Keith T. Flaherty, MD
The armamentarium for advanced melanoma was sparse in March 2011, when ipilimumab (Yervoy) became the first drug in 13 years to earn approval FDA approval for the disease. Since then, the armamentarium has rapidly expanded.
“In the last 5 years, there have been FDA approvals for 12 new agents and combination therapies for patients with advanced melanoma,” said Keith T. Flaherty, MD, who moderated an OncLive
Peer Exchange panel titled “Treatment of Advanced Melanoma and Basal Cell Carcinoma.”
Novel melanoma treatments fall broadly into 2 categories: agents that target MAPK pathway signaling or agents that target immune system proteins. Several more melanoma treatments are poised to emerge from the pipeline. Data on the optimal way to incorporate these novel drugs into practice lag far behind the breakneck pace of approvals.
An Unusual Malignancy
What sets melanoma apart from other malignancies is its high mutational burden and immunogenicity. Jeffrey S. Weber, MD, PhD, explained how the interplay between these 2 factors makes melanoma highly susceptible to targeted therapies. “If you look at average mutational load, melanoma is No. 1 of all tumors, with a median of about 600 to 700 individual non-synonymous mutations,” he said.
Non-synonymous means the mutation is found only in tumor cell DNA, where it encodes peptides and protein fragments not expressed by normal cells. This is important because melanoma derives from transformed melanocytes, and one function of melanocytes is to present antigens to immune cells. When the melanoma melanocytes present the “alien” mutation-encoded antigens to T cells, it triggers an immune response.
“A lot of mutations means the cells grow out of control and make cancers, [but the cell] contains within it the potential seed of its own destruction… by the immune system,” Weber said.
Georgina Long, PhD, MBBS, identified the 3 most common genetic drivers of melanoma as BRAF V600
mutations, and NF1
alterations. Approximately 40% of patients with cutaneous melanoma have a BRAF mutation, up to 25% have an NRAS mutation, and about 12% have an NF1
Jeffrey S. Weber, MD, PhD
Other driver mutations include MEK1
, and GNAQ
. Long said BRAF V600
mutations are the most critical aberrations to test for when evaluating patients for treatment. Long’s institution also routinely tests for RAS, NF1, and KIT aberrations in case patients are eligible for a clinical trial.
The frequency of driver mutations varies according to melanoma site and sun damage. As Jason J. Luke, MD, explained, “There are melanocytic melanomas that can rise in other parts of the body, including acral lentiginous melanomas or mucosal melanomas, as well as uveal melanomas, and we see a different mutational spectrum in those types of tumors.”
For example, 40% of patients with cutaneous melanoma have a BRAF
mutation compared with 5% of patients with mucosal melanoma. Conversely, 20% of patients with mucosal melanoma have a KIT mutation compared with only 2% of patients with cutaneous melanoma.1
Clinical trials are evaluating therapies in melanoma patients that target mutations other than BRAF
. “We haven’t cured melanoma, and there’s a lot of work still to be done,” Luke said.
Circling back to the interplay between mutational burden and immunogenicity, Luke said he and his colleagues are investigating whether certain genetic aberrations compromise the immune system’s ability to attack melanoma cells through pathway disruption. The findings could lead to novel targeted therapies that hone in on signaling pathways instead of driver mutations.
Approaching Advanced Disease
“The toughest issue right now in melanoma medical oncology [is] what to do with stage III patients,” Luke said. These are patients whose melanoma has spread to regional lymph nodes or lymphatic vessels. The first approach is excision of the primary tumor with wide margins and removal of regional lymph nodes.