Complex renal cysts associated with crizotinib treatment

Abstract

An apparent causal association between crizotinib treatment and renal cyst development emerged during clinical trials in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Serious adverse event (SAE) reports of renal cysts from a safety database of 1375 patients from four clinical trials were reviewed. A blinded, retrospective, independent radiologic review (IRR) was performed using scans from patients on study for ≥ 6 months in three clinical trials; risk factors for renal cyst development were assessed. Among 17 patients with renal cysts reported as SAEs, evidence of invasion into adjacent structures was noted in seven patients, with no evidence of malignancy found. These patients generally did not require dose reductions, none required permanent crizotinib discontinuation due to this AE, and most continued treatment with clinical benefit. In the blinded IRR, among 255 crizotinib-treated patients, 22%, 3%, and 2% had preexisting simple cysts, complex cysts, or both, respectively. At the 6-month tumor assessment, 9% of all patients had acquired new cysts, and 2% of patients with preexisting cysts had developed new cysts and enlargements (>50%) of preexisting simple cysts. Asians appeared to have an increased risk of developing new cysts on treatment; Koreans in particular had 5.18 times higher odds of developing cysts than non-Asians (95% confidence interval, 1.51-17.78; P = 0.05). Crizotinib treatment appears to be associated with an increased risk of development and progression of renal cysts in patients with ALK-positive NSCLC. While close monitoring is recommended, dosing modification was not generally necessary, allowing patients to remain on crizotinib treatment.

Keywords: Crizotinib; NSCLC; independent radiologic review; renal cysts; risk factors.

Figure 1

Computed tomography images of a 61-year-old woman with ALK-positive NSCLC who developed complex renal cysts during treatment with crizotinib (patient 1, Table 1). (A) baseline and (B) 2.5 months, (C) 4.1 months, (D) 5.5 months, (E) 6.3 months (just prior to cyst resection), and (F) 18.1 months after initiation of treatment. The images show progressive growth of multiseptated renal cystic lesions infiltrating the perirenal space and involving the left psoas muscle. Additionally, a cystic lesion in the anterior abdominal wall developed (drain in place, F), which was resected. Pathology showed degenerated muscular tissue with fibrosis and acute inflammation. NSCLC, non–small cell lung cancer. ALK, anaplastic lymphoma kinase.

Figure 2

Treatment and responses at data cutoff (31 December 2012) in patients with renal cysts reported as serious adverse events. Cyst diagnosis dates were based on radiologic assessment at the study sites. Derived response data are depicted per RECIST. Relevant data were not available for patient 12. RECIST, response evaluation criteria in solid tumors.