Crizotinib resulted in a decline in creatinine-based estimates of renal function mostly over the first 2 weeks of treatment. However, there was minimal evidence of cumulative effects with prolonged treatment and these changes were largely reversible following treatment discontinuation, consistent with previous reports suggesting this may be predominantly an effect on creatinine secretion as opposed to true nephrotoxicity.

Median serum creatinine increased from 0.79 mg/dL at baseline to 0.93 mg/dL after 2 weeks of treatment (median percentage increase from baseline, 21.2%), was stable from week 12 (0.96 mg/dL) to week 104 (1.00 mg/dL), and decreased to 0.90 mg/dL at 28 days after last dose (median percentage increase from baseline, 13.1%). Median eGFR decreased over time (96.42, 80.23, 78.06 and 75.45 mL/min/1.73 m 2 at baseline, week 2, week 12, and week 104, respectively) and increased to 83.02 mL/min/1.73 m 2 at 28 days after the last dose. Median percentage decrease from baseline was 14.9%, 17.0%, and 10.4% at week 2, week 12, and 28 days after last dose of crizotinib, respectively. Overall, 12.6% of patients had a shift from eGFR grade less than or equal to 3a (≥45 mL/min/1.73 m 2 ) at baseline to greater than or equal to 3b (<45 mL/min/1.73 m 2 ) post-baseline.

Changes from baseline data in serum creatinine and eGFR, calculated using the Chronic Kidney Disease Epidemiology Collaboration creatinine-based equation, were assessed over time. eGFR was graded using standard chronic kidney disease criteria.

We retrospectively analyzed the effects of crizotinib on serum creatinine and creatinine-based estimated glomerular filtration rate (eGFR) in patients with anaplastic lymphoma kinase–positive advanced NSCLC across four trials ( NCT00585195 NCT00932893 , and NCT01154140 ).

The objective of this retrospective analysis was to investigate the effect of crizotinib on creatinine-based eGFR over time across four clinical trials of patients with ALK-positive NSCLC (PROFILE 1001, NCT00585195 ; PROFILE 1005, NCT00932451 ; PROFILE 1007, NCT00932893 ; and PROFILE 1014, NCT01154140 ).

The safety profile of crizotinib that was established in the aforementioned clinical trials was characterized by mild or moderate adverse events of visual disorders, gastrointestinal effects, and elevated transaminases.Additional adverse events, including interstitial lung disease, have also been reported.A retrospective study involving 38 patients with ALK-positive NSCLC who were treated with crizotinib showed a statistically significant reduction in estimated glomerular filtration rate (eGFR) over 12 weeks of crizotinib therapy compared with baseline (mean decrease in eGFR, 23.9%; 95% confidence intervals: 21.3–26.6%; p < 0.0001), with the largest decline occurring within the first 2 weeks. However, minimal cumulative effects beyond the initial reduction, and rapid reversibility following the discontinuation of crizotinib treatment, were observed.

Crizotinib is an orally available, small-molecule tyrosine kinase inhibitor that selectively targets anaplastic lymphoma kinase (ALK), ROS1, and the hepatocyte growth factor receptor/MNNG HOS transforming gene (c-Met) kinase.The efficacy and safety of crizotinib have been shown in a series of clinical trials, including a phase I dose-escalation and expansion study in patients with various tumor types including ALK-positive advanced NSCLC (PROFILE 1001), a phase II study in patients with ALK-positive advanced NSCLC (PROFILE 1005), and two phase III trials of crizotinib in ALK-positive advanced NSCLC, one in the second-line (PROFILE 1007) and one in the first-line (PROFILE 1014) setting.The results of these trials led to the approval of crizotinib for use as first-line treatment of patients with ALK-positive advanced or metastatic NSCLC.

Adverse events associated with renal impairment or renal failure, consisting of preferred terms from the standard Medical Dictionary for Regulatory Activities queries for CKD, renovascular disorders, and acute renal failure were analyzed. These adverse events were based on Medical Dictionary for Regulatory Activities version 17.0 and were summarized by Common Terminology Criteria for Adverse Events (CTCAE) grade. CTCAE version 3.0 was used in PROFILE 1001 and CTCAE version 4.0 was used in PROFILE 1005, PROFILE 1007, and PROFILE 1014.

eGFR was graded using the standard chronic kidney disease (CKD) criteria (grade 1: ≥90, grade 2: 60 to <90, grade 3a: 45 to <60, grade 3b: 30 to <45, grade 4: 15 to <30, and grade 5: <15 mL/min/1.73 m), with grade 3b or higher indicative of clinically significant renal impairment.Maximum shifts in eGFR grade over the assessment period and by race (Asian versus non-Asian), sex (male versus female), and age group (<65 years versus ≥65 years) were analyzed.

For all patients, eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine-based equation, as follows:Where Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is –0.329 for females and –0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1.

Renal function was assessed based on serum creatinine levels and eGFR values over time in the pooled crizotinib dataset and across the four individual studies. Assessments of serum creatinine and eGFR were made at baseline and changes from baseline were determined at 2 weeks, 6 weeks (in all studies except PROFILE 1001), 8 weeks (in PROFILE 1001 only), 12 weeks, 24 weeks, 52 weeks, 104 weeks on treatment, and 28 days after the last dose of crizotinib.

The analyses included data from each of the four clinical trials, as well as pooled data across all studies, with a data cutoff date of July 15, 2014 (all studies were ongoing at the time of data cutoff). The detailed methodologies for these trials have been previously described.All patients provided written informed consent. The protocols were approved by the institutional review board or independent ethics committee at each participating site, and complied with the International Ethical Guidelines for Biomedical Research Involving Human Subjects, Good Clinical Practice guidelines, the Declaration of Helsinki, and local laws.

This retrospective analysis examined safety data from patients with ALK-positive NSCLC who received crizotinib at a starting dose of 250 mg twice daily in the following four clinical trials: (1) PROFILE 1001 ( NCT00585195 ) including 154 patients with ALK-positive NSCLC from a phase I study of crizotinib in patients with advanced cancer; (2) PROFILE 1005 ( NCT00932451 ) including 1065 patients from phase II study investigating the safety and efficacy of crizotinib in previously treated ALK-positive advanced NSCLC; (3) PROFILE 1007 ( NCT00932893 ) including 343 patients with ALK-positive advanced NSCLC who had received one prior platinum-based regimen from a phase III study comparing the efficacy and safety of crizotinib (n = 172) versus standard chemotherapy (pemetrexed [n = 99] or docetaxel [n = 72]); and (4) PROFILE 1014 ( NCT01154140 ) including 340 previously untreated patients with ALK-positive advanced NSCLC from a phase III study comparing the efficacy and safety of crizotinib (n = 171) versus platinum-based chemotherapy (pemetrexed/cisplatin [n = 91] or pemetrexed/carboplatin [n = 78]). In addition, 124 patients who crossed over from chemotherapy to receive crizotinib treatment were included in the pooled crizotinib dataset.

Permanent crizotinib treatment discontinuations associated with renal-related adverse events were reported in five patients (0.3%). Renal failure was reported in two (0.1%) patients; increased blood creatinine, encephalopathy, acute renal failure, and renal impairment were reported in one (<0.1%) patient each. One patient had both renal failure acute and increased blood creatinine.

The frequency of adverse events was higher in patients with worst onstudy eGFR grade 3b or higher (55.1%) than in patients with worst onstudy eGFR grade 3a or lower (21.7%).

Overall, 446 of 1686 patients (26.5%) had at least one all-causality adverse event associated with renal impairment or renal failure ( Supplementary Table S3 ). The majority of these adverse events were grades 1 or 2 in severity (19.8%). Grade 3 or 4 adverse events were reported in 6.6% of patients. A grade 5 adverse event, renal failure, was reported in one patient (0.1%) but was not related to crizotinib treatment. The most common (≥1.0%) all-causality adverse events were hypoalbuminemia (8.2%), increased blood creatinine (8.0%), hypocalcemia (7.5%), hyponatremia (4.9%), hyperkalemia (2.4%), and decreased blood calcium (1.3%). Increased blood creatinine, which occurred in 8.0% of patients, was predominantly a grade 1 event (106 of 135 events [78.5%]).

The shifts in eGFR grade from baseline to worst onstudy eGFR (≤3a versus ≥3b) analyzed by race, sex, and age group are presented in Figure 5 . A shift to eGFR grade 3b or greater occurred in a higher percentage of patients aged 65 years or older (37.2%) compared with patients aged younger than 65 years (8.5%) ( Fig. 5 A). A slightly higher percentage of non-Asian (14.3%) compared with Asian patients (11.1%) had a shift in eGFR grade from 3a or lower to 3b or higher ( Fig. 5 B). A higher percentage of female patients reported a shift from eGFR grade 3a or lower to 3b or higher than male patients (15.3% versus 9.7%, respectively) ( Fig. 5 C).

Shift to maximum estimated glomerular filtration rate grade postbaseline in patients with baseline grade 3a using the Chronic Kidney Disease Epidemiology Collaboration estimation equation data including pooled data across PROFILE 1001, PROFILE 1005, PROFILE 1007, and PROFILE 1014. (A) By age group (<65 years, ≥65years). (B) By race group (Asian, non-Asian). (C) By sex (male, female).

Figure 5 Shift to maximum estimated glomerular filtration rate grade postbaseline in patients with baseline grade 3a using the Chronic Kidney Disease Epidemiology Collaboration estimation equation data including pooled data across PROFILE 1001, PROFILE 1005, PROFILE 1007, and PROFILE 1014. (A) By age group (<65 years, ≥65years). (B) By race group (Asian, non-Asian). (C) By sex (male, female).

Overall, 375 (22.2%) of 1686 patients remained stable or improved in maximum (worst) eGFR grade throughout the observation period ( Table 1 ). The shift in eGFR grade from baseline over time is shown in Supplementary Table S2 . Across the ontreatment timepoints (week 2 through week 104), 46.5% to 58.8% of patients assessed had no increase in eGFR grade; 0.7% to 3.5% had a lower eGFR grade compared with baseline. Increases by 1, 2, and 3 or more eGFR grades were seen in 39.7% to 49.3%, 0.7% to 4.8%, and 0.1% to 0.7% of patients while on treatment, respectively. At 28 days after the last dose of crizotinib, 66.7% of patients assessed had no increase in eGFR grade compared with baseline.

In the pooled analysis, 1647 of 1686 patients (97.7%) had a baseline eGFR grade 3a or less (≥45 mL/min/1.73 m). Two hundred twelve of 1686 patients (12.6%) had a shift to worst on-study eGFR grade 3b or greater (<45 mL/min/1.73 m) post-baseline. Of these patients, 169 (10.0%) had a shift to eGFR grade 3b (30 to <45 mL/min/1.73 m), 37 (2.2%) had a shift to eGFR grade 4 (15 to <30 mL/min/1.73 m), and 6 (0.4%) had a shift to eGFR grade 5 (<15 mL/min/1.73 m) ( Table 1 ). Post-baseline eGFR grade 3b or greater generally presented within 2 months of treatment initiation (median time to onset, 57.5 days [range, 7 to 1630 days]) and the median duration of treatment following onset was 344 days.

One patient with baseline eGFR grade 1 met criterion for eGFR grade 5 because an incorrect creatinine value was reported at the time of database snapshot; revised eGFR grade would be 2.

a One patient with baseline eGFR grade 1 met criterion for eGFR grade 5 because an incorrect creatinine value was reported at the time of database snapshot; revised eGFR grade would be 2.

Median eGFR decreased from 96.42 mL/min/1.73 mat baseline (n = 1681) to 80.23 mL/min/1.73 mat week 2 (n = 1499) and 78.06 mL/min/1.73 mat week 12 (n = 1338); median percentage decrease from baseline was 14.9% and 17.0%, respectively. Median eGFR remained relatively stable from week 12 until week 104 (75.45 mL/min/1.73 m; n = 315) with a median percentage decrease from baseline of 16.8%. At 28 days after the last dose of crizotinib, an increase in median eGFR to 83.02 mL/min/1.73 m(n = 123) was observed and the median percentage decrease from baseline was 10.4% ( Fig. 3 and Supplementary Table S1 ). This increase in eGFR post-treatment, returning towards baseline value, was observed across the four individual trials ( Fig. 4 ).

Median estimated glomerular filtratin rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration estimation equation) from baseline over time inlcuding pooled data across PROFILE 1001 a , PROFILE 1005, PROFILE 1007, and PROFILE 1014. n, number of patients assessed at each time point. a Only data from PROFILE 1001 was evaluated at week 8; thus, this data point was excluded from the graph.

Figure 3 Median estimated glomerular filtratin rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration estimation equation) from baseline over time inlcuding pooled data across PROFILE 1001 a , PROFILE 1005, PROFILE 1007, and PROFILE 1014. n, number of patients assessed at each time point. a Only data from PROFILE 1001 was evaluated at week 8; thus, this data point was excluded from the graph.

In the pooled analysis, median serum creatinine increased from 0.79 mg/dL at baseline (n = 1681) to 0.93 mg/dL at week 2 (n = 1499); median percentage increase from baseline was 21.2%. Median serum creatinine increased to 0.96 mg/dL at week 12 (n = 1338) and remained relatively stable through week 104 (1.00 mg/dL; n = 315); median percentage increase from baseline was 23.1% and 21.0%, respectively. At 28 days after the last dose of crizotinib, median serum creatinine decreased to 0.90 mg/dL (n = 123) and median percentage increase from baseline decreased to 13.1% ( Fig. 1 and Supplementary Table S1 ). A decrease in serum creatinine following treatment discontinuation was observed in the four individual trials ( Fig. 2 ).

Median serum creatinine from baseline over time including pooled data across PROFILE 1001 a , PROFILE 1005, PROFILE 1007, and PROFILE 1014. n, number of patients assessed at each timepoint. a Only data from PROFILE 1001 was evaluated at week 8; thus, this data point was excluded from the graph.

Figure 1 Median serum creatinine from baseline over time including pooled data across PROFILE 1001 a , PROFILE 1005, PROFILE 1007, and PROFILE 1014. n, number of patients assessed at each timepoint. a Only data from PROFILE 1001 was evaluated at week 8; thus, this data point was excluded from the graph.

A total of 1686 patients with ALK-positive NSCLC received crizotinib across the four trials and were included in the pooled safety analysis. Patients’ demographic and disease characteristics at baseline have been summarized previously.

Discussion

In this retrospective analysis of pooled data from 1686 patients with ALK-positive NSCLC across four clinical trials, crizotinib was associated with a decline in renal function based on creatinine levels and creatinine-based eGFR over the first 2 weeks of treatment. Median serum creatinine increased from 0.79 mg/dL at baseline to 0.93 mg/dL after 2 weeks on treatment (median percentage increase, 21.2%) and median eGFR, as estimated by CKD-EPI, decreased from 96.42 mL/min/1.73 m2 at baseline to 80.23 mL/min/1.73 m2 and 78.06 mL/min/1.73 m2 after 2 and 12 weeks, respectively (median percentage decrease, 14.9% and 17.0%, respectively). Both parameters remained relatively constant throughout the remainder of the treatment period suggesting that there was little cumulative toxicity with prolonged crizotinib use. This analysis was conducted on laboratory test values for all patients, with no preselection by the investigator for whether these laboratory test changes were perceived as treatment-related.

9 Brosnan E.M.

Weickhardt A.J.

Lu X.

et al. Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive non–small cell lung cancer treated with the ALK inhibitor crizotinib. Overall and across individual studies, post-therapy assessments taken at 28 days after the last dose of crizotinib indicated that this increase in serum creatinine levels and associated decrease in creatinine-based eGFR were trending toward reversibility. Findings from this large population of patients with ALK-positive NSCLC reflected those previously reported by Brosnan et al.

9 Brosnan E.M.

Weickhardt A.J.

Lu X.

et al. Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive non–small cell lung cancer treated with the ALK inhibitor crizotinib. 11 Camidge D.R.

Brosnan E.M.

DeSilva C.

et al. Crizotinib effects on creatinine and non-creatinine–based measures of glomerular filtration rate. Given the rapid onset, peak effect of about a 20% decrease in eGFR, lack of cumulative effects, and rapid reversibility, the Brosnan et al.study raised the hypothesis that a significant proportion of these changes in eGFR could be related to an effect of crizotinib on creatinine-secretion, which suggested potential alterations to the validity of creatinine-based estimates of GFR, rather than a direct nephrotoxic effect. Subsequently, creatinine-based and non–creatinine-based GFR estimates were explored before, during, and after crizotinib in two cases, with minimal change observed in non–creatinine-based estimates of GFR acutely, supporting the creatinine–secretion effect hypothesis.However, chronic increases in creatinine levels, including an element of true nephrotoxicity, cannot be ruled out.

The current analysis and the preceding single-center studies suggest that if changes in dosing of either crizotinib or concomitant medications that are renally excreted are being considered in the context of crizotinib-associated changes in creatinine-based assessments of kidney function, use of a non–creatinine-based assessment of kidney function should be considered before making a final patient management decision.

In the current analysis, a shift in eGFR using creatinine-based measures to grade 3b or higher post-baseline (defined as clinically significant renal impairment) occurred in 12.6% of patients. In general, however, patients continued to receive crizotinib following the onset of this level of apparent renal impairment (median crizotinib duration of 344 days after shift to grade ≥3b)

2 compared with 100.05 mL/min/1.73 m2, respectively, which may have accounted for this difference. There were also slight differences in the percentages of patients who had a shift in eGFR grade from 3a or lower to 3b or higher with respect to sex (higher proportion of females versus males) and race (higher proportion of non-Asians versus Asians). In PROFILE 1007, patients were required to have received only one platinum-based chemotherapy regimen before enrollment, whereas in PROFILE 1014, patients were required to be systemic treatment–naïve for advanced disease. Therefore, assessing the changes in creatinine and eGFR from these study populations could provide a surrogate for comparing changes of eGFR according to prior platinum exposure. The associated figures (serum creatinine: A greater percentage of patients aged 65 years or older had a shift from eGFR grade 3a or lower to grade 3b or higher compared with patients aged younger than 65 years. Both age groups followed a similar trend to the pooled analysis with median eGFR decreasing on crizotinib treatment and increasing towards baseline values following treatment cessation. However, patients aged 65 years or older had a lower median eGFR at baseline (which met the eGFR grade 2 criterion) than patients aged younger than 65 years at 78.50 mL/min/1.73 mcompared with 100.05 mL/min/1.73 m, respectively, which may have accounted for this difference. There were also slight differences in the percentages of patients who had a shift in eGFR grade from 3a or lower to 3b or higher with respect to sex (higher proportion of females versus males) and race (higher proportion of non-Asians versus Asians). In PROFILE 1007, patients were required to have received only one platinum-based chemotherapy regimen before enrollment, whereas in PROFILE 1014, patients were required to be systemic treatment–naïve for advanced disease. Therefore, assessing the changes in creatinine and eGFR from these study populations could provide a surrogate for comparing changes of eGFR according to prior platinum exposure. The associated figures (serum creatinine: Figs. 2 C [PROFILE 1007] and D [PROFILE 1014]; eGFR: Figs. 4 C [PROFILE 1007] and D [PROFILE 1014]) show similar changes in creatinine and eGFR over time with a trend towards reversibility across both studies, suggesting that there are no differences between platinum-pretreated and platinum-naïve patients. However, there was a small percentage of patients (7.0% of the crizotinib arm) who had received prior systemic platinum-based therapies in PROFILE 1014, predominantly in the adjuvant setting (Pfizer, data on file).

12 Drilon A.

Siena S.

Ou S.I.

et al. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1). , 13 Shaw A.T.

Kim T.M.

Crino L.

et al. Ceritinib versus chemotherapy in patients with ALK-rearranged non–small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. , 14 Tamura T.

Kiura K.

Seto T.

et al. Three-year follow-up of an alectinib phase I/II study in ALK-positive non–small-cell lung cancer: AF-001JP. 14 Tamura T.

Kiura K.

Seto T.

et al. Three-year follow-up of an alectinib phase I/II study in ALK-positive non–small-cell lung cancer: AF-001JP. 15 Shimada M.

Fukuda M.

Kitazaki T.

et al. Adverse renal effects of anaplastic lymphoma kinase inhibitors and the response to alectinib of an ALK+ lung cancer patient with renal dysfunction. Across the four trials, adverse events associated with renal impairment or renal failure were reported in 26.5% of crizotinib-treated patients, with hypoalbuminemia as the most frequently reported (8.2%). These adverse events were mostly grade 2 or lower, with one grade 5 event (renal failure) reported that was considered not related to crizotinib treatment. Overall, rates of permanent crizotinib discontinuation due to adverse events associated with renal impairment or renal failure were low. An increase in blood creatinine, which occurred at a frequency of 8.0%, was among the most frequently reported adverse events, most of which were grade 1 or 2 in severity with no grade 4 or higher events. Increases in blood creatinine have also been reported with second-generation ALK inhibitors including ceritinib and alectinib.In a Japanese phase I/II trial, alectinib was associated with an increase in blood creatinine in 19 of 58 (33%) patients.However, there have been few studies assessing renal effects associated with second-generation ALK inhibitors. Shimada et al.reported a case in which alectinib had an adverse effect on renal function, indicated by an increase in serum creatinine and a decrease in eGFR, within the first 2 weeks of treatment initiation in patients who had pre-existing renal impairment, which was manageable with dosing modifications. Whether the effects associated with these other ALK inhibitors reflect true nephrotoxicity or an effect on creatinine secretion is unknown. Further analyses of these and other new ALK inhibitors may be warranted to determine whether they are associated with renal impairment and whether this is potentially a drug-class effect.

16 Peters S.

Camidge D.R.

Shaw A.T.

et al. Alectinib versus crizotinib in untreated ALK-positive non–small-cell lung cancer. , 17 Soria J.C.

Tan D.S.W.

Chiari R.

et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non–small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. , 18 Shaw A.T.

Ou S.H.

Bang Y.J.

et al. Crizotinib in ROS1-rearranged non–small-cell lung cancer. , 19 Shaw A.T.

Friboulet L.

Leshchiner I.

et al. Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F. , 20 Heist R.S.

Shim H.S.

Gingipally S.

et al. MET exon 14 skipping in non–small cell lung cancer. , 21 Lu X.

Peled N.

Greer J.

et al. MET exon 14 mutation encodes an actionable therapeutic target in lung adenocarcinoma. , 22 Paik P.K.

Drilon A.

Fan P.D.

et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. , 23 Tan X.

Dai L.

Wang Y.

et al. Responses to crizotinib and disease monitoring with circulating tumor cells in lung adenocarcinoma patient with MET exon 14 skipping mutation: a case report. This analysis, while limited by its retrospective design, was conducted in the largest population of ALK tyrosine kinase inhibitor–treated patients evaluated over 2 years for the effect of crizotinib on creatinine-based estimates of renal function. Although next-generation ALK inhibitors have displaced crizotinib as the first-line treatment choice in many countries, crizotinib continues to have therapeutic roles in NSCLC: as the standard of care in ROS1-positive NSCLC, in the setting of novel resistance mechanisms to next-generation ALK inhibitors, and as an exploratory MET inhibitor.

In conclusion, in this retrospective analysis of four clinical trials, crizotinib treatment resulted in a decline in creatinine-based measures of renal function predominantly over the first 2 weeks of treatment in patients with ALK-positive NSCLC. However, there was little cumulative effect with continued treatment and effects were largely reversible following crizotinib discontinuation, consistent with previous reports suggesting this outcome may be predominantly due to an effect on creatinine secretion rather than true nephrotoxicity.