Clinical impact of proteinuria on renal function and treatment outcomes in patients with radioiodine-refractory thyroid cancer treated with lenvatinib

Abstract

Proteinuria has been described as a major on-target adverse event of lenvatinib, although its long-term impact on renal function and clinical outcomes remains unclear. We conducted a retrospective observational study to assess renal function and prognosis in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) receiving lenvatinib. Overall, 70 patients with RR-DTC treated with lenvatinib were enrolled. When proteinuria was observed, the dose and schedule of lenvatinib were adjusted to achieve a urine protein-to-creatinine ratio (UPCR) of less than 3.5 g/gCre according to the study protocols of recent pivotal trials. In total, 50 (71%) and 25 (36%) patients presented with any-grade and grade 3 proteinuria, respectively. Multivariate analysis revealed that age [>65; odds ratio (OR) 8.24, 95% confidence interval (CI) 1.74–39.00, p < 0.01], history of diabetes mellitus (OR 7.79, 95% CI 1.31–46.20, p = 0.02), and hypertension (OR 4.07, 95% CI 1.22–13.60, p = 0.02) were significantly associated with the development of grade 3 proteinuria. Overall, the median estimating glomerular filtration rate (eGFR) gradually decreased every 3 months during treatment. However, no significant deterioration in eGFR was observed in patients with grade 3 proteinuria compared with patients with grades 0–2 proteinuria until 48 months. Patients who developed proteinuria had better survival outcomes than those without proteinuria. In conclusion, the proteinuria grade was not significantly associated with decreased eGFR under UPCR monitoring in our study. Therefore, lenvatinib can carefully be continued targeting UPCR of less than 3.5 g/gCre.

LENVATINIB is an orally administered, multitargeted tyrosine kinase inhibitor that acts against a variety of receptors, including vascular endothelial growth factor (VEGF) receptors 1–3, fibroblast growth factor receptors 1–4, the RET proto-oncogene, stem cell factor receptor, and platelet-derived growth factor receptor alpha [1-3]. The SELECT trial was a large, double-blind, randomized phase 3 trial that compared lenvatinib with placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). In that trial, median progression-free survival (PFS) was 18.3 months with lenvatinib, versus 3.6 months with placebo [hazard ratio (HR) 0.21, p < 0.001] [4]. In Japan, lenvatinib was first approved for the treatment of RR-DTC in 2015. Subsequently, lenvatinib has displayed substantial clinical benefit in several malignancies, including hepatocellular carcinoma, renal cell carcinoma, and endometrial carcinoma, and it has been approved for use worldwide [5-7].

Given its mechanism of action, lenvatinib is associated with a wide range of treatment-related adverse events (AEs). Proteinuria is one of the common AEs attributable to VEGF inhibitors, including lenvatinib. Podocytes generate VEGF, which plays a critical role in maintaining the integrity of the glomerular slit diaphragm. Inhibition of VEGF can lead to the downregulation of nephrin, which constitutes the primary structural component of the slit diaphragm, resulting in podocyte injury and the development of proteinuria [8]. In the SELECT trial, the rates of all-grade and grade ≥3 proteinuria were 31% and 10%, respectively. It is noteworthy that in the SELECT trial, the incidence of proteinuria was particularly high among the Japanese subgroup (any grade: 63%; grade ≥3: 20%) [9]. A large-scale prospective cohort study found that proteinuria is an independent risk factor for end-stage renal disease [10]. In patients with type 2 diabetes mellitus, proteinuria was identified as a significant risk factor for declining serum creatinine levels [11]. Furthermore, proteinuria was associated with an increased risk of cardiovascular disease mortality after adjustment for potential confounding factors, including renal function [12]. Because the development of such complications, including renal dysfunction and cardiovascular diseases, can cause the discontinuation of systemic anticancer therapy, managing proteinuria is essential to continue cancer treatment.

The management of proteinuria is usually determined by the Common Terminology Criteria for Adverse Events (CTCAE) grade. In the SELECT trial, if the proteinuria grade was 1 or 2, lenvatinib was continued. However, if the proteinuria grade was 3 or higher [as defined as urinary protein ≥3.5 g/day or urine protein-to-creatinine ratio (UPCR) ≥3.5 g/gCre], it was recommended to interrupt treatment. Once proteinuria has improved or resolved to grade 1 or lower, lenvatinib was resumed with a modified dose [4]. Several instances of irreversible nephrotic syndrome associated with sunitinib, another anti-VEGF multikinase inhibitor, have been reported, highlighting the need for proteinuria monitoring during anti-VEGF therapy [13]. A recent study also reported gradual decreases in the estimated glomerular filtration rate (eGFR) during long-term lenvatinib treatment [14]. In the present study, we examined the long-term impact of proteinuria on renal function and clinical outcomes during lenvatinib therapy in patients with RR-DTC.

Materials and Methods

Patients

We retrospectively reviewed the medical records of patients with recurrent or metastatic RR-DTC who were administrated lenvatinib between January 2012 and April 2022 at the Department of Medical Oncology of Cancer Institute Hospital of the Japanese Foundation for Cancer Research.

Treatment procedure

The treatment regimen entailed administering a 24-mg oral dose of lenvatinib on a daily basis. Dose adjustments and interruptions were made at the discretion of the treating physician in accordance with the institution’s standard protocols. Patients who were enrolled in the clinical trials were treated according to the study protocol. To monitor proteinuria in daily practice, the following approach was employed in accordance with expert consensus and recent trial protocols of lenvatinib-containing therapy: 1) urine dipstick testing was conducted during routine patient visits; 2) if proteinuria was identified by a dipstick test result of ≥2+; UPCR was subsequently evaluated; 3) if UPCR <3.5 g/gCre (CTCAE grade 2), then lenvatinib was continued at the same dose; 4) if UPCR ≥3.5 g/gCre (CTCAE grade ≥3), then lenvatinib was temporarily discontinued; and 5) once proteinuria improved (UPCR <3.5 g/gCre), lenvatinib was resumed at a reduced dose or with scheduled interruptions (e.g., 2 weeks on/1 week off) [6, 7]. Treatment was continued until disease progression, the emergence of unacceptable toxicity despite appropriate dose reduction and/or interruption, or the patient’s withdrawal from treatment.

Definition and evaluation of the outcomes

The efficacy of treatment was evaluated utilizing computed tomography in adherence to the Response Evaluation Criteria in Solid Tumors version 1.1 [15]. The overall response rate (ORR) was calculated as the proportion of patients with a complete response (CR) or partial response (PR) as their optimal overall response. The disease control rate (DCR) was determined as the percentage of patients who exhibited a best overall response of CR, PR, or stable disease (SD). Progression-free survival (PFS) was defined as the interval between the first day of treatment and the occurrence of either objective evidence of disease progression or death caused by any reason. Overall survival (OS) was defined as the interval from the first day of treatment to death caused by any reason. AEs were evaluated utilizing CTCAE version 4.0. Renal function was evaluated by eGFR (mL/min/1.73 m²) in accordance with a previous report that utilized the Japanese eGFR estimation formula [16]. The chronological change of eGFR was assessed at 3-month intervals (with a permissible deviation of ±1 month) following the initiation of lenvatinib. Pre-treatment hypertension was defined as arterial pressure measurements greater than 140/90 mmHg or the utilization of antihypertensive medication. Pre-treatment diabetes mellitus was defined as glycated hemoglobin levels ≥6.5% or the utilization of antidiabetic medication.

Statistical analysis

EZR software (version 4.0.2, Saitama Medical Center, Jichi Medical University, Saitama, Japan) was employed for statistical analysis [17]. PFS and OS were estimated via the Kaplan-Meier method and were compared using the log-rank test. The survival outcomes were denoted as the median and 95% confidence interval (CI). Wilcoxon’s signed-rank test was applied to analyze continuous data, whereas Fisher’s exact test was utilized to compare categorical variables. The Mann-Whitney U-test was utilized to compare the differences in medians between the groups. Logistic analysis was applied to analyze the significance of baseline characteristics on the risk of proteinuria. In the logistic analysis, factors with a p-value less than 0.05 in univariate analysis were incorporated into multivariate analysis (backward stepwise methods). Statistical tests were two-sided, and the 5% level was regarded as significant.

Ethical approval

This investigation was granted ethical clearance by the institutional review board of Cancer Institute Hospital of the Japanese Foundation for Cancer Research (2022-GB-151), and it adhered to the guidelines outlined in the Declaration of Helsinki of 1964 and its subsequent revisions. Because of the retrospective nature of the study, which utilized pre-existing clinical data and did not involve any interventions, an opt-out strategy for patient enrollment was employed in accordance with Japanese government policy [18].

Results

Patients’ characteristics

Between January 2012 and April 2022, 70 patients with RR-DTC were treated with lenvatinib. Baseline patient characteristics are described in Table 1.

Table 1

Patients’ characteristics

Characteristics	N = 70
Age (years), median (range)	69 (22–83)
Sex, n (%)
Male	24 (34.3%)
Female	46 (65.7%)
Histological subtype, n (%)
Papillary thyroid cancer	61 (87.1%)
Follicular thyroid cancer	8 (11.4%)
Poorly differentiated thyroid cancer	1 (1.4%)
ECOG PS, n (%)
0	30 (42.9%)
1	40 (57.1%)
Body weight (kg), median (range)	54.2 (37.0–108.5)
eGFR (mL/min/1.73m2), mean (SD)	78.9 (19.2)
Metastatic sites, n (%)
Lung	62 (88.6%)
Lymph node	35 (50.0%)
Bone	14 (20.0%)
Prior surgery, n (%)	70 (100.0%)
Mean cumulative dose of iodine-131 therapy, mCi (SD)	160.3 (119.5)
Prior multi-kinase inhibitor, n (%)
Sorafenib	7 (10.0%)
Vandetanib	1 (1.4%)
History of hypertension, n (%)	30 (42.9%)
Use of renin-angiotensin system inhibitor	17 (24.2%)
Use of calcium channel blocker	22 (31.4%)
History of diabetes mellitus, n (%)	10 (14.3%)
Use of dipeptidyl peptidase 4 inhibitor	6 (8.6%)
Use of metformin	4 (5.7%)
Use of non-steroidal anti-inflammatory drugs, n (%)	4 (5.7%)
Starting dose of lenvatinib, n (%)
24 mg	47 (67.1%)
≤20 mg	23 (32.9%)

Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; SD, standard deviation

Treatment delivery and efficacy

At the data collection cutoff date of September 1, 2022, the median follow-up time for all enrolled patients was 19.0 months (range, 0.6–112.1). The starting dose of lenvatinib was 24 mg in 47 (67.1%) patients, 20 mg in 17 (24.2%) patients, and 14 mg in 6 (8.6%) patients. The reasons for reducing the starting dose were older age in 11 patients, bloody sputum in 5 patients, general condition in 4 patients, risk of fistula in 2 patients, and congenital liver disease in 1 patient. The median duration of lenvatinib treatment was 14.4 months (range, 0.1–112.3). Treatment discontinuation was observed in 30 (44.1%) patients (because of disease progression in 23 patients and AEs in 7 patients). Adverse events leading to treatment discontinuation were anorexia in 2, bleeding in 2, fatigue in 1, proteinuria in 1, and gastrointestinal perforation in 1 patient, respectively. Fourteen (20.0%) patients experienced a grade 1 increase in serum creatinine levels, and 4 (5.7%) experienced a grade 2 increase. One (1%) patient with a history of diabetes mellitus discontinued lenvatinib because of irreversible proteinuria. The ORR and DCR were 67.1% and 94.3%, respectively. Median PFS and OS were 20.3 (95% CI, 12.7–23.5) and 36.6 months (95% CI, 30.7–not reached), respectively.

The incidence and risk factors of proteinuria

Among the 70 patients, 50 (71%) patients exhibited any-grade proteinuria. The number of patients who developed UPCR ≥3.5 g/gCre (grade 3 proteinuria) was 25 (36%). The median time to develop UPCR ≥3.5 g/gCre was 3.5 months (95% CI 1.6–4.9; Fig. 1A).

Fig. 1

The onset of grade 3 proteinuria in the entire cohort (A) and the onset of grade 3 proteinuria in patients with pre-treatment complications of hypertension according to the baseline use of renin-angiotensin inhibitors (B)

Univariate and multivariate analysis revealed that age [odds ratio (OR) 8.24, 95% CI 1.74–39.00, p < 0.01], history of diabetes mellitus (OR 7.79, 95% CI 1.31–46.20, p = 0.02), and hypertension (OR 4.07, 95% CI 1.22–13.60, p = 0.02) were significantly associated with the development of grade 3 proteinuria (Table 2). Among the 30 patients who used antihypertensive drugs at baseline, the onset of grade 3 proteinuria was not different between patients who used renin-angiotensin system (RAS) inhibitors at baseline and those who used other treatments (Fig. 1B).

Table 2

Risk factors for grade 3 proteinuria

Factors	Univariate			Multivariate
	OR	95% CI	p-value	OR	95% CI	p-value
Age
≤65 years	Reference			Reference
>65 years	6.70	1.75–25.70	<0.01	8.24	1.74–39.00	<0.01
Body weight
<60 kg	Reference
≥60 kg	1.64	0.54–4.97	0.38
ECOG PS
0	Reference
≥1	1.14	0.42–3.09	0.07
History of hypertension
No	Reference			Reference
Yes	3.81	1.35–10.70	0.01	4.07	1.22–13.60	0.02
History of diabetes mellitus
No	Reference			Reference
Yes	9.88	1.90–51.40	<0.01	7.79	1.31–46.20	0.02
Pretreatment eGFR
≥60 mL/min/1.73 m2	Reference
<60 mL/min/1.73 m2 (CKD grade 3)	2.00	0.52–7.72	0.32
Pretreatment eGFR
≥90 mL/min/1.73 m2	Reference
<90 mL/min/1.73 m2 (CKD grade 2)	2.37	0.69–8.21	0.17
Starting dose of lenvatinib
24 mg	Reference
≤20 mg	0.83	0.30–2.33	0.72

Abbreviations: OR, odds ratio; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group Performance Status; eGFR, estimating the glomerular filtration rate; CKD, chronic kidney disease

Chronological change of eGFR and UPCR

The chronological change in eGFR every 3 months during lenvatinib treatment is presented in Fig. 2. In this analysis, patients who were enrolled in clinical trials were excluded because the management strategy of proteinuria for these patients was strictly determined by the study protocol (n = 11). There was no significant difference in the incidence of creatinine elevation (any grade, 27% vs. 18%, p = 0.49) and proteinuria (grade ≥3, 27% vs. 37%, p = 0.74) between the patients in the clinical trial and those in the real-world setting. After excluding the 11 patients in clinical trials, 59 patients who were permitted to continue lenvatinib with a target of UPCR <3.5 g/gCre (CTCAE grade 2) were included in this chronological analysis. Fig. 3 presents the chronological changes of eGFR according to the grade of proteinuria. No significant difference was observed between patients with grade 3 proteinuria and those with grade 0–2 proteinuria during lenvatinib treatment (Fig. 3, Supplementary Table 1). The chronological changes of UPCR in individual patients are described in Supplementary Fig. 1. The maximum degree of UPCR among all patients included in this study was 17.1 g/gCre. In that patient, lenvatinib could be continued for up to 3 years with dose reduction and interruption to reduce UPCR.

Fig. 2

Chronological changes of the median estimated glomerular filtration rate in patients who underwent lenvatinib treatment in daily practice

Fig. 3

Chronological changes of the median estimated glomerular filtration rate in patients who underwent lenvatinib treatment in daily practice according to the grade of proteinuria

Prognostic impact of proteinuria

Patients who experienced any-grade proteinuria exhibited improvements in both PFS (HR 0.34, 95% CI 0.17–0.66, p < 0.002) and OS (HR 0.36, 95% CI 0.16–0.83, p < 0.02) compared with patients without proteinuria. Median PFS and OS were 22.5 (95% CI, 17.0–40.6) and 59.6 (95% CI, 35.2–not reached) months, respectively, in patients with proteinuria, whereas median PFS and OS were 10.6 (95% CI, 4.0–19.3) and 27.6 (95% CI, 10.3–not reached) months, respectively, in patients without proteinuria (Fig. 4). In addition, no significant differences in PFS (p = 0.10) and OS (p = 0.64) were observed between patients with grade 1–2 proteinuria and those with grade 3 proteinuria (Supplementary Fig. 2).

Fig. 4

Kaplan-Meier curves for progression-free survival (A) and overall survival (B) according to the presence of proteinuria

Discussion

Our investigation sought to determine the clinical implications of proteinuria on renal function and prognosis in patients undergoing lenvatinib treatment for recurrent or metastatic RR-DTC. Our findings illustrated that the long-term use of lenvatinib can result in a gradual decline in eGFR regardless of the severity of proteinuria. This time-lapse observation, a novel contribution to the field, suggests that even in instances in which patients experience grade 3 proteinuria during lenvatinib treatment, the incidence of severe renal impairment is unlikely with appropriate management of proteinuria aimed at maintaining UPCR <3.5 g/gCre.

The management of proteinuria attributable to VEGF-TKI treatment is frequently challenging. Because a specific treatment for proteinuria has not been established, dose interruption and/or reduction of VEGF-TKIs are among the few measures against proteinuria. In a meta-analysis, RAS inhibitors, including angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors, reduced urinary protein excretion regardless of the underlying kidney disease (diabetic or non-diabetic) [19]. In a case series of patients with renal cell carcinoma who were treated with axitinib, RAS inhibitor use was significantly associated with a reduced incidence of grade ≥2 proteinuria [20]. However, these results were not replicated in our analysis. One possible explanation for this is the difference in the underlying disease. The subjects of the studies included in the previous meta-analysis had chronic kidney disease as opposed to malignancy treated with VEGF-TKIs [19]. The mechanism of proteinuria should differ between patients with chronic kidney disease and VEGF-TKI-treated patients [21]. Overall, RAS inhibitors potentially reduce proteinuria associated with VEGR-TKIs, although the impact can be limited under potent VEGF inhibition with lenvatinib.

Routine monitoring of proteinuria is essential for the use of lenvatinib. UPCR is a convenient surrogate for the quantitative assessment of proteinuria that does not require 24-h urine collection [22]. The optimal cutoff of UPCR in monitoring VEGF-TKI-related proteinuria is controversial. In the study protocol of the SELECT trial, which was the first large-scale phase 3 trial of lenvatinib in patients with RR-DTC, lenvatinib treatment should be interrupted when grade 3 proteinuria (UPCR ≥3.5 g/gCre) appears. When proteinuria recovered to grade 1 or lower (UPCR <1.0), lenvatinib can be resumed at a modified dose [4]. However, in clinical trials after the SELECT trial, lenvatinib can be resumed when proteinuria recovers to grade 2 if tolerable [5, 6]. This modification was possible because proteinuria was one of the primary reasons for treatment discontinuation and long-term dose interruption in the SELECT trial [23]. In the present study, although physicians tried to modify the lenvatinib dosage to manage proteinuria with a UPCR target of less than 3.5 g/gCre, some patients could not easily achieve this target during lenvatinib treatment. It is occasionally required to continue lenvatinib even under certain risks of AEs considering cancer aggressiveness in daily practice. The results of the present study indicate that the risk of eGFR deterioration is not significantly different between patients with and without proteinuria. Severe renal impairment was also rare. Although several patients temporally experienced high-grade UPCR, it was controlled below 3.5 g/gCre with dose reduction/interruption of lenvatinib in most patients. Although patients with high-grade proteinuria can likely experience dose reduction/interruption, the development of grade 3 proteinuria did not significantly deteriorate the prognosis. In addition, patients with all grade proteinuria even showed a better prognosis than those without proteinuria. These results suggest that a strategy of managing proteinuria with a target UPCR of 3.5 g/gCre regardless of the temporal high degree of UPCR during lenvatinib treatment might be carefully permitted if cancer treatment is required in patients with RR-DTC.

In the present study, pre-existing complications of hypertension and diabetes mellitus were found to be independent risk factors for proteinuria. This finding is consistent with previous research, which indicated that pre-existing diabetes mellitus and hypertension were independent risk factors for on-treatment proteinuria in various malignancies [24, 25]. Additionally, diabetes mellitus and hypertension are well-established risk factors for proteinuria in the general population [26, 27]. Hypertension can increase intraglomerular pressure, which is one potential cause of proteinuria [28]. Although microvascular damage resulting from diabetes mellitus is irreversible, hypertension itself can be treated with antihypertensive medications. Therefore, intensive management of hypertension might also facilitate the management of proteinuria.

Most recently, a retrospective study investigating the association between the degree of proteinuria using a dipstick test and renal function was published [29]. The authors concluded that lenvatinib could be continued with attention to renal function regardless of the degree of proteinuria. In both that study and the present study, dose adjustments and interruptions were made at the discretion of the treating physician. Moreover, these results could only reveal the association between the degree of proteinuria and renal function. Therefore, we could not provide the optimal dose reduction or interruption methods for lenvatinib. At our institution, we adopted a management approach that follows the protocol of the recent clinical trials, which had relatively robust evidence [6, 7]. The results of the two retrospective studies also suggest that proteinuria could be ignored with careful monitoring of renal function. The hypothesis should be prospectively investigated; nevertheless, it is ethically difficult to perform a prospective study to evaluate whether proteinuria can be ignored. Therefore, physicians should consider treatment adjustment in each case based on the safety information of pivotal trials at present.

The present study had several limitations. First, this was a retrospective, observational study with a small sample size performed at a single institute. Second, as mentioned in the previous paragraph, the results of our study cannot provide a method for lenvatinib dose adjustment. Third, we cannot provide any specific treatment for proteinuria. Despite these limitations, the results of the present study provided essential insights into the management of proteinuria in daily clinical practice.

In conclusion, despite the gradual decrease in eGFR with lenvatinib, if the UPCR is monitored to within 3.5 g/gCre, lenvatinib can be carefully continued without compromising the therapeutic effect by optimal dose reduction/interruption, even if a temporary high grade of proteinuria develops.

Acknowledgment

We thank Joe Barber Jr., PhD, from Edanz (www.edanz.com/ac) for editing a draft of this manuscript.

Disclosure

NF received personal fees from Eisai outside the submitted work. JT received personal fees from Eisai outside the submitted work. The authors report no other conflicts of interest related to this study.

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