We conducted a retrospective search for patients with mRCC with chronic renal insufficiency not requiring dialysis who had received the mTOR inhibitors everolimus or temsirolimus between January 2008 and December 2014 at Yonsei Cancer Center and Busan Paik Hospital, in South Korea. The Cockcroft-Gault formula was used for calculation of the glomerular filtration rate (GFR). Patients with a GFR of ≥ 15 mL/min/1.73 m² but < 60 mL/min/1.73 m² were considered eligible for analysis. The patients were divided into two groups according to the degree of renal insufficiency, as defined by the National Kidney Foundation [24]: moderate renal impairment (30 mL/min/1.73 m² ≤ GFR < 60 mL/min/1.73 m²) and severe renal impairment (15 mL/min/1.73 m² ≤ GFR < 30 mL/min/1.73 m²). The following clinical data were obtained retrospectively: demographics (age and sex), Eastern Cooperative Oncology Group (ECOG) performance status, stage at diagnosis, prognostic risk group based on the Memorial Sloane Kettering Cancer Center Criteria (MSKCC), results after prior nephrectomy, and serum creatinine concentrations. The following data regarding mTOR inhibitors were obtained: initial dose and schedule of mTOR inhibitors, serum creatinine concentration during and after use of mTOR inhibitors, dose reductions, and adverse events (AEs) and abnormal laboratory findings graded according to the National Cancer Institute Common Terminology Criteria for AEs ver. 3.0. The best response defined according the Response Evaluation Criteria In Solid Tumors (RECIST), progression-free survival (PFS), and overall survival (OS) data were also collected. PFS was defined as time from date of first dose of mTOR inhibitors to the first documentation of disease progression or death from any cause; OS was defined as time from date of first dose of mTOR inhibitors to the final documentation of death from any cause or to last follow-up. The study was approved by the Protocol Review Committee of the Korean Cancer Study Group (KCSG GU) 14-08.

Categorical data are presented as frequency counts and percentages, and continuous variables, as medians and ranges. PFS and OS durations were evaluated using the Kaplan-Meier method. Log-rank tests were used for comparison of PFS and OS data between the two patient groups and by mTOR inhibitor regimen (everolimus or temsirolimus). All analyses were performed using SPSS ver. 22.0 (IBM Co., Armonk, NY).

From both centers, 18 patients were eligible. Patient characteristics are listed in Table 1. The median age at diagnosis was 59 years. Fifteen patients had clear cell histology and three patients had non-clear cell histology. All patients had renal insufficiency at diagnosis of RCC. Eight of these patients had renal insufficiency due to hypertension and diabetes, but others had renal insufficiency due to unknown causes. Sixteen patients had undergone prior nephrectomy. The median GFR was 51.2 mL/min/1.73 m². Sixteen patients were classified as having moderate renal insufficiency and two as having severe renal insufficiency. In the moderate renal insufficiency group, five patients were treated with mTOR inhibitors as a first-line treatment. Two patients in this group were treated with bevacizumab plus temsirolimus due to enrollment in a clinical trial, and two were treated with temsirolimus due to non-clear cell histology. One patient in this group was treated with everolimus due to enrollment in a clinical trial. Eleven patients were treated with mTOR inhibitors as a second-line treatment, including four who were treated with temsirolimus and the others with everolimus. All patients with severe renal impairment had an ECOG performance status of 1 and had undergone prior nephrectomy, although all patients presented with stage IV disease at diagnosis.

All patients with severe renal impairment were treated with everolimus as a second-line treatment. One patient was treated with sunitnib as a first-line treatment, and another with sorafenib. In the severe renal impairment group, the median GFR of patients was 22 mL/min/1.73 m². According to MSKCC risk grouping, one patient with severe renal impairment had a favorable prognosis and one patient had an intermediate prognosis.

The starting oral dose of everolimus was 10 mg daily for 10 patients and the starting intravenous dose for temsirolimus was 25 mg weekly for eight patients in the overall series. All patients were started on the original dose of mTOR inhibitors regardless of GFR. In the moderate renal impairment group, six patients treated with everolimus were dose delayed due to non-renal toxicity, including one patient treated with everolimus as a first-line treatment and the others treated with everolimus as a second-line treatment. Three patients treated with temsirolimus were dose delayed due to non-renal toxicity, including one patient treated with temsirolimus as a first-line treatment and two patients treated with temsirolimus as a second-line treatment.

In the moderate renal insufficiency group, six patients had dose reduction because of non-renal toxicity. Four of them received everolimus as a second-line treatment, and two received temsirolimus as a second-line treatment. The median duration of delay was 2 weeks for everolimus and 2 weeks for temsirolimus. In the moderate renal insufficiency group, one patient had dose delay and dose reduction because of grade 3 creatinine level elevation; this patient was receiving bevacizumab plus temsirolimus as a first-line treatment. None of the patients with severe renal insufficiency experienced delays or required dose reductions. The median relative dose intensity during mTOR inhibitor treatment was 97% for the everolimus group and 98% for the temsirolimus group. The treatment-related AEs are summarized in Table 2. The most common non-hematologic and grade 3/4 AEs included stomatitis, fatigue, flu-like symptoms, and anorexia as well as creatinine level elevation. The changes of median GFR of patients according to the degree of renal insufficiency are summarized in Table 3.

Of the 18 patients, three achieved partial response, the best tumor response observed, of whom two received bevacizumab plus temsirolimus as a first-line treatment and one received temsirolimus as a second-line treatment; 14 patients showed stable disease. Overall response rate (ORR) was 16% and disease-control rate was 94%. The median PFS duration was 8 months (95% confidence interval [CI], 0 to 20.5) and the median OS duration was 25 months (95% CI, 12.9 to 37.1). In patients treated with mTOR inhibitors as a first-line treatment, median PFS duration was 32 months (95% CI, not estimated) and the median OS duration was 32 months (95% CI, 8.7 to 55.2). In patients treated with mTOR inhibitors as a second-line treatment, median PFS duration was 4 months (95% CI, 1.1 to 6.9) and the median OS duration was 18 months (95% CI, 6.9 to 29.1) (Fig. 1). We evaluated PFS and OS rates in patients stratified according to the severity of renal impairment. In the group with moderate/stage 3 renal impairment, the median PFS duration was 5.0 months (95% CI, 0 to 12.8) and the median OS duration was 25 months (95% CI, 13.9 to 36.1).

We also evaluated PFS and OS rates in patients stratified according to the mTOR inhibitor regimens. Patients treated with temsirolimus and those treated with temsirolimus plus bevacizumab were included in the analysis. In patients treated with temsirolimus, the median PFS duration was 13 months (95% CI, 0 to 33.8) and the median OS duration was 18 months (95% CI, 0 to 38.8). In patients treated with everolimus, the median PFS duration was 5 months (95% CI, 0 to 11.2) and the median OS was 24 months (95% CI, 9.2 to 38.8).