Crizotinib is an inhibitor of several receptor tyrosine

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1 Brief Report Development of Renal Cysts after Crizotinib Treatment in Advanced ALK-Positive Non Small-Cell Lung Cancer Yen-Ting Lin, MD,* Yu-Fen Wang, MD, James Chih-Hsin Yang, MD, PhD, Chong-Jen Yu, MD, PhD, Shang-Gin Wu, MD,* Jin-Yuan Shih, MD, PhD, and Pan-Chyr Yang, MD, PhD, Introduction: The development of complex renal cysts after crizotinib treatment for non small-cell lung cancer (NSCLC) is a reported side effect. However, its occurrence and characteristics have not been reported. Methods: Medical records and computed tomography images of crizotinib-treated patients in three prospective clinical trials were reviewed. The size and Bosniak category of the renal cysts before and after crizotinib treatment were determined. Patients clinical characteristics, tumor stage, treatment response, renal function, and outcomes were analyzed. Results: During December 2010 to March 2013, we enrolled 32 patients who received crizotinib. There were 23 patients who had renal cysts before crizotinib. The median follow-up time was 493 days. Seven patients (22%, six with baseline renal cyst and one without baseline renal cyst) had significant renal cyst change. Four (13% of all) had new complex renal cysts. The median time from crizotinib treatment to first recognization of significant renal cyst change was 77 days. After stopping crizotinib, complex renal cysts regressed significantly. Patients with significant renal cyst change received more previous anticancer therapy (median, 5 lines versus 3 lines, p = 0.04) and received crizotinib for longer duration (median, 956 days versus 248 days, p = 0.007) compared with those without significant renal cyst change. Conclusions: Change of renal cysts after crizotinib treatment is not uncommon. Development of complex renal cysts reverses after stopping crizotinib. Key Words: Crizotinib, Non small-cell lung cancer, Renal cyst. (J Thorac Oncol. 2014;9: ) *Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan; Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan; Department of Oncology, National Taiwan University Hospital and Graduate Institute of Oncology and Cancer Research Centre, College of Medicine, National Taiwan University, Taipei, Taiwan; and Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan. Disclosure: James Chih-Hsin Yang has received advisory fees from AstraZeneca, Roche, Genentech, Pfizer, and Clovis and has been an uncompensated advisor to Boehringer Ingelheim and Eli Lilly. Chong- Jen Yu and Jin-Yuan Shih have received speaking honoraria from AstraZeneca, Roche, Pfizer, Boehringer Ingelheim, and Eli Lilly. Address for correspondence: Jin-Yuan Shih, MD, PhD, Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, No. 7, Zhongshan South Road, Taipei 100, Taiwan. jyshih@ntu.edu.tw DOI: /JTO ISSN: /14/ Crizotinib is an inhibitor of several receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (HGFR, c-met), 1 and c-ros oncogene 1. 2 It has been approved for the treatment of advanced ALK-positive non small-cell lung cancer (NSCLC) in many countries. The development of complex renal cyst has been observed in seven (4%) patients as stated in the latest label of crizotinib published by the US Food and Drug Administration (FDA). 3 However, its occurrence and characteristics have not been reported. Renal cysts are common radiologic findings. Bosniak published the well-known classification of renal cysts based on computed tomography (CT) scan in The classification was proven to be correlated with the risk of malignancy by several studies. 5,6 In general, more complex renal cysts are at increased risk of being malignant. 6 We systematically reviewed renal cyst development by size and Bosniak category in crizotinib-treated patients. PATIENTS AND METHODS This study enrolled patients who received crizotinib in three prospective clinical trials [PROFILE 1005 (NCT ), 7 PROFILE 1007 (NCT ), 8 and an exploratory study of crizotinib efficacy (NCT )] at the National Taiwan University Hospital during December 2010 to March 2013 for advanced ALK-positive NSCLC. The clinical trials were approved by the Research Ethics Committee and all patients gave written informed consent. The patients were followed up by 5-mm slice chest and abdominal CT scans as dictated by the study protocol. Those who did not receive CT scan follow-up for any reason were excluded. Those with only noncontrast CT follow-up were also excluded. Although noncontrast enhanced CT scans may also identify renal cysts, CT scans with contrast enhancement, on which the Bosniak classification is based, 4 are more valuable for the evaluation of renal cystic lesions. The patient s clinical characteristics, use of previous anticancer therapy, details of crizotinib treatment, and clinical outcomes were recorded. A radiologist, who was blinded to the patients clinical characteristics, reviewed the CT scans before and after the start of crizotinib. Renal cysts were recorded individually based on the maximum diameter of axial section on contrast-enhanced CT. The Bosniak category 4 6 of renal cystic disease was given. Significant renal cyst change was defined as the presence of new renal cysts more than 4 mm in size, enlargement or 1720 Journal of Thoracic Oncology Volume 9, Number 11, November 2014

2 Journal of Thoracic Oncology Volume 9, Number 11, November 2014 Crizotinib and Renal Cysts TABLE 1. Details of Patients with Significant Renal Cyst Change a (n = 7) Patient No Sex Age (Years) Time from Crizotinib to First Recognition of Significant Renal Cyst Change (Day) Increase in Renal Cysts Number Presence of New Complex Renal Cysts Highest Bosniak Category of New Cysts Increase in Renal Cyst Size (Maximal Change Crizotinib of Axial Diameter, mm) b Withheld Renal Cysts Regression after Stopping Crizotinib Total days on crizotinib c 1 F Right: 1 to 9 Left: 3 to 10 Yes IV Right: Yes (+42) Left: Yes (+39) Yes Yes M Right: 2 to 6 Left: 3 to 4 Yes III Right: Yes (+45) Left: Yes (+41) Yes Yes M Right: 1 to 1 d Left: no cyst No I Right: Yes d (+5) Left: No Yes No d F Right: 0 to 1 Left: no cyst Yes III Right: Yes (+19) Left: No Yes No F Right: 1 to 3; Left: 0 to 1 Yes II Right: Yes (+24) Left: Yes (+9) No F Right: no cyst Left: 1 to 2 No I Right: No Left: Yes (+8) Yes Yes e M Right: 2 to 2; Left: 3 to 2 No I Right: Yes (+14) Left: Yes (+6) No 837 a Significant renal cyst change was defined as the presence of new renal cysts more than 4 mm in size, enlargement or regression of previous renal cysts for more than 4 mm, or complicated renal cysts that were initially simple cysts (Bosniak category I) and became Bosniak category IIF or higher. b Maximal axial diameter of renal cysts were measured on contrast-enhanced CT. Maximal change of axial diameter refers to the maximal diameter difference before and after crizotinib treatment. c Number of days recorded up until March 16, d This patient had transient increase in renal cyst size during the first 4 months on crizotinib. His crizotinib was held on the tenth month of treatment and the renal cyst was stationary while crizotinib was withheld. e The patient s new left renal cyst decreased in size and eventually disappeared after stopping crizotinib. 1721

3 Lin et al. Journal of Thoracic Oncology Volume 9, Number 11, November 2014 regression of previous renal cysts of more than 4 mm, or complicated renal cysts (Bosniak category IIF or higher) that were initially simple cysts (Bosniak category I). Continuous variables were reported as median with upper to third quartiles. The Mann-Whitney U test was used as appropriate. Categorical data were compared using Fisher s exact test. Statistical significance was set at p < RESULTS Patient Demographic and Clinical Characteristics During December 2010 to March 2013, there were 39 patients who were enrolled in crizotinib trials. Seven patients (four with no follow-up CT and three with noncontrast CT follow-up) were excluded. The remaining 32 were enrolled into this study. Among the patients, 15 (47%) were male, 21 (66%) were never smokers, and 31 (97%) had adenocarcinoma. The median age was 58 years (range, 32 82). Development of Renal Cysts after Crizotinib There were 23 patients (72%) who had renal cysts before receiving crizotinib treatment. All cysts were Bosniak category I. During the treatment period, seven patients (22%, six with baseline renal cyst and one without baseline renal cyst) had significant renal cyst change (Table 1). Four (13% of all) had new complex renal cysts. The median time from crizotinib to first recognization of significant renal cyst change was 77 (range, ) days. Patient 1 was the representative case of complex renal cyst formation. She had simple renal cysts upon enrollment into the trial (Fig. 1A). Significant renal cyst change had been noted since treatment day 42. CT showed that her previous renal cysts had enlarged and multiple new renal cysts developed bilaterally 3 months after crizotinib treatment (Figs. 1B, 2A). The renal cysts had thickened and enhanced septa, corresponding to category III renal cysts (Fig. 2A). Six months (Figs. 1C, 2B) following crizotinib, the renal cysts become more complex. In Figure 2B, the right renal cyst had irregular margins and extended to abut the ascending colon. The left renal cyst also had irregular margins and extended to abut the left psoas muscle. Both were large, bizarre cysts, indicating category IV renal cysts. Category III or higher renal cysts on the Bosniak classification are associated with high risk of malignancy 4 6 and surgical excision should be considered. However, because the patient had advanced lung cancer and the complex renal cysts occurred bilaterally, such major operation may be at risks. Therefore, immediate excision was not performed after detection of the cysts. Her creatinine level increased from 0.9 mg/dl (pretreatment) to 2.02 mg/dl 6 months after treatment. She did not have significant diarrhea or dehydration. The urine analysis was within normal limit. Crizotinib was held for 6 weeks for decreased renal function. Her creatinine level decreased to 1.1 mg/dl. Follow-up CT scan found significantly decreased size of the renal cysts (Fig. 2D). Thus, crizotinib was resumed and biopsy or excision was not performed. Seventeen months after crizotinib treatment, her renal cysts became very large and complex (Figs. 1E, 2C), indicating category IV renal cysts. However, her renal function was not affected. Enlargement of the lung tumor and disease progression were noted. Crizotinib was stopped and local radiotherapy was started for lung tumor control. Two month after stopping crizotinib, her renal cysts regressed again (Fig. 1F). Patient 2 was another representative case of complex renal cyst formation. He only had simple renal cysts upon enrollment into the trial (Fig. 3A). Significant renal cyst change had been noted since treatment day 84. CT scan 12 months (Fig. 3B) and 27 months (Fig. 3C) after crizotinib treatment showed progressively increasing numbers of complex cysts FIGURE 1. Renal cyst evolution in patient 1. A, Abdominal contrastenhanced CT scan with reconstruction to coronal view before crizotinib treatment. B, Three months after crizotinib, there were new renal cysts bilaterally. C, Six months after crizotinib treatment, there were multiple bilateral bizarre complex renal cysts. Crizotinib was stopped. D, Six weeks after withholding crizotinib, bilateral renal cysts decreased in size. Crizotinib was resumed. E, Seventeen months after crizotinib treatment, the renal cysts became very large and complex. Crizotinib was stopped and radiotherapy was started because of lung cancer progression. F, Two months after stopping crizotinib, the renal cysts regressed. 1722

4 Journal of Thoracic Oncology Volume 9, Number 11, November 2014 Crizotinib and Renal Cysts FIGURE 2. Parts of CT scans of patient 1 after crizotinib treatment. A, Three months after crizotinib. There were thickened and enhanced septa in the left renal cyst (arrow), indicating a category III renal cyst. B, Six months after crizotinib. The right renal cyst had irregular margins and extended to abut the ascending colon. The left renal cyst also had irregular margins and extended to abut the left psoas muscle (arrows). Both were category IV renal cysts. C, Seventeen months after crizotinib. The left renal cyst had irregular margins and enhancing solid part (arrows), indicating a category IV renal cyst. bilaterally (Bosniak category III). His renal function was stable and urine analysis was unremarkable. Because of lung cancer progression, crizotinib was held and local radiotherapy given. Two months after stopping crizotinib, the renal cysts regressed significantly (Fig. 3D). Crizotinib was resumed after completing radiotherapy. Two months after resuming crizotinib, the renal cysts progressed again (Fig. 3E). Because of progressive bony metastases, crizotinib was stopped after 32 months of treatment. He was then given alectinib for crizotinib-resistant ALK-positive lung cancer. Four months later, the renal cysts regressed, and only small residual cysts were left (Fig. 3F). Details of other patients are shown in Table 1. Comparison of Clinical Features between Patients with and those Without Significant Renal Cyst Change Comparisons of clinical characteristics between those with and those without significant renal cyst change are shown in Table 2. Patients with significant renal cyst change have more previous anti-tumor therapy (p = 0.04) and longer duration on crizotinib (p = 0.007). The progression free survival was not significantly different between the two groups (median, 509 days versus 210 days, p = 0.09) because of the small number of patients. The demographic characteristics and crizotinib treatment duration were not significantly different between patients with and without baseline renal cyst (Table 3). Further analysis of patients with renal cyst change FIGURE 3. Evolution of renal cysts in patient 2. A, Before crizotinib, abdominal contrast-enhanced CT at the level of renal veins revealed a simple cyst in the left kidney. B, One year after crizotinib treatment, the left renal cyst had enlarged and became complex. C, Twenty-seven Months after crizotinib treatment, the left cyst became larger and there was a new complex cyst on the right. Crizotinib was stopped. D, Two months after withholding crizotinib, renal cysts in both kidneys regressed. E, CT scan 2 months after resuming crizotinib showed that the renal cysts had progressed. F, Four months after shifting crizotinib to alectinib, the renal cysts regressed, and only small residual cysts were left. 1723

5 Lin et al. Journal of Thoracic Oncology Volume 9, Number 11, November 2014 TABLE 2. Comparison of Patient Characteristics (n = 32) Patients with Significant Renal Cyst Change (n = 7) Patients Without Significant Renal Cyst Change (n = 25) p Value Age 62 (44 69) 56 (51 62) 0.80 Male sex 3 (43%) 12 (48%) 0.99 Adenocarcinoma cell type 7 (100%) 24 (96%) 0.99 Never smoker 3 (43%) 18 (72%) 0.20 Stage IV at diagnosis 6 (86%) 15 (60%) 0.37 Underwent curative operation for lung cancer 1 (17%) 7 (28%) 0.65 Previous anti-cancer therapy (line) 5 (4 6) 3 (2 4) 0.04 Baseline creatinine (mg/dl) 0.8 ( ) 0.9 ( ) 0.50 Renal cyst presented before crizotinib 6 (86%) 17 (68%) 0.65 Crizotinib treatment duration (day) a 956 ( ) 248 ( ) Progression-free survival after crizotinib (day) a 509 ( ) 210 ( ) 0.09 Continuous variables presented as median (first to third quartiles) and compared by Mann-Whitney U test. a Data recorded up until March 16, (n = 7), patients with baseline renal cyst but without renal cyst change (n = 17) and patients without baseline renal cyst and without renal cyst change (n = 8) revealed that crizotinib treatment duration for the three groups were 956 ( ) days, 238 ( ) days, and 311 (78 643) days, respectively. Patients with renal cyst change had longer crizotinib treatment duration than patients without renal cyst change, whether they had baseline renal cyst (p = 0.008) or not (p = 0.04). Among patients without renal cyst change, crizotinib treatment duration did not differ significantly between patients with or without baseline renal cyst (p = 0.68). DISCUSSION We described changes in renal cysts in patients who received crizotinib for ALK-positive advanced NSCLC. Seven (22%) of 32 patients had significant renal cyst change after crizotinib treatment. These renal cysts developed early after crizotinib treatment and may be complex (Bosniak category III or higher) and resemble malignancy. However, after stopping crizotinib, the cysts regressed spontaneously. Patients with significant renal cysts change had received more anticancer treatment prior to crizotinib and had a longer crizotinib treatment duration. Renal cysts development after crizotinib treatment seems to have a benign course. In the representative patients 1 and 2, new renal cysts developed after crizotinib was started and regressed after withholding crizotinib. Renal function was impaired as the cysts progressed only in patient 1 after 6 months of crizotinib treatment. Her renal function returned to baseline after stopping crizotinib. However, after crizotinib rechallenge, her renal function was unaffected. In the present cohort, the lung cancer continues to be responsive to crizotinib even after developing complex renal cyst. The complex renal cysts should not be mistaken as new metastases and preclude crizotinib use. The prevalence of renal cyst before crizotinib is high (23 of 32, 72%) in our study cohort. Prevalence of renal cyst is reported variably. In autopsy, more than 50% of patients aged over 50 have at least one simple renal cyst. 6 As medical imaging advances, renal cysts are identified more TABLE 3. Comparison of Patients with and Without Baseline Renal Cysts (n = 32) Patients Without Baseline Renal Cyst (n = 9) Patients with Baseline Renal Cyst (n = 23) p Value Age 52 (44 65) 60 (51 64) 0.28 Male sex 2 (22%) 13 (57%) 0.12 Adenocarcinoma cell type 9 (100%) 22 (96%) 0.99 Never smoker 7 (78%) 14 (61%) 0.44 Stage IV at diagnosis 6 (67%) 15 (65%) 0.99 Underwent curative operation for lung cancer 2 (22%) 6 (26%) 0.99 Previous anti-cancer therapy (lines) 3 (1 5) 4 (2 5) 0.48 Baseline creatinine (mg/dl) 0.8 ( ) 0.9 ( ) 0.37 Significant renal cyst change 1 (11%) 6 (26%) 0.36 Crizotinib treatment duration (day) a 335 ( ) 297 ( ) 0.95 Progression-free survival after crizotinib (day) a 248 ( ) 249 ( ) 0.82 Continuous variables presented as median (first to third quartiles) and compared by Mann-Whitney U test. a Data recorded up until March 16,

6 Journal of Thoracic Oncology Volume 9, Number 11, November 2014 Crizotinib and Renal Cysts frequently. 6 Using spiral computer tomography for screening for renal cysts, it is reported that the prevalence of renal cysts in patients aged 40 60, 60 80, and aged over 80 were 27.5%, 49.0%, and 60.6%, respectively. 9 Our patients were highly selected. It is not known if lung cancer or anticancer therapy can influence renal cyst development. Moreover, the case numbers are limited. There might also be selection bias. Although there was only one patient without baseline renal cyst developed new complex renal cyst, it is still possible that patients without baseline renal cyst can develop complex renal cyst after crizotinib therapy. In the latest FDA label for crizotinib published in November 2013, 3 seven (4%) patients was reported to have renal cysts formation. The prevalence of renal cyst formation was much lower than our report (22%). It may be because of the different definition of significant renal cyst change and lack of systematic review. In addition, in the FDA s previous label published in August 2011, 10 only two patients (1%) was reported to have complex renal cyst formation. As crizotinib becomes more commonly prescribed, more patients with renal cyst formation may be reported. Most of the renal cysts formed reported in the FDA label, as our study, were complex renal cysts and some were very complicated and resembled abscess formation. Our patients did not have any signs of infection and were not treated with any antibiotics. The renal cysts persisted for months to years, regressed after withholding crizotinib and reappeared after resuming crizotinib. The cyst formations were not likely infectious processes. It is worth emphasizing that patients who were enrolled into the trials were highly selected. They have received multiple lines of anti-cancer therapy and survived. The tumor biology and tumor patient relationship in these patients may not be representative of the general population. Comparing patients with significant renal cyst change to those without, patients who received more previous anti-cancer chemotherapy had more significant renal cyst change. The precise reason is unknown. It may be related to the relative small patient numbers or there are still other mechanisms between renal cyst development and tumor responsiveness to treatment. Crizotinib is an inhibitor of ALK and c-met. 1 c-met is found in normal renal tissue but is limited to the cell membrane and/or cytoplasm of epithelial cells in specific tubular segments. 11 In c-met knock-out mice, there are no significant defects in kidney morphology or function. 12 In patients with autosomal dominant polycystic kidney disease (ADPKD), the hepatocyte growth factor (HGF), and its receptor c-met are thought to contribute to cyst formation in an autocrine manner. 13 Another recent study demonstrates that c-met may promote renal cystogenesis. 14 In a mouse model of ADPKD, the inhibition of c-met by Su and PHA lead to the inhibition of cystogenesis. 15 It remains doubtful if crizotinib can have the opposite effect on renal cyst formation. Our patient 2 whose crizotinib failed after 32 months of treatment was given alectinib for further lung cancer treatment. The complex renal cysts regressed significantly. It seems that renal cysts formation is not a class effect of ALK inhibitor. Mechanism of how crizotinib contributes to renal cyst formation warrants further studies. In conclusion, renal cysts change during crizotinib therapy for ALK-positive advanced NSCLC is not uncommon. Development of complex renal cysts reverses after stopping crizotinib. Acknowledgment The patients described in this study were treated in crizotinib clinical trials (NCT , NCT , and NCT ) that were sponsored by Pfizer. REFERENCES 1. Ou SH. Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond. Drug Des Devel Ther 2011;5: Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;30: FDA. Available from: label/2013/202570s006lbl.pdf. [Last accessed on 2014 Mar 23] Bosniak MA. The current radiological approach to renal cysts. 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