Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/07/15 For personal use only.
Case Report
When crizotinib-induced bradycardia becomes symptomatic: role of concomitant drugs Expert Rev. Anticancer Ther. 15(7), 761–763 (2015)
Giuseppina Gallucci1, Alfredo Tartarone*2, Lucia Lombardi2 and Michele Aieta2 1 Cardiology Unit, IRCCS, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture (PZ), Italy 2 Department of Onco-Ematology, IRCCS Centro di Riferimento Oncologico della Basilicata, via Padre Pio 1, Rionero in Vulture, Italy *Author for correspondence: [email protected]
informahealthcare.com
Crizotinib is an orally active multi-target tyrosine kinase inhibitor which is the standard of care in patients with anaplastic lymphoma kinase translocated non-small-cell lung cancer. Common adverse events in clinical trials with crizotinib included visual disorders, nausea–vomiting, diarrhea and elevated transaminases. Less common toxicities are emerging, such as bradycardia and QT interval prolongation. We report on a case of a presyncopal episode which occurred under crizotinib and metoclopramide treatment. KEYWORDS: cardiotoxicity . crizotinib . drug interactions . metoclopramide . non-small-cell lung cancer
The employment of targeted therapies for molecularly defined tumors has brought about a paradigm shift in non-small-cell lung cancer (NSCLC) treatment. In 2007, a chromosome rearrangement between the N-terminal portion of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the tyrosine kinase of the anaplastic lymphoma kinase (ALK) gene that encodes a cytoplasmic chimeric protein with kinase activity was identified as a driver of lung cancer [1]. The EML4–ALK fusion oncogene or its variants have been found in 5–7% of NSCLC patients, more frequently in those who are young, have adenocarcinoma histology and are never or light smokers [2]. Crizotinib is an orally active multi-target tyrosine kinase inhibitor and it represents the standard of care in patients with ALKtranslocated (ALK+) NSCLC [3]. Common adverse events in clinical trials with crizotinib included visual disorders, nausea–vomiting, diarrhea and elevated transaminases [4–6]. Due to the increasing clinical experience with crizotinib, other toxicities are emerging, such as QT interval prolongation, bradycardia, hypogonadism, renal impairment, renal cysts and hypersensitivity [4–6]. We report on a case of a presyncopal episode that occurred under crizotinib and metoclopramide treatment.
10.1586/14737140.2015.1045493
Clinical case
In January 2014, a 63-year-old man was diagnosed with ALK+ metastatic adenocarcinoma of the lung. The patient received combination chemotherapy with cisplatin plus pemetrexed. A computed tomography scan performed after the third cycle of chemotherapy showed a pulmonary progressive disease; therefore, he was started on crizotinib 250 mg orally twice a day as second line of treatment. He achieved a rapid improvement in respiratory symptoms; but due to crizotinib-related nausea and vomiting, he was put on therapy with metoclopramide 10 mg three times daily while continuing pantoprazole 40 mg daily. After 7 days of concomitant crizotinib plus metoclopramide treatment, the patient was hospitalized for a serious presyncopal episode. ECG showed sinus bradycardia with a heart rate (HR) of 49 beats per minute (bpm) and a normal QTc interval (0.44 s). Normal levels of oxygen saturation, electrolytes, troponine I and thyroid hormones were found. The patient received atropine 0.4 mg intravenously (iv.) that resulted in a rapid increase in HR and improvement of symptoms. Crizotinib and metoclopramide were withdrawn. The patient’s HR increased to 58 bpm after 3 days and to 69 bpm after 9 days of washout. Then
2015 Informa UK Ltd
ISSN 1473-7140
761
Case Report
Gallucci, Tartarone, Lombardi & Aieta
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/07/15 For personal use only.
Table 1. Drug interactions between crizotinib and concurrent medications. CYP3A inhibitors†
CYP3A inducers‡
CYP3A substrates§
Atazanavir Clarithromycin Indinavir Itraconazole Ketoconazole Nefazodone Nelfinavir Ritonavir Saquinovir Telithromycin Troleandomycin Voriconazole Grapefruit Grapefruit juice
Carbamazepine Phenobarbital Phenytoin Rifabutin Rifampin St. John’s wort
Alfentanil Cyclosporine Dihydroergotamine Ergotamine Fentanyl Pimozide Quinidine Sirolimus Tacrolimus
†
Drugs that may increase plasma concentrations of crizotinib. Drugs that may decrease plasma concentrations of crizotinib. Drugs whose plasma concentrations may be altered by crizotinib. Data taken from [14]. ‡ §
crizotinib therapy was restarted at a dosage of 200 mg twice a day; at rechallenge, sinus bradycardia with an HR of 50 bpm (grade 1 according to Common Toxicity Criteria Adverse Events version 4.0) was also registered, but the patient remained clinically asymptomatic. In December 2014, due to a radiological evidence of progressive disease, crizotinib was discontinued and the patient was treated with docetaxel 75 mg/m2 iv. and zoledronic acid 4 mg iv. every 3 weeks plus radiotherapy on bone metastases. Currently, the patient is alive and still receiving treatment with docetaxel plus zoledronic acid. Discussion
In clinical practice, crizotinib is associated with two main cardiac effects: QT interval prolongation and bradycardia [4–6]. Bradycardia, typically of grade 1–2, was reported in about 5% of patients receiving crizotinib [4–6]. The pathogenesis of bradycardia under crizotinib is probably related to the antagonist effect of the drug on L-type calcium channels, a chronotropic effect on sinoatrial node or an anti-mesenchimal epithelial transition effect [7]. Ou et al. investigated the frequency and timing of sinus bradycardia in 42 NSCLC patients enrolled in two crizotinib trials (PROFILE 1001 and PROFILE 1005) [7]. All patients received crizotinib 250 mg twice daily and none of them required dose reduction during crizotinib treatment. Thirty eight patients (90.4%) experienced at least one episode of an absolute decrease in HR >10 bpm from baseline, 29 patients (69%) had at least one episode of sinus bradycardia (HR
Case Report
When crizotinib-induced bradycardia becomes symptomatic: role of concomitant drugs Expert Rev. Anticancer Ther. 15(7), 761–763 (2015)
Giuseppina Gallucci1, Alfredo Tartarone*2, Lucia Lombardi2 and Michele Aieta2 1 Cardiology Unit, IRCCS, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture (PZ), Italy 2 Department of Onco-Ematology, IRCCS Centro di Riferimento Oncologico della Basilicata, via Padre Pio 1, Rionero in Vulture, Italy *Author for correspondence: [email protected]
informahealthcare.com
Crizotinib is an orally active multi-target tyrosine kinase inhibitor which is the standard of care in patients with anaplastic lymphoma kinase translocated non-small-cell lung cancer. Common adverse events in clinical trials with crizotinib included visual disorders, nausea–vomiting, diarrhea and elevated transaminases. Less common toxicities are emerging, such as bradycardia and QT interval prolongation. We report on a case of a presyncopal episode which occurred under crizotinib and metoclopramide treatment. KEYWORDS: cardiotoxicity . crizotinib . drug interactions . metoclopramide . non-small-cell lung cancer
The employment of targeted therapies for molecularly defined tumors has brought about a paradigm shift in non-small-cell lung cancer (NSCLC) treatment. In 2007, a chromosome rearrangement between the N-terminal portion of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the tyrosine kinase of the anaplastic lymphoma kinase (ALK) gene that encodes a cytoplasmic chimeric protein with kinase activity was identified as a driver of lung cancer [1]. The EML4–ALK fusion oncogene or its variants have been found in 5–7% of NSCLC patients, more frequently in those who are young, have adenocarcinoma histology and are never or light smokers [2]. Crizotinib is an orally active multi-target tyrosine kinase inhibitor and it represents the standard of care in patients with ALKtranslocated (ALK+) NSCLC [3]. Common adverse events in clinical trials with crizotinib included visual disorders, nausea–vomiting, diarrhea and elevated transaminases [4–6]. Due to the increasing clinical experience with crizotinib, other toxicities are emerging, such as QT interval prolongation, bradycardia, hypogonadism, renal impairment, renal cysts and hypersensitivity [4–6]. We report on a case of a presyncopal episode that occurred under crizotinib and metoclopramide treatment.
10.1586/14737140.2015.1045493
Clinical case
In January 2014, a 63-year-old man was diagnosed with ALK+ metastatic adenocarcinoma of the lung. The patient received combination chemotherapy with cisplatin plus pemetrexed. A computed tomography scan performed after the third cycle of chemotherapy showed a pulmonary progressive disease; therefore, he was started on crizotinib 250 mg orally twice a day as second line of treatment. He achieved a rapid improvement in respiratory symptoms; but due to crizotinib-related nausea and vomiting, he was put on therapy with metoclopramide 10 mg three times daily while continuing pantoprazole 40 mg daily. After 7 days of concomitant crizotinib plus metoclopramide treatment, the patient was hospitalized for a serious presyncopal episode. ECG showed sinus bradycardia with a heart rate (HR) of 49 beats per minute (bpm) and a normal QTc interval (0.44 s). Normal levels of oxygen saturation, electrolytes, troponine I and thyroid hormones were found. The patient received atropine 0.4 mg intravenously (iv.) that resulted in a rapid increase in HR and improvement of symptoms. Crizotinib and metoclopramide were withdrawn. The patient’s HR increased to 58 bpm after 3 days and to 69 bpm after 9 days of washout. Then
2015 Informa UK Ltd
ISSN 1473-7140
761
Case Report
Gallucci, Tartarone, Lombardi & Aieta
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/07/15 For personal use only.
Table 1. Drug interactions between crizotinib and concurrent medications. CYP3A inhibitors†
CYP3A inducers‡
CYP3A substrates§
Atazanavir Clarithromycin Indinavir Itraconazole Ketoconazole Nefazodone Nelfinavir Ritonavir Saquinovir Telithromycin Troleandomycin Voriconazole Grapefruit Grapefruit juice
Carbamazepine Phenobarbital Phenytoin Rifabutin Rifampin St. John’s wort
Alfentanil Cyclosporine Dihydroergotamine Ergotamine Fentanyl Pimozide Quinidine Sirolimus Tacrolimus
†
Drugs that may increase plasma concentrations of crizotinib. Drugs that may decrease plasma concentrations of crizotinib. Drugs whose plasma concentrations may be altered by crizotinib. Data taken from [14]. ‡ §
crizotinib therapy was restarted at a dosage of 200 mg twice a day; at rechallenge, sinus bradycardia with an HR of 50 bpm (grade 1 according to Common Toxicity Criteria Adverse Events version 4.0) was also registered, but the patient remained clinically asymptomatic. In December 2014, due to a radiological evidence of progressive disease, crizotinib was discontinued and the patient was treated with docetaxel 75 mg/m2 iv. and zoledronic acid 4 mg iv. every 3 weeks plus radiotherapy on bone metastases. Currently, the patient is alive and still receiving treatment with docetaxel plus zoledronic acid. Discussion
In clinical practice, crizotinib is associated with two main cardiac effects: QT interval prolongation and bradycardia [4–6]. Bradycardia, typically of grade 1–2, was reported in about 5% of patients receiving crizotinib [4–6]. The pathogenesis of bradycardia under crizotinib is probably related to the antagonist effect of the drug on L-type calcium channels, a chronotropic effect on sinoatrial node or an anti-mesenchimal epithelial transition effect [7]. Ou et al. investigated the frequency and timing of sinus bradycardia in 42 NSCLC patients enrolled in two crizotinib trials (PROFILE 1001 and PROFILE 1005) [7]. All patients received crizotinib 250 mg twice daily and none of them required dose reduction during crizotinib treatment. Thirty eight patients (90.4%) experienced at least one episode of an absolute decrease in HR >10 bpm from baseline, 29 patients (69%) had at least one episode of sinus bradycardia (HR
