Effectiveness and safety of sorafenib for renal cell, hepatocellular and thyroid carcinoma: pooled analysis in patients with renal impairment

Purpose Sorafenib is an oral multikinase inhibitor with regulatory approval in advanced renal cell carcinoma (RCC), hepatocellular carcinoma (HCC) and refractory differentiated thyroid carcinoma (DTC). Vascular endothelial growth factor receptor (VEGFR) inhibitors like sorafenib may cause proteinuria. This study aimed to analyze the effectiveness and safety of sorafenib in RCC, HCC and DTC patients with chronic kidney disease (CKD). Methods This retrospective study analyzed integrated data from prospective post-marketing surveillance studies for advanced RCC, HCC and DTC. Background factors considered to affect patients’ prognosis were balanced by propensity score matching using eGFR cut-off values of 60 mL/min/1.73 m 2 . Results In the combined matched population ( N = 2430), sorafenib was equally effective in patients with lower and higher eGFR values. Sorafenib had an overall response rate (ORR: complete + partial responses) of 18.9% and a disease control rate (DCR: complete + partial responses + stable disease) of 67.0%. There were no significant differences between lower and higher eGFR groups for response rates. Renal function was maintained throughout the 12-month study period in the combined population and in each indication. Adverse events (AEs) and serious AEs were reported in 91.6% and 58.2% of propensity score-matched patients, and with no significant differences between lower and higher eGFR groups. Conclusion The effectiveness and safety of sorafenib were similar in patients with eGFR < 60 and ≥ 60 mL/min/1.73 m 2 during the 12-month observation period, and without impairing renal function.


Introduction
Sorafenib is an oral multikinase inhibitor with inhibitory effects on angiogenesis and tumor cell growth [1].Following completion of a large phase 3 trial [2], sorafenib was approved by the U.S. Food and Drug Administration (FDA) in December 2005 for the treatment of patients with advanced renal cell carcinoma (RCC) [3].FDA approval of sorafenib for advanced hepatocellular carcinoma (HCC) in November 2007 [4] followed the completion of multinational phase 3 trials of sorafenib in advanced HCC [5], including patients in the Asia-Pacific region [6].In November 2013, sorafenib was approved by the FDA for advanced and metastatic radioactive iodine-refractory differentiated thyroid carcinoma (DTC) [7,8].
KDIGO (Kidney Disease: Improving Global Outcomes) defines chronic kidney disease (CKD) "as abnormalities of kidney structure or function, present for > 3 months, with implications for health" [14].Both KDIGO and The Japanese Society of Kidney Disease consider that the diagnostic threshold for CKD is an estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73m 2 lasting for more than 3 months [14][15][16].CKD is associated with an increased incidence of myocardial infarction, heart failure, stroke and risk of death [17][18][19][20].Reduced eGFR has a graded association with all-cause mortality, brain vascular events and sharp rises in hospitalization rates [17,18].
Although sorafenib has been reported to be effective and safe for CKD patients in RCC [21], the safety of sorafenib for CKD in HCC [22] and thyroid carcinoma [23] remains unclear.The aim of the study was to investigate the safety and effectiveness of sorafenib in patients with reduced eGFR (< 60 ml/min/1.73m 2 ) in an integrated analysis of three indications-RCC, HCC and DTC-using propensity score matching to adjust baseline factors affecting patient prognosis.

Study design
This retrospective study analyzed integrated data from prospective post-marketing surveillance (PMS) studies conducted after the approval of sorafenib for each indication, at the request of the Pharmaceuticals and Medical Devices Agency (PMDA), the Japanese regulatory authority: Japanese patients with metastatic RCC [24], unresectable HCC [22], or metastatic DTC were included.There were no dose restrictions or dose reduction criteria for sorafenib administration, including patients with severe disease (eGFR < 30 mL/min/1.73m 2 ).Background factors considered to affect patients' prognosis were balanced by propensity score matching using eGFR cut-off values of 60 mL/ min/1.73m 2 (i.e., eGFR < 60 and ≥ 60 mL/min/1.73m 2 ).We set the eGFR cut-off value at 60 mL/min/1.73m 2 because we suspected CKD in patients with eGFR < 60 mL/min/1.73m 2 .Analysis of data using this selected cut-off value did not produce extreme data bias.Propensity score matching was calculated by logistic modelling for each disease population (RCC, HCC and DTC) and then applied to the combined population.
Criteria for propensity score matching for RCC were age, TNM (tumor, node, metastasis) stage, prior surgery, primary disease (unresectable/metastatic), C-reactive protein (CRP) level, and disease subtype (clear cell/non-clear cell carcinoma).Before propensity score matching, numbers of RCC patients in the eGFR < 60 and ≥ 60 mL/min/1.73m 2 groups were 1930 and 933, respectively; following matching, there were 583 patients in each group.
Criteria for propensity score matching for HCC were age, TNM stage, prior surgery, metastatic site (bone, lung), presence/absence of lymphatic metastases; comorbidities (cardiac, hypertension, diabetes); weight by sex; Child-Pugh score; baseline alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hemoglobin concentrations, baseline platelet count; hepatitis B and hepatitis C status; alcohol consumption, liver cirrhosis, blood biomarker risk factors; treated with transcatheter arterial infusion (TAI), percutaneous ethanol injection (PEIT), percutaneous radiofrequency ablation (RFA), transarterial infusion chemotherapy (TAE) or transcatheter arterial chemoembolization (TACE) and/or radiotherapy.The number of HCC patients before propensity score matching in the eGFR < 60 and ≥ 60 mL/min/1.73m 2 groups was 423 and 1023, respectively; after matching, there were 364 patients in each group.
Criteria for propensity score matching for DTC were age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), any prior systemic anti-cancer therapy, any metastatic site, cardiac comorbidity, initial sorafenib dose, median baseline ALT, AST and hemoglobin concentrations, median baseline platelet count; days from diagnosis, and anti-hypertensive dose.Before propensity score matching, there were 129 and 263 patients in the eGFR < 60 and ≥ 60 mL/min/1.73m 2 groups, respectively; after matching, there were 98 patients in each group.
For the combined population (n = 4834), criteria for propensity score matching were age, ECOG performance status, prior systemic anticancer therapy, metastasis at any site, cardiac comorbidity, initial sorafenib dose, median baseline ALT, AST and hemoglobin concentrations, median baseline platelet count, weight by sex, time from diagnosis, and antihypertensive dose.Numbers of patients with eGFR of < 60 and ≥ 60 mL/min/1.73m 2 were 2531 and 2303, respectively; following matching, there were 1215 patients per group.
Disease-specific adverse events (AEs) were excluded from the integrated analysis.Remaining AEs were recorded according to MedDRA System Organ Class (SOC) and preferred term.

Statistical analysis
Continuous variables were summarized using mean, standard deviation (SD), median and interquartile range (IQR), and categorical data by number and percentage.Statistical comparisons of continuous variables were performed using Student's t-test and the Mann-Whitney U-test; and for categorical data, Pearson χ 2 test was used.Kaplan-Meier survival curves for PFS were constructed and hazard ratios (HRs) with 95% confidence interval (CI) calculated.Significance of HRs was determined using log-rank tests.When selecting the background factors used in propensity score matching for all cancer types, consideration was given to the following points: clinically important variables, whilst excluding variables with an extremely skewed distribution and those with a high proportion of missing data (even if clinically important); multicollinearity; correlations between variables.

Results
Patients' baseline demographics in the combined population, before and after propensity score matching, are summarized in Table 1.Before propensity score matching, there were significant differences between eGFR < 60 mL/min/1.73m 2 (n = 2482) and eGFR ≥ 60 mL/min/1.73m 2 (n = 2219) groups for age, ECOG PS, baseline eGFR, TNM stage, prior surgery, prior systemic anticancer therapy, metastases at any site, lung metastases, cardiac and renal comorbidities, baseline AST, ALT, total bilirubin, albumin and creatinine concentrations, number of observation days, baseline platelet count, initial sorafenib dose, initial antihypertensive dose, distribution of indications (all p < 0.0001), and baseline hemoglobin concentration (p = 0.0009).After propensity score matching (n = 1215 in both groups), there were no significant differences between these variables except for renalassociated variables: baseline eGFR, renal comorbidity, and baseline creatinine (all p < 0.0001); and prior surgery (p < 0.0001), baseline albumin (p = 0.0145), and distribution of indications (p = 0.0150).Demographics and clinical characteristics of RCC, HCC and DTC cohorts are summarized in Supplementary Tables S1, S2 and S3, respectively.
Before propensity score matching, patients in the eGFR < 60 mL/min/1.73m 2 group received significantly lower mean daily sorafenib doses (491.8 vs. 529.3mg/d) than patients with eGFR ≥ 60 mL/min/1.73m 2 , had lower relative sorafenib doses (66.5% vs. 69.7%)and prolonged treatment (median 5.22 vs. 3.71 months) (all p < 0.0001).After propensity score matching, duration of treatment was similar in each group whereas there were significant differences for mean daily sorafenib doses (p = 0.0028) and relative sorafenib doses (p = 0.0034).Before propensity score matching, patients with lower eGFR values had significantly higher rates of dose reductions (52.9% vs. 43.5%;p < 0.0001), similar rates of treatment interruption (41.4% vs. 39.2%) and lower rates of treatment discontinuation (74.1% vs. 82.8%;p < 0.0001) compared with patients with higher eGFR.Following propensity score matching, patients in the lower eGFR group had higher rates of dose reductions (50.8% vs. 46.3%;p = 0.0256), and comparable rates of treatment interruption and treatment discontinuation.Before propensity score matching, patients in the lower eGFR group had higher rates of discontinuation due to AEs (55.7% vs. 50.5%;p = 0.0011) and lower rates due to insufficient effectiveness (34.4% vs. 39.7%;p = 0.0007).After propensity score matching, rates for reasons for discontinuation were comparable in each group (Table 2).
In all propensity score-matched patients (N = 1881), sorafenib had a complete response rate of 1.3%, and rates for partial response, stable disease and progressive disease were 17.5%, 48.1% and 22.1%, respectively, producing an overall response rate (ORR: complete + partial responses) of 18.9% and a disease control rate (DCR: complete + partial responses + stable disease) of 67.0%.There were no significant differences between lower and higher eGFR groups for response rates (Table 4).The ORR and DCR in propensity score-matched RCC patients (N = 1079), was 26.4% and 83.6%, respectively; and in propensity score-matched HCC patients (N = 490), was 7.6% and 54.7%, respectively.No comparable data for DTC were collected.

R E T R A C T E D A R T I C L E
In the combined propensity score-matched population (N = 2430), mean ± SD baseline eGFR in the lower and higher eGFR groups was 45.6 ± 12.0 and 77.5 ± 17.2 mL/ min/1.73m 2 , respectively.The degree of change in eGFR from baseline was relatively constant throughout the 12-month observation period (Fig. 2).

Discussion
Since the multi-kinase inhibitor sorafenib inhibits VEGF, it may worsen renal function in CKD patients as has been described for VEGF inhibitors such as bevacizumab [25,26].This is a particular concern for Japanese patients as biopsy results from living kidney donors indicate that Japanese donors have around 25% fewer total nephrons than American donors [27].Although there are reports investigating the effects of molecular-targeted agents, including sorafenib, on changes in renal function [28], there are no large-scale studies covering multiple indications.This study examined the effectiveness and safety in CKD patients by integrating PMS data for sorafenib in RCC, HCC and DTC which were analyzed using propensity score matching.In contrast to a previous real-world study which showed that sorafenib had similar safety and efficacy in advanced RCC stratified using an eGFR cut-off of 45 mL/min/1.73m 2 [21], we used an  Generally, propensity score matching removed imbalances in baseline parameters between lower eGFR (< 60 mL/ min/1.73m 2 ) and higher eGFR (≥ 60 mL/min/1.73m 2 ) groups.Renal-associated variables (baseline eGFR, renal comorbidity, and baseline creatinine) remained very highly statistically significant between groups (p < 0.0001), as did prior surgery which was mainly attributable to nephrectomy in RCC patients.In propensity-matched RCC patients, nephrectomy was performed in 538 of 583 (92.3%) cases with lower eGFR values and 528 of 583 (90.6%) with higher eGFR values.Differences in baseline albumin (p = 0.0145) and distribution of indications (p = 0.0150) after propensity score matching were also recorded, but with much lower levels of statistical significance.
The number of patients with CKD both in Japan and globally, is increasing within an aging population due to lifestylerelated diseases such as diabetes and hypertension [15,29].The results of this study showed that in the combined population, sorafenib was equally effective in patients with lower and higher eGFR values, with no significant differences in PFS found between the two groups.In RCC, the 1-year PFS for each group was 34.5% (95% CI 30.2-38.9) and 29.5% (95% CI 25.4-33.7),respectively, and there was no statistically significant difference between the survival curves of the two groups according to the log-rank test (p = 0.2198).The HR of the eGFR > 60 mL/min/1.73m 2 group compared to the eGFR < 60 mL/min/1.73m 2 group was 1.096 (95% CI 0.946-1.270),which was also not statistically significant.Renal function was maintained throughout the 12 month study period in both lower and higher eGFR groups in the combined population and also in each indication.As mean eGFR was lower in RCC than in HCC and DTC patients, the rate of change of eGFR from baseline was used for assessing the effect of sorafenib on renal function.No new safety concerns were identified.
Current European (ESMO) and NCCN guidelines for first-line advanced clear cell RCC recommend combination axitinib plus pembrolizumab in all prognostic groups and ipilimumab plus nivolumab in patients with poor/intermediate prognosis [30,31].In addition, ESMO guidelines also recommend first-line cabozantinib plus nivolumab in all risk groups [30] and additional first-line options recommended by NCCN guidelines are singleagent pazopanib and sunitinib in patients with a favorable prognosis and cabozantinib monotherapy in the poor/ intermediate-risk group [31].Although sorafenib has been shown to be effective and safe in PMS [22], it is primarily used in patients who have difficulty using sunitinib or pazopanib as first-line treatment.A retrospective analysis of the effectiveness and safety of sorafenib in RCC, compared patients with eGFR of < 45 and ≥ 45 mL/min/1.73m 2 , and used propensity score matching to match patients' background (n = 613 per group) [21].PFS, tumor response rates, mean daily dose, median treatment duration, the incidence of SAEs, and dose modification rates were similar between groups [21].These robust data support the use of sorafenib in RCC patients with impaired renal function.
Sunitinib and pazopanib, like sorafenib, inhibit VEGF and may affect renal function.A retrospective, registrybased study compared the effectiveness and safety of sunitinib in RCC patients with severe (< 30 mL/min/1.73m 2 ), moderate (30-60 mL/min/1.73m 2 ) and mild renal insufficiency or normal renal function (> 60 mL/min/1.73m 2 ), although the study was limited by a low number of cases (n = 22) with severe renal insufficiency compared with moderate (n = 234), and mild renal insufficiency/normal renal function (n = 534).No significant differences in PFS, OS or disease control rates were found, but patients with renal insufficiency were more likely to discontinue treatment due to AEs and had a significantly shorter duration of therapy [32].A retrospective study of pazopanib in RCC patients (n = 229) found no significant difference in PFS, OS and incidence of AEs between patients with GFR ≤ 60 mL/min/1.73m 2 or > 60 mL/min/1.73m 2 , but dose reductions were significantly more frequent in the lower GFR group [33].
In advanced unresectable HCC, sorafenib [5] and, more recently, lenvatinib [13], were approved for first-line treatment.A recent phase 3 trial showed that atezolizumab and bevacizumab combination therapy significantly prolonged OS and PFS compared with sorafenib [34].This combination therapy was approved for first-line therapy.Other systemic treatment options are ramucirumab [35] and regorafenib which showed survival benefit in HCC patients progressing on sorafenib treatment [36].The present study demonstrated the safety and effectiveness of sorafenib in HCC patients with CKD.
Sorafenib [7] and lenvatinib [12] are approved for firstline therapy of unresectable DTC.Although there are no studies comparing sorafenib with lenvatinib directly, NCCN guidelines recommend the administration of lenvatinib or sorafenib to patients with progressive or symptomatic DTC refractory to radioactive iodine therapy.Lenvatinib is described as the preferred agent due to its higher efficacy [37], but the decision of whether to use lenvatinib or sorafenib should be individualized for each patient based on the likelihood of response and comorbidities.Both of these multiple kinase inhibitors have different side effect profiles.Treatment-related AEs occurring in 50% or more patients with lenvatinib were hypertension, diarrhea, fatigue or asthenia, and decreased appetite [12], while high-frequency AEs with sorafenib were skin toxicity (HFSR, alopecia, rash or desquamation) and diarrhea [7].The results presented here may help with the selection of treatment options in DTC cases with renal dysfunction.

R E T R A C T E D A R T I C L E
There are three main limitations of this study.First, the study was retrospective and used propensity score matching.Propensity score matching aligns patients' background to reduce bias in observational studies, but confounding factors may still remain after matching.In addition, data from some patients may be excluded during matching which potentially is another source of bias.In this integrated analysis, propensity score matching was applied to three different indications, but matching factors common to each indication was not always possible and this may have introduced a degree of bias into the results.Second, potential bias may have resulted from prescribing physicians being unfamiliar with sorafenib, as data were collected immediately after approval of sorafenib for each indication.This may have led to suboptimal side effect management and treatment.Third, the observation period in this study was up to 1 year after administration for each indication and further studies are needed on the efficacy and eGFR transition for longer sorafenib treatment periods.

Conclusion
Integrated analysis of RCC, HCC and DTC showed that the effectiveness and safety of sorafenib were similar in patients with eGFR < 60 and ≥ 60 mL/min/1.73m 2 , during the 12-month observation period, and without impairing renal function.

Table 2
Distribution of initial and median sorafenib dose, dose modification, and reason for treatment discontinuation

Table 3
Adverse events (AEs) and serious adverse events (SAEs) in propensity score-matched patients

Table 4
Tumor response for sorafenib treatment *2 × 2 Pearson χ 2 tests for each type of response † Pearson χ 2 test for overall independence (excludes non-evaluable data)