In separate decisions, the European Commission has approved panobinostat (Farydak, Novartis) for the treatment of multiple myeloma and the combination of dabrafenib (Tafinlar, Novartis) and trametinib (Mekinist, Novartis) for use in advanced melanoma.
The European approvals follow positive opinions on both products issued in June.
The approval of panobinostat, an oral drug, is for use in combination with bortezomib (Velcade, Millennium) and the anti-inflammatory agent dexamethasone for the treatment of adults with relapsed and/or refractory multiple myeloma who have received at least two previous regimens, including bortezomib and an immunomodulatory agent.
In the United States, panobinostat has been approved for the same indication.
Panobinostat, the first histone deacetylase inhibitor available in the European Union, represents a new treatment option for patients living with multiple myeloma whose disease has progressed after standard-of-care therapy, according to a company press statement.
"Patients with multiple myeloma often relapse or stop responding to treatments. Panobinostat offers a new mechanism of action, which may improve the effectiveness of response to standard-of-care treatment in patients," said Philippe Moreau, MD, from the Centre Hospitalier Universitaire de Nantes in France, in the statement.
It is theorized that the epigenetic activity of panobinostat helps restore cell function in patients with multiple myeloma.
The European approval of panobinostat is based on a subgroup analysis of 147 patients enrolled in the pivotal phase 3 PANORAMA-1 trial who had received at least two previous regimens, including bortezomib and an immunomodulatory agent.
In PANORAMA-1, the combination of panobinostat, bortezomib, and dexamethasone was compared with the combination of placebo, bortezomib, and dexamethasone in patients with relapsed and/or relapsed and refractory multiple myeloma.
Median progression-free survival was 7.8 months longer in the panobinostat group than in the placebo group (12.5 vs 4.7 months; hazard ratio [HR], 0.47).
The most common nonhematologic adverse reactions included diarrhea, fatigue, nausea, and vomiting. Treatment-emergent hematologic toxicities included thrombocytopenia, anemia, neutropenia, and lymphopenia.
Cardiac events — most frequently atrial fibrillation, tachycardia, palpitation, and sinus tachycardia — were more common in the panobinostat group than in the placebo group (17.6% vs 9.8%), as were syncope events (6.0% vs 2.4%). The tachycardia-associated metric of QTc prolongation of more than 480 msec and less than 500 msec was recorded in 1.3% of patients, and a change from baseline of more than 60 msec was recorded in 0.8% of patients. No patients had an absolute QTc prolongation of more than 500 msec.
Discontinuation related to adverse events occurred in 36.2% of patients. The most common adverse events leading to treatment discontinuation were diarrhea (4.5%), asthenia (2.9%), fatigue (2.9%), and pneumonia (1.3%).
On-treatment deaths not related to multiple myeloma were more common in the panobinostat group than in the placebo group (6.8% vs 3.2%).
Melanoma Combination Is Better Than Monotherapy
The approval of the combination of dabrafenib and trametinib is for use in adults with unresectable or metastatic melanoma with a BRAF V600 mutation, which accounts for about 40% of all melanomas and is particularly aggressive.
Both drugs are already approved for use in melanoma in Europe, but for individual use. The combination is already approved in the United States.
The new European marketing authorization is based on results from the phase 3 COMBI-d and COMBI-v studies.
In COMBI-d, median overall survival was 6 months longer with the combination than with dabrafenib monotherapy (25.1 vs 18.7 months; HR, 0.71; P = .011). More patients in the combination group than in the monotherapy group were alive at 1 year (74% vs 68%) and at 2 years (51% vs 42%).
Safety results from the COMBI-d study were consistent with the profile observed to date for the combination, and no new safety concerns were observed.
In the combination group, the most common adverse events (affecting at least 20% of patients) were pyrexia, fatigue, nausea, headache, chills, diarrhea, rash, joint pain (arthralgia), hypertension, vomiting, cough, and peripheral edema.
The COMBI-v study used another BRAF inhibitor, vemurafenib (Zelboraf, Plexxikon/Roche), as the comparator. The 705-patient trial was stopped early because of the benefit that emerged at an interim analysis.
At that time, median overall survival, the primary end point of COMBI-v, was significantly better with the combination of dabrafenib and trametinib than with vemurafenib monotherapy (not yet reached vs 17.2 months; HR, 0.69; P = .005). At a median follow-up of 10 to 11 months, the mortality rate was lower in the combination group than in the monotherapy group (28% vs 35%).
Early results from COMBI-v were presented at the 2014 European Society for Medical Oncology Congress. At the time, melanoma experts said the combination of a BRAF inhibitor and a MEK inhibitor should become the standard of care in patients with advanced melanoma that is BRAF-mutation-positive, and urged that the combination be used instead of a BRAF inhibitor alone.
Updated results from COMBI-v will be presented at an upcoming medical congress.
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Cite this: Europe Approves Multiple Myeloma, Melanoma Therapies - Medscape - Sep 04, 2015.