Lenvatinib: Breakthrough Therapy Status for RCC
The FDA has granted Breakthrough Therapy designation to
lenvatinib (marketed under the brand name, Lenvima, by Eisai Inc.) for
the treatment of patients with advanced or metastatic renal cell
carcinoma who were previously treated with a vascular endothelial growth
factor (VEGF)-targeted therapy.
Lenvatinib is a receptor tyrosine kinase inhibitor that
inhibits the kinase activities of vascular endothelial growth factor
receptors VEGFR1-3.
The drug was approved earlier this year for the
treatment of patients with differentiated thyroid cancer whose disease
has progressed despite receiving radioactive iodine therapy (OT 3/10/15 issue).
The Breakthrough Therapy designation, enacted as part of
the FDA's 2012 Safety and Innovation Act, was created to expedite the
development and review time of a potential new drug for serious or
life-threatening disease where early clinical evidence suggests the drug
may demonstrate substantial improvement compared with existing
therapies.
The new designation for lenvatinib was based on the
results of a Phase II open-label, multicenter study of 153 patients who
had previously been treated with a VEGF-targeted therapy. Patients were
randomized to receive lenvatinib and everolimus, lenvatinib alone, or
everolimus alone—and the combination showed a clear benefit in terms of
progression-free survival compared with the patients receiving either
monotherapy (OT 7/25/15 issue).
The median duration of response was longest in the
patients receiving the drug combination (13.1 months), compared with
patients receiving only lenvatinib (7.5 months) or only everolimus (8.5
months).
Priority Review to Combination for Melanoma
The FDA also gave Priority Review status to the
combination of Tafinlar (dabrafenib) and Mekinist (trametinib) for the
treatment of patients with unresectable or metastatic melanoma with a
BRAF V600 mutation.
The drugs are oral agents used to block signaling in
different sites of the same molecular pathway that promotes cancer cell
growth—Tafinlar is a BRAF inhibitor and Mekinist is a MEK inhibitor.
Tafinlar and Mekinist were each already approved in 2013 as single agents (OT 6/25/13 issue); and the drug combination therapy was approved last year under the FDA's Accelerated Approval program (OT 2/10/14 issue).
That approval, though, was contingent on the results of the COMBI-d
study, which was designed to evaluate the clinical benefit of the
Tafinlar/Mekinist combination therapy in patients with unresectable or
metastatic melanoma with a BRAF V600 mutation.
The FDA's priority review designation shortens the time
to complete a drug's review and aims to deliver a decision on marketing
approval designation for drugs that may offer major advances in
treatment or provide a treatment where no adequate therapy exists within
six months under the Prescription Drug User Fee Act (PDUFA). The FDA
action date for the drug combination is November 2015.
The double-blinded, Phase III COMBI-d study included 423
patients with unresectable or metastatic BRAF V600E/K mutation-positive
cutaneous melanoma, who were randomized to receive the
Tafinlar/Mekinist combination or therapy with Tafinlar and placebo. The
updated results showed that patients receiving the Tafinlar/Mekinist
combination had a median survival of 25.1 months compared with 18.7
months for patients receiving Tafinlar and placebo.
Seventy four percent of patients receiving Tafinlar and
Mekinist were alive after one year of receiving the combination and 51
percent of the patients in that study arm were alive at two years,
compared with 68 percent and 42 percent respectively for patients in the
Tafinlar/placebo arm.
The safety results were consistent with the profile
observed to date for the combination and consistent with the profile
observed for Tafinlar monotherapy; no new safety concerns were observed.
The most common adverse events for patients receiving the
Tafinlar/Mekinist combination were pyrexia, fatigue, nausea, headache,
chills, diarrhea, rash, arthralgia, hypertension, vomiting, cough, and
peripheral edema.
There was a lower incidence of cutaneous squamous cell
carcinoma including keratoacanthoma with the Tafinlar/Mekinist arm (3%)
compared with the Tafinlar/placebo arm (10%). Eleven percent of patients
in the Tafinlar/Mekinist arm had to discontinue treatment due to
adverse events compared with seven percent of patients receiving
Tafinlar/placebo.
Both Tafinlar and Mekinist are marketed by Novartis.
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