Dabrafenib/Trametinib Combo Study Stopped Early Following Positive Interim Analysis

Rafael Amado, MD, Head of Oncology R&D at GSK

Rafael Amado, MD

A phase III study comparing trametinib (Mekinist) plus dabrafenib (Tafinlar) with single-agent vemurafenib (Zelboraf) has been stopped early following a positive interim analysis, according to an announcement from GlaxoSmithKline (GSK), the company developing the combination.

The randomized trial, labeled COMBI-v, investigated the combination in 704 patients with stage IIIc or IVBRAF V600E/K-mutated melanoma. The decision to stop the trial early followed a recommendation from an independent data monitoring committee that found a significant prolongation in the primary endpoint of overall survival (OS) during an interim analysis.

In the study, dabrafenib was administered at 150 mg twice daily plus trametinib at 2 mg once daily or vemurafenib at 960 mg twice daily. The primary endpoint was OS, with secondary endpoints focused on progression-free survival (PFS), overall response rate (ORR), and duration of response. The decision to stop the trial provides the opportunity for eligible patients in the vemurafenib arm to crossover to receive the combination.

“Today’s headline results for the combination of dabrafenib and trametinib add to the body of evidence our phase III program has provided thus far, which we hope will more fully characterize the efficacy and safety profile of this combination for patients withBRAF V600-mutant metastatic melanoma," Rafael Amado, MD, Head of Oncology R&D at GSK, said in a release. "We will continue to analyze this data versus vemurafenib over the coming months and look forward to sharing these with the scientific community once the analysis is complete.”

The FDA approved the combination of dabrafenib and trametinib for patients with unresectable or metastatic melanoma who harbor aBRAF V600E/Kmutation in January 2014. This accelerated approval was based on an open-label phase I/II trial that demonstrated a median PFS of 9.4 months with the combination compared with 5.8 months for dabrafenib alone. However, due to crossover in the study, a significant OS advantage was not demonstrated.

To support the accelerated approval, the combination of dabrafenib and trametinib was explored in a number of phase III trials for patients with metastatic melanoma. In the phase III COMBI-d study that was presented at the 2014 ASCO Annual Meeting, the combination was compared with dabrafenib plus placebo in patients with unresectable stage IIIc or IVBRAFV600E/K-mutant melanoma.

In this study, 423 patients were randomized in a 1:1 ratio to receive dabrafenib plus trametinib (n = 211) or dabrafenib with placebo (n = 212). After a median follow up of 9 months, the median PFS was 9.3 months with the combination versus 8.8 months for dabrafenib plus placebo (HR = 0.75;P= .035). The median ORR was 67% versus 51%, for the combination versus dabrafenib monotherapy, respectively.

The hazard ratio for OS was 0.63 in favor of the combination (95% CI, 0.42-0.94;P= .023). At the time of the analysis, there were 40 deaths in the combination arm compared with 55 for dabrafenib monotherapy. An updated OS analysis is planned following 70% of events.

In general, the rates of adverse events were similar in both arms. However, more dose modifications were required in the combination arm compared with single-agent dabrafenib. Additionally, the dabrafenib plus trametinib was associated with a higher rate of pyrexia (51% vs 28%) and chills (30% vs 16) compared with dabrafenib alone.

The number of patients developing cutaneous squamous cell carcinoma and keratoacanthoma was less with the combination (2% versus 9%). Additionally, secondary cutaneous malignancies and new primary melanomas were less common in the combination arm. However, in earlier trials, the combination of dabrafenib plus trametinib was associated with an increased incidence of basal cell carcinoma (9% vs 2%).

Updated OS findings from COMBI-d and full results from COMBI-v are expected later this year. Additionally, the phase III COMBI-AD study is currently exploring dabrafenib plus trametinib as an adjuvant treatment for patients with high-riskBRAF V600-mutated melanoma following surgical resection. Results from this analysis are expected in mid-2015.