lenvatinib and Proteinuria

Lenvatinib (LEN) is a multi-kinase anti-angiogenic drug recently approved in several cancers. LEN is not easily manageable due to its complex safety profile. Proteinuria and renal failure (RF) were reported among the most frequent LEN-induced adverse events (AEs), often leading to discontinuations or dose modifications. Understanding the pathogenesis of these AEs could ameliorate the management of LEN-induced renal toxicity. Areas covered: We present two cases of LEN-induced renal failure (LIRF) with different pathogenesis. 1) LIRF with severe proteinuria in a man treated for a metastatic papillary thyroid carcinoma. Kidney biopsy showed a glomerular damage secondary to LEN, having excluded other causes of RF. 2) LIRF without proteinuria in a woman with metastatic adenoid cystic carcinoma of minor salivary gland. A tubulointerstitial nephropathy was supposed by clinical evaluation and laboratory tests. Effective management was obtained by oral steroids without interrupting LEN. Expert opinion: The case 1 presented for the first time the histological picture of LIRF with a classical glomerular damage leading to secondary proteinuria and tubular failure. Case 2 showed an alternative LIRF pattern of likely tubulointerstitial injury without proteinuria. These reports reflect two sides of the same coin, both to be considered in case of LIRF.

Topics: Adult; Antineoplastic Agents; Carcinoma, Adenoid Cystic; Carcinoma, Papillary; Female; Humans; Male; Middle Aged; Phenylurea Compounds; Proteinuria; Quinolines; Renal Insufficiency; Salivary Gland Neoplasms; Thyroid Cancer, Papillary; Thyroid Neoplasms

Proteinuria monitoring is required in patients receiving lenvatinib, however, current methodology involves burdensome overnight urine collection.. To determine whether the simpler urine protein:creatinine ratio (UPCR) calculated from spot urine samples could be accurately used for proteinuria monitoring in patients receiving lenvatinib, we evaluated the correlation between UPCR and 24-hour urine protein results from the phase 3 REFLECT study. Paired data (323 tests, 154 patients) were analysed.. Regression analysis showed a statistically significant correlation between UPCR and 24-hour urine protein (R. Incorporation of UPCR into the current algorithm for proteinuria management can enable optimisation of lenvatinib treatment, while minimising patient inconvenience.. NCT01761266.

Topics: Carcinoma, Hepatocellular; Creatinine; Humans; Liver Neoplasms; Phenylurea Compounds; Proteinuria; Quinolines; Sorafenib

In the study of (E7080) lenvatinib in differentiated cancer of the thyroid, most patients experienced an adverse event. In this report, we examine common lenvatinib-emergent adverse events in this phase three, randomized, double-blind study.. Adverse events were graded per Common Terminology Criteria for Adverse Events v4.0. 392 patients were enrolled (lenvatinib: 261, placebo: 131) and received lenvatinib 24 mg/day or placebo. The main outcome measures were: associations with progression-free survival and overall survival in exploratory univariate and multivariate analyses along with additional variables.. The most common any-grade adverse events (any grade; grade 3) in lenvatinib-treated patients included proteinuria (32%; 10%), diarrhea (67%; 9%), fatigue/asthenia/malaise (67%; 10%), rash (23%; 0.4%), and palmar-plantar erythrodysesthesia syndrome (33%; 3%). There were no grade 4 events for these adverse events. They generally occurred early (median time to first onset [weeks]: proteinuria [6.1], diarrhea [12.1], fatigue/asthenia/malaise [3.0], rash [7.3], and palmar-plantar erythrodysesthesia syndrome [5.9]), and were resolved primarily with dose modifications (median time to resolution [weeks]: proteinuria [8.8], diarrhea [18.1], fatigue/asthenia/malaise [16.3], rash [5.9], and palmar-plantar erythrodysesthesia syndrome [20.0]). Discontinuation due to these adverse events occurred in 2 (1%) patients with proteinuria and 4 (2%) with fatigue. Progression-free survival was not associated with any of the adverse events. Eastern Cooperative Oncology Group performance status (P = 0.001), follicular histology (P = 0.002), and diarrhea (P = 0.023) were associated with overall survival in multivariate analyses (median overall survival for patients with diarrhea: not reached; without: 17.1 months).. In the study of (E7080) lenvatinib in differentiated cancer of the thyroid, the most common adverse events typically occurred early and were primarily managed with dose modifications. Overall survival was significantly associated with diarrhea.

Topics: Antineoplastic Agents; Diarrhea; Disease-Free Survival; Double-Blind Method; Exanthema; Fatigue; Female; Humans; Incidence; Male; Phenylurea Compounds; Proteinuria; Quinolines; Thyroid Neoplasms; Treatment Outcome

Hypertension and proteinuria are commonly observed side-effects for anti-angiogenic drugs targeting the VEGF pathway. In most cases, hypertension can be controlled by prescription of anti-hypertensive (AH) therapy, while proteinuria often requires dose reductions or dose delays. We aimed to construct a pharmacokinetic-pharmacodynamic (PK-PD) model for hypertension and proteinuria following treatment with the experimental VEGF-inhibitor E7080, which would allow optimization of treatment, by assessing the influence of anti-hypertensive medication and dose reduction or dose delays in treating and avoiding toxicity. Data was collected from a phase I study of E7080 (n = 67), an inhibitor of multiple tyrosine kinases, among which VEGF. Blood pressure and urinalysis data were recorded weekly. Modeling was performed in NONMEM, and direct and indirect response PK-PD models were evaluated. A previously developed PK model was used. An indirect response PK-PD model described the increase in BP best, while the probability of developing proteinuria toxicity in response to exposure to E7080, was best described by a Markov transition model. This model may guide clinical interventions and provide treatment recommendations for E7080, and may serve as a template model for other drugs in this class.

Topics: Angiogenesis Inhibitors; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Hypertension; Models, Biological; Neoplasms; Phenylurea Compounds; Proteinuria; Quinolines; Urinalysis

Hypertension (HTN) is the most frequent adverse event during treatment with lenvatinib (LEN), but data on its best management are limited.. The objective of this study was to assess incidence, features and best management of LEN-related HTN in a consecutive single tertiary-care centre cohort.. Twenty-nine patients were followed up for a mean time of 29.8 months (6-77 months).. After a mean follow-up of 6.8 months, HTN was recorded in 76% of cases, as a de novo occurrence in half of them. HTN significantly correlated with LEN dose and was of grade 1, grade 2 and grade 3 in 5%, 50% and 45% of patients, respectively. The majority (77%) of patients with HTN developed proteinuria. There was no correlation between HTN and proteinuria or clinical features or best morphological response or any other adverse event (AE), with the exception of diarrhoea. Patients with or without pre-existing HTN or any other cardiovascular disease had a similar incidence of HTN during LEN, thus excluding the impact of this potential predisposing factor. After evaluation by a dedicated cardiologist, medical treatment was introduced in 21/22 patients (polytherapy in 20 of them). The most frequently used drugs were calcium channel blockers (CCBs) due to their effect on vasodilation. In case of poor control, CCBs were associated with one or more anti-hypertensive drug.. HTN is a frequent and early AE in patients on LEN treatment. We suggest a diagnostic and therapeutic algorithm to be applied in clinical practice to allow efficient HTN control and improve patient compliance, reducing LEN discontinuation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Follow-Up Studies; Humans; Hypertension; Incidence; Male; Middle Aged; Phenylurea Compounds; Proteinuria; Quinolines; Retrospective Studies; Thyroid Neoplasms

Lenvatinib, a tyrosine kinase inhibitor (TKI), is a stronger inhibitor of vascular endothelial growth factor receptor, fibroblast growth factor receptors 1 to 4, and platelet-derived growth factor receptor (PDGFR) than other TKIs. We herein report a 77-year-old Japanese woman who received the minimum dose of lenvatinib for treatment of hepatocellular carcinoma. Within one month of starting treatment, she developed severe proteinuria, hypertension, and renal dysfunction. A kidney biopsy showed drug-induced thrombotic microangiopathy, podocytopathy, and polar vasculosis. We also observed damage to the renal tubules, where PDGFR is located. To our knowledge, this is the first report of lenvatinib-induced damage to the renal tubules.

Topics: Aged; Antineoplastic Agents; Female; Humans; Kidney Diseases; Liver Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Proteinuria; Quinolines; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Thrombotic Microangiopathies; Vascular Endothelial Growth Factor A

Anti-VEGF drugs, such as tyrosine kinase inhibitors, play an important role in systemic therapy for unresectable hepatocellular carcinoma (uHCC). We examined the effects of sorafenib and lenvatinib on proteinuria and renal function.Patients who were administered sorafenib (n = 85) or lenvatinib (n = 52) as first line treatment for uHCC from July 2009 to October 2020, were enrolled in this retrospective observational study. A propensity score analysis including 13 baseline characteristics was performed. Eighty four patients were selected (sorafenib, n = 42; lenvatinib, n = 42) by propensity score matching (one-to-one nearest neighbor matching within a caliper of 0.2). We analyzed changes in estimated glomerular filtration rate (eGFR) during tyrosine kinase inhibitor treatment, as well as the development of proteinuria in both groups. A multivariate analysis was performed to identify predictors of a deterioration of eGFR.At 4, 8, 12, and 16 weeks, ΔeGFR was significantly lower in the lenvatinib group than in the sorafenib group (P < .05). The lenvatinib group showed a significantly higher frequency of proteinuria than the sorafenib group (30.9% vs 7.1%, P = .005) and had a higher rate of decrease in eGFR than the sorafenib group (P < .05). Multivariate analysis revealed that lenvatinib use was the only predictive factor of eGFR deterioration (odds ratio 2.547 [95% CI 1.028-6.315], P = .043). In cases of proteinuria ≤1+ during lenvatinib treatment, eGFR did not decrease. However, eGFR decreased in the long term (>24 weeks) in patients who have proteinuria ≥2+.Lenvatinib has a greater effect on proteinuria and renal function than sorafenib. In performing multi-molecular targeted agent sequential therapy for uHCC, proteinuria and renal function are important factors associated with drug selection after atezolizumab-bevacizumab combination therapy currently used as the first-line treatment.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Kidney; Liver Neoplasms; Phenylurea Compounds; Proteinuria; Quinolines; Sorafenib

Proteinuria induced by lenvatinib is a class effect that occurs secondary to VEGFR suppression. Withholding of lenvatinib is required in cases with severe proteinuria. Urine protein-creatinine ratio (UPCR, g/gCre) has recently attracted attention as an alternative to 24-h urine collection for assessing proteinuria. The aim of this study was to examine the correlation between the results of proteinuria assessed by the dipstick test and UPCR, and to investigate the influence of proteinuria grading with UPCR on lenvatinib dose adjustment compared to that with only the dipstick test.. Three hundred and ten urine samples from 63 patients with advanced thyroid cancer under treatment with lenvatinib, which were tested by both the dipstick test and UPCR were analyzed. Lenvatinib was withheld when there was evidence of CTCAE grade 3 proteinuria, and restarted when it resolved. The frequency of proteinuria, correlation between the results of the dipstick test and UPCR test, and the effect of dose withholding in cases with results of 3 + in the dipstick test were calculated.. Proteinuria was seen in 56 (88.9%) patients. Of the 154 dipstick 3 + samples, only 56 (36.4%) were judged as more than 3.5 g/gCre by UPCR (grade 3 proteinuria), although none of the 1 + and only 3.7% of 2 + samples were judged as grade 3 proteinuria. We were able to prevent unnecessary lenvatinib interruption due to proteinuria in 63.6% of dipstick 3 + samples by assessment of UPCR.. Urinalysis by combination of the dipstick test and UPCR assessment might be a better strategy for preventing unnecessary interruption of lenvatinib.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Creatinine; Female; Humans; Kidney Function Tests; Male; Middle Aged; Phenylurea Compounds; Proteinuria; Quinolines; Thyroid Neoplasms; Urinalysis

Lenvatinib (an inhibitor of vascular endothelial growth factor (GF) receptors 1-3, fibroblast GF receptors 1-4, platelet-derived GF receptor α, rearranged during transfection, and stem cell factor receptor) was non-inferior to sorafenib in a phase 3 (REFLECT) trial of advanced hepatocellular carcinoma. This study examined the efficacy and safety of lenvatinib in a real-world setting.. This was a retrospective, multicenter, observational study. Inclusion and exclusion criteria were based on the phase 3 trial, and participants were observed for at least 12 weeks. Therapeutic effect was determined using the modified Response Evaluation Criteria In Solid Tumors (m-RECIST) at the 8th week. Patients received oral lenvatinib 12 mg/day (body weight > 60 kg) or 8 mg/day (body weight < 60 kg). Dose interruptions followed by reductions for lenvatinib-related toxicities were permitted. Grades of adverse events (AEs) complied with the Common Terminology Criteria for Adverse Events version 4.0.. All 16 patients included in this study had prior treatment history, and a median 3.9 years had passed since the first treatment. Fatigue, hypertension, and proteinuria were the most frequent AEs, and were higher than Grade 2. AEs could be controlled by appropriate dose reduction, interruption, and symptomatic treatment according to the protocol. In the m-RECIST evaluation at the 8th week, 0, 6, 8, and 1 patients had achieved complete response, partial response, stable disease, and progressive disease, respectively. The objective response rate was 40%.. Lenvatinib treatment could be accomplished with safety and good response in a real-world setting.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Hepatocellular; Fatigue; Female; Humans; Hypertension; Liver Neoplasms; Male; Middle Aged; Phenylurea Compounds; Proteinuria; Quinolines; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Treatment Outcome

Sorafenib and lenvatinib showed efficacy for patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) in pivotal phase 3 clinical trials. Although the efficacy of lenvatinib in patients who received previous treatment with multi-target kinase inhibitors (m-TKIs), including sorafenib, was reported, the efficacy of sorafenib in patients who previously received lenvatinib remains unknown. A 75-year-old woman diagnosed as RAI-refractory poorly differentiated carcinoma with multiple lung metastases and started treatment with lenvatinib. She continued to receive lenvatinib but with repeated dose interruptions and reductions due to continuous proteinuria. Because of severe and persistent proteinuria as well as newly developed renal impairment, lenvatinib was suspended after two years of treatment. After the 7-month suspension, her proteinuria and renal impairment were partially improved, but her lung metastases progressed. Because she was unable to tolerate previous treatment with lenvatinib, sorafenib was started. At 7 months of treatment with sorafenib, her lung metastases shrank and she could continue sorafenib without exacerbation of proteinuria or renal impairment. This case may suggest that sorafenib does not exacerbate the proteinuria or renal impairment induced by lenvatinib, and may be an effective treatment option for RAI-refractory DTC patients who are unable to tolerate lenvatinib.

Topics: Aged; Antineoplastic Agents; Drug Substitution; Female; Humans; Iodine Radioisotopes; Lung Neoplasms; Phenylurea Compounds; Proteinuria; Quinolines; Radiation Tolerance; Sorafenib; Thyroid Cancer, Papillary; Thyroid Neoplasms; Tomography, X-Ray Computed; Treatment Outcome

To evaluate dosing and intervention strategies for the phase II programme of a VEGF receptor inhibitor using PK-PD modelling and simulation, with the aim of maximizing (i) the number of patients on treatment and (ii) the average dose level during treatment.. A previously developed PK-PD model for lenvatinib (E7080) was updated and parameters were re-estimated (141 patients, once daily and twice daily regimens). Treatment of lenvatinib was simulated for 16 weeks, initiated at 25 mg once daily. Outcome measures included the number of patients on treatment and overall drug exposure. A hypertension intervention design proposed for phase II studies was evaluated, including antihypertensive treatment and dose de-escalation. Additionally, a within-patient dose escalation was investigated, titrating up to 50 mg once daily unless unacceptable toxicity occurred.. Using the proposed antihypertension intervention design, 82% of patients could remain on treatment, and the mean dose administered was 21.5 mg day⁻¹. The adverse event (AE) guided dose titration increased the average dose by 4.6 mg day⁻¹, while only marginally increasing the percentage of patients dropping out due to toxicity (from 18% to 20.8%).. The proposed hypertension intervention design is expected to be effective in maintaining patients on treatment with lenvatinib. The AE-guided dose titration with blood pressure as a biomarker yielded a higher overall dose level, without relevant increases in toxicity. Since increased exposure to lenvatinib seems correlated with increased treatment efficacy, the adaptive treatment design may thus be a valid approach to improve treatment outcome.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antihypertensive Agents; Blood Pressure; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Computer Simulation; Drug Administration Schedule; Female; Humans; Hypertension; Male; Markov Chains; Middle Aged; Models, Biological; Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Proteinuria; Quinolines; Receptors, Vascular Endothelial Growth Factor; Research Design; Treatment Outcome