FDA Grants Dabrafenib/Trametinib Full Approval for BRAF-Mutant Melanoma

Bruno Strigini

The FDA has granted a full approval to the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) for patients with unresectable or metastatic BRAF-mutated melanoma, based on an extension in overall survival (OS) from two phase III studies.

In the COMBI-v trial, OS was extended by 7.6 months with dabrafenib and trametinib compared with single-agent vemurafenib (Zelboraf).¹ In the COMBI-d trial, OS was improved by 6.4 months compared with dabrafenib 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 dabrafenib plus trametinib (n = 352) or vemurafenib (n = 352). In the combination arm, dabrafenib was administered at 150 mg twice daily with trametinib at 2 mg once daily. Vemurafenib 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 (P <.0214). Crossover from the combination arm to vemurafenib was not allowed.

In an analysis presented at the 2015 European Cancer Congress,¹ the median OS with dabrafenib/trametinib was 25.6 months compared with 18 months with vemurafenib (HR, 0.66; 95% CI, 0.53-0.81; P <.001). The estimated 2-year OS rate was 51% with the combination compared with 38% with vemurafenib monotherapy.

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

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 vemurafenib, the median OS was 17.2 months. Median PFS with the combination was 11.4 versus 7.3 months with vemurafenib alone (HR, 0.56; 95% CI, 0.46-0.69, P <.001).

In the phase III COMBI-d trial, 423 patients with BRAFV600E/K-mutant melanoma were randomized to receive dabrafenib with trametinib (n = 211) or placebo (n = 212). 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 the 2015 ASCO Annual Meeting,² the combination of dabrafenib and trametinib demonstrated a median OS of 25.1 months compared with 18.7 months with dabrafenib alone (HR, 0.71; 95% CI, 0.55-0.92; P = .011). The 2-year OS rate with the combination was 51% versus 42% with the single-agent.

Median PFS was 11.0 months with the combination compared with 8.8 months for dabrafenib plus placebo (HR, 0.67; 95% CI, 0.53-0.84; P <.001). The ORR was 69% versus 53%, for the combination and single-agent, respectively. The complete response rate was 16% in the combination arm compared with 13% for dabrafenib. 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 dabrafenib plus trametinib was 25.1 versus 18.7 months with dabrafenib alone (HR, 0.71; 95% CI, 0.55-0.92; P = .01). The median PFS was 9.3 months with the combination versus 8.8 months with dabrafenib alone (HR, 0.75; 95% CI, 0.57-0.99; P = .035).

In the COMBI-v trial, the most frequently reported AEs with the combination compared with vemurafenib, respectively, were pyrexia (53% vs 21%), chills (31% vs 8%), and vomiting (29% vs 15%). Discontinuation of treatment due to AEs was similar between the treatment groups (13% vs 12%).

A number of events were lower with the combination, particularly the incidence of rash (22% vs 43%), particularly grade 3 rash (1% vs 9%). Additionally, AEs were less frequent with the combination versus single-agent for photosensitivity reaction (4% vs 22%), hand-foot syndrome (4% vs 25%), skin papillomas (2% vs 23%), squamous-cell carcinomas and keratoacanthomas (1% vs 18%), and hyperkeratosis (4% vs 25%).

For the COMBI-d trial, treatment-related grade 3 AEs occurred in 30% of patients with the single-agent versus 32% with the combination. Discontinuation of treatment due to AEs occurred in 11% of patients with the combination versus 7% for the monotherapy.

The most common AE with the combination was pyrexia (52% vs 25%). The incidence of cutaneous squamous cell carcinoma and keratoacanthoma was 9% with single-agent dabrafenib and 3% 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.

References:

1. Robert C, Karaszewska B, Schachter J, et al. Two year estimate of overall survival in COMBI-v, a randomized, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (Vem) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 3301.
2. Long GV, Stroyakovsky DK, Gogas H, et al. COMBI-d: a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAFV600E/K mutation-positive cutaneous melanoma. J Clin Oncol. 2015;33 (suppl; abstr 102).
3. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30-39.
4. Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444-451.