MAPK Alterations Not Associated With Dabrafenib-Trametinib Benefit in BRAF-refractory Melanoma

Pretreatment mitogen-activated protein kinase (MAPK) pathway mutations or activations were not associated with benefit from the combined treatment of dabrafenib plus trametinib in patients with metastatic melanoma refractory to a BRAF inhibitor, a study published in JAMA Oncology has shown.¹

Only about 15% of patients with metastatic melanoma refractory to a BRAF inhibitor achieve a clinical response with combination dabrafenib and trametinib therapy as opposed to the higher response rate observed in BRAF inhibitor-naïve patients. Therefore, researchers sought to identify biomarkers that correlate with response and mechanisms of resistance in this patient population to determine who may benefit more from treatment.

For the single-center, open-label, phase 2 trial, researchers at the University of Texas MD Anderson Cancer Center in Houston, TX, enrolled 23 patients with BRAF V600 metastatic melanoma resistant to BRAF inhibitor monotherapy. Participants received dabrafenib 150 mg orally twice daily and trametinib 2 mg orally daily continuously until disease progression or unacceptable toxicity.

Investigators conducted whole-exome sequencing, reverse transcription polymerase chain reaction analysis for BRAF splicing, RNA sequencing, and immunohistochemical analysis on tumor samples. Blood was also analyzed for levels of circulating BRAF V600.

Results showed that the overall response rate was 10% and the disease control rate was 45%. Median progression-free survival was 13 weeks.

Clinical and molecular analyses demonstrated that duration of prior BRAF inhibitor therapy greater than 6 months a reduction in circulating BRAF V600 at day 8 of cycle 1 were associated with improved clinical benefit (both P=.02). In contrast, the baseline presence of MAPK pathway alterations was not associated with clinical benefit.

“Failure to inhibit the MAPK pathway provides a likely explanation for the limited clinical benefit of combined treatment with dabrafenib and trametinib in this setting,” the authors concluded. “Circulating BRAF V600 is a promising early biomarker of clinical response.”

Reference

1. Chen G, McQuade JL, Panka DJ, et al. Clinical, molecular, and immune analysis of dabrafenib-trametinib combination treatment for BRAF inhibitor–refractory metastatic melanoma: A phase 2 clinical trial [published online ahead of print April 28, 2016]. JAMA Oncol. doi: 10.1001/jamaoncol.2016.0509.