Factors Associated With Response to Dabrafenib/Trametinib in BRAF Inhibitor–Refractory Metastatic Melanoma


Key Points

  • A higher disease control rate was associated with longer prior BRAF inhibitor treatment and reduced circulating BRAF V600 in patients with metastatic melanoma.
  • Absence of significant MAPK pathway inhibition or immune infiltration was observed in most specimens obtained during treatment.

Poor response to combined BRAF and MEK inhibition with dabrafenib (Tafinlar)/trametinib (Mekinist) in patients with BRAF inhibitor–refractory metastatic melanoma may be associated with failure to significantly inhibit the MAPK pathway, according to a single-center phase II study reported in JAMA Oncology by Chen et al.

Study Details

In the study, performed at the MD Anderson Cancer Center, 20 evaluable patients with BRAF V600 metastatic melanoma resistant to prior BRAF inhibitor monotherapy were treated with dabrafenib at 150 mg twice daily and trametinib at 2 mg/d until disease progression or intolerance. All participants underwent baseline biopsy, and optional biopsy specimens were obtained during treatment and at progression. Tumor samples were assessed by whole-exome sequencing, reverse transcription polymerase chain reaction analysis for BRAF splicing, RNA sequencing, and immunohistochemical analysis, and blood was analyzed for circulating BRAF V600. The primary endpoint was overall response rate. Response was assessed every two cycles (8 weeks).

Factors Associated With Benefit

The confirmed overall response rate was 10%, the disease control rate was 45%, and the median progression-free survival was 13 weeks. Disease control rates were higher among patients with prior BRAF inhibitor therapy for > 6 months (73% vs 11%, P = .02) and among those with decreased circulating BRAF V600 at day 8 of cycle one (75% vs 18% for no decrease, P = .02). There was no significant difference in disease control rate for patients with vs without MAPK pathway mutations (P = .36) or for those with vs without high baseline MAPK activation (P > .99). Specimens obtained during treatment showed the absence of significant MAPK pathway inhibition or immune infiltration in most patients.

The investigators concluded: “The baseline presence of MAPK pathway alterations was not associated with benefit from CombiDT [combination of dabrafenib and trametinib] in patients with BRAF [inhibitor]-refractory metastatic 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.”

The work was supported by the Cancer Prevention and Research Institute of Texas, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the University of Texas MD Anderson Cancer Center Melanoma Moon Shots Program.

Michael A. Davies, MD, PhD, of the University of Texas MD Anderson Cancer Center, is the corresponding author of the JAMA Oncology article.

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