Clinical, molecular, and immune analysis of dabrafenib-Trametinib combination treatment for braf inhibitor-refractorymetastatic melanoma a phase 2 clinical trial

IMPORTANCE Combined treatment with dabrafenib and trametinib (CombiDT) achieves clinical responses in only about 15%of patients with BRAF inhibitor (BRAFi)-refractory metastatic melanoma in contrast to the higher response rate observed in BRAFi-naïve patients. Identifying correlates of response and mechanisms of resistance in this population will facilitate clinical management and rational therapeutic development. OBJECTIVE To determine correlates of benefit from CombiDT therapy in patients with BRAFi-refractorymetastatic melanoma. DESIGN, SETTING, AND PARTICIPANTS Single-center, single-Arm, open-label phase 2 trial of CombiDT treatment in patients with BRAF V600 metastatic melanoma resistant to BRAFi monotherapy conducted between September 2012 and October 2014 at the University of Texas MD Anderson Cancer Center. Key eligibility criteria for participants included BRAF V600 metastatic melanoma, prior BRAFi monotherapy, measurable disease (RECIST 1.1), and tumor accessible for biopsy. INTERVENTIONS Patients were treated with dabrafenib (150mg, twice daily) and trametinib (2mg/d) continuously until disease progression or intolerance. All participants underwent a mandatory baseline biopsy, and optional biopsy specimens were obtained on treatment and at disease progression. Whole-exome sequencing, reverse transcription polymerase chain reaction analysis for BRAF splicing, RNA sequencing, and immunohistochemical analysis were performed on tumor samples, and blood was analyzed for levels of circulating BRAF V600. MAIN OUTCOMES AND MEASURES The primary end pointwas overall response rate (ORR). Progression-free survival (PFS) and overall survival (OS) were secondary clinical end points. RESULTS A total of 28 patients were screened, and 23 enrolled. Among evaluable patients, the confirmed ORR was 10%; disease control rate (DCR) was 45%, and median PFS was 13 weeks. Clinical benefit was associated with duration of prior BRAFi therapy greater than 6 months (DCR, 73%vs 11% for6 months; P = .02) and decrease in circulating BRAF V600 at day 8 of cycle 1 (DCR, 75%vs 18%for no decrease; P = .02) but not with pretreatment mitogen-Activated protein kinase (MAPK) pathway mutations or activation. Biopsy specimens obtained during treatment demonstrated that CombiDT therapy failed to achieve significant MAPK pathway inhibition or immune infiltration in most patients. CONCLUSIONS AND RELEVANCE The baseline presence of MAPK pathway alterations was not associated with benefit from CombiDT in patients with BRAFi-refractorymetastatic melanoma. Failure to inhibit the MAPK pathway provides a likely explanation for the limited clinical benefit of CombiDT in this setting. Circulating BRAF V600 is a promising early biomarker of clinical response.