Clinical Pearls & Morning Reports

Posted by Carla Rothaus

Published June 9, 2021


What is the major limitation of BRAF plus MEK targeted therapy in patients with melanoma?

Treatment and survival for patients with localized or metastatic melanoma have improved dramatically in the past 10 years. Read the NEJM Review Article here.

Clinical Pearls

Q: What are the described genomic subtypes of melanoma?

A: Most mutations in melanoma are passenger mutations, but several driver mutations that can be targeted by drugs have revolutionized treatment. Approximately 50% of melanomas have BRAF mutations resulting in constitutive activation of MEK and ERK signaling, providing a rationale for combined BRAF and MEK inhibition. The other described genomic subtypes are mutated RAS (accounting for approximately 28% of cases), mutated NF1 (approximately 14%), and triple wild type, although these other subtypes have not been as successfully targeted with therapy to date.

Q: How have surgical approaches to localized or regional melanoma changed in recent years?

A: More than 90% of patients with melanoma have localized or regional disease, and the primary treatment for such patients is surgical. Current standard surgical approaches are now markedly less invasive and associated with lower morbidity than previous approaches yet have equivalent or superior accuracy and effectiveness.

Morning Report Questions

Q: Describe the benefits and limitations, to date, of checkpoint immunotherapy in patients with advanced melanoma.

A: The outcome for patients with advanced melanoma has been transformed with combined checkpoint antibody therapy. Ipilimumab combined with nivolumab has been associated with a 53% response rate and is now the standard of care for immunotherapy in most patients with advanced melanoma. In a span of 3 years, therapy for advanced melanoma changed from ipilimumab monotherapy, with a 10% response rate and an incremental survival benefit, to checkpoint combination therapy, which has more than a 50% response rate and a significant survival benefit, with approximately 10% of patients requiring no further melanoma therapy. Checkpoint immunotherapy can induce regression of melanoma in any organ, including the brain. The remarkable success of combination checkpoint therapy has transformed melanoma treatment, but many questions remain. We do not know the best sequence of immunotherapy and targeted therapy in patients with BRAF-mutated melanoma. Survival is significantly increased among patients with advanced melanoma, but the probability of a cure remains low. The use of biomarkers to predict treatment response and toxic effects has limited value. Other melanoma subtypes, including mucosal and uveal melanomas, have proved less responsive to checkpoint inhibition, although early, encouraging results with combined CTLA-4 and PD-1 inhibition have been reported.

Q: What is the major limitation of BRAF plus MEK targeted therapy in patients with advanced melanoma?

A: In 2011, vemurafenib became the first BRAF-targeted therapy approved by the Food and Drug Administration for the treatment of melanoma on the basis of a 48% response rate and a 63% reduction in the risk of death, as compared with dacarbazine chemotherapy. Although the initial response to vemurafenib was rapid and clinically meaningful, progression-free survival was only 5.3 months, which is indicative of the rapid development of resistance through mitogen-activated protein kinase reactivation with monotherapy. Combined BRAF and MEK inhibition addresses this mechanism of resistance and is now the standard of care for targeted therapy in patients with melanoma. BRAF plus MEK targeted therapy can achieve disease control that lasts for years, but the major limitation is the acquisition of resistance. In community practice, targeted therapy is usually offered as first-line treatment to symptomatic patients with a high tumor burden, since the response may be more rapid than the response to immunotherapy. Ultimately, most patients with advanced, BRAF-mutated melanoma receive both targeted therapy and immunotherapy.

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