BRAF-targeted therapy has been established as a treatment standard for patients who have metastatic melanoma with activating BRAF mutations, on the basis of improvement in the rate of survival, as compared with conventional chemotherapy.4
However, clinical evidence of resistance appears on average 6 to 7 months after the initiation of therapy.2–4,6
Several mechanisms of MAPK-dependent resistance to BRAF inhibitors have been described in vitro and corroborated in tumor specimens obtained from patients.9,10,12,13,18
Inhibition of the MAPK pathway downstream of BRAF was hypothesized to suppress mechanisms of resistance. MEK inhibition has been validated as a therapeutic approach in the same patient population,8
providing an opportunity to investigate a regimen combining a BRAF inhibitor with a MEK inhibitor.
We showed that dabrafenib and trametinib could be safely combined when each agent was administered at its full single-agent dose. In comparison with patients receiving dabrafenib monotherapy, patients receiving combination therapy had more frequent and more severe pyrexia and chills; they also had more frequent gastrointestinal toxic effects (e.g., nausea and vomiting), but most of these events were grade 1 or 2. Pyrexia was generally manageable with antipyretic agents. However, recurrent fevers required the use of low-dose oral glucocorticoids. The definition of dose-limiting toxic effects in this protocol pertained only to toxic effects observed during the 21 days of treatment. The combination 150/2 dose was chosen on the basis of the median duration of therapy (11 months). It is possible that higher doses of either agent could be administered and will be considered in other cancers with activating BRAF mutations.
The incidence of acneiform dermatitis, the most common and dose-limiting toxic effect of trametinib, is reduced when dabrafenib and trametinib are coadministered. In a phase 3 trial,8
grade 3 or 4 acneiform dermatitis occurred in 8% of trametinib-treated patients, whereas no patient in the combination 150/2 group had grade 3 or 4 acneiform dermatitis. Proliferative skin lesions, including cutaneous squamous-cell carcinomas, papillomas, and hyperkeratosis, which are commonly seen with dabrafenib monotherapy, were less frequently observed with dabrafenib–trametinib combination therapy. In light of the evidence that BRAF and MEK inhibitors have different effects on the MAPK pathway in BRAF wild-type cells,19–21
it appears likely that trametinib attenuates dabrafenib-induced activation of the MAPK pathway. The mechanism underlying this interaction has been described in a mouse model of squamous-cell carcinoma.17
We hypothesized that progression-free survival would be an important measure of the ability of a MEK inhibitor to overcome acquired or de novo resistance to BRAF inhibition. Indeed, the combination 150/2 (full-dose) group had significantly longer progression-free survival than did the monotherapy group (hazard ratio, 0.39; 95% CI, 0.25 to 0.62; P<0.001). The percentage of patients who were alive and progression-free at 1 year was also substantially higher (41% vs. 9%, P<0.001). The extent of tumor regression was also greater in the combination 150/2 group, with an objective response rate of 76%, as compared with 54% with monotherapy (P = 0.03). In addition, the median duration of response was substantially improved with combination therapy, as compared with dabrafenib monotherapy (10.5 months vs. 5.6 months). Although we did not evaluate trametinib monotherapy in this trial, progression-free survival with trametinib in patients with BRAF V600 melanoma was similar to the outcome with dabrafenib or vemurafenib monotherapy observed in our trial and several other trials.3,4,6,8
Together, these data corroborate previous reports that resistance to BRAF-inhibitor therapy is dependent on the MAPK pathway and that the addition of a MEK inhibitor to a BRAF inhibitor represents one strategy for delaying the emergence of this resistance mechanism.
Currently, we have very little insight into the mechanisms of resistance for this combination regimen. It is critical to determine whether resistance is mediated by reactivation of the MAPK pathway or by MAPK-independent compensatory signaling pathways that have been described previously in preclinical models of melanoma with BRAF mutations. Our trial provides evidence supporting the efficacy of a combination regimen of BRAF–MEK inhibitors in advanced melanoma. Two randomized, phase 3 trials involving patients with metastatic melanoma have been initiated (ClinicalTrials.gov numbers, NCT01584648 and NCT01597908). Interpretation of the survival data may be confounded by the inclusion of a minority of patients who received immunotherapy before enrollment, and additional patients would be expected to receive such therapy on disease progression.
Despite successful development of oncogene-targeted therapy for chronic myeloid leukemia,22
gastrointestinal stromal tumor,23
and subtypes of breast cancer and non–small-cell lung cancer,24–26
it has not yet been possible to develop combination targeted therapies that circumvent acquired resistance. The combination regimen of BRAF–MEK inhibitors described here represents a successful attempt to combine targeted therapies in an oncogene-defined patient population. Furthermore, as a consequence of unique biochemical effects observed with BRAF inhibitors, this combination appears to be associated with a reduced incidence and severity of some of the toxic effects of monotherapy with either a BRAF or MEK inhibitor. We believe that the combination of dabrafenib and trametinib warrants further evaluation as a potential treatment for metastatic melanoma with BRAF V600 mutations and other cancers with these mutations.