Indirect treatment comparison of dabrafenib plus trametinib versus vemurafenib plus cobimetinib in previously untreated metastatic melanoma patients

Metastatic melanoma is an uncommon but aggressive form of skin cancer, with a high mortality rate [1, 2]. Although melanoma represents less than 5% of all diagnosed skin cancers, the World Health Organization has indicated that its incidence is increasing faster than any other type of malignancy, mainly due to the general population’s increasing exposure to ultraviolet light [3–5]. Estimates put new diagnoses of melanoma at 132,000 globally in 2015 [3, 5]. The year-on-year increase in global incidence of melanoma is estimated to be between 3 and 7%; based on these estimates, thus a doubling in the incidence of melanoma occurs every 10–20 years [3].

Up to 70% of patients diagnosed with melanoma and approximately 50% of patients with the advanced form of melanoma possess a mutation in the BRAF gene, leading to aberrant activation of the mitogen-activated protein kinase (MAPK) pathway, a well-documented cancer pathway [6–9]. Patients with distant metastases and a BRAF mutation have significantly reduced median overall survival (OS) when compared with patients with distant metastases and BRAF wild-type [10]. These attributes have provided the impetus for significant drug development efforts that target BRAF-mutated metastatic melanoma.

The introduction of BRAF inhibitors such as vemurafenib and dabrafenib have yielded significantly improved outcomes in patients with metastatic melanoma with either BRAF V600E or V600K mutations [11, 12]. However, BRAF inhibitors have substantial therapeutic disadvantages. Acquired resistance to such inhibitors frequently develops due to reactivation of the MAPK pathway. This reactivation occurs primarily through three mechanisms: mutations in the upstream RAS proteins, mutant BRAF amplification, and alternative splicing mechanisms [9, 13]. This acquired resistance limits the median progression-free survival (PFS) and OS achievable with BRAF inhibitors to 6–8 months [14, 15]. In addition, the use of BRAF inhibitors may result in the development of secondary skin cancer, further limiting the therapeutic benefit of this monotherapy [11, 13, 16–20].

The addition of a MEK inhibitor along with a BRAF inhibitor can combat the BRAF inhibitor-related resistance and side effects that occur during monotherapy. This combination therapy has demonstrated an increase in median PFS and OS, along with a decrease in the incidence of BRAF-inhibited induced skin tumors [10, 16, 21]. The 2015 United States and European guidelines recommend the use of dabrafenib plus trametinib for metastatic melanoma patients with a BRAF V600 mutation [22, 23]. More recently, the Food and Drug Administration in the United States and European Medicines Agency have approved vemurafenib plus cobimetinib as a combination therapy for patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma [24, 25].

In the absence of evidence from head-to-head trials providing a direct comparison of treatments, health technology assessment agencies require an indirect comparison to help them in their evaluations. In addition, these types of comparisons can inform therapeutic decisions. Srivastava et al. in 2015 published an indirect treatment comparison (ITC) of dabrafenib versus vemurafenib, showing that both dabrafenib and trametinib monotherapies demonstrated comparable PFS and OS, and different tolerability and safety profiles, when indirectly compared with vemurafenib [26].

The objective of this study was to conduct an ITC between two common BRAF/MEK inhibitor combinations, dabrafenib plus trametinib and vemurafenib plus cobimetinib, in patients with metastatic melanoma without prior therapy for the metastatic disease stage in order to further understand the therapeutic and tolerability profile of these therapies.