Jeffrey Sosman, MD
Metastatic melanoma is associated with a poor prognosis, but recent breakthroughs in tumor biology and immune regulation have led tothe development of agents that could change clinical practice, according to a panel of experts who participated in a recent OncLive
And, while standard high-dose interferon for patients with advanced melanoma remains an option, a recent study from the 2014 ESMO Congress involving the PD-1 inhibitor nivolumab, as well as results from ongoing phase III studies of ipilimumab, may well mark a change in the treatment paradigm for this population.
The panelists cited two major developments in the treatment of melanoma. The first was the identification of BRAF mutations in the mitogen activated protein kinase (MAPK) pathway that has led to the development of therapies that inhibit their activity. “Clinical trials are under way that explore the use of BRAF inhibitors alone or in combination with MEK inhibitors for patients with BRAF-mutated, high-risk melanoma,” said Jeffrey A. Sosman, MD.
The second advancement is the development of immune checkpoint–blocking agents, including PD-1 and PD-L1 antibodies.
“From an immunotherapy point of view, PD-1 and PD-L1 antibodies have demonstrated 30% to 40% response rates for long durations,” said Jeffrey S. Weber, MD, PhD.
For targeted therapies, the BRAF inhibitor, vemurafenib, was approved in 2011 as a treatment for BRAF-mutated metastatic melanoma. “The efficacy of the BRAF/MEK combination is somewhat questionable,” said Weber. “But in the long run, the combination will likely show superiority once more clinical trial data are available.”Adjuvant Ipilimumab
The current explosion of novel therapies was initially sparked by the FDA’s approval of ipilimumab in 2011. But choosing an optimal adjuvant therapy for patients with high-risk melanoma remains a challenge for the clinician. “Given the level of efficacy seen in patients with metastatic disease, the next phase for these novel immunotherapy agents will be the adjuvant setting,” Weber said, “particularly as more data are compiled for adjuvant ipilimumab.”
Jeffery Weber, MD, PhD
In the EORTC 18701 study,1 treatment with adjuvant ipilimumab improved recurrence-free survival (RFS) compared with placebo for patients with stage III node-positive melanoma. At a median follow-up of 2.7 years, RFS rates were 46.5% with ipilimumab versus 34.8% with placebo. Patients experienced high rates of toxicity, including hypophysitis and colitis. The most common grade 3/4 immune-related adverse events for ipilimumab compared with placebo were gastrointestinal (15.9% vs 0.8%), hepatic (10.6% vs 0.2%), and endocrine (8.5% vs 0%). Approximately half of ipilimumab-treated patients discontinued treatment (52%) and 1.1% died as a result of treatment-related side effects.
The trial used a 10 mg/kg dose of ipilimumab, which is not approved in the United States, and the costs associated with this large of a dose in the adjuvant setting would be astronomical, Sosman added.Mario Sznol, MD,
panel moderator, pointed out that experience among community oncologists with ipilimumab varies greatly. He recommends that community oncologists who are unfamiliar with ipilimumab contact him prior to administration. “In addition to community oncologists and nurses, patients also need education on the side effects of ipilimumab,” added Sosman. Side effect management remains an important aspect of treatment with ipilimumab, especially as its role continues to expand as a treatment for patients with melanoma. Clinical trials have demonstrated that ipilimumab is an effective adjuvant therapy, placing it earlier in the treatment paradigm.