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Dabrafenib/Trametinib Combination and Nivolumab New Adjuvant Treatment Options for Stage III Melanoma

The current adjuvant treatment options for high-risk patients with resectable melanoma include interferon and the cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab. Compared to placebo, ipilimumab (10 mg/kg) prolonged relapse free survival (RFS) and showed significant 5-year survival benefit in high-risk patients with melanoma, but at the cost of serious toxicity. In the metastatic setting, combinations of BRAF/MEK inhibitors in patients harboring BRAF mutations, and immunotherapy with programmed death receptor 1 (PD-1) inhibitors (± ipilimumab) regardless of BRAF status are standard of care based on evidence of survival benefit and manageable toxicity. The efficacy of these regimens has, thus, been investigated in the adjuvant setting, and results from two of these studies presented at the third Presidential Session at the 2017 European Society for Medical Oncology (ESMO) Congress are practice changing.

The COMBI-AD trial (N = 870), presented by Axel Hauschild, MD, PhD (University Hospital Schleswig-Holstein, Kiel, Germany), compared the combination of dabrafenib (150 mg twice daily) and trametinib (2 mg daily) to placebo in patients with resected, high-risk, stage IIIA-C melanoma with BRAF V600E/K mutation (Abstract LBA6_PR). At 2.8 years follow-up, the combination of dabrafenib and trametinib had significantly improved RFS compared to placebo (not reached vs 16.6 months; HR 0.47, P<.001). The 3-year RFS rate was 58% with the combination compared to 39% with placebo. The benefit of dabrafenib plus trametinib adjuvant therapy was seen across all patient subgroups, regardless of disease stage or risk factors. Furthermore, combination therapy significantly improved overall survival (OS) (HR 0.57, P = .0006), with 3-year OS rates of 86% with combination versus 77% with placebo. Dabrafenib plus trametinib was associated with an increase in adverse events (AEs) compared to placebo (grade 3/4: 41% vs 14%), but there were no deaths due to AE. A greater number of patients receiving the combination discontinued treatment due to AE (26% vs 3%), with the most common reasons being pyrexia and chills. In his conclusion, Dr Hauschild highlighted the RFS and OS benefits of dabrafenib plus trametinib, along with the manageable safety profile, indicating that this combination should become a new treatment option for patients with resected, stage III, BRAF-mutated melanoma. Results from the COMBI-AD trial were simultaneously published in The New England Journal of Medicine.

Jeffery Weber, MD, PhD (New York University, New York, New York, United States), presented results from the phase III CheckMate-238 trial (N = 906), which compared one year of adjuvant therapy with nivolumab (3 mg/kg IV every 2 weeks) to ipilimumab (10 mg/kg IV every 3 weeks for 4 doses, then every 12 weeks) in patients with resected stage III/IV melanoma (Abstract LBA8_PR). Significantly more patients treated with nivolumab remained relapse-free at 18 months compared to ipilimumab (66% vs 53%; HR 0.65, P<.0001). Relapse-free survival benefit favored nivolumab regardless of PD-L1 expression level, disease stage, or BRAF mutation status. Adjuvant treatment with nivolumab was more tolerable than ipilimumab. There were fewer grade 3/4 treatment-related AEs in the nivolumab arm (14% vs 46%), and fewer patients treated with nivolumab experienced a treatment-related AE leading to discontinuation (8% vs 42%). There were no treatment-related deaths in the nivolumab group, while 2 patients in the ipilimumab group died due to AE. Dr Weber concluded that nivolumab should be considered as a new standard treatment option for patients with resected stage IIIB/IIIC/IV melanoma, regardless of BRAF mutation status. Results from this trial were also simultaneously published in The New England Journal of Medicine.

In their discussions of these studies, Alexander Eggermont, MD, PhD (Gustave Roussy, Villejuif, France), and Reinhard Dummer, MD, PhD (Cancer Center Zurich, Zurich, Switzerland), indicated that these trials represent the death knell for both ipilimumab and interferon as adjuvant therapies for melanoma. Moving forward, either nivolumab or dabrafenib plus trametinib will be the adjuvant therapy of choice for stage III melanoma, with treatment choice dependent on BRAF mutation status and physician and patient preference.

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