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FDA grants priority review for full approval of Tafinlar and Mekinist combination in BRAF V600 mutation-positive melanoma


The FDA ( Food and Drug Administration ) granted Priority Review in metastatic melanoma for the supplemental New Drug Application ( sNDA ) for the combination of Tafinlar ( Dabrafenib ) and Mekinist ( Trametinib ), which included data from the COMBI-d and COMBI-v studies.

Since January 2014, the combination of Tafinlar and Mekinist has been approved for use in the US in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma as detected by an FDA-approved test. The combination was approved through the FDA's Accelerated Approval program and reviewed under a Priority Review designation.
The approval was contingent on the results of the COMBI-d study, which was designed to evaluate the clinical benefit of the combination in patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

COMBI-d study

COMBI-d is a pivotal phase III, randomized, double-blinded study comparing the combination of the BRAF inhibitor, Tafinlar, and the MEK inhibitor, Mekinist, to single agent therapy with Tafinlar and placebo in patients with unresectable ( stage IIIC ) or metastatic ( stage IV ) BRAF V600E/K mutation-positive cutaneous melanoma.

The study randomized 423 patients at investigative sites in Australia, Europe and North and South America.
The primary endpoint of this study was investigator-assessed progression-free survival. Secondary endpoints included overall survival, overall response rate ( ORR ), duration of response ( DoR ), and safety.

Updated results from the COMBI-d study showed that the combination of Tafinlar and Mekinist achieved a statistically significant overall survival benefit compared to Tafinlar monotherapy ( median of 25.1 months vs 18.7 months; hazard ratio, HR 0.71 [ 95% CI, 0.55-0.92 ], p=0.011 ). In those who received the Tafinlar and Mekinist combination, overall survival was 74% at 1 year and 51% at 2 years versus 68% and 42% for those who received Tafinlar only, respectively.

The analysis for the combination also showed median progression-free survival of 11.0 months, overall response rate of 69%, and median duration of response of 12.9 months.

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 ( greater than or equal to 20% ) in the combination arm were pyrexia, fatigue, nausea, headache, chills, diarrhea, rash, joint pain ( arthralgia ), hypertension, vomiting, cough, and peripheral edema.
More patients had adverse effects leading to dose modifications in the combination arm compared to Tafinlar monotherapy. Increased incidence ( 57% vs 33% ) and severity ( grade 3, 7% [ n=15 ] vs 2% [ n=4 ] ) of pyrexia occurred with combination treatment as compared to Tafinlar monotherapy.
There was a lower incidence of cutaneous squamous cell carcinoma ( cuSCC ) including keratoacanthoma with the combination arm ( 3% [ n=6 ] ) compared to the Tafinlar monotherapy arm ( 10% [ n=22 ] ).

Discontinuation of treatment due to adverse events occurred in 11% ( n=24 ) vs 7% ( n=14 ) of patients in the combination group and the monotherapy group, respectively.

COMBI-v study

COMBI-v was a two-arm, open-label, phase III study comparing the combination of Tafinlar and Mekinist combination therapy with Vemurafenib monotherapy in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. The primary endpoint of this study was overall survival.

Results from the COMBI-v study showed a 31% decrease in the risk of death for patients treated with Tafinlar and Mekinist combination therapy compared to Vemurafenib monotherapy ( HR=0.69 [ 95% CI, 0.53-0.89 ], p=0.005 ).

At 12 months, the rate of overall survival was 72% for the combination of Tafinlar and Mekinist and 65% for Vemurafenib monotherapy.

The analysis for the combination also showed median progression-free survival of 11.4 months, overall response rate of 64%, and median duration of response of 13.8 months.

The most frequent adverse events in the Tafinlar and Mekinist combination arm ( greater than or equal to 30% ) were pyrexia, nausea, diarrhea, and chills.
More patients had adverse effects leading to dose modifications in the combination arm compared to the Vemurafenib monotherapy arm.

For the combination group compared to the Vemurafenib group, there was a lower incidence of rash, 22% ( n=76 ) vs 43% ( n=149 ); photosensitivity reaction, 4% ( n=13 ) vs 22% ( n=78 ); hand-foot syndrome, 4% ( n=14 ) vs 25% ( n=87 ); skin papillomas, 2% ( n=6 ) vs 23% ( n=80 ); squamous-cell carcinomas and keratoacanthomas, 1% ( n=5 ) vs 18% ( n=63 ); and hyperkeratosis, 4% ( n=15 ) vs 25% ( n=86 ).
Adverse events occurring more frequently in the combination arm compared with the Vemurafenib arm included pyrexia, 53% ( n=184 ) vs 21% ( n=73 ), respectively, and bleeding events, 18% ( n=62 ) vs 7% ( n=25 ), respectively.

Discontinuation of treatment due to adverse events was similar between the treatment groups: 13% ( n=44 ) for the combination group compared to 12% ( n=41 ) for the monotherapy group. ( Xagena )

Source: Novartis, 2015

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