Approval Announcement
WOODCLIFF LAKE, N.J., May 13, 2016 /PRNewswire/ -- Eisai Inc. announced that the U.S. Food and Drug Administration (FDA) has approved Lenvima (lenvatinib) — a multiple receptor tyrosine kinase inhibitor — in combination with everolimus for the treatment of patients with advanced renal cell carcinoma (aRCC) who were previously treated with an anti-angiogenic therapy.
Approval Designations
Lenvima was granted Breakthrough Therapy designation by the FDA for this indication.
The application received Priority Review — a designation for drugs that the FDA believes have the potential to provide a significant improvement in the treatment of a serious condition.
Basis for Approval: Study 205 (Phase 2 Trial)
The approval is based on results from the registration study Study 205, a Phase 2 trial that compared the combination of Lenvima plus everolimus (LEN+EVE) versus everolimus alone (a standard of care for patients with aRCC who received prior anti-angiogenic therapy). The recommended dosage for the combination is 18 mg Lenvima plus 5 mg everolimus, administered once daily.
Key Efficacy Results
Progression-Free Survival (PFS):
Median PFS for the LEN+EVE combination (n=51) was 14.6 months (95% CI: 5.9–20.1), nearly three times that of everolimus alone (n=50), which had a median PFS of 5.5 months (95% CI: 3.5–7.1).
The combination resulted in a 63% reduction in the risk of disease progression or death (HR 0.37; 95% CI: 0.22–0.62).
The treatment effect on PFS was supported by a retrospective independent review.
Objective Response Rate (ORR):
ORR was 37% (95% CI: 24–52) in the combination group (35% partial response + 2% complete response).
ORR was 6% (all partial response, 95% CI: 1–17) in the everolimus alone group.
Overall Survival (OS):
Median OS for the LEN+EVE combination was 25.5 months (95% CI: 16.4–32.1), a 10.1-month increase compared to everolimus monotherapy (15.4 months [95% CI: 11.8–20.6]; HR 0.67; 95% CI: 0.42–1.08).
This OS analysis was conducted when 63% of deaths had occurred in the combination arm and 74% of deaths had occurred in the everolimus arm.
Expert Commentary
"Lenvatinib plus everolimus is the first and only FDA-approved regimen that successfully combines treatments that employ tyrosine kinase and mTOR inhibition, the primary targets of advanced RCC treatment for the past decade," said Robert Motzer, M.D., from Memorial Sloan Kettering Cancer Center, New York, and principal investigator of Study 205. "This combination regimen led to enhanced efficacy and helped patients with advanced RCC live longer without disease progression or death than those treated with everolimus alone. These noteworthy findings advance the treatment paradigm for this patient population."
Safety Profile (LEN+EVE Combination)
The safety of the Lenvima plus everolimus combination was evaluated in Study 205, with key safety findings as follows:
Serious Risks and Adverse Reactions
Serious Risks: May include hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, proteinuria, diarrhea, renal failure and impairment, gastrointestinal perforation and fistula formation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid-stimulating hormone suppression/thyroid dysfunction, and embryofetal toxicity.
Most Common Adverse Reactions (≥30%, in decreasing frequency)
Diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, weight decreased, hemorrhagic events, and proteinuria.
Most Common Serious Adverse Reactions (≥5%)
Renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%).
Dose Modifications Due to Adverse Reactions
89% of patients receiving Lenvima plus everolimus required dose reductions or interruption.
54% of patients receiving everolimus alone required dose reductions or interruption.
Most common adverse reactions (≥5%) leading to dose reductions in the combination group: diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%).
