Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive non-small cell lung cancer treated with the ALK inhibitor crizotinib

Abstract

Background: To the best of the authors' knowledge, the renal side effects of crizotinib have not been investigated previously.

Methods: The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration creatinine-based prediction equation during the first 12 weeks of crizotinib therapy and after crizotinib but before the introduction of any further systemic therapy.

Results: A total of 38 patients with stage IV anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer who were treated with crizotinib were identified. The mean eGFR decreased by 23.9% compared with baseline (P < .0001; 95% confidence interval, 21.3%-26.6%), with the majority of the decrease occurring within the first 2 weeks of therapy. Clinical history and blood urea nitrogen/creatinine ratios did not suggest prerenal causes. The objective response rate among evaluable patients (n = 27) was 41%. Tumor shrinkage was not correlated with changes in eGFR (correlation coefficient, -0.052; P = .798). Among the 16 patients for whom data after treatment with crizotinib were available, recovery to within 84% of the baseline eGFR occurred in all patients. After adjusting for the number of scans with intravenous contrast and the use of known nephrotoxic drugs, the issue of whether a patient was on or off crizotinib treatment was found to be significantly associated with changes in eGFR (P < .0001).

Conclusions: As assessed by the Chronic Kidney Disease Epidemiology Collaboration prediction equation, eGFR is reduced by treatment with crizotinib, but the majority of patients will recover their eGFR after the cessation of therapy. The early onset, size of the change, minimal cumulative effect, and rapid reversibility raise the possibility that this may be a pharmacological and/or tubular creatinine secretion effect rather than a direct nephrotoxic effect. Increased vigilance with regard to the concomitant use of renally cleared medications or nephrotoxic agents should be considered for patients receiving crizotinib and, when eGFR is reduced, additional renal investigations should be undertaken.

Keywords: anaplastic lymphoma kinase (ALK) gene rearrangements; crizotinib; glomerular filtration rate (GFR); kidney injury; non-small cell lung cancer; renal function.

Figure 1. Breakdown of Cohort of 38 patients

Figure 2

A) Serum creatinine readings (mg/dL) in a single patient with pre-existing renal impairment secondary to cisplatinum exposure showing initial elevations during crizotinib exposure and re-elevation on re-exposure 17 months later. The patient's tumor responded to the crizotinib each time. B) Expansion of area from panel A, showing details of dose modifications tried during initial crizotinib exposure. Each cycle was 21 days in length. The blue and green lines represent the upper and lower limits of the normal range, respectively.

Figure 3. Percentage change in creatinine-derived eGFR from baseline during first 12 weeks of crizotinib therapy (individual patient data; n=38)

Figure 4. Correlation between percentage change in tumor size at first radiographic assessment and change in eGFR at equivalent time point (n=27)

Figure 5. Recovery of eGFR at maximum time post-crizotinib (compared to last day of treatment) and change in eGFR (compared to baseline) at equivalent time-matched point on crizotinib (individual patient data; n=16)

Figure 6. Recovery of eGFR compared to baseline after stopping crizotinib (individual patient data; n=16)