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Lenvima™ - lenvatinib
Manufacturer: Patheon Inc.
FDA Approval Date: February 13, 2015
LENVIMA™ - lenvatinib
Clinical Application
• Indications:
• Treatment of patients with locallyrecurrent or metastatic, progressive,
radioactive iodine-refractory
differentiated thyroid cancer (DTC)
• Place in therapy:
• Used in conjunction with thyroidhormone-suppression therapy for DTC
that is refractory to iodine-131 therapy
LENVIMA™ - lenvatinib
Clinical Application
• Contraindications:
• None
• Black Box Warnings
• None
LENVIMA™ - lenvatinib
Clinical Application
• Warnings and Precautions
• HTN, cardiac failure, QT prolongation
• Proteinuria, renal impairment
• Hepatotoxicity, GI perforation/fistulas
• Hemorrhage, arterial thrombosis
• Hypocalcemia, impaired TSH suppression
• Reversible posterior leukoencephalopathy
syndrome
• Embryofetal toxicity
LENVIMA™ - lenvatinib
Clinical Application
• Pregnancy:
• Based on its mechanism and data from
animal studies, can cause fetal harm
• Reproductive-age females should use
effective contraception while on
lenvatinib and for at least 2 weeks
following discontinuation
• Lactation:
• Discontinue during lenvima treatment
LENVIMA™ - lenvatinib
Drug Facts
• Pharmacology:
• Receptor tyrosine kinase (RTK) inhibitor
which inhibits the kinase activities of
vascular endothelial growth factor
(VEGF) receptors VEGFR1 (FLT1),
VEGFR2 (KDR), and VEGFR3 (FLT4)
• Also inhibits other RTKs implicated in
angiogenesis, tumor growth, and cancer
progression.
LENVIMA™ - lenvatinib
Drug Facts
• Pharmacokinetics:
A
D
M
E
Tmax: 1-4 hours; delayed ~2 hours by
administration with food
Protein binding: 98-99%
Primarily CYP3A4; also aldehyde
oxidase and non-enzymatic
processes
Feces (64%), urine (25%). Elimination
t1/2: ~28 hours
LENVIMA™ - lenvatinib
Drug Interactions
• Pharmacokinetic
• None known to be clinically significant
• Pharmacodynamic
• May result in  QTc-prolongation when
used with other QTc-prolonging agents
LENVIMA™ - lenvatinib
Adverse Effects (≥ 20%)
Hypertension (73%) [16%]
Headache (38%) [11%]
Diarrhea (67%) [17%]
Vomiting (36%) [15%]
Fatigue (67%) [35%]
Proteineuria (34%) [11%]
Arthralgia/myalgia (62%) [28%]
Dysphonia (31%) [5%]
Decreased appetite (54%) [18%]
Abdominal pain (31%) [11%]
Weight decreased (51%) [15%]
Constipation (29%) [15%]
Nausea (47%) [25%]
Oral pain (25%) [2%]
Stomatitis (41%) [8%]
Rash (21%) [3%]
Palmar-plantar
Peripheral edema (21%) [8%]
erythrodysesthesia (32%) [1%]
LENVIMA™ - lenvatinib
Monitoring Parameters
• Efficacy Monitoring:
• Radiographic evidence of disease
progression
• Toxicity Monitoring
• BP, proteinuria on urinalysis
• Liver/renal function, electrolytes, TSH
• QTc interval, LVEF
• Symptoms of cardiac decompensation,
thromboembolism, GI perforation/fistula,
RPLS
LENVIMA™ - lenvatinib
Prescription Information
• Dosing: 24 mg PO once daily at the
same time each day (not to exceed 2
doses within a 12 hour period)
Dose adjustments
• CrCl ≤ 30 mL/min: 14 mg PO once daily
• Severe hepatic impairment (Child-Pugh
C): 14 mg PO once daily
LENVIMA™ - lenvatinib
Prescription Information
• Adjustments for Toxicity
• Grade 2/3 adverse reaction or grade 4 lab
abnormality: interrupt lenvatinib therapy
until resolved, then resume at:
• 20 mg PO once daily (1st occurrence)
• 14 mg PO once daily (2nd occurrence)
• 10 mg PO once daily (3rd occurrence)
LENVIMA™ - lenvatinib
Prescription Information
• Discontinuation criteria
• Life-threatening HTN, grade 4 cardiac
dysfunction, arterial thrombotic event,
hepatic failure, nephrotic syndrome,
severe renal impairment, GI perforation,
life-threatening fistula, severe RPLS,
grade 4 hemorrhage
LENVIMA™ - lenvatinib
Prescription Information
• Cost: 24 mg (30d): $14,371
• Cost Comparison
• Caprelsa®- vandetanib: 300 mg (30d):
$12,331
• Nexavar®- sorafenib: 400mg BID (30d):
$12,588
• All costs per GoodRx.com, accessed
03/14/2015
LENVIMA™ - lenvatinib
Literature Review
• Purpose: assess progression-free
survival among patients with iodine131-refractory, progressive DTC who
received levatinib as compared with
those who received placebo
• Design: phase 3, randomized, double-
blind, placebo-controlled, multicenter
Schlumberger M, et al. N Engl J Med 2015;372(7):621-630.
LENVIMA™ - lenvatinib
Literature Review
Inclusion
•Age ≥18
Exclusion
• > 1 prior treatment regimen
•Iodine-131 refractory DTC w/ with a tyrosine kinase inhibitor
evidence of progression
•Any anticancer treatment 21
within the past 13 months
days before randomization
•Thyroid-hormone-
suppression therapy (TSH ≤
0.50 mIU/L)
Schlumberger M, et al. N Engl J Med 2015;372(7):621-630.
LENVIMA™ - lenvatinib
Literature Review
• Primary end point: progression-free
survival (PFS)
• Secondary end points: response rate,
overall survival
Schlumberger M, et al. N Engl J Med 2015;372(7):621-630.
LENVIMA™ - lenvatinib
Literature Review
• Allocation: 2:1 to lenvatinib 24 mg PO
once daily or placebo in 28-day cycles
• Dose interruptions and dose
reductions (to 20 mg, 14 mg, or 10 mg
per day) were permitted for toxicity
• Upon evidence of progression,
placebo-assigned patients could
receive open-label lenvatinib
Schlumberger M, et al. N Engl J Med 2015;372(7):621-630.
LENVIMA™ - lenvatinib
Literature Review
Baseline
Characteristics
Lenvatinib
(n=261)
Placebo
(n=131)
64
61
Male sex (%)
47.9
57.3
ECOG status 0-1 (%)
95.0
98.5
Prior TKI use (%)
25.3
20.6
Papillary
50.6
51.9
Poorly different.
10.7
14.5
Follicular
20.3
16.8
Hürthle cell
18.4
16.8
Bony
39.5
36.6
Pulmonary
86.6
94.7
Median age (years)
Subtype
Metastatic lesions
Schlumberger M, et al. N Engl J Med 2015;372(7):621-630.
LENVIMA™ - lenvatinib
Literature Review
Results- Efficacy Outcomes
Lenvatinib
(n=261)
Median PFS
(months)
Response
rate (%)
Overall
survival
18.3
64.8
N/A
Placebo
(n=131)
HR/OR (CI)
HR 0.21
3.6
(99% CI 0.14-0.31)
OR 28.87 (95% CI
1.5
12.46-66.86)
N/A
HR 0.73
(95% CI 0.50-1.07)
P value
< 0.001
< 0.001
0.10
Schlumberger M, et al. N Engl J Med 2015;372(7):621-630.
LENVIMA™ - lenvatinib
Literature Review
• Most Common AEs: HTN (67.8%)
[9.2%], diarrhea (59.4%) [8.4%],
fatigue/asthenia (59.0%) [27.5%]
• In the levatinib group, more dose
interruptions (82.4% vs. 18.3%) & dose
reductions (67.8% vs. 4.6%) vs.
placebo mean levatinib dose: 17.2
mg per day
Schlumberger M, et al. N Engl J Med 2015;372(7):621-630.
LENVIMA™ - lenvatinib
Literature Review
• Study drug discontinuation because
of AEs: 14.5% of levatinib group vs
2.3% of placebo group
• Levatinib group: 6/20 deaths that
occurred were attributed to treatment
Schlumberger M, et al. N Engl J Med 2015;372(7):621-630.
LENVIMA™ - lenvatinib
Literature Review
• Conclusions
• In patients with progressive, radioactive
iodine-refractory DTC, levatinib increased
progression-free survival and response
rate but did not affect overall survival
• Levatinib was associated with many
adverse effects which often required
dose interruption or reduction
Schlumberger M, et al. N Engl J Med 2015;372(7):621-630.
LENVIMA™ - lenvatinib
Summary
• Lenvima™, lenvatinib is an oral receptor
tyrosine kinase (RTK) inhibitor indicated for
the treatment of locally-recurrent or
metastatic, progressive, radioactive iodinerefractory differentiated thyroid cancer (DTC)
• Used in conjunction with thyroid-hormone-
suppression therapy
• The most common adverse effects are
hypertension (sometimes severe), diarrhea,
and fatigue
LENVIMA™ - lenvatinib
References
1.
http://www.lenvima.com
2.
Lenvima package insert. Patheon Inc. February
2015.
3.
Schlumberger M, Tahara M, Wirth LJ, et al.
Lenvatinib versus placebo in radioiodinerefractory thyroid cancer. N Engl J Med
2015;372(7):621-630.