BRAF inhibition for advanced locoregional BRAF V600E mutant melanoma

Abstract

Selective BRAF inhibitors (BRAFi) yield objective responses in 50% of patients with metastatic BRAF V600E mutant melanoma. Adding an MEK inhibitor increases this response rate to 70%. Limited data are available on the outcomes of unresectable stage III patients, and it remains unclear whether BRAF-targeted therapy can be utilized as a neoadjuvant strategy. Data on patients with advanced locoregional BRAF V600E mutant melanoma treated with BRAF-targeted therapy at Moffitt Cancer Center were analyzed to determine response rates, subsequent resection rates after tumor downsizing, pathologic responses, and patient survival. Fifteen patients with locoregional disease treated with BRAF-targeted therapy, either BRAFi alone (vemurafenib; 11 patients) or a combination of BRAFi and an MEK inhibitor (dabrafenib plus trametinib or placebo; four patients), were identified. The median age was 50 years; the median follow-up was 25.4 months. The median BRAF-targeted therapy treatment duration was 6.0 months (range 1.2-29.4 months). Response Evaluation Criteria In Solid Tumors-based evaluation demonstrated objective response in 11 patients (73.3%). Six patients underwent resection of the remaining disease after therapy. Pathological analysis showed complete pathologic response (n=2), partial pathologic response (n=2), or no pathologic response (n=2). Four of six patients undergoing surgery have been alive for more than 2 years, including three patients currently free from active disease. No complications attributable to BRAF-targeted therapy were observed in the perioperative period. Dose reduction or discontinuation because of toxicities occurred in 10/15 patients. Neoadjuvant BRAF-targeted therapy may be effective in advanced locoregional BRAF V600E mutant melanoma patients in increasing resectability, yielding pathological responses, and achieving prolonged survival.

Preoperative BRAF Inhibition in Patients with Irresectable Locally Advanced Stage III Melanoma

“…In this series BRAF inhibitor treatment led to fibrosis of tumor tissue and added a challenge to the surgical procedure itself; however, it did not lead to intraoperative complications in our series. This is compatible with previous reports which do not describe increased postoperative complications after BRAF inhibitor treatment [ 19 , 20 ].…”

“…Pathologic responses seen in the resected specimens were comparable to those in our series. The objective response rate was, however, lower, with only six out of 15 patients receiving surgical resection following BRAF inhibitor treatment [ 19 ].…”

Perioperative BRAF inhibitors in locally advanced stage III melanoma

“…Their combined use (approved in 2014) has recently been shown in metastatic cases to provide a better complete response (CR) rate than Dabrafenib alone . The success of these novel inhibitors in systemically advanced disease was followed by case studies of locally advanced disease unsuitable for surgery which showed complete regression using either isolated BRAF inhibitor therapy with Vemurafenib or combined inhibitor therapy with Dabrafenib plus Trametinib . Up to now, irresectable stage III tumors where previously treated as stage IV disease, as no other recourse was available to achieve any kind of disease control.…”

Surgical Resection of Metastatic Melanoma in the Era of Immunotherapy and Targeted Therapy

“…The patient remained disease-free at 5-month follow-up [26]. In another case series of 15 patients, they observed a 70% response rate in patients with locally advanced melanoma; in addition six of the 15 patients underwent conversion from unresectable to resectable disease [27].…”