these TKIs.

Our case was also rare in that osimertinib-induced TdP occurred. To our knowledge, there is only one reported case of TdP during osimertinib treatment [7]. However, unlike our case, an 85-year-old Chinese man had various risk factors for TdP, including severe diarrhea, poor appetite, reduced food intake, hypokalemia, hypomagnesemia, hospital-acquired infection, and quinolone antibiotic use. In that case, the authors suspected that quinolone may have induced TdP as it suddenly appeared 20 min after ending the moxifloxacin infusion, while osimertinib was stopped 3 days prior. Thus, our case may be the first report of osimertinib-induced TdP.

In conclusion, careful monitoring for cardiac AEs is required during osimertinib treatment as it may cause life threatening, but typically reversible, cardiac events.

Funding

None.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

For this type of study formal consent is not required.

Informed consent

Informed consent was obtained from the patient.