Investigators Explore New Therapeutic Options for Metastatic Melanoma
The approval of several new drugs to treat patients with malignant melanoma is creating tremendous excitement, but the decisions to be made about their use, sequencing, and combination have raised new dilemmas and opened up new areas for further research.
An update on these treatments and some answers to the questions they raise were discussed at Saturday’s Education Session “New Options, New Questions: How to Select and Sequence Therapies for Metastatic Melanoma.”
Session Chair Michael B. Atkins, MD, of Georgetown-Lombardi Comprehensive Cancer Center, opened by noting that although new therapeutic options are available for patients with advanced melanoma, the treatment of these patients is also much more complicated.
The approval of high-dose interleukin- 2 therapy (HD IL-2) was a result of data showing a response rate of 16%, a median durable response rate of 8.9 months, and a median 12-month survival rate.
“Eleven percent of patients survived for more than 5 years, which is the hallmark of effective chemotherapy,” Dr. Atkins said. “Unfortunately, that’s only a minority of patients, and we need more information on who those patients are to better select.”
Subsequent investigation showed that elevated lactate dehydrogenase (LDH) is a negative predictor for response to HD IL-2, but further study of molecular factors revealed more information.
“You can’t talk about melanoma anymore without talking about molecular pathways,” he said. A significantly larger proportion of patients with BRAF- or NRAS-mutant tumors achieved complete or partial response to HD IL-2 compared with those with wild type (WT) tumors.
“This is good to know, but hard to determine,” he said.
Advances in the understanding of immune system function and tolerance have led to the development of a new generation of targeted immunotherapy.
Ipilimumab, an antibody directed against CTLA-4, showed a significant survival benefit in two phase III studies of patients with advanced melanoma, leading to its U.S. Food and Drug Administration approval in 2011. Again, the question of which patients derive the greatest benefit is still under evaluation, Dr. Atkins said. There is evidence that ipilimumab appears to confer a survival advantage for patients with both M1c and non-M1c disease, but this is less clear in patients with elevated LDH.
“Ipilimumab does enable immune response and antitumor responses in some individuals, and its activity is powerful enough to work in the central nervous system and overcome concurrent immunosuppression,” he said. “Ipilimumab represents an option for the majority of patients with advanced melanoma, but the timing of therapy and dealing with its severe autoimmune toxicities require more attention.”
Regarding treatment selection, he pointed out that not all melanoma cells are the same and that delineating between noninfl amed and infl amed phenotype cells may be clinically useful.
Sequencing treatment is another area for more research. “Current data suggest that for some patients with BRAFV600E melanoma, starting with immunotherapy offers them a chance for long-term benefit without compromising their benefit from subsequent BRAF-inhibitor therapy,” Dr. Atkins said.
“We’re beginning to see a glimmer of hope on the horizon, but there is still a lot of work to be done,” he concluded.
The dilemmas faced by clinicians when a patient with BRAF-mutant metastatic melanoma presents for treatment can be agonizing, said Keith T. Flaherty, MD, of Massachusetts General Hospital Cancer Center. Noting that treating patients with this disease is often a “race against time,” knowing which patients can survive and which patients require palliative care is difficult.
“With ipilimumab, the kinetics of response are somewhat delayed, and one’s tolerance for waiting 3 months for response or salvage therapy is a difficult issue to navigate,” Dr. Flaherty said. The focus often is on patients with low or medium disease burden, but for patients with a high, symptomatic disease burden, “we may have very little to offer them.”
Other agents, such as vemurafenib, show impressive early response data, but subsequent disease progression also occurs. “The issue of trying to predict who these patients are that do benefit is diffi cult and, frankly, we have very little data,” he said.
A review of the clinical trial data with vemurafenib and the emerging data with BRAF/MEK combinations emphasizes the unique features of the responses one sees to this type of targeted therapy, explained Dr. Flaherty. The onset of response is quite rapid and even patients with very advanced and symptomatic disease obtain some degree of clinical benefit.
Reviewing studies that draw correlations between normal LDH level and a transient antitumor effect, and others that show short-lived responses in some patients and long-term responses in others, Dr. Flaherty said that making decisions based on available evidence is not possible.
“Clinical grounds alone do not give us insight in knowing which patients will have short- or long-term survival,” he said.
Early evidence into the molecular pathways may be of some help in determining treatment sequencing or combinations. However, Dr. Flaherty explained, this issue will be complicated further when data is presented regarding a combination of BRAF and MEK inhibitor therapy in patients with BRAF-mutant melanoma (“Mutated Melanoma: The Role for MEK Inhibitors,” Monday, 3:00 PM-4:30 PM, E354a). Similarly, clinical trials that will be presented regarding the PD-1 antibody MDX-1106 also point toward further advances in the immunotherapy field and could infl uence this clinical conundrum.
He concluded that BRAF inhibitors are effective palliative therapy for patients who present with symptomatic metastatic disease, and early antitumor activity is consistently observed regardless of line of therapy.
The complexities of tumor mutation profiling, and the importance of using it for optimal clinical efficacy, were outlined by Jeffrey A. Sosman, MD, of Vanderbilt-Ingram Cancer Center.
“Mutation profiling is important, and it can be justified as a way of directing patients into relevant clinical trials,” Dr. Sosman said. Determining the link between certain mutations and clinical effect is critical to determining associations between tumor genotype and clinical efficacy.
BRAF-WT mutation accounts for nearly 60% of melanoma molecular profiles, one-third of which includes patients with NRAS-mutation melanoma. “This is a large group with no driver mutation identifi ed,” he said. These undefined driver mutations potentially can be targeted by the right drug or by immunotherapy.
Efforts are underway to investigate approaches to NRAS-mutant melanoma, including identification of potential therapeutic targets downstream of NRAS, and understanding the role of MEK inhibitors alone or in combination with inhibitors of the PI3K/AKT and mTOR pathway, or with immunotherapy. The definition of other driver kinases within the BRAF-WT population can allow for the development of personalized treatment options for this patient population.