BRAF and MEK inhibitors in the era of immunotherapy in melanoma patients

Abstract

The treatment landscape in advanced melanoma is changing dramatically with the approval of new drugs. Vemurafenib was the first approved targeted agent for the treatment of BRAF-mutant advanced melanoma. However, treatment with a BRAF inhibitor is linked with acquired resistance occurring in half of the patients after approximately six months. Combination of MEK and BRAF inhibitor therapy results in extension of the time to resistance, translating into longer overall survival of treated patients. Similar clinical benefits are observed with therapy using antibodies against immune-checkpoint inhibitors in the same patient population. Due to the fact that results of randomised studies comparing these two treatment strategies back to back have not been presented yet, the best first and second line treatment option in patients with BRAF-mutant melanoma is unknown. Currently, phase 3 studies are also evaluating the efficacy of targeted therapy combined with immunotherapy in patients with BRAF-mutant and BRAF wild-type advanced melanoma. Identifying a biomarker for the selection of patients benefiting most from the treatment will be crucial for further survival improvement in patients with advanced melanoma.

Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

“…These findings suggested that the occurrence of acquired resistance could be prevented or delayed in combination therapy, which included downstream target inhibition and BRAF inhibition. Consistent with our study, a number of studies demonstrated that combination therapy would be more efficient to inhibit acquired resistance in the process of development and showed better survival benefit . Studies of recent development and obstacles of melanoma with BRAF and MEK inhibition as MAPK pathway inhibitor significantly overcame acquired resistance and had a higher survival rate and a more durable response rate .…”

“…20 About half of all melanoma patients harbor an activating BRAF mutation. 21 Our meta-analysis suggests that BRAF inhibition in combination with MEK has a protective effect compared to BRAF inhibition alone owing to the better overall survival, response rate and reduction the risk of death events. And skin-related adverse events such as hyperkeratosis, cutaneous squamous-cell carcinoma were less compared with monotherapy.…”

“…Melanoma is a highly mutated malignancy with poor prognosis . About half of all melanoma patients harbor an activating BRAF mutation . Our meta‐analysis suggests that BRAF inhibition in combination with MEK has a protective effect compared to BRAF inhibition alone owing to the better overall survival, response rate and reduction the risk of death events.…”

Targeting ERK beyond the boundaries of the kinase active site in melanoma

“…However, these current therapies are not always successful. Immune checkpoint inhibitors can be met with toxicity issues when given concomitantly or post‐treatment with ERK pathway inhibitors, and rationales for optimal sequencing and choice of agents are still in development . Acquired resistance is also known to limit the efficacy of immunotherapies for patients with metastatic melanoma .…”

“…Immune checkpoint inhibitors can be met with toxicity issues when given concomitantly or post-treatment with ERK pathway inhibitors, and rationales for optimal sequencing and choice of agents are still in development. 70,71 Acquired resistance is also known to limit the efficacy of immunotherapies for patients with metastatic melanoma. 72 In addition, 10% to 20% of BRAF V600mutant melanoma patients fail to respond to any current MAPK pathway inhibitors, and resistance almost inevitably results in patients that do initially respond.…”