The US Food and Drug Administration (FDA) has approved the first-ever combination therapy for advanced melanoma.
The combination of trametinib (Mekinist, GlaxoSmithKline), a MEK inhibitor, and dabrafenib (Tafinlar, GlaxoSmithKline), a BRAF inhibitor, was approved through the FDA Accelerated Approval Program.
Both drugs were approved last year for single-agent use.
The 2-drug combination is indicated for the treatment of patients with unresectable or metastatic melanoma and BRAF V600E or V600K mutations. These mutations must be detected with an FDA-approved test.
The approval of the combination is based on the response rate and median duration of response seen in a phase 1/2 study. The combination has not yet demonstrated an improvement in disease-related symptoms or overall survival.
This accelerated approval is contingent on the results of the ongoing phase 3 trial (known as MEK115306 or Combi-D).
"This approval marks another key moment in what continues to be a rapid evolution of the treatment landscape for metastatic melanoma patients. Combining agents that target different mechanisms regulating the growth of cancer cells is one of the promising areas in cancer research," said Paolo Paoletti, MD, president of oncology at GlaxoSmithKline, in a press statement.
Results That Led to Approval
The results that led to the accelerated approval come from a randomized phase 2 open-label study in which patients treated with the combination had an overall response rate (ORR) of 76%, compared with 54% for patients treated with single-agent dabrafenib.
In addition, the median duration of response was longer with the combination than with single-agent dabrafenib (10.5 vs 5.6 months).
These were the findings that were reported by the investigators.
However, a blinded independent radiologic review committee (IRRC) assessed the same results somewhat differently.
The IRRC-assessed ORR was 57% for patients treated with the combination and 46% for patients treated with single-agent dabrafenib. The IRRC-assessed median duration of response was 7.6 for both the combination and single-agent therapy.
Adverse Effects With the Combination
Trametinib in combination with dabrafenib can cause serious adverse effects, including new primary cutaneous and noncutaneous malignancies.
The combination comes with a warning that the therapy is associated with an increased incidence of basal cell carcinoma. The incidence was 9% (5 of 55) in patients receiving the combination, compared with 2% (1 of 53) in patients receiving dabrafenib alone.
Dabrafenib also resulted in an increased incidence of cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma. Cutaneous squamous cell carcinoma, including keratoacanthoma, occurred in 7% of patients receiving the combination and 19% of patients receiving single-agent dabrafenib.
However, the secondary cutaneous squamous cell carcinomas and keratoacanthomas are relatively benign, compared with melanoma, and are no reason to discontinue BRAF inhibition, a melanoma expert previously told Medscape Medical News.
Nonetheless, all patients on a BRAF inhibitor should be tested for RAS mutations; if present, the mutations place a patient at increased risk for secondary cancers in organs beyond the skin, advised Ashani T. Weeraratna, PhD, from The Wistar Institute in Philadelphia.
"Although cutaneous squamous cell carcinomas are not deadly, these lesions can be life-threatening when they occur in other organs," Dr. Weeraratna explained.
Other serious adverse effects seen in patients treated with the combination include hemorrhagic events, venous thromboembolic events, cardiomyopathy, ocular toxicities, interstitial lung disease, serious febrile drug reactions, serious skin toxicity, hyperglycemia, hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency, and embryo-fetal toxicity.
In the phase 2 study, the most common adverse effects at the recommended dose of trametinib 2 mg once daily in combination with dabrafenib 150 mg twice daily (all grades in more than 20% of patients) include pyrexia (71%), chills (58%), fatigue (53%), rash (45%), nausea (44%), vomiting (40%), diarrhea (36%), abdominal pain (33%), edema peripheral (31%), cough (29%), headache (29%), arthralgia (27%), night sweats (24%), decreased appetite (22%), constipation (22%), and myalgia (22%).
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Cite this: FDA Approves First Combination Therapy for Melanoma - Medscape - Jan 09, 2014.