Esophagitis: A Novel Adverse Event of Crizotinib in a Patient with ALK-Positive Non–Small-Cell Lung Cancer
Authors: Neeharika Srivastava, Paul A. VanderLaan, Ciaran P. Kelly, Daniel B. Costa
Journal: Journal of Thoracic Oncology (2013)

Crizotinib is an oral tyrosine kinase inhibitor that can inhibit anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor, proto-oncogene tyrosine kinase c-ROS 1, recepteur d'origine nantais, among other kinases.1Yasuda H de Figueiredo-Pontes LL Kobayashi S Costa DB Preclinical rationale for use of the clinically available multitargeted tyrosine kinase inhibitor crizotinib in ROS1-translocated lung cancer.J Thorac Oncol. 2012; 7: 1086-1090Crossref PubMed Scopus (128) Google Scholar On August 26, 2011, the Food and Drug Administration (FDA) granted accelerated approval to crizotinib for the treatment of patients with locally advanced or metastatic non–small-cell lung cancer (NSCLC) that is ALK-positive as detected by an FDA-approved test; the test approved was the Vysis ALK Break-Apart FISH probe (Abbott Molecular, Inc., Des Plaines, IL). Crizotinib has been studied in phase I, II, and III trials in more than 300 human subjects.2Kwak EL Bang YJ Camidge DR et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703Crossref PubMed Scopus (3831) Google Scholar,3Camidge DR Bang YJ Kwak EL et al.Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.Lancet Oncol. 2012; 13: 1011-1019Abstract Full Text Full Text PDF PubMed Scopus (1067) Google Scholar The drug has bioavailability and a favorable pharmacokinetic profile.2Kwak EL Bang YJ Camidge DR et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703Crossref PubMed Scopus (3831) Google Scholar The major side effects include visual field disturbances, nausea, vomiting, diarrhea, edema, liver function test abnormalities, among others.2Kwak EL Bang YJ Camidge DR et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703Crossref PubMed Scopus (3831) Google Scholar,4Gaughan EM Costa DB Genotype-driven therapies for non-small cell lung cancer: focus on EGFR, KRAS and ALK gene abnormalities.Ther Adv Med Oncol. 2011; 3: 113-125Crossref PubMed Scopus (82) Google Scholar,5Pfizer Inc. Crizotinib (Xalkori) full prescribing information.Available at: http://labeling.pfizer.com/showlabeling.aspx?id=676Date: February 1, 2012Google Scholar Less than a third of patients develop significant adverse events that require dose interruptions or reductions.3Camidge DR Bang YJ Kwak EL et al.Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.Lancet Oncol. 2012; 13: 1011-1019Abstract Full Text Full Text PDF PubMed Scopus (1067) Google Scholar Esophageal disorders, and more specifically severe esophagitis, have not been commonly associated with the use of crizotinib. In the current report, we describe the association of crizotinib and clinically significant esophagitis. An 80-year-old, never-smoker, Chinese woman presented to medical attention with chest pain and hemoptysis. Diagnostic workup included imaging studies that demonstrated a 7.2-cm right upper lobe mass that compressed the right upper lobe bronchus along with osseous destruction in the right fifth rib. Endobronchial ultrasound with biopsy of the mass demonstrated a squamous cell carcinoma. The tumor was found to have wild-type EGFR and KRAS. Vysis ALK Break-Apart FISH probe disclosed 16% positive nuclei for an ALK rearrangement. The patient was started on crizotinib 250-mg capsules twice a day and developed visual changes and nausea (relieved by ondansetron) within the first week of treatment. Within 2 weeks of use, she reported a sensation of “food being stuck” in her lower thoracic/upper abdominal area. She had no history of gastroesophageal reflux disease. After a 10-day trial of a proton pump inhibitor (omeprazole), the patient reported that she continued to have dysphagia but was now also experiencing odynophagia. Repeat imaging studies disclosed severe lower esophageal wall thickening (Fig. 1). Crizotinib was discontinued at the 1-month mark of treatment. Esophagogastroduodenoscopy highlighted an impression of soft esophageal extrinsic compression in the middle third of the esophagus. Pathologic findings from esophageal biopsies demonstrated active esophagitis with surface ulceration, fibrinopurulent exudate, and granulation tissue formation (Fig. 2). Within 10 days of stopping crizotinib, the patient's symptoms had completely resolved and the patient reported that she was able to follow a normal diet and had no dysphagia nor odynophagia. Crizotinib was not reintroduced because of tumor progression.FIGURE 2Midesophagus mucosal biopsies (hematoxylin and eosin stain). Representative images taken at (A) 200× and (B) 400× magnification demonstrate active esophagitis with surface ulceration and fibrinopurulent exudate (blue arrows), and granulation tissue formation (black arrows). The predominantly neutrophilic infiltrate has admixed eosinophils. Stains for microorganisms were negative (not shown).View Large Image Figure ViewerDownload (PPT) The largest published cohort of patients with ALK-positive NSCLC included 149 patients from the original phase I trial of crizotinib.2Kwak EL Bang YJ Camidge DR et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703Crossref PubMed Scopus (3831) Google Scholar,3Camidge DR Bang YJ Kwak EL et al.Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.Lancet Oncol. 2012; 13: 1011-1019Abstract Full Text Full Text PDF PubMed Scopus (1067) Google Scholar Among these, 144 (97%) had adverse events. The most commonly reported events were visual effects (64% of patients), nausea (56%), diarrhea (50%), vomiting (39%), peripheral edema (30%), constipation (28%), dizziness (21%), anorexia (16%), fatigue (16%), increased alanine aminotransferase (12%), rash (11%), dysgeusia (11%), and increased aspartate aminotransferase (10%).3Camidge DR Bang YJ Kwak EL et al.Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.Lancet Oncol. 2012; 13: 1011-1019Abstract Full Text Full Text PDF PubMed Scopus (1067) Google Scholar Among the Common Terminology Criteria for Adverse Events (CTCAE) grade 3 and 4 events reported—which totaled 24% of the patients experiencing it—neutropenia (6%), increased alanine aminotransferase (4%), hypophosphatemia (4%), lymphopenia (4%), aspartate aminotransferase (3%), pneumonitis (2%), and fatigue (1%) were the most common.3Camidge DR Bang YJ Kwak EL et al.Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.Lancet Oncol. 2012; 13: 1011-1019Abstract Full Text Full Text PDF PubMed Scopus (1067) Google Scholar The FDA label for crizotinib expands the adverse event profile incorporating data for 255 patients treated as part of the phase I and II clinical trials of crizotinib, and the adverse event frequencies mirror those of the aforementioned report. Esophageal disorders—listed as dyspepsia, dysphagia, epigastric discomfort or pain or burning, esophagitis, esophageal obstruction or pain or spasm or ulcer, gastroesophageal reflux, odynophagia, and reflux esophagitis—were reported to occur in 20% of the 255 patients, but in only 11% were they attributed to crizotinib. In addition, no cases of CTCAE grade 3 or 4 esophageal disorder occurrences were attributed to crizotinib. A detailed review of the phase I trial report indicates that 1 out of the 149 (0.6%) patients had grade 3 dysphagia. The current report describes the rapid development of a CTCAE grade 3 esophagitis—manifested as dysphagia and odynophagia—without preceding esophageal disease in a patient treated with crizotinib 250-mg capsules twice daily. The clinical, radiographic, and pathologic findings confirmed severe esophagitis. The clinical symptoms improved with discontinuation of crizotinib. In summary, we report the first direct association of severe esophagitis as an adverse event of crizotinib. As the use of crizotinib expands to a larger population of patients with ALK-positive NSCLC, it is likely that rare adverse events will be encountered in clinical practice. The timely reporting of novel adverse events from crizotinib will improve management of patients receiving this valuable tyrosine kinase inhibitor. This work was funded in part through an American Cancer Society grant RSG 11–186 (DBC).