Lenvatinib, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent.1, 2, 5, 9, 10
Lenvatinib mesylate is used for the treatment of locally recurrent or metastatic, progressive, radioactive iodine (iodine-131)-refractory differentiated thyroid cancer (DTC) in adults.1, 2, 10 The drug has been designated an orphan drug by the FDA for the treatment of follicular, medullary, anaplastic, and metastatic or locally advanced papillary thyroid cancer.3, 14 Currently available evidence indicates that lenvatinib therapy is associated with significantly prolonged progression-free survival and improved response rates compared with placebo in patients with locally recurrent or metastatic, radioactive iodine-refractory DTC.1, 2
Efficacy and safety of lenvatinib for the treatment of DTC are based principally on the results of a randomized, multicenter, double-blind, placebo-controlled, phase 3 study (SELECT) conducted in patients with locally recurrent or metastatic, radioactive iodine-refractory DTC and radiographic evidence of progressive disease within 12 months prior to randomization.1, 2 Patients in the study were considered refractory to radioactive iodine if at least one of the following occurred: uptake of radioactive iodine did not occur in at least 1 measurable lesion on any iodine-131 scan, progression of at least 1 measurable lesion with iodine uptake within 12 months of radioactive iodine therapy, or cumulative iodine-131 activity exceeding 600 mCi with the last dose administered at least 6 months prior to study entry.1, 2 In this study, 392 patients were randomized in a 2:1 ratio to receive either lenvatinib (24 mg) or placebo orally once daily in 28-day cycles until disease progression or intolerable toxicity occurred.1, 2 The primary efficacy end point of this study was progression-free survival (as evaluated by a blinded independent review committee) according to Response Evaluation Criteria in Solid Tumors (RECIST); secondary endpoints included objective response rate and overall survival.1, 2
The median age of patients enrolled in the SELECT study was 63 years; 24% of the patients had received one prior therapy with a vascular endothelial growth factor (VEGF) or vascular endothelial growth factor receptor (VEGFR) inhibitor.1, 2 Most patients (66%) had papillary thyroid cancer and 34% had follicular thyroid cancer; of the patients with follicular histology, 44 and 11% had Hürthle and clear cell subtypes, respectively.1 Most patients (67%) in the lenvatinib treatment arm did not demonstrate uptake of radioactive iodine on any scan and 59% of the patients in the lenvatinib treatment arm had progressed within 12 months of prior radioactive iodine therapy.1 The median cumulative radioactive iodine activity administered prior to study entry was 350 mCi.1
The median progression-free survival was substantially longer in patients receiving lenvatinib (18.3 months) compared with those receiving placebo (3.6 months) in the SELECT study.1, 2 Improved progression-free survival was observed in the lenvatinib-treated patients regardless of gender, age, ethnicity, previous therapy with a tyrosine kinase inhibitor, geographic region, histologic findings, and baseline thyrotropin concentrations.2 The objective response rate was 65% for patients receiving lenvatinib and 2% for those receiving placebo; partial response was achieved in 63% and complete response was achieved in 2% of the lenvatinib-treated patients.1, 2 Median overall survival had not been reached at the time of the analysis.1, 2 Upon radiographic confirmation of progression, 83% of patients previously randomized to receive placebo crossed over to receive open-label lenvatinib treatment;1, 2 the median progression-free survival among evaluable patients entering the open-label phase was 10.1 months and the objective response rate was 52.3%.2
Lenvatinib mesylate is used in combination with pembrolizumab for the treatment of previously untreated advanced renal cell carcinoma (RCC), or in combination with everolimus for the treatment of advanced RCC following therapy with an anti-angiogenic agent.1
First-line Treatment of Advanced Renal Cell Carcinoma
Efficacy and safety of lenvatinib in combination with pembrolizumab for the first-line treatment of advanced RCC are based primarily on results from the multicenter, open-label, randomized, phase 3 CLEAR trial.1, 18 Patients enrolled in the study were adults with treatment-naive advanced RCC with clear-cell histology and at least one measurable lesion.18 Patients were enrolled regardless of programmed-death ligand-1 (PD-L1) tumor expression; however, patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.1 In this study, 1069 patients were randomized in a 1:1:1 ratio (stratified by geographic region and prognostic risk group) to receive lenvatinib 20 mg orally once daily on days 1-21 and pembrolizumab 200 mg IV on day 1 of each 21-day cycle, lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily of each 21-day cycle, or sunitinib 50 mg orally once daily for 4 consecutive weeks followed by a 2-week period without treatment.1, 18 Treatment was continued until disease progression or unacceptable toxicity occurred; however, clinically stable patients with disease progression receiving lenvatinib in combination with pembrolizumab could continue treatment if they were considered to be deriving clinical benefit.1 The maximum duration of therapy for pembrolizumab was 24 months; however, lenvatinib therapy could continue beyond 24 months.1 The primary endpoint of the CLEAR trial was progression-free survival (as determined by an independent review committee); overall survival and objective response rate were key secondary endpoints.1, 18 All of these endpoints were evaluated by an independent review committee.1, 18
The median age of patients enrolled in the study was 62 years; 75% were male, 74% were white, 21% were Asian, 1% were Black, 82% had a baseline Karnofsky performance status score of 90 to 100.1 Memorial Sloan Kettering Cancer Center (MSKCC) risk categories were favorable, intermediate, and poor risk in 27, 64, and 9% of patients, respectively.1 Common sites of metastases in patients were lung (68%), lymph node (45%), and bone (25%).1 At the protocol-specified interim analysis, median progression-free survival was substantially longer in patients receiving lenvatinib in combination with pembrolizumab (23.9 months) and those receiving lenvatinib in combination with everolimus (14.7 months) compared with those receiving sunitinib alone (9.2 months).1, 18 Results of a subgroup analysis (based on age, sex, geographic region, MSKCC prognostic risk group, International Metastatic Renal Cell Carcinoma Database Consortium [IMDC] risk group, baseline Karnofsky performance status score, number of organs with metastases, and PD-L1 combined positive score) suggested that the effect of pembrolizumab on progression-free survival was evident across all subgroups.18 Median overall survival had not been reached at the time of interim analysis; however, the risk of death was decreased by 34% in patients receiving lenvatinib in combination with pembrolizumab compared with those receiving sunitinib.1, 18 Overall survival was not substantially longer in patients receiving lenvatinib in combination with everolimus compared with those receiving sunitinib.1, 18 Objective response rate was observed in 71, 53.5, or 36.1% of patients receiving lenvatinib in combination with pembrolizumab, lenvatinib in combination with everolimus, or sunitinib alone, respectively.1, 18
A final overall survival analysis was performed after approximately 304 deaths had been observed.1, 23 The median follow-up at the time of final overall survival analysis was 49.8 months in the lenvatinib plus pembrolizumab group and 49.4 months in the sunitinib group.23 Median overall survival was 53.7 months in the lenvatinib plus pembrolizumab group and 54.3 months in the sunitinib group (hazard ratio 0.79).1, 23
Previously Treated Advanced Renal Cell Carcinoma
Efficacy and safety of lenvatinib in combination with everolimus for the treatment of adults with advanced RCC following one prior anti-angiogenic therapy are based primarily on results from a multicenter, open-label, randomized, phase 2 study (Study 205).1, 19 Patients enrolled in the study had clear cell histology and radiographic evidence of progressive advanced or metastatic RCC within 9 months of discontinuing prior therapy.19 Patients also were enrolled if they had measurable disease and previous disease progression with anti-angiogenic therapy.19 In this study, 153 patients were randomized (stratified by hemoglobin level and corrected serum calcium concentration) to receive lenvatinib (18 mg orally once daily) in combination with everolimus (5 mg orally once daily), lenvatinib (24 mg orally once daily) alone, or everolimus (10 mg orally once daily) alone.1, 19 Treatment cycles were repeated every 28 days and continued until disease progression or unacceptable toxicity occurred.19 The primary endpoint was investigator-assessed progression-free survival; overall survival and objective response rate were key secondary efficacy endpoints.1, 19
The median age of patients randomized to receive lenvatinib in combination with everolimus or everolimus alone was 60 years; 72% were male, 96% were white, and 95% had metastatic disease.1 All patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (54%) or 1 (46%).1 MSKCC favorable, intermediate, and poor risk categories were observed in 24, 37, and 39%, respectively, of patients receiving lenvatinib in combination with everolimus, and 24, 38, and 38%, respectively, of patients receiving everolimus alone.1 Median progression-free survival was substantially improved in patients receiving the combination of lenvatinib and everolimus (14.6 months) compared with those receiving everolimus alone (5.5 months).1, 19 At the time of analysis, median overall survival was 25.5 months in patients receiving lenvatinib in combination with everolimus and 15.4 months in those receiving everolimus alone (hazard ratio 0.64).1 An objective response was observed in 37% of patients receiving lenvatinib in combination with everolimus compared with 6% of those receiving everolimus monotherapy; complete response was achieved in one patient receiving lenvatinib in combination with everolimus and none of the patients receiving everolimus monotherapy.1
Prognosis is generally poor in patients with metastatic RCC, including those who have undergone complete tumor resection.17 First-line therapy with vascular endothelial growth factor receptor (VEGFR) inhibitors has been shown to provide benefits in patients with advanced RCC; however, relapsed or refractory RCC eventually develops in most patients.18 Combination regimens (e.g., immune checkpoint inhibitor in combination with a tyrosine kinase inhibitor) have become a standard for the treatment of advanced RCC.17
The American Society of Clinical Oncology (ASCO) recommends that all patients with metastatic RCC who require systemic therapy in the first-line setting undergo risk stratification.50 Patients with intermediate- or poor-risk disease should be offered combination treatment with 2 immune checkpoint inhibitors (i.e., ipilimumab and nivolumab) or an immune checkpoint inhibitor in combination with a VEGFR tyrosine kinase inhibitor (e.g., pembrolizumab plus axitinib, nivolumab plus cabozantinib, avelumab plus axitinib, pembrolizumab plus lenvatinib).50 Treatment selection should be based on adverse events, comorbid conditions, provider experience, and treatment cost.50 Patients with favorable-risk disease who require systemic therapy may be offered an immune checkpoint inhibitor in combination with a VEGFR tyrosine kinase inhibitor.50
Lenvatinib mesylate is used for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC).1, 21 The drug has been designated an orphan drug by the FDA for the treatment of this cancer.3
Efficacy and safety of lenvatinib for the first-line treatment of unresectable HCC are principally based on results from a multicenter, open-label, randomized, non-inferiority, phase 3 study (REFLECT) in patients with previously untreated unresectable HCC who were ineligible for local liver-directed therapy and had at least one measurable target lesion according to modified RECIST for HCC.1, 21 In this study, 954 patients were randomized in a 1:1 ratio (stratified by geographic region, presence of macroscopic portal vein invasion or extrahepatic spread, ECOG performance status, body weight) to receive lenvatinib (12 mg orally once daily in patients weighing 60 kg or more, or 8 mg orally once daily in those weighing less than 60 kg) or sorafenib (400 mg orally twice daily).1, 21 Treatment cycles were repeated every 28 days until disease progression or unacceptable toxicity occurred.1, 21 The primary endpoint was overall survival; secondary endpoints included progression-free survival, time to progression, and objective response rate.1, 21
The median age of patients enrolled in the study was 62 years; 84% of patients were male, 69% were Asian, 29% were white, and 63% had an ECOG performance status score of 0.1 The majority (62%) of patients had at least one site of documented distant metastatic disease; 52, 45, or 16% of patients had lung, lymph node, or bone metastases, respectively.1 Macroscopic portal vein invasion, extra-hepatic spread, or both were present in 70% of patients.1 HCC was categorized as Child-Pugh class A and Barcelona Clinic Liver Cancer (BCLC) stage C in 79% of patients and Child-Pugh class A and BCLC stage B in 21% of patients.1 The majority (75%) of patients had radiographic evidence of cirrhosis at baseline.1 Chronic hepatitis B virus (HBV), chronic hepatitis C virus (HCV) infection, or alcohol consumption was the cause of HCC in 50, 23, or 6% of patients, respectively.1, 21 At a median duration of 27 months, lenvatinib demonstrated non-inferiority to sorafenib for overall survival.21 Median overall survival was 13.6 or 12.3 months for lenvatinib-treated or sorafenib-treated patients, respectively.1, 21 Median progression-free survival (7.3 versus 3.6 months) was prolonged in patients receiving lenvatinib compared with those receiving sorafenib.1 Objective response rate was 19 or 7% in patients receiving lenvatinib or sorafenib, respectively; complete response was achieved in 0.4 or 0.2% of patients receiving these respective treatments.1, 21
For the treatment of early stage HCC, liver transplantation, surgical resection, and ablation offer a potential cure and high rates of complete response; however, survival is usually less than 6 months in patients with untreated advanced stage HCC.20
The ASCO guideline on systemic therapy for advanced HCC states that lenvatinib, sorafenib, or durvalumab may be offered as first-line therapy for patients with advanced HCC, Child-Pugh class A, and an ECOG performance status of 0 or 1 if therapy with atezolizumab plus bevacizumab or durvalumab plus tremelimumab is contraindicated.51 ASCO also states that tyrosine kinase inhibitors (i.e., cabozantinib, lenvatinib, sorafenib) may be used as second-line therapy† following therapy with atezolizumab plus bevacizumab or durvalumab plus tremelimumab.51 The decision to pursue second-line therapy and choice of treatment should be based on patient and clinician preferences and other factors (i.e., comorbidities, liver function, performance status, potential for benefit and risk of harm).51
Guideline recommendations from the American Gastroenterological Association (AGA) and the American Association for the Study of Liver Diseases (AASLD) are generally similar to the ASCO guidelines.52, 53 The AGA guideline suggests either lenvatinib or sorafenib over no systemic therapy for first-line treatment of patients with HCC and preserved liver function who are not eligible for locoregional therapy or resection or who have metastatic disease and are not eligible for treatment with atezolizumab plus bevacizumab.52 The AASLD guideline recommends sorafenib or lenvatinib as first-line therapy for advanced HCC patients with Child-Pugh class A cirrhosis in whom atezolizumab plus bevacizumab and durvalumab plus tremelimumab are contraindicated.53
Lenvatinib mesylate is used in combination with pembrolizumab for the treatment of advanced endometrial carcinoma that is mismatch repair proficient (pMMR), as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), in patients who have disease progression following prior systemic therapy and who are not candidates for curative surgery or radiation.1
Efficacy and safety of lenvatinib in combination with pembrolizumab for the treatment of advanced endometrial carcinoma are based on results from a multicenter, open-label, randomized, phase 3 trial (KEYNOTE-775; Study 309).1, 24, 25 Patients with endometrial sarcoma, including carcinosarcoma, and patients with a history of active autoimmune disease or a medical condition that requires immunosuppression were ineligible for the study.1 In this study, 697 patients with cancer that was pMMR or not MSI-H were randomized (stratified by ECOG performance status, geographic region, and history of pelvic radiation) to receive lenvatinib 20 mg orally once daily continuously in combination with pembrolizumab 200 mg IV every 3 weeks or an investigator's choice chemotherapy (doxorubicin hydrochloride 60 mg/m2 IV every 3 weeks or paclitaxel 80 mg/m2 IV on days 1, 8, and 15 of each 28-day cycle).1
Among the cohort of patients with advanced endometrial carcinoma that was pMMR or not MSI-H, the median age of patients was 65 years; 62% were white, 22% were Asian, 3% were Black, and 60% had an ECOG performance status of 0.1 The histologic subtypes were endometrioid carcinoma (55%), serous (30%), clear-cell carcinoma (7%), mixed (4%), and other (3%).1 All patients received prior systemic therapy for endometrial carcinoma; 67, 30, or 3% of patients previously received 1, 2, or ≥3 systemic therapies, respectively.1 Approximately one-third (37%) of patients received prior neoadjuvant or adjuvant therapy.1 The primary endpoints were progression-free survival and overall survival; objective response rate was a key secondary efficacy endpoint.1 In the cohort of patients with advanced endometrial carcinoma that was pMMR or not MSI-H, median progression-free survival was 6.6 months in patients receiving lenvatinib in combination with pembrolizumab and 3.8 months in those receiving an investigator's choice chemotherapy.1 Median overall survival was prolonged (17.4 versus 12.0 months) and objective response rate was higher (30 versus 15%) in patients receiving lenvatinib in combination with pembrolizumab compared with those receiving an investigator's choice of chemotherapy.1 A final overall survival analysis and updated progression-free survival analysis was performed at a median follow-up of 14.7 months.25 Among patients with cancer that was pMMR, the median overall survival in this analysis was 18 months for the combination of lenvatinib and pembrolizumab and 12.2 months for chemotherapy.25 The median progression-free survival was 6.7 months for the combination of lenvatinib and pembrolizumab and 3.8 months for chemotherapy.25
Endometrial cancer is usually diagnosed at an early stage that can be treated with surgery alone.22 Options for advanced endometrial cancer may include surgery followed by chemotherapy or radiation therapy; chemotherapy and radiation therapy; hormone therapy; biological therapy; or immunotherapy (e.g., pembrolizumab plus lenvatinib).22 A panel of international experts recommends pembrolizumab plus lenvatinib for the second-line treatment of patients with pMMR or microsatellite stable advanced or recurrent endometrial cancer.54
Administer lenvatinib mesylate orally without regard to meals at the same time each day.1 Swallow the capsules whole; do not crush or chew the capsules.1
If lenvatinib capsules cannot be swallowed whole, an oral suspension may be prepared from the capsules using water or apple juice.1 If preparing a suspension for feeding tube administration, use water.1 To prepare a suspension from the capsules, place the required amount of unopened capsules (up to a maximum of 5), into a small container or oral syringe (approximately 20 mL capacity).1 For doses that require 6 capsules, prepare 3 capsules at a time according to instructions.1 Add 3 mL of liquid to the small container or oral syringe without breaking or crushing the capsules.1 Allow the capsules to remain in the liquid for at least 10 minutes to allow the capsule shell to disintegrate, and then stir or shake for at least 3 minutes.1 After the mixture has been consumed, add an additional 2 mL of liquid to the container or syringe, swirl and shake, then administer.1 Repeat this step at least once and until no residue is visible to ensure all of the dose is consumed.1 If the suspension cannot be used immediately, it may be stored under refrigeration (2-8ºC) for 24 hours in a covered container.1 After 24 hours, discard any remaining suspension.1
For feeding tube administration, lenvatinib suspension is compatible with polypropylene syringes, with polyvinyl chloride (PVC) and polyurethane feeding tubes of at least 5 French diameter, and with silicone feeding tubes of at least 6 French diameter.1
If a dose of lenvatinib is missed and cannot be taken within 12 hours, skip the missed dose and take the next dose at the regularly scheduled time.1
Store lenvatinib capsules at controlled room temperature (20-25ºC).1 Excursions are permitted to 15-30ºC.1
Dosage of lenvatinib mesylate is expressed in terms of lenvatinib.1
The recommended adult dosage of lenvatinib for the treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC) is 24 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
First-line Treatment of Advanced Renal Cell Carcinoma
The recommended adult dosage of lenvatinib for the treatment of previously untreated advanced renal cell carcinoma (RCC) is 20 mg once daily in combination with pembrolizumab 200 mg by IV infusion over 30 minutes every 3 weeks.1 Lenvatinib in combination with pembrolizumab should be continued for up to 2 years or until disease progression or unacceptable toxicity occurs.1 Following completion of 2 years of combination therapy with pembrolizumab, lenvatinib monotherapy may be continued until disease progression or unacceptable toxicity occurs.1
The prescribing information for pembrolizumab should be consulted for detailed information on dosage modifications for this drug.1 If adverse effects occur, modify the dosage of lenvatinib and/or pembrolizumab as appropriate.1
Previously Treated Advanced Renal Cell Carcinoma
The recommended adult dosage of lenvatinib for the treatment of advanced RCC following therapy with an anti-angiogenic agent is 18 mg once daily in combination with everolimus 5 mg orally once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
The prescribing information for everolimus should be consulted for detailed information on dosage modifications for this drug.1 If adverse effects associated with both lenvatinib and everolimus occur during combination therapy, withhold lenvatinib therapy or reduce the dosage of lenvatinib first, and then reduce the dosage of everolimus.1
The recommended adult dosage of lenvatinib for the first-line treatment of unresectable hepatocellular carcinoma (HCC) is based on actual body weight.1 For patients weighing ≥60 kg, the recommended dosage is 12 mg once daily.1 For patients weighing <60 kg, the recommended dosage is 8 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
The recommended adult dosage of lenvatinib for the treatment of advanced endometrial carcinoma that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H) is 20 mg once daily in combination with pembrolizumab 200 mg by IV infusion over 30 minutes every 3 weeks.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
If adverse effects occur during lenvatinib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary.1 If dosage modification is required, the dosage of lenvatinib should be reduced as described in Table 1 in patients with DTC, RCC, or endometrial carcinoma and in Table 2 in patients with HCC.1
Dosage Reduction Level | DTC (Starting Dosage = 24 mg daily) | RCC (Starting Dosage = 20 mg daily in combination with pembrolizumab or 18 mg in combination with everolimus) | Endometrial Carcinoma (Starting Dosage = 20 mg daily) |
|---|---|---|---|
First | Restart at 20 mg once daily | Restart at 14 mg once daily | Restart at 14 mg once daily |
Second | Restart at 14 mg once daily | Restart at 10 mg once daily | Restart at 10 mg once daily |
Third | Restart at 10 mg once daily | Restart at 8 mg once daily | Restart at 8 mg once daily |
Dosage Reduction Level | Patients Weighing ≥60 kg (Starting Dosage = 12 mg daily) | Patients Weighing <60 kg (Starting Dosage = 8 mg daily) |
|---|---|---|
First | Restart at 8 mg once daily | Restart at 4 mg once daily |
Second | Restart at 4 mg once daily | Restart at 4 mg every other day |
Third | Restart at 4 mg every other day | Discontinue therapy |
Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of lenvatinib may be necessary in patients experiencing certain adverse effects (see Table 3).1
Adverse Reaction and Severity | Modification |
|---|---|
Hypertension | |
Grade 3 (despite optimal antihypertensive therapy) | Withhold therapy; when toxicity improves to ≤ grade 2, resume at reduced dosage (see Table 1) |
Grade 4 | Permanently discontinue therapy |
Cardiac Dysfunction | |
Grade 3 | Withhold therapy; when toxicity resolves or improves to grade 0 or 1, resume at reduced dosage (see Table 1) or discontinue therapy depending on severity and persistence of the toxicity |
Grade 4 | Permanently discontinue therapy |
Arterial Thromboembolic Events |
|
Any grade | Permanently discontinue therapy |
Hepatotoxicity | |
Grade 3 or 4 | Withhold therapy; when toxicity resolves or improves to grade 0 or 1, resume at reduced dosage (see Table 1) or discontinue therapy depending on severity and persistence of hepatotoxicity |
Hepatic Failure | Permanently discontinue therapy |
Nephrotoxicity |
|
Grade 3 or 4 (including renal failure) | Withhold therapy; when toxicity resolves or improves to grade 0 or 1, resume at reduced dosage (see Table 1) or discontinue therapy depending on severity and persistence of renal impairment |
Proteinuria | |
≥2 g proteinuria per 24 hours | Withhold therapy; when proteinuria improves to ≤2 g per 24 hours, resume at reduced dosage (see Table 1) |
Nephrotic syndrome | Permanently discontinue therapy |
GI Perforation |
|
Any grade | Permanently discontinue therapy |
Fistula Formation |
|
Grade 3 or 4 | Permanently discontinue therapy |
QT Prolongation | |
>500 msec or >60 msec increase from baseline | Withhold therapy; when toxicity resolves or improves to ≤480 msec, resume at a reduced dosage (see Table 1) |
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) | |
Any grade | Withhold therapy; when RPLS fully resolves, resume at reduced dosage (see Table 1) or discontinue therapy depending on severity and persistence of neurologic symptoms |
Other Adverse Effects | |
Grade 2 or 3 (persistent or intolerable) | Withhold therapy; when toxicity resolves or improves to grade 0 or 1, resume at reduced dosage (see Table 1) |
Grade 4 adverse effect | Permanently discontinue therapy |
Grade 4 laboratory abnormality | Withhold therapy; when the laboratory abnormality resolves or improves to grade 0 or 1, resume at reduced dosage (see Table 1) |
No dosage adjustment is recommended for patients with HCC and pre-existing mild hepatic impairment.1 The manufacturer makes no specific dosage recommendations for patients with HCC and pre-existing moderate or severe hepatic impairment.1
No dosage adjustment is recommended for patients with DTC, RCC, or endometrial carcinoma and mild or moderate hepatic impairment; however, reduced dosages are recommended in such patients with severe hepatic impairment.1
For patients with DTC, RCC, or endometrial carcinoma and pre-existing severe hepatic impairment (Child-Pugh class C), the manufacturer recommends reducing the lenvatinib dosage as described in Table 4.1
Indication | Reduced Initial Dosage |
|---|---|
DTC | 14 mg once daily |
RCC | 10 mg once daily |
Endometrial carcinoma | 10 mg once daily |
Dosage adjustment is not necessary in patients with pre-existing mild (creatinine clearance of 60-89 mL/minute) or moderate (creatinine clearance of 30-59 mL/minute) renal impairment.1
Use of lenvatinib in patients with end-stage renal disease has not been studied, and the manufacturer provides no specific dosage recommendations for such patients.1
There is no recommended dosage of lenvatinib in patients with HCC and severe renal impairment.1
For patients with RCC, DTC, or endometrial carcinoma and pre-existing severe renal impairment (creatinine clearance <30 mL/minute), the manufacturer recommends reducing the lenvatinib dosage as described in Table 5.1
Indication | Reduced Initial Dosage |
|---|---|
DTC | 14 mg once daily |
RCC | 10 mg once daily |
Endometrial carcinoma | 10 mg once daily |
The manufacturer makes no specific dosage recommendations for geriatric patients.1
In the SELECT study evaluating lenvatinib in patients with differentiated thyroid cancer (DTC), hypertension occurred in 73% of patients receiving lenvatinib 24 mg once daily.1 Grade 3 hypertension was reported in 44% and grade 4 hypertension was reported in less than 1% of the lenvatinib-treated patients.1 In the REFLECT study evaluating lenvatinib in patients with hepatocellular carcinoma (HCC), hypertension occurred in 45% of patients receiving lenvatinib 8 or 12 mg once daily, with grade 3 and grade 4 hypertension reported in 24 and 0% of patients, respectively.1 In Study 205 evaluating lenvatinib in combination with everolimus in patients with renal cell carcinoma (RCC), hypertension occurred in 42% of patients receiving lenvatinib 18 mg once daily in combination with everolimus, with grade 3 hypertension reported in 13% of patients.1
In the SELECT and REFLECT trials, the median time to onset of new or worsening hypertension was 16 or 26 days, respectively, after initiating the drug.1 Hypertension necessitated discontinuance of therapy in approximately 1% of lenvatinib-treated patients.1, 2
Blood pressure should be assessed and controlled, if necessary, prior to initiating lenvatinib therapy.1 Blood pressure should be monitored following 1 week of therapy, every 2 weeks for the first 2 months of therapy, and then at least monthly thereafter.1 If hypertension occurs, temporary interruption of lenvatinib therapy, dosage reduction, or discontinuance of therapy may be necessary.1
Lenvatinib may cause serious and fatal cardiac dysfunction.1 In clinical trials evaluating lenvatinib in patients with DTC, RCC, or HCC, grade 3 or higher cardiac dysfunction (i.e., cardiomyopathy, left or right ventricular dysfunction, congestive heart failure, ventricular hypokinesia, decrease in left or right ventricular ejection fraction of >20% from baseline) occurred in 3% of lenvatinib-treated patients.1
Patients receiving lenvatinib should be monitored for manifestations of cardiac dysfunction.1 If cardiac dysfunction occurs, temporary interruption of lenvatinib therapy, dosage reduction, or discontinuance of therapy may be necessary.1
Arterial Thromboembolic Events
In the SELECT, REFLECT, and Study 205 trials, arterial thromboembolic events occurred in 5, 2, and 2% of patients, respectively.1 Across all trials, the occurrence of grade 3 to 5 thromboembolic events ranged from 2-3%.1 In the CLEAR trial evaluating lenvatinib in combination with pembrolizumab in patients with RCC, arterial thrombotic events of any severity occurred in 5% of patients.1 These events included myocardial infarction (3.4%) and cerebrovascular accident (2.3%).1
Lenvatinib therapy should be permanently discontinued if an arterial thromboembolic event occurs.1 The safety of resuming lenvatinib therapy following such an event has not been established, and the drug has not been evaluated in patients who have had an arterial thromboembolic event within the previous 6 months.1
In clinical studies evaluating lenvatinib in patients with malignancies other than HCC, serious hepatic adverse effects occurred in 1.4% of lenvatinib-treated patients and were fatal in 0.5% of patients.1 In the REFLECT trial, hepatic encephalopathy was reported in 8% of lenvatinib-treated patients versus 3% of sorafenib-treated patients.1 Among lenvatinib- and sorafenib-treated patients in the REFLECT trial, grade 3 to 5 hepatic encephalopathy occurred in 5% versus 2% of patients, respectively, and grade 3 to 5 hepatic failure occurred in 3% of patients in both treatment groups.1 Discontinuation of lenvatinib therapy due to hepatic encephalopathy occurred in 2% of lenvatinib-treated patients versus 0.2% of sorafenib-treated patients.1 Overall, 1% of patients in both treatment groups discontinued therapy due to hepatic failure.1
Liver function tests should be evaluated prior to initiation of therapy and monitored every 2 weeks for the first 2 months of therapy and then at least monthly thereafter during therapy.1 Patients with HCC should be monitored closely for signs of hepatic failure.1 If hepatotoxicity occurs, temporary interruption of lenvatinib therapy, dosage reduction, or discontinuance of therapy may be necessary.1
In the SELECT and REFLECT trials, proteinuria occurred in 34 and 26% of lenvatinib-treated patients, respectively, with grade 3 proteinuria occurring in 11 and 6% of patients, respectively.1 In Study 205, 31% of patients administered lenvatinib in combination with everolimus experienced proteinuria compared to 14% of patients administered everolimus alone; grade 3 proteinuria occurred in 8% of patients receiving combination therapy compared with 2% of those receiving everolimus alone.1
Patients should be monitored for proteinuria prior to initiation of lenvatinib and periodically during treatment with the drug.1 In patients with a 2+ or greater urine dipstick reading for proteinuria, a 24-hour urine protein measurement should be obtained.1 If proteinuria occurs, temporary interruption of lenvatinib therapy, dosage reduction, or discontinuance of therapy may be necessary.1
In the SELECT and REFLECT trials, renal impairment occurred in 14 and 7% of lenvatinib-treated patients, respectively, with grade 3 to 5 renal failure or impairment occurring in 3 and 2% of patients, respectively.1 In Study 205, 18% of patients administered lenvatinib in combination with everolimus developed renal impairment or renal failure; grade 3 renal impairment was observed in 10% of patients.1
In patients experiencing diarrhea or dehydration/hypovolemia, appropriate management should be promptly initiated.1 If nephrotoxicity occurs, temporary interruption of lenvatinib therapy, dosage reduction, or discontinuance of therapy may be necessary.1
In the SELECT and REFLECT trials, diarrhea occurred in 49% of lenvatinib-treated patients, with grade 3 diarrhea observed in 6% of patients.1 In Study 205, 81% of patients administered lenvatinib in combination with everolimus experienced diarrhea; grade 3 diarrhea was observed in 19% of patients.1 In this trial, diarrhea was the most frequent cause of dose interruption or reduction.1 Diarrhea recurred despite dosage reduction.1
Prompt management of diarrhea should be initiated if necessary.1 If diarrhea occurs, temporary interruption of lenvatinib therapy, dosage reduction, or discontinuance of therapy may be necessary.1
Fistula Formation and GI Perforation
GI perforation and fistula formation have been reported in patients receiving lenvatinib or other tyrosine kinase inhibitors.1, 2, 14, 16 In most cases, GI perforation and fistula occurred in patients with risk factors (e.g., prior surgery, recent sigmoidoscopy or colonoscopy, radiotherapy, underlying tumor, diverticulitis, bowel obstruction).14, 16 In the SELECT, REFLECT, and Study 205 trials, GI perforation or fistula formation was reported in 2% of lenvatinib-treated patients.1
Lenvatinib should be permanently discontinued in patients who develop GI perforation of any severity or grade 3 or 4 fistula.1
Prolongation of the QT interval has been reported in patients receiving lenvatinib.1, 2 In the SELECT study, prolongation of the QT interval or the corrected QT (QTc) interval was reported in 9% of lenvatinib-treated patients and QT interval prolongation (>500 msec) occurred in 2% of patients.1 In the REFLECT and Study 205 trials, QTc interval increases of >60 msec occurred in 11 and 8% of lenvatinib-treated patients, respectively; QTc interval >500 msec occurred in 6 and 2% of lenvatinib-treated patients, respectively.1
Monitor serum electrolyte concentrations (e.g., potassium, magnesium, calcium) at baseline and periodically during lenvatinib therapy, and correct any abnormalities.1 ECGs should be monitored during lenvatinib therapy in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, and/or in those concurrently receiving other drugs known to prolong the QT interval.1 If QT interval prolongation occurs, temporary interruption of lenvatinib therapy, dosage reduction, or discontinuance of therapy may be necessary.1
In the SELECT and Study 205 trials, grade 3 to 4 hypocalcemia occurred in 9 and 6% of lenvatinib-treated patients, respectively.1 In the REFLECT trial, grade 3 hypocalcemia occurred in 0.8% of lenvatinib-treated patients.1 Among patients with grade 3 to 4 hypocalcemia in the SELECT trial, hypocalcemia improved or resolved in 65% of patients following calcium replacement therapy, with or without lenvatinib dose interruption or reduction.1
Blood calcium concentrations should be monitored at least monthly during lenvatinib therapy.1 If hypocalcemia occurs, calcium replacement therapy should be administered as necessary; temporary interruption of lenvatinib therapy, dosage reduction, or discontinuance of therapy may be necessary.1
Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome (RPLS) occurred rarely (0.3%) in patients treated with lenvatinib as a single agent in clinical studies.1, 2 Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS.1
If RPLS occurs, temporary interruption of lenvatinib therapy, dosage reduction, or discontinuance of therapy may be necessary.1
In the SELECT, REFLECT, and Study 205 trials, hemorrhagic events of any grade occurred in 29% of patients receiving lenvatinib.1 The incidence of grade 3-5 hemorrhage (including fatal hemorrhagic events) occurred in 2, 5, and 8% of lenvatinib-treated patients in the SELECT, REFLECT, and Study 205 trials, respectively.1 The most common hemorrhagic event in these studies occurring in ≥5% of patients were epistaxis and hematuria.1 In lenvatinib-treated patients in clinical trials and in postmarketing surveillance, serious tumor related bleeds, including fatal hemorrhagic events, have been reported.1 In postmarketing surveillance, serious and fatal carotid artery hemorrhagic events occurred more frequently in patients with anaplastic thyroid carcinoma than in other tumor types.1 The safety and efficacy of lenvatinib in patients with anaplastic thyroid carcinoma have not been demonstrated in clinical trials.1
The risk of severe or fatal hemorrhagic events associated with tumor invasion or infiltration of major blood vessels (e.g., carotid artery) should be considered during lenvatinib therapy.1 If hemorrhagic events occur, temporary interruption of lenvatinib therapy, dosage reduction, or discontinuance of therapy may be necessary.1
Impairment of Thyroid-stimulating Hormone Suppression/Thyroid Dysfunction
Lenvatinib impairs exogenous thyroid suppression.1 Among patients with a normal thyroid-stimulating hormone (TSH) concentration at baseline in the SELECT study, elevated TSH concentrations (exceeding 5 microunits/L) were observed in 57% of patients treated with lenvatinib.1 In the REFLECT and Study 205 trials, grade 1 or 2 hypothyroidism occurred in 21 and 24% of lenvatinib-treated patients, respectively.1 An increase in TSH levels from normal or low at baseline was observed in 70 and 60% of lenvatinib-treated patients in REFLECT and Study 205 trials, respectively.1
Thyroid function should be monitored prior to initiation and at least monthly during lenvatinib therapy.1 Hypothyroidism should be treated according to standard medical practice.1
Lenvatinib may impair wound healing and this adverse effect has been reported among patients treated with the drug.1
Lenvatinib should be withheld for at least 1 week prior to an elective surgery and should not be administered for at least 2 weeks following major surgery and until adequate wound healing has occurred.1 The safety of resuming lenvatinib therapy after resolution of wound healing complications has not been established.1
Lenvatinib therapy is associated with the occurrence of osteonecrosis of the jaw.1 The risk of osteonecrosis of the jaw may be increased by concomitant exposure to other risk factors (e.g., bisphosphonate or denosumab therapy, dental disease, or invasive dental procedures).1
An oral examination should be performed prior to, and periodically during, lenvatinib therapy.1 Patients should be advised to regularly practice good oral hygiene practices.1
Invasive dental procedures should be avoided, particularly in patients at higher risk for osteonecrosis of the jaw, during lenvatinib therapy, if possible.1 Lenvatinib therapy should be withheld for at least 1 week before a scheduled dental surgery or invasive dental procedure, if possible.1 In patients receiving concomitant bisphosphonate therapy, discontinuance of bisphosphonate therapy may reduce the risk of osteonecrosis of the jaw in patients requiring invasive dental procedures.1 If osteonecrosis of the jaw occurs, withhold lenvatinib therapy and resume based on clinical judgment of adequate resolution.1
Fetal/Neonatal Morbidity and Mortality
Lenvatinib may cause fetal harm in humans based on its mechanism of action and animal findings; the drug has been shown to be teratogenic, embryotoxic, and fetotoxic in animals.1 There are no available data regarding the risk of lenvatinib use in pregnant women to date.1 In animal reproduction studies, dose-related decreases in mean fetal body weight; delayed fetal ossifications; and dose-related increases in fetal external, visceral, and skeletal anomalies were observed in rats at daily lenvatinib doses ≥0.3 mg/kg (approximately 0.14 times the recommended clinical dose of 24 mg based on body surface area).1 Postimplantation loss was observed in more than 80% of pregnant rats at a lenvatinib dosage of 1 mg/kg per day (approximately 0.5 times the recommended human dosage based on body surface area).1 Fetal external, visceral, and skeletal anomalies and postimplantation loss (including one fetal death) also were observed in rabbits receiving dosages below the recommended human dosa the drug also was abortifacient.1
Pregnancy should be avoided during lenvatinib therapy.1 Verify the pregnancy status of females of reproductive potential before initiating lenvatinib.1 Females of reproductive potential should be advised to use an effective method of contraception while receiving lenvatinib and for 30 days after discontinuance of therapy.1 If lenvatinib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
Lenvatinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 In animal reproduction studies, oral lenvatinib administered during organogenesis at doses below the recommended human doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits.1
Verify the pregnancy status of females of reproductive potential before initiating lenvatinib.1 If lenvatinib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
Lenvatinib and its metabolites are distributed into milk in rats at concentrations higher than maternal plasma; it is not known whether the drug is distributed into milk in humans.1 Because of the potential for serious adverse reactions to lenvatinib in breast-fed infants, women should be advised to discontinue nursing during lenvatinib therapy and for at least 1 week after the last dose.1
Females and Males of Reproductive Potential
Prior to initiation of lenvatinib therapy, verify pregnancy status of females of reproductive potential and such females should be advised to use effective contraceptive methods during lenvatinib therapy and for 30 days after the last dose.1
Lenvatinib may impair fertility in males and females of reproductive potential.1
Safety and efficacy of lenvatinib have not been established in pediatric patients.1
Growth retardation (decreased weight gain, food consumption, and femur and tibia width and/or length), secondary delays in physical development, and reproductive organ immaturity have been observed in juvenile rats receiving daily oral administration of lenvatinib for 8 weeks.1
Safety and efficacy of lenvatinib were investigated but not established in pediatric patients 2 to <17 years of age with relapsed or refractory solid tumors, including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and high-grade glioma.1 Hypothyroidism and pneumothorax were observed at a higher rate in pediatric patients compared to adult patients.1
In the SELECT, REFLECT, CLEAR, Study 205, and Study 309 trials, 45, 44, 45, 36, and 50% of lenvatinib-treated patients, respectively, were 65 years of age or older.1 The percentages of patients receiving lenvatinib who were 75 years of age or older in the SELECT, REFLECT, and CLEAR trials, were 11, 12, and 13%, respectively.1 No overall differences in safety and efficacy were observed between these geriatric patients and younger adults.1
In a pharmacokinetic population analysis, age did not have a substantial effect on the clearance of lenvatinib.1
Following administration of a single 10-mg dose of lenvatinib, dose-adjusted total exposure to the drug in individuals with pre-existing mild or moderate hepatic impairment (Child-Pugh class A or B) was 119 or 107% higher, respectively, compared with individuals with normal hepatic function;1 no dosage adjustment is required in patients with DTC, RCC, or endometrial carcinoma and pre-existing mild or moderate hepatic impairment.1, 13 In patients with HCC and pre-existing mild hepatic impairment, no dosage adjustment is necessary; however, the manufacturer makes no specific recommendations for patients with HCC and pre-existing moderate hepatic impairment.1
Following administration of a single 5-mg dose of lenvatinib, dose-adjusted total exposure to the drug was 180% in individuals with pre-existing severe hepatic impairment (Child-Pugh class C) compared with that in individuals with normal hepatic function;1 therefore, dosage adjustment is necessary in patients with DTC, RCC, or endometrial carcinoma and pre-existing severe hepatic impairment.1, 13 The manufacturer makes no specific dosage recommendations for patients with HCC and pre-existing severe hepatic impairment.1
Pre-existing renal impairment (creatinine clearance 15-89 mL/minute) does not significantly impact oral clearance of lenvatinib.1 No dosage adjustment is recommended in patients with mild (creatinine clearance 60-89 mL/minute) or moderate (creatinine clearance 30-59 mL/minute) renal impairment.1
The manufacturer recommends dosage adjustment in patients with DTC, RCC, and endometrial carcinoma and severe renal impairment (creatinine clearance 15-29 mL/minute).1, 5 The manufacturer makes no specific dosage recommendations for patients with HCC and severe renal impairment.1
Lenvatinib has not been studied in patients with end-stage renal disease.1
Adverse effects reported in ≥30% of patients receiving lenvatinib for the treatment of DTC include hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite and weight, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, and dysphonia.1
Adverse effects reported in ≥20% of patients receiving lenvatinib in combination with pembrolizumab for the treatment of RCC include fatigue, diarrhea, musculoskeletal pain, hypothyroidism, hypertension, stomatitis, decreased appetite, rash, nausea, decreased weight, dysphonia, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, hemorrhagic events, vomiting, constipation, hepatotoxicity, headache, and acute kidney injury.1
Adverse effects reported in ≥30% of patients receiving lenvatinib in combination with everolimus for the treatment of RCC include diarrhea, fatigue, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, decreased weight, hemorrhagic events, and proteinuria.1
Adverse effects reported in ≥20% of patients receiving lenvatinib for the treatment of HCC include hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite and weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea.1
Adverse effects reported in ≥20% of patients receiving lenvatinib for the treatment of endometrial carcinoma include hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite and weight, vomiting, stomatitis, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia syndrome, dysphonia, and rash.1
Lenvatinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.1, 5 In vitro studies indicate that lenvatinib inhibits CYP isoenzymes 2C8, 1A2, 2B6, 2C9, 2C19, 2D6, and 3A, and also uridine diphosphate-glucuronosyl transferases (UGT) 1A1, 1A4, and 1A9, but does not inhibit CYP isoenzymes 2A6 or 2E1.1, 5 The drug also does not inhibit UGT 1A6 or 2B7 or aldehyde oxidase.1 Lenvatinib induces CYP3A, but does not induce CYP isoenzymes 1A1, 1A2, 2B6, or 2C9, and UGT 1A1, 1A4, 1A6, 1A9, or 2B7.1
In vitro, the drug is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but is not a substrate for organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)1, OCT2, organic anion transport protein (OATP)1B1, OATP1B3, multidrug and toxin extrusion (MATE) 1, MATE2-K, or the bile salt export pump (BSEP).1 Lenvatinib does not have the potential to inhibit MATE1, MATE2-K, OCT1, OCT2, OAT1, OAT3, BSEP, OATP1B1, or OATP1B3 in vivo.1
Drugs Affecting Hepatic Microsomal Enzymes and/or Efflux Transport Systems
Inhibitors of CYP3A and Efflux Transport Systems
When ketoconazole (a CYP3A4, P-gp, and BCRP inhibitor) 400 mg was administered once daily for 18 days with a single 5-mg dose of lenvatinib on day 5, peak plasma concentrations and systemic exposure of lenvatinib were increased by 19 and 15%, respectively.1, 5
When the P-gp inhibitor, rifampin (single 600-mg dose), was administered concomitantly with lenvatinib (single 24-mg dose), peak plasma concentrations and systemic exposure of lenvatinib were increased by 33 and 31%, respectively.1
Inducers of CYP3A and Efflux Transport Systems
When rifampin (a CYP3A and P-gp inducer) 600 mg was administered once daily for 21 days with a single 24-mg dose of lenvatinib on day 15, systemic exposure of lenvatinib was decreased by 18% and peak plasma concentrations were unchanged.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Clinically important pharmacokinetic interactions between drugs that are substrates of CYP3A4 (e.g., midazolam) and lenvatinib are not expected during concurrent use.1
Clinically important pharmacokinetic interactions between drugs that are substrates of CYP2C8 (e.g., repaglinide) and lenvatinib are not expected during concurrent use.1
Drugs that Prolong the QT Interval
Avoid concurrent administration of lenvatinib with drugs that are known to prolong the QT/QTc interval.1 Because lenvatinib has been associated with QT-interval prolongation, the manufacturer recommends ECG monitoring in lenvatinib-treated patients concurrently receiving other drugs known to prolong the QT interval, including class IA antiarrhythmics (e.g., quinidine, procainamide) and class III antiarrhythmics (e.g., amiodarone, sotalol).1 In addition, electrolyte monitoring and correction of any electrolyte abnormalities are recommended in all patients receiving lenvatinib at baseline and periodically during treatment.1
Lenvatinib, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent.1, 2, 5, 9, 10 Receptor tyrosine kinases (RTKs) are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis, inhibition of apoptosis), based on the respective kinase.6, 7, 8 Lenvatinib inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR-1, VEGFR-2, and VEGFR-3.1, 2, 5, 9 The drug also inhibits other RTKs involved in pathogenic angiogenesis, tumor growth, and cancer progression, including fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3, and FGFR4), the platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (c-Kit), and ret proto-oncogene (RET).1, 2, 5, 9 Lenvatinib also demonstrates antiproliferative activity in hepatocellular carcinoma (HCC) cell lines dependent on FGFR signaling with concurrent inhibition of FGF-receptor substrate 2 α(FRS2α) phosphorylation.1
In syngeneic mouse tumor models, the combination of lenvatinib and an anti-PD-1 monoclonal antibody demonstrated greater antitumor activity compared to either agent alone.1 The combination of lenvatinib and an anti-PD-1 monoclonal antibody also decreased tumor-associated macrophages and increased activated cytotoxic T cells.1 The combination of lenvatinib and everolimus demonstrated greater antiangiogenic and antitumor activity in mouse xenograft models of human renal cell cancer compared to either agent alone.1
In a randomized study of patients with radioactive iodine-refractory differentiated thyroid cancer (DTC), a dose-response relationship for overall response rate (ORR) was observed over the oral dose range of 18 mg (less than the recommended dose) to 24 mg (recommended dose), with a higher ORR reported in patients receiving the recommended dose of 24 mg once daily.1 No dose-response relationship was observed over the oral dose range of 18—24 mg for adverse reactions (including serious adverse reactions), or adverse reactions leading to discontinuation or treatment interruption.1
Following oral administration, lenvatinib is rapidly absorbed with peak plasma concentrations usually occurring within 1-4 hours.1, 5 Peak plasma concentrations and systemic exposure to lenvatinib are proportional to dose following single or repeated administration of the drug over the dosage range of 3.2-32 mg once daily.1 Administration of lenvatinib with food delayed the rate of absorption (time to reach peak concentrations delayed by 2 hours), but did not affect the extent of absorption.1 Lenvatinib is metabolized in the liver principally by cytochrome P-450 (CYP) 3A4, aldehyde oxidase, and nonenzymatic processes.1, 5 Lenvatinib is highly bound (97-99%) to plasma proteins.1 The elimination half-life of the drug is approximately 28 hours.1 Following oral administration of a single radiolabeled dose of lenvatinib, approximately 64% of the dose is recovered in the feces and approximately 25% of the dose is recovered in urine within 10 days.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Lenvatinib is obtained through designated specialty pharmacies.4 Contact the manufacturer or consult the Lenvima® website for specific availability information.4
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 4 mg (of lenvatinib) | Lenvima® | |
10 mg (of lenvatinib) | Lenvima® | Eisai |
1. Eisai Inc. Lenvima® (lenvatinib) capsules prescribing information. Nutley, NJ; 2024 Apr.
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5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 206947Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]
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17. National Cancer Institute. Renal cell cancer treatment - health professional version. Revised March 1, 2024. Accessed 2024 Apr 26. [Web]
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