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  1. Development & Approval Process (Drugs)

Drug Trials Snapshot: LENVIMA

Drug Trials Snapshot: LENVIMA

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the LENVIMA Package Insert for complete information.

LENVIMA™ (lenvatinib)
lehn-veema
Eisai Inc.
Approval date: February 13, 2015


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

LENVIMA is a medicine used to treat people with a type of thyroid cancer called differentiated thyroid cancer (DTC) that is progressing and can no longer be treated with a therapy called radioactive iodine. LENVIMA is a type of drug called a kinase inhibitor that works by blocking certain proteins from helping cancer cells grow and divide.

How is this drug used?

LENVIMA is a capsule that is taken by mouth once daily.

What are the benefits of this drug?

In the main trial that supported the FDA approval of LENVIMA, half of the patients treated with LENVIMA were alive without tumor growth for 18.3 months or longer, compared to 3.6 months for patients who received a placebo.

What are the benefits of this drug (results of trials used to assess efficacy)?

In the trial, half of the patients in the LENVIMA arm were alive with no growth of their tumor for 18.3 months or longer, compared to 3.6 months for patients who received a placebo.

Table 3 summarizes information on Progression Free Survival (time from the start of treatment until tumor growth or death) in the LENVIMA arm compared to placebo.

Table 3. Efficacy Results from the Clinical Trial

 

LENVIMA
N=261

Placebo
N=131

Progression-free Survival

Number of events (%)

107 (41)

113 (86)

Progressive disease

93 (36)

109 (83)

Death

14 (5)

4 (3)

Median PFS in months (95% CI)

18.3 (15.1, NE)

3.6 (2.2, 3.7)

Hazard ratio (95% CI)

0.21 (0.16, 0.28)

P-value

<>

Extracted from LENVIMA Package Insert, Table 4

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

Subgroup analyses were conducted for sex, race, and age.

  • Sex:  LENVIMA appeared to work similarly in men and women.
  • Race: Subgroup analysis was conducted for whites and Asians. LENVIMA appeared to work similarly in these groups. The number of non-white, non-Asian patients was limited, and therefore differences in response in these groups could not be determined.
  • Age:  Subgroup analysis was conducted for patients below and above 65 years of age. LENVIMA appeared to work similarly in these age groups.

Were there any differences in how well the drug worked in clinical trials among sex, race and age groups?

Subgroup analyses were conducted for sex, race, and age.

  • Sex:  LENVIMA appeared to work similarly in men and women.
  • Race: Subgroup analysis was conducted for whites and Asians. LENVIMA appeared to work similarly in these groups. The number of non-white, non-Asian patients was limited.
  • Age:  Subgroup analysis was conducted for patients below and above 65 years of age. LENVIMA appeared to work similarly in these age groups.

Figure 4. Progression Free Survival by demographic subgroup

Extracted from Statistical Review, Figure 4.1. A hazard ratio of less than 1 indicates that the treatment with lenvatinib is associated with lower risk of progression or death compared to the placebo treatment.

Extracted from Statistical Review, Figure 4.1

What are the possible side effects?

LENVIMA can cause serious side effects, including: high blood pressure (hypertension), heart problems, problems with blood clots in blood vessels (arteries), liver problems, increased protein in urine (proteinuria) and kidney failure, an opening in the wall of the stomach or intestines (perforation) or an abnormal connection between two parts of the gastrointestinal tract (fistula), changes in the electrical activity of the heart called QT prolongation that may lead to sudden death, low levels of blood calcium (hypocalcemia), low levels of calcium in the blood (hypocalcemia), the simultaneous occurrence of headache, confusion, seizures and visual changes (in a condition called Reversible Posterior Leukoencephalopathy Syndrome), serious bleeding (hemorrhage), risks to an unborn child if a patient becomes pregnant during treatment, and impairing suppression of the production of thyroid-stimulating hormone.

In the clinical trial, the most common side effects of LENVIMA were high blood pressure (hypertension), fatigue, diarrhea, joint and muscle pain (arthralgia/myalgia), decreased appetite, decreased weight, nausea, inflammation of the lining of the mouth (stomatitis), headache, vomiting, excess protein in the urine (proteinuria), swelling and pain in the palms, hands and/or the soles of the feet (called palmar-plantar erythrodysesthesia syndrome, or PPE), abdominal pain and changes in voice volume or quality (dysphonia).

What are the possible side effects (results of trials used to assess safety)?

The table below summarizes adverse reactions that occurred in at least 10% of the LENVIMA-treated group.

Table 4. Adverse Reactions Occurring in at Least 10% of LENVIMA-treated Patients


Adverse Reaction
LENVIMA 24 mg
N=261
(%)
Placebo
N=131
(%)
Hypertension7316
Diarrhea6717
Fatigue6735
Arthralgia/Myalgia6228
Decreased appetite5418
Weight decreased5115
Nausea4725
Stomatitis418
Headache3811
Vomiting3615
Proteinuria343
Palmar-plantar erythrodysesthesia321
Abdominal pain3111
Dysphonia315
Constipation2915
Oral pain252
Cough2418
Edema peripheral218
Rash213
Dysgeusia183
Dry mouth178
Dizziness159
Dyspepsia134
Alopecia125
Epistaxis121
Insomnia123
Urinary tract infection115
Dental and oral infections101

Extracted from LENVIMA Package Insert, Table 2

Were there any differences in side effects among sex, race and age?

Subgroup analyses were conducted for sex, race and age.

  • Sex: Although the incidence of overall side effects was similar for men and women, certain side effects—called serious adverse events1—were observed more frequently in women compared to men. Other events (listed in MORE INFO) were observed more frequently in women compared to men.
  • Race: Certain side effects (listed in MORE INFO) were seen more frequently in Whites compared with Asians, while others were seen less frequently. It is unclear if these differences are clinically meaningful. The number of non-White, non-Asians was limited and therefore differences could not be determined.
  • Age: Subgroup analyses were conducted for ages below 65, ages 65 to 74, and 75 years and above. The incidence of overall side effects was similar across these age groups. Certain side effects—called serious adverse events1—were seen more frequently in patients 75 years and above.

 1 Serious adverse event was defined as any event that resulted in one of the following: death, life-threatening event, required hospitalization or extended a current hospital stay, persistent or significant disability/incapacity, or congenital anomaly or birth defect.

Table 5. Percentage of Subjects with AEs and SAEs by Sex

 LENVIMA
N=261
%
Placebo
N=131
%
CategoryMale
N=125
Female
N=136
Male
N=75
Female
N=56
Subjects with
an AE
100998991
Subjects with
an SAE
46602423

Extracted from Clinical Review, Table 64

Table 6. Adverse Events Observed More Frequently (at least 10% difference) in Females Compared to Males in LENVIMA-treated Patients

 Male
N=200
Female
N=192
LENVIMA
N=125
n (%)
Placebo
N=75
n (%)
LENVIMA
N=136
n (%)
Placebo
N=56
n (%)
Hypertension79 (63.2)8 (10.7)102 (75)12 (21.4)
Headache40 (32)5 (6.7)60 (44.1)10 (17.9)
Nausea42 (33.6)18 (24)80 (58.8)15 (26.8)
Stomatitis38 (30.4)5 (6.7)58 (42.6)4 (7.1)
Fatigue46 (36.8)20 (26.7)65 (47.8)12 (21.4)
Proteinuria33 (26.4)3 (4.0)55 (40.4)1 (1.8)
Vomiting32 (25.6)12 (16)61 (44.9)7 (12.5)

Extracted from Applicant’s Submission

Table 7. Adverse Events Observed More Frequently (at least 10% difference) in Asians Compared to Whites 

 

 

White
N=311

Asian
N=70

LENVIMA
N=208
n (%)

Placebo
N=103
n (%)

LENVIMA
N=46
n (%)

Placebo
N=24
n (%)

Hypertension

140 (67.3)

12 (11.7)

37 (80.4)

4 (16.7)

Peripheral edema

37(17.8)

7 (6.8)

15 (32.6)

2 (8.3)

PPE

51 (24.5)

1 (1)

28 (60.9)

0

Thrombocytopenia

9 (4.3)

1 (1)

14 (30.4)

2 (8.3)

PPE=Palmar-Plantar Erythrodysesthesia Syndrome
Extracted from Summary of Clinical Safety

Table 8. Adverse Events Observed More Frequently (at least 10% difference) in Whites Compared to Asians

 

 

White
N=311

Asian
N=70

LENVIMA
N=208
n (%)

Placebo
N=103
n (%)

LENVIMA
N=46
n (%)

Placebo
N=24
n (%)

Weight decreased

112 (53.8)

13 (12.6)

16 (34.8)

5 (20.8)

Extracted from Summary of Clinical Safety

Table 9. Incidence of Adverse Events by Age Group

 

LENVIMA
N=261
n (%)

Placebo
N=131
n (%)

 

Category

below 65 yrs
(N=143)

n (%)

65-<75yrs>
(N=89)

n (%)

≥75yrs
(N=29)

n (%)

<65yrs>
(N=77)

n (%)

65-<75yrs>
(N=45)

n (%)

≥75yrs
(N=9)

n (%)

Subjects with an SAE

75 (52)

46 (52)

18 (62)

17 (22)

13 (29)

1 (11)

Subjects with AE

143 (100)

89 (100)

28 (97)

67 (87)

43 (96)

8 (89)

SAE=serious adverse event; AE=adverse event
Extracted from Clinical Review for LENVIMA, Table 63

WHO WAS IN THE STUDIES?

Who participated in the clinical trials?

The FDA approved LENVIMA based on evidence from one clinical trial of 392 patients with differentiated thyroid cancer (DTC) that was worsening and could no longer be treated with a treatment called radioactive iodine. The trial was conducted in North America, South America, Europe, Asia, Africa, and Australia.

Figure 1 summarizes how many men and women were enrolled in the clinical trial.

Figure 1. Baseline Demographics by Sex  

Pie chart summarizing how many men and women were enrolled in the clinical trials used to evaluate efficacy of the drug LENVIMA.  In total, 200 men (51%) and 192 women (49%) participated in the clinical trials used to evaluate efficacy of the drug LENVIMA.

Extracted from Clinical review for LENVIMA, Table 12

Figure 2 and Table 1 summarize the percentage of patients by race enrolled in the clinical trial.

Figure 2. Baseline Demographics by Race

Bar chart summarizing the percentage of patients by race enrolled in the clinical trials used to evaluate efficacy of the drug LENVIMA. In total, 311 White (79.3%), 8 Black (2.0%), 70 Asian (17.9%), 1 Native Hawaiian/other Pacific Islander (0.3%), and 2 identified as Other (0.5%), participated in the clinical trials used to evaluate efficacy of the drug LENVIMA.

Extracted from Clinical review for LENVIMA, Table 12

Table 1. Demographics of Trial by Race

Race

Number of Patients

Percentage

White

311

79.3%

Black/African American

8

2.0%

Asian

70

17.9%

Native Hawaiian/other
Pacific Islander

1

0.3%

Other

2

0.5%

Extracted from Clinical review for LENVIMA, Table 12 

Figure 3 and Table 2 summarizes the percentage of patients enrolled in the clinical trial by age.

Figure 3. Baseline Demographics by Age

Pie chart summarizing how many individuals below and above 65 years of age were enrolled in the clinical trials used to evaluate efficacy of the drug LENVIMA.  In total, 156 were over the age of 65 (40%) and 236 were 65 years of age or under (60%).

Extracted from Clinical review for LENVIMA, Table 12, page 56

Table 2. Baseline Demographics of Trial by Age

 

LENVIMA
N=261

Placebo
N=131

Total
N=392

Age (mean years)

62.1

61.5

61.9

Age group n (%)

 

Less than or equal to 65 years

155 (59.4)

81 (61.8)

236 (60.2)

Greater than 65 years

106 (40.6)

50 (38.2)

156 (39.8)

Extracted from Clinical review for LENVIMA, Table 12

Who participated in the trials?

LENVIMA was evaluated in one clinical trial in 392 patients with locally recurrent or metastatic radioactive iodine-refractory differentiated thyroid cancer and evidence of disease progression within 12 months prior to randomization on scans, confirmed by independent review by a radiology physician. The trial was conducted in North America, South America, Europe, Asia, Africa, and Australia.

Table 10. Demographic and Baseline Characteristics (Intent to Treat Population)


Variable

LENVIMA
(N=261)

Placebo
(N=131)

Total
(N=392)

Age (year)

Mean

62.1

61.5

61.9

Median

64

61

63

Age group n (%)

 

 

 

≤ 65yrs

155 (59.4)

81 (61.8)

236 (60.2)

> 65yrs

106 (40.6)

50 (38.2)

156 (39.8)

Sex n (%)

   

Male

125 (47.9)

75 (57.3)

200 (51)

Female

136 (52.1)

56 (42.7)

192 (49)

Region n (%)

   

Europe

131 (50.2)

64 (48.9)

195 (49.7)

North America

77 (29.5)

39 (29.8)

116 (29.6)

Other

53 (20.3)

28 (21.4)

81 (20.7)

Race n (%)

 

 

 

White

208 (79.7)

103 (78.6)

311 (79.3)

Black/African American

4 (1.5)

4 (3.1)

8 (2.0)

Asian

46 (17.6)

24 (18.3)

70 (17.9)

Japanese

30 (11.5)

11 (8.4)

41 (10.5)

Other Asian

16 (6.1)

13 (9.9)

29 (7.4)

Native Hawaiian/other
Pacific Islander

1 (0.4)

0

1 (0.3)

Other

2 (0.8)

0

2 (0.5)

Source:  Clinical review for LENVIMA, Table 12, page 56

How were the trials designed?

In the trial, two-thirds of the patients were chosen at random to receive LENVIMA and one-third were given a placebo. Neither the patients nor the health care professionals administering the drug knew which patients were taking LENVIMA and which ones were taking a placebo. They remained in these groups until their disease began to get worse.  If the disease progressed, those taking placebo were allowed to receive LENVIMA.

How were the trials designed?

Efficacy of LENVIMA was evaluated in a multicenter, randomized (2:1), double-blind, placebo-controlled trial in 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, confirmed by independent radiologic review.

Patients were randomized to receive LENVIMA 24 mg once daily or placebo until disease progression. Randomization was stratified by geographic region, prior VEGF/VEGFR-targeted therapy, and age.

The major efficacy outcome measure was progression-free survival as determined by blinded independent radiologic review using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PACKAGE INSERT

MEDICAL REVIEW

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