FDA Approves New Melanoma Combination Therapy

Tafinlar plus Mekinist found to improve overall survival in unresectable or metastatic BRAF-mutated melanoma.

The FDA has granted full approval to a new combination therapy for melanoma.

Dabrafenib (Tafinlar) and trametinib (Mekinist) was found to improve overall survival (OS) in unresectable or metastatic BRAF-mutated melanoma, according to data from from a pair of phase 3 studies.

In the COMBI-v trial, the drug combination extended OS by 7.6 months compared with single-agent vemurafenib (Zelboraf). In the COMBI-d trial, Tafinlar and Mekinist combination therapy improved OS by 6.4 months compared with Tafinlar alone. Additionally, the combination caused fewer adverse events (AEs) compared with either agent alone across both trials.

"We’re inspired by the difference Tafinlar plus Mekinist can make for patients battling such a serious disease as metastatic melanoma," said Bruno Strigini, president of the drug’s developer Novartis Oncology. “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.”

The COMBI-v trial enrolled 704 patients randomized to receive Tafinlar plus Mekinist (n = 352) or Zelboraf (n = 352). In the combination treatment cohort, Tafinlar was administered at 150 mg twice daily with Mekinist administered at 2 mg once daily. Zelboraf was administered at 960 mg twice daily, with baseline characteristics well balanced between the treatment groups.

OS was the primary endpoint of the trial, while secondary endpoints analyzed progression-free survival (PFS), response, and safety.

Median OS with the combination therapy was 25.6 months compared with 18 months with Zelboraf (HR, 0.66; 95% CI, 0.53-0.81; P <.001), while the projected 2-year OS rate was 51% with the combination therapy compared with 38% with Zelboraf monotherapy.

Median PFS was 12.6 months with the combination compared with 7.3 months in Zelboraf (HR, 0.61; 95% CI, 0.51-0.73; P <.001). The objective response rate (ORR) was 64% with Tafinlar plus Mekinist compared with 13% for Zelboraf alone, as the median duration of response was 13.8 months in the combination compared with 7.5 months with Zelboraf.

The approval followed an FDA review of early data from the COMBI-v trial published in The New England Journal of Medicine, in which median OS had not yet been reached in the combination arm.

In the single-agent Zelboraf group, median OS was 17.2 months. Median PFS with the combination was 11.4 months, compared with 7.3 months in Zelboraf alone (HR, 0.56; 95% CI, 0.46-0.69, P <.001).

For the phase 3 COMBI-d trial, 423 patients with BRAFV600E/K-mutant melanoma were randomized to receive Tafinlar plus Mekinist (n = 211) or placebo (n = 212), with a primary endpoint of investigator-assessed PFS and OS was a secondary endpoint.

The combination showed a median OS of 25.1 months compared with 18.7 months with Tafinlar monotherapy (HR, 0.71; 95% CI, 0.55-0.92; P = .011), while the 2-year OS rate with the combination was 51% compared 42% in single-agent therapy.

The combination showed a median PFS of 11 months versus 8.8 months for Tafinlar plus placebo (HR, 0.67; 95% CI, 0.53-0.84; P <.001). The most frequently reported AEs with the combination were pyrexia, chills, and vomiting, with similar treatment discontinuation rates between the treatment groups.

The FDA previously granted accelerated approval to the combination for patients with BRAF-mutant melanoma in January 2014. It was also granted breakthrough therapy designation patients with non—small cell lung cancer.