Igor Puzanov, MD, MSci, FACP
A new 10-year analysis, led by Igor Puzanov, MD, MSci, FACP, Director of Early Phase Clinical Trials and Chief of Melanoma at Roswell Park Comprehensive Cancer Center and recently published in JAMA Oncology,1 provides new insights into an important question: whether BRAF V600E/K–mutation status or previous BRAF inhibitor therapy with or without a MEK inhibitor affects response to pembrolizumab in patients with advanced melanoma.
This retrospective analysis of three randomized clinical trials (KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006) involved 1,558 patients with advanced melanoma and known BRAF tumor status (BRAF wild-type or BRAF V600E/K–mutant melanoma). All patients had been treated with pembrolizumab, and some had undergone prior treatment with BRAF inhibitors, with or without MEK inhibitors.
Patients with BRAF wild-type and BRAF V600E/K–mutant melanoma had objective response rates of 39.8% and 34.3%, respectively, and similar respective rates of both 4-year progression-free survival (22.9% and 19.8%) and overall survival (37.5% and 35.1%).
Patients with BRAF V600E/K–mutant melanoma who received a previous BRAF inhibitor with or without MEK inhibitors had baseline characteristics with a worse prognosis—lower objective response rates (28.4% vs 44.2%), 4-year progression-free survival (15.2% vs 27.8%), and overall survival (26.9% vs 49.3%)—compared with those who had not received earlier targeted therapy.
The STUDY results support the use of pembrolizumab in the treatment of advanced melanoma regardless of BRAF V600E/K–mutation status or prior BRAF inhibitor therapy, with or without the use of a MEK inhibitor.
“Our findings confirmed the long-term, lasting benefits of pembrolizumab for patients with unresectable advanced melanoma and show that the effect is seen regardless of BRAF-mutation status—and regardless of earlier treatment with a BRAF-targeting therapy,” said Dr. Puzanov.
Some 40% of patients with metastatic melanoma have BRAF mutations, meaning a particular gene and protein in their tumor cells is modified. Of that group, 90% have an activating BRAF mutation.
“Our long-term view provides evidence to support giving immunotherapy early in a patient’s treatment, before turning to targeted therapies. This course of treatment is now the standard of care, but this is important affirmation for this approach, which was not standard at the time these patients were treated,” Dr. Puzanov noted.
These study findings may help explain the striking decline in deaths from melanoma reported by the American Cancer Society earlier in the year. A January 2020 report from the Society documented a 7% per year decline in the overall melanoma death rate between 2013 and 2017 in people between the ages of 20 and 64.2
“The study reinforces the fact that immunotherapy can significantly extend the life of patients with melanoma and even lead to cures,” Dr. Puzanov noted. “But importantly, we also still see a role for targeted therapies. Having both of these treatment options at our disposal has helped to drive incredible progress against a cancer type that was almost universally fatal a decade ago.”
The authors noted that ongoing randomized controlled trials should support clearer and more specific conclusions about the optimal sequencing of these treatments.
1. Puzanov I, Ribas A, Robert C, et al: Association of BRAF V600E/K mutation status and prior BRAF/MEK inhibition with pembrolizumab outcomes in advanced melanoma. JAMA Oncol. July 16, 2020 (early release online).
2. American Cancer Society: Facts & Figures 2020 Reports Largest One-Year Drop in Cancer Mortality. Available at https://www.cancer.org/latest-news/facts-and-figures-2020.html. Accessed July 29, 2020.