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The approval was based on an extension in overall survival from two phase 3 studies.
The FDA has granted a full approval to the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) for patients with unresectable or metastatic BRAF-mutated melanoma, based on an extension in overall survival (OS) from two phase 3 studies.
In the COMBI-v trial, OS was extended by 7.6 months with Tafinlar and Mekinist compared with single-agent Zelboraf (vemurafenib).1 In the COMBI-d trial, OS was improved by 6.4 months compared with Tafinlar alone.2 Moreover, across both studies, the combination was found to induce fewer adverse events (AEs) compared with either agent alone.
"We’re inspired by the difference Tafinlar plus Mekinist can make for patients battling such a serious disease as metastatic melanoma," Bruno Strigini, president, Novartis Oncology the company developing the drug, said in a statement. “This approval of the combination in the US allows us to communicate more broadly with the melanoma community about the role of targeted therapies, our data, the possibility to improve clinical outcomes for patients, and our commitment to develop these medicines to their fullest potential.”
In the COMBI-v trial, 704 patients were randomized to receive Tafinlar plus Mekinist (352 patients) or Zelboraf (352 patients). In the combination arm, Tafinlar was administered at 150 mg twice daily with Mekinist at 2 mg once daily. Zelboraf was administered at 960 mg twice daily. Baseline characteristics were well balanced between the two groups.
The primary endpoint of the trial was OS, with secondary endpoints focused on progression-free survival (PFS), response and safety. The study was stopped early at the recommendation of an Independent Data Monitoring Committee, following the demonstration of benefit at an interim analysis. Crossover from the combination arm to Zelboraf was not allowed.
In an analysis presented at the 2015 European Cancer Congress,1 the median OS with Tafinlar/Mekinist was 25.6 months compared with 18 months with Zelboraf. The estimated two-year OS rate was 51 percent with the combination compared with 38 percent with Zelboraf monotherapy.
The median PFS was 12.6 months with the combination versus 7.3 months for Zelboraf. The objective response rate (ORR) was 64 percent with the combination versus 13 percent for Zelboraf alone. The median duration of response was 13.8 months compared with 7.5 months with Zelboraf.
For the approval, the FDA reviewed early data from the COMBI-v trial, which was published in The New England Journal of Medicine.3 In this analysis, the median OS had not yet been reached in the combination arm. For single-agent Zelboraf, the median OS was 17.2 months. Median PFS with the combination was 11.4 versus 7.3 months with Zelboraf alone.
In the phase 3 COMBI-d trial, 423 patients with BRAFV600E/K-mutant melanoma were randomized to receive Tafinlar with Mekinist (211 patients) or placebo (212 patients). The primary endpoint of the study was investigator-assessed PFS and OS was a secondary endpoint.
In a final analysis of the study presented at 2015 annual meeting of the American Society of Clinical Oncology (ASCO),2 the combination of Tafinlar and Mekinist demonstrated a median OS of 25.1 months compared with 18.7 months with Tafinlar alone. The two-year OS rate with the combination was 51 percent versus 42 percent with the single-agent.
Median PFS was 11.0 months with the combination compared with 8.8 months for Tafinlar plus placebo. The ORR was 69 percent versus 53 percent, for the combination and single-agent, respectively. The complete response rate was 16 percent in the combination arm compared with 13 percent for Tafinlar. Duration of response was 12.9 and 10.6 months in the combination and monotherapy arms, respectively.
The approval was based on an earlier assessment of data from the COMBI-d trial that was published in The Lancet.4 In this analysis, the median OS with Tafinlar plus Mekinist was 25.1 versus 18.7 months with Tafinlar alone. The median PFS was 9.3 months with the combination versus 8.8 months with Tafinlar alone.
In the COMBI-v trial, the most frequently reported AEs with the combination compared with Zelboraf, respectively, were pyrexia (53 percent vs 21 percent), chills (31 percent vs 8 percent) and vomiting (29 percent vs 15 percent). Discontinuation of treatment due to AEs was similar between the treatment groups (13 percent vs 12 percent).
A number of events were lower with the combination, particularly the incidence of rash (22 percent vs 43 percent), particularly grade 3 rash (1 percent vs 9 percent). Additionally, AEs were less frequent with the combination versus single-agent for photosensitivity reaction (4 percent vs 22 percent), hand-foot syndrome (4 percent vs 25 percent), skin papillomas (2 percent vs 23 percent), squamous-cell carcinomas and keratoacanthomas (1 percent vs 18 percent) and hyperkeratosis (4 percent vs 25 percent).
For the COMBI-d trial, treatment-related grade 3 AEs occurred in 30 percent of patients with the single-agent versus 32 percent with the combination. Discontinuation of treatment due to AEs occurred in 11 percent of patients with the combination versus 7 percent for the monotherapy.
The most common AE with the combination was pyrexia (52 percent vs 25 percent). The incidence of cutaneous squamous cell carcinoma and keratoacanthoma was 9 percent with single-agent Tafinlar and 3 percent with the combination. Additionally, other skin-related AEs were lower with the combination.
The FDA initially granted an accelerated approval to the combination for patients with BRAF-mutant melanoma in January 2014. This initial decision was based on ORR in a phase I/II trial. In addition to melanoma, the FDA granted a breakthrough therapy designation to the combination for patients with non—small cell lung cancer.