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LENVIMA® + everolimus—results in 3 efficacy measures.
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Prescribing Information
Important Safety Information
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Lenvatinib
+ everolimus
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CATEGORY 1 RECOMMENDATION
by the National Comprehensive Cancer Network® (NCCN®)1*†
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Indication
LENVIMA® is indicated in combination with everolimus for the treatment of patients with advanced renal cell carcinoma (RCC) following one prior anti‑angiogenic therapy.
Important Safety Information
Warnings and Precautions
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Hypertension was reported in 42% of patients on LENVIMA + everolimus vs 10% with everolimus alone (13% vs 2% grade 3). Blood pressure should be controlled prior to treatment and monitored throughout. Withhold dose for grade 3 hypertension despite optimal antihypertensive therapy; resume at reduced dose when controlled at grade ≤2. Discontinue for life-threatening hypertension
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Please see additional Important Safety Information below and full Prescribing Information.
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Substantial benefits across 3 efficacy measures with LENVIMA + everolimus (LEN+EVE) vs everolimus alone2
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Median progression-free survival (PFS)
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LEN+EVE
14.6 months
(95% CI: 5.9-20.1)
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Everolimus
5.5 months
(95% CI: 3.5-7.1)
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HR (95% CI): 0.37 (0.22-0.62)
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26 events (51%) occurred in the LENVIMA + everolimus arm vs 37 events (74%) in the everolimus arm
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21 patients (41%) who received LENVIMA + everolimus progressed vs 35 patients (70%) who received everolimus
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Death occurred in 5 patients (10%) who received LENVIMA + everolimus vs 2 patients (4%) who received everolimus
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Confirmed objective response rate (ORR)
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LEN+EVE
37% (2% CR, 35% PR)
(95% CI: 24%-52%)
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Everolimus
6% (all PR)
(95% CI: 1%-17%)
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Learn more
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Median overall survival (OS)
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LEN+EVE
25.5 months
(95% CI: 16.4-32.1)
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Everolimus
15.4 months
(95% CI: 11.8-20.6)
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HR (95% CI): 0.67 (0.42-1.08)
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CI=confidence interval; HR=hazard ratio; CR=complete response; PR=partial response.
Study 205 randomized 153 patients with advanced or metastatic RCC who had previously received anti‑angiogenic therapy 1:1:1 to LENVIMA 18 mg + everolimus 5 mg, LENVIMA 24 mg monotherapy, or everolimus 10 mg monotherapy. All medications were administered orally once daily. Patients were required to have histological confirmation of clear cell RCC and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were stratified by hemoglobin level (≤13 g/dL vs >13 g/dL for males and ≤11.5 g/dL vs >11.5 g/dL for females) and corrected serum calcium (≥10 mg/dL vs <10 mg/dL). The major efficacy outcome measure was investigator-assessed PFS evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Other efficacy outcome measures included OS and ORR.
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Learn more about LEN+EVE in advanced RCC.
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Important Safety Information (cont'd)
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Cardiac dysfunction was reported in 10% of patients on LENVIMA + everolimus vs 6% with everolimus alone (3% vs 2% grade 3). Monitor for signs/symptoms of cardiac decompensation. Withhold for grade 3 cardiac dysfunction. Resume at reduced dose or discontinue based on severity and persistence of cardiac dysfunction. Discontinue for grade 4 cardiac dysfunction
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Arterial thromboembolic events were reported in 2% of patients on LENVIMA + everolimus vs 6% with everolimus alone (2% vs 4% grade ≥3). Discontinue following an arterial thrombotic event. The safety of resuming LENVIMA after an arterial thromboembolic event has not been established, and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months
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Across clinical studies in which 1,160 patients received LENVIMA monotherapy, hepatic failure (including fatal events) was reported in 3 patients and acute hepatitis in 1 patient. ALT and AST increases (grade ≥3) occurred in 3% of patients on LENVIMA + everolimus vs 2% and 0% with everolimus alone, respectively. Monitor liver function before initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Withhold dose for liver impairment grade ≥3 until resolved to grade 0, 1, or baseline. Resume at reduced dose or discontinue based on severity/persistence of hepatotoxicity. Discontinue for hepatic failure
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Proteinuria was reported in 31% of patients on LENVIMA + everolimus vs 14% with everolimus alone (8% vs 2% grade 3). Monitor for proteinuria before and during treatment. Withhold dose for proteinuria ≥2 g/24 h. Resume at reduced dose when proteinuria is <2 g/24 h. Discontinue for nephrotic syndrome
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Diarrhea was reported in 81% of patients on LENVIMA + everolimus vs 34% with everolimus alone (19% vs 2% grade ≥3). Initiate prompt medical management for the development of diarrhea. Monitor for dehydration. Withhold dose for diarrhea grade ≥3. Resume at a reduced dose when diarrhea resolves to grade 1 or baseline. Discontinue for grade 4 diarrhea despite medical management
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Events of renal impairment were reported in 18% of patients on LENVIMA + everolimus vs 12% with everolimus alone (10% vs 2% grade ≥3). Withhold LENVIMA for grade 3 or 4 renal failure/impairment. Resume at reduced dose or discontinue, depending on severity/persistence of renal impairment. Active management of diarrhea and any other gastrointestinal (GI) symptoms should be initiated for grade 1 events
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Events of GI perforation, abscess, or fistula (grade ≥3) were reported in 2% of patients on LENVIMA + everolimus vs 0% with everolimus alone. Discontinue in patients who develop GI perforation or life-threatening fistula
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QTc interval increases >60 ms were reported in 11% of patients on LENVIMA + everolimus (6% >500 ms) vs 0% with everolimus alone. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or patients taking drugs known to prolong the QT interval. Monitor and correct electrolyte abnormalities in all patients. Withhold dose for QTc interval prolongation >500 ms. Resume at reduced dose when QTc prolongation resolves to baseline
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Hypocalcemia (grade ≥3) was reported in 6% of patients on LENVIMA + everolimus vs 2% with everolimus alone. Monitor blood calcium levels at least monthly and replace calcium as necessary. Interrupt and adjust LENVIMA as necessary
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Across clinical studies in which 1,160 patients received LENVIMA monotherapy, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 4 patients. Withhold LENVIMA for RPLS until fully resolved. Resume at reduced dose or discontinue based on the severity and persistence of neurologic symptoms
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Hemorrhagic events occurred in 34% of patients on LENVIMA + everolimus vs 26% with everolimus alone (8% vs 2% grade ≥3). The most frequently reported hemorrhagic event was epistaxis (23% for LENVIMA + everolimus vs 24% with everolimus alone). There was 1 fatal cerebral hemorrhage case. Discontinuation due to hemorrhagic events occurred in 3% of patients on LENVIMA + everolimus. Consider the risk of severe or fatal hemorrhage associated with tumor invasion/infiltration of major blood vessels (eg, carotid artery). Withhold dose for grade 3 hemorrhage. Resume at reduced dose or discontinue based on severity/persistence of hemorrhage. Discontinue for grade 4 hemorrhage
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Grade 1 or 2 hypothyroidism occurred in 24% of patients on LENVIMA + everolimus vs 2% with everolimus alone. In patients with normal or low thyroid-stimulating hormone (TSH) at baseline, elevation of TSH was observed postbaseline in 60% of patients on LENVIMA + everolimus vs 3% with everolimus alone. Monitor thyroid function prior to treatment initiation and monthly thereafter. Treat hypothyroidism according to standard medical practice to maintain a euthyroid state
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LENVIMA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy
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Adverse Reactions
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The most common adverse reactions observed in patients treated with LENVIMA + everolimus vs everolimus alone were diarrhea (81% vs 34%), fatigue (73% vs 40%), arthralgia/myalgia (55% vs 32%), decreased appetite (53% vs 18%), vomiting (48% vs 12%), nausea (45% vs 16%), stomatitis/oral inflammation (44% vs 50%), hypertension/increased blood pressure (42% vs 10%), peripheral edema (42% vs 20%), cough (37% vs 30%), abdominal pain (37% vs 8%), dyspnea/exertional dyspnea (35% vs 28%), rash (35% vs 40%), weight decreased (34% vs 8%), hemorrhagic events (32% vs 26%), and proteinuria/urine protein present (31% vs 14%)
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Adverse reactions led to dose reductions or interruption in 89% of patients receiving LENVIMA + everolimus and in 54% of patients receiving everolimus. The most common adverse reactions (≥5%) resulting in dose reductions in the LENVIMA + everolimus–treated group were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients in the LENVIMA + everolimus–treated group and in 12% of patients in the everolimus-treated group
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Use in Specific Populations
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Because of the potential for serious adverse reactions in nursing infants, advise women to discontinue breastfeeding during treatment
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LENVIMA may result in reduced fertility in females of reproductive potential and may result in damage to male reproductive tissues, leading to reduced fertility of unknown duration
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View the full Prescribing Information for LENVIMA.
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Relapsed or stage 4 and surgically unresectable disease with predominantly clear cell histology.
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Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer V.1.2017. © National Comprehensive Cancer Network, Inc 2016. All rights reserved. Accessed November 10, 2016. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.
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References: 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Kidney Cancer. Version 1.2017. www.NCCN.org. Published September 26, 2016. Accessed November 10, 2016. 2. LENVIMA [package insert]. Woodcliff Lake, NJ: Eisai Inc.; 2016.
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