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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.

August 16, 2018–Lenvatinib capsules (Lenvima, Eisai Inc.) for first-line treatment of patients with unresectable hepatocellular carcinoma (HCC) (with Pharmacist's Applications to Practice)

May 13, 2016–Lenvatinib (Lenvima®) capsules approved in combination with everolimus, for the treatment of advanced renal cell carcinoma.

February 13, 2015–Lenvatinib (LENVIMA) approved for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer.


August 16, 2018 with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206947s007lbl.pdf

On August 16, 2018, the Food and Drug Administration approved lenvatinib capsules (Lenvima, Eisai Inc.) for first-line treatment of patients with unresectable hepatocellular carcinoma (HCC).

Approval was based on an international, multicenter, randomized, open-label, non-inferiority trial (REFLECT; NCT01761266) conducted in 954 patients with previously untreated, metastatic or unresectable HCC. Patients were randomized (1:1) to receive lenvatinib (12 mg orally once daily for patients with a baseline body weight of ≥60 kg and 8 mg orally once daily for patients with a baseline body weight of <60 kg) or sorafenib (400 mg orally twice daily). Treatment continued until radiological disease progression or unacceptable toxicity.

REFLECT demonstrated that lenvatinib was non-inferior but not statistically superior to sorafenib for overall survival (OS) (HR 0.92; 95% CI: 0.79, 1.06). Median OS in the lenvatinib arm was 13.6 months and 12.3 months in the sorafenib arm. REFLECT also demonstrated a statistically significant improvement in progression-free survival (PFS) with lenvatinib as compared to sorafenib. Median PFS was 7.3 months in the lenvatinib arm and 3.6 months in the sorafenib arm (HR 0.64; 95% CI: 0.55, 0.75; p<0.001) per modified RECIST for HCC (mRECIST); findings were similar according to RECIST 1.1. The overall response rate was higher for the lenvatinib arm as compared to sorafenib (41% vs. 12% per mRECIST and 19% vs. 7% per RECIST 1.1).

The most common adverse reactions observed in the lenvatinib-treated patients with HCC (≥20%) in order of decreasing frequency were hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea.

The recommended lenvatinib dosages for patients with HCC are the following:

  • 12 mg orally once daily in patients 60 kg or greater actual body weight or
  • 8 mg orally once daily in patients less than 60 kg actual body weight.

View full prescribing Information for Lenvima.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Lenvatinib for the Treatment of Unresectable Hepatocellular Carcinoma

Author: Alyssa Heiden, PharmD BCOP
Pediatric Clinical Pharmacist—Oncology and Stem Cell Transplant
Children’s Hospital Colorado
Aurora, Colorado

What is the potential role for lenvatinib in the treatment of unresectable hepatocellular carcinoma (HCC)?

  • Lenvatinib is a receptor tyrosine kinase inhibitor approved in August 2018 for the first-line treatment of patients with unresectable HCC.1 Lenvatinib works by inhibiting vascular endothelial growth factor receptors (VEGFR1, VEGFR2, VEGFR3) and such growth-signaling targets as fibroblast growth factor and platelet-derived growth factor to block tumor growth and cancer progression by interrupting cellular functions.2
  • Approval was based on a phase 3 open-label multicenter non-inferiority trial in which 954 patients were randomized to receive either lenvatinib or sorafenib for first-line treatment of HCC. Lenvatinib was dosed at 12 mg given orally once daily for patients weighing 60 kg or more, or 8 mg orally once daily for patients weighing less than 60 kg. Sorafenib was dosed at 400 mg orally twice daily. Treatment continued until radiological disease progression or until an unacceptable level of toxicity was reached.3
    • Baseline characteristics were similar between both study groups; the median age was 62 years (range 20–88 years).3
    • The results of the trial showed that lenvatinib was non-inferior but not statistically superior to sorafenib. The median overall survival time for lenvatinib was 13.6 months versus 12.3 months for sorafenib (hazard ratio [HR] 0.92; 95% confidence interval [CI]: 0.79–1.06). Progression-free survival was significant for lenvatinib at 7.3 months versus 3.6 months for sorafenib (HR 0.64; 95% CI: 0.55, 0.75; p < .0001).3
    • The most common adverse events of any grade for lenvatinib were hypertension (42%), diarrhea (39%), decreased appetite (34%), and decreased weight (31%). The most common adverse events of any grade for sorafenib were hand-foot syndrome (52%), diarrhea (46%), hypertension (30%), and decreased appetite (27%). Grade 3 or greater adverse events occurred in 270 patients in the lenvatinib group (57%) and in 231 patients in the sorafenib group (49%).3
    • Treatment-related adverse events in the lenvatinib group led to drug interruption in 190 patients (40%), dose reduction in 176 patients (37%), and drug withdrawal in 42 patients (9%). Treatment-related adverse events in the sorafenib group led to drug interruption in 153 patients (32%), dose reduction in 181 patients (38%), and drug withdrawal in 34 patients (7%).3
  • HCC is the most common type of liver cancer and occurs primarily in patients with chronic liver disease like cirrhosis, which limits the use of surgery as a treatment option. Until the approval of lenvatinib, sorafenib was the only available first-line systemic treatment for advanced unresectable HCC.3
  • According to the National Comprehensive Cancer Network (NCCN) guidelines, the preferred first-line systemic therapy for HCC is sorafenib for Child-Pugh Class A (category 1) or B7, or lenvatinib for Child-Pugh Class A only.4 Limited safety data are available on sorafenib for Child-Pugh Class B or C patients, so NCCN has recommendations for use in Child-Pugh Class A or B7 (not B8 or B9) because of the caution that should be used when giving sorafenib to patients with elevated bilirubin levels. Currently, lenvatinib is used only in Child-Pugh Class A.4,5

What role can the pharmacist play in the management of patients on lenvatinib?

  • Lenvatinib dosing is based on actual body weight:2
    • Patients weighing less than 60 kg: 8 mg orally once daily
    • Patients weighing 60 kg or more: 12 mg orally once daily
  • Patients taking lenvatinib should be monitored closely for side effects and efficacy. Monitoring should include the following:2
    • Liver function tests at baseline, and then every 2 weeks for the first 2 months of treatment at minimum, and monthly thereafter
    • Proteinuria at baseline and then periodically during treatment
    • Renal function at baseline and then periodically during treatment
    • Electrolytes (including calcium) at baseline and then periodically during treatment
    • Thyroid function at baseline and monthly thereafter
    • Electrocardiogram (ECG) in patients who have long QT syndrome, congestive heart failure, or bradyarrhythmias or who are on concurrent QT-prolonging drugs
    • Blood pressure at baseline, 1 week after treatment initiation, every 2 weeks for the first 2 months of treatment, and then monthly thereafter
    • Negative pregnancy test before starting treatment for female patients
  • The most common adverse effects for lenvatinib include fatigue (44%–73%), hypertension (42%–73%), decrease in appetite (34%–54%), decreased weight (31%–51%), nausea (20%–47%), stomatitis (41%–44%), peripheral edema (14%–42%), headache (10%–38%), abdominal pain (31%–37%), cough (24%–37%), rash (14%–35%), proteinuria (26%–34%), hand-foot syndrome (27%–32%), and difficulty speaking (18%–31%).2
  • Severe adverse effects for lenvatinib include vomiting (16%–48%); diarrhea (39%); dyspnea (35%); hepatitis, hepatorenal syndrome, liver failure, and renal impairment (7%–18%); prolonged QT interval (2%–11%); dehydration (9%–10%); myocardial dysfunction (7%–10%); hepatic encephalopathy (8%); and arterial thrombosis (2%–5%).2
  • The NCCN guidelines for antiemesis list lenvatinib as having a “moderate to high emetic risk,” which indicates that it may cause a frequency of emesis of 30% or more if patients do not receive prophylaxis. Pharmacists can play a role in ensuring that patients have adequate antiemetics prescribed to help avoid this side effect.6
    • The NCCN guidelines recommend scheduling a 5-HT3 receptor antagonist for all oral chemotherapy that has a “moderate to high emetic risk,” starting before chemotherapy and continuing daily. Dosing recommendations include dolasetron 100 mg orally daily, granisetron 1–2 mg (total dose) orally daily or 3.1 mg/24-hour transdermal patch every 7 days, or ondansetron 8–16 mg (total dose) orally daily.6
    • A drug interaction occurs with lenvatinib and QT-prolonging medications, so caution should be used when scheduling 5-HT3 receptor antagonists in patients with long QT syndrome, congestive heart failure, or bradyarrhythmias. The package insert for the granisetron transdermal patch refers to a pharmacodynamic study that suggests that it does not prolong the QT interval and therefore may be an option for patients who cannot tolerate other 5-HT3 receptor antagonists for this reason.7
  • For grade 3 or 4 renal toxicity or renal failure, withhold lenvatinib until the condition has resolved to grade 0, grade 1, or baseline and then resume administration at a reduced dose.2
  • For mild hepatic impairment, lenvatinib does not require a dose adjustment. For grade 3 or 4 hepatotoxicity, withhold lenvatinib until the condition resolves to grade 0 or 1 or baseline and then resume administration at a reduced dose. Permanently discontinue the drug in cases of hepatic failure.2
  • For grade 3 cardiac dysfunction, withheld lenvatinib until the condition resolves to grade 0 or 1 or baseline and then resume administration at a reduced dose. Discontinue lenvatinib if an arterial thrombotic event or grade 4 cardiac dysfunction occurs.2
  • For grade 3 hypertension despite hypertensive therapy, withhold the drug until hypertension is controlled at grade 2 or below and then resume administration at the reduced dose.2
  • For proteinuria (2 g/day or higher), withhold the drug until proteinuria is less than 2 g/day and then resume administration at a reduced dose. Permanently discontinue it in cases of nephrotic syndrome.2
  • For QT prolongation (greater than 500 msec or greater than 60 msec increase from baseline), withhold the drug until the prolongation resolves to 480 msec or less or baseline and then resume administration at a reduced dose.2
  • Dose reductions should be managed as follows:
    • For the first occurrence, reduce the dose to 4 mg/day in patients weighing less than 60 kg and to 8 mg/day in patients weighing 60 kg or greater.
    • For the second occurrence, reduce the dose to 4 mg every other day in patients less than 60 kg and to 4 mg/day in patients 60 kg or greater.
    • For the third occurrence, discontinue therapy in patients less than 60 kg and reduce the dose to 4 mg every other day in patients 60 kg or greater.

Clinical Pearls

  • Lenvatinib is available as 4-mg and 10-mg capsules. Lenvatinib is taken with or without food and is continued until disease progression or unacceptable toxicity.2
    • For patients unable to swallow capsules whole, lenvatinib may be dissolved in 1 tablespoon of water or apple juice. Patients should be advised not to break or crush the capsules but to allow them to sit in the liquid for 10 minutes. Then the liquid should be stirred for at least 3 minutes. After drinking the liquid, the patient should add another tablespoon of water or apple juice to the glass and then swirl and swallow the liquid.2
    • Lenvatinib should be taken at the same time every day, and missed doses should be taken within 12 hours of the schedule time or skipped and then the next dose taken at the usual time. Doses should not be doubled up.2
    • Lenvatinib capsules are supplied in cartons of 6 cards, and each card is a 5-day blister card, which creates a 30-day supply.
    • For the 12-mg oral daily dose, a carton with 6 cards contains fifteen 4-mg capsules per card (90 capsules total, a 30-day supply). For the 8-mg oral daily dose, a carton with 6 cards contains ten 4-mg capsules per card (60 capsules total, a 30-day supply). Additional cartons are available for patients who require dose adjustments (e.g., 10-mg dose, 4-mg dose).2
  • Lenvatinib capsules should be stored at room temperature and kept out of reach of children.2
  • Coadministration of lenvatinib and medications known to cause QT or QTc interval prolongation should be avoided if possible.2
  • The Eisai Assistance program on the Lenmiva website is a complimentary program that provides one-on-one assistance for patients to help with out-of-pocket costs and copay reimbursement.8
    • It may also be available for eligible uninsured and financially burdened patients who have been prescribed lenvatinib.

 

References

  1. FDA approves lenvatinib for unresectable hepatocellular carcinoma. August 16, 2018. Available at https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm617185.htm. Accessed January 14, 2019.
  2. Lenvima (lenvatinib) [package insert]. Woodcliff Lake, NJ: Eisai Inc.
  3. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomized phase 3 non-inferiority trial. Lancet. 2018;391:1163-1173.
  4. National Comprehensive Cancer Network. Hepatobiliary Cancers. Version 2.2019. Available at https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed March 12, 2019.
  5. Miller AA, Murry DJ, Owzar K, et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol. 2009;27:1800-1805.
  6. National Comprehensive Cancer Network. Antiemesis. Version 1.2019. Available at https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed March 12, 2019.
  7. Sancuso (granisetron transdermal system) [package insert]. Bedminster, NJ: Kyowa Kirin, Inc.
  8. Lenvima financial assistance. Eisai Assistance Program. Available at http://www.lenvima.com/inoperable-liver-cancer/financial-support. Accessed January 14, 2019.

May 13, 2016

http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206947s003lbl.pdf

On May 13, 2016, the U. S. Food and Drug Administration approved lenvatinib capsules (Lenvima®, Eisai, Inc.), in combination with everolimus, for the treatment of advanced renal cell carcinoma following one prior anti-angiogenic therapy. Lenvatinib was first approved in 2015 for the treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer.

The current approval was based on a randomized, multicenter study in patients with advanced or metastatic renal cell carcinoma who previously received anti-angiogenic therapy. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS) evaluated according to RECIST v1.1.  

The trial randomized 153 patients 1:1:1 to lenvatinib 18 mg plus everolimus 5 mg (N=51), lenvatinib 24 mg monotherapy (N=52), or everolimus 10 mg monotherapy (N=50). All medications were administered orally once daily. Metastases were present in 95% of patients. Memorial Sloan Kettering Cancer Center favorable, intermediate, and poor risk prognostic categories were seen, respectively, in 24%, 37%, and 39% of patients receiving lenvatinib plus everolimus and were well balanced between arms.

The hazard ratio for the comparison of investigator-assessed PFS between lenvatinib plus everolimus and everolimus was 0.37 (95% CI: 0.22, 0.62). The median PFS was 14.6 (95% CI: 5.9, 20.1) months for the lenvatinib plus everolimus arm versus 5.5 (95% CI: 3.5, 7.1) months for patients on the everolimus arm. This treatment effect was supported by a retrospective independent review of radiographs in these two arms with an observed hazard ratio of 0.43 (95% CI: 0.24, 0.75). The hazard ratio for a post-hoc, updated comparison of overall survival between the lenvatinib plus everolimus and everolimus arms was 0.67 (95% CI: 0.42, 1.08).

Comparison of investigator-assessed PFS between lenvatinib monotherapy and everolimus monotherapy supported the activity of lenvatinib in renal cell cancer. The combination of lenvatinib plus everolimus demonstrated numerically superior PFS, objective response rate, and overall survival, compared to lenvatinib monotherapy. There was no pre-specified plan for multiple comparisons.

The most common adverse reactions (greater than 30%) with lenvatinib in combination with everolimus were diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, decreased weight, bleeding events, and proteinuria. Diarrhea was increased with the combination of lenvatinib plus everolimus, 19 % grade 3-4, and was added to the package insert as a new safety Warning.

The recommended dose and schedule is lenvatinib 18 mg plus everolimus 5 mg taken by mouth once daily.

This application was approved before the Prescription Drug User Fee Act (PDUFA) goal date of May 16, 2016. Lenvatinib in combination with everolimus received Breakthrough Therapy Designation for the treatment of advanced renal cell cancer following one prior anti-angiogenic therapy and the application was granted Priority Review. A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206947s003lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

 

February 13, 2015

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206947s000lbl.pdf

 On February 13, 2015, the U. S. Food and Drug Administration approved lenvatinib (LENVIMA) for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer.

The approval of lenvatinib was based on the demonstration of improved progression free survival (PFS) in a multicenter, double-blind, placebo-controlled trial (E7080-G00-303). The trial enrolled 392 patients with locally recurrent or metastatic radioactive iodine-refractory differentiated thyroid cancer and radiographic evidence of disease progression within 12 months prior to randomization. Patients were randomized (2:1) to receive either lenvatinib 24 mg orally per day (n = 261) or matching placebo (n = 131). Patients in the placebo arm were allowed to receive lenvatinib following independent radiologic confirmation of disease progression.

A statistically significant prolongation of PFS as determined by independent radiology review was demonstrated [HR 0.21 (95% CI: 0.16, 0.28); p < 0.001, stratified log-rank test]. Median PFS was 18.3 months in the lenvatinib arm and 3.6 months in the placebo arm. Objective response rates were 65% and 2% in the lenvatinib and placebo arms, respectively. No statistically significant difference in overall survival between the two arms was demonstrated. Upon confirmation of progression, 109 (83%) patients randomly assigned to placebo received open-label lenvatinib. The most common adverse reactions, in order of decreasing frequency, observed in the lenvatinib treated patients were hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia.

The most common serious adverse reactions were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of patients receiving lenvatinib and 18% of patients discontinued lenvatinib for adverse reactions.

The recommended dose of lenvatinib is 24 mg taken orally once daily. Treatment should continue until disease progression or unacceptable toxicity.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206947s000lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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