New Strategies but Modest Benefit in Uveal Melanoma

Roxanne Nelson, BSN, RN

November 23, 2015

Uveal melanoma is a rare form of melanoma and is difficult to treat, with low response rates to therapies currently in use. Findings from two small studies that investigated two treatment strategies in patients with advanced disease show a hint of promise, but no significant benefit.

The studies were presented in posters at the Society for Melanoma Research (SMR) 2015 International Congress, being held in San Francisco November 18 - 21.

In the first study, a combination of everolimus (Afinitor, Novartis Pharmaceuticals Corporation) and pasireotide long-acting release (Signifor, Novartis Pharmaceuticals Corporation) was evaluated in patients with advanced uveal melanoma, but only 3 of 13 patients (23%) experienced clinical benefit.

For the second study, researchers reviewed the efficacy of the MEK inhibitor trametinib (Mekinist, GlaxoSmithKline) in five patients with metastatic uveal melanoma who had been treated at their institution. They found that trametinib showed "reasonable clinical efficacy," with all patients experiencing eventual disease progression on trametinib. In one patient, disease remained stable for 34 weeks.

Biologically Distinct From Cutaneous Melanoma

Uveal melanoma is the most common intraocular malignancy in adults, and the uvea is the second most common location for primary melanoma after skin. Overall survival is low, because almost half of all patients develop metastatic disease, which usually involves the liver and is nearly always fatal.

It is biologically distinct from cutaneous melanoma, and no approved systemic therapy has been shown to prolong survival in patients with metastatic disease.

In a study presented at last year's SMR Congress, researchers found that the immunomodulator ipilimumab (Yervoy, Bristol-Myers Squibb Company) showed efficacy in some patients. Although the study just missed its primary endpoint of improving overall survival, the researchers reported that they were encouraged by finding "objective responses in a population of highly metastatic patients."

The disease control rate was close to 50%, with stable disease seen in 39.71% of patients and partial response seen in 6.45%.

Combination Therapy

At this year's SMR meeting, Alexander N. Shoushtari, MD, a medical oncologist from Memorial Sloan Kettering Cancer Center, in New York City, and colleagues hypothesized that on the basis of preclinical models, concurrent inhibition of mTOR and insulin growth factor-1 (IGF-1) with everolimus plus the somatostatin receptor agonist pasireotide long-acting release would lead to antitumor effects in patients with uveal melanoma.

Fourteen patients with metastatic disease were enrolled in a small phase 2 trial, and 13 were evaluable for the primary endpoint before the study was terminated early owing to slow accrual. Patients received everolimus 10 mg daily plus pasireotide long-acting release 60 mg every 28 days.

The primary endpoint was clinical benefit rate, defined as RECIST 1.1 stable disease at 16 weeks or any objective response.

Three of 13 patients (23%) achieved a clinical benefit. Stable disease was the best response in seven patients, lasting a median of 8 weeks (range, 8 - 16 weeks). Two patients achieved minor responses.

"For this rare tumor subtype, there isn't any standard therapy," said Dr Shoushtari. "We set a relatively modest bar for success, requiring 5 of 25 planned patients to have significant shrinkage or disease stability for 16 weeks.

"Three patients met that modest bar, but we halted the trial before full enrollment," he told Medscape Medical News. "This was because other trials competed for the same patients, and dose reductions were common for side effects like mouth sores and nausea/loss of appetite."

Reasons for stopping therapy included disease progression (n = 9), toxicity (n = 3), or change in therapy (n = 2). All 14 patients in the cohort experienced at least one adverse event, including grade 3 hyperglycemia (n = 7), oral mucositis (n = 2), diarrhea (n = 1), hypophosphatemia (n = 1), and anemia (n = 1). There were no grade 4 or 5 adverse events.

The researchers performed baseline octreotide scans in eight evaluable patients, of whom seven had at least one avid lesion. Overall, 50% of lesions (13/26) were octreotide-avid across all patients and had no association with RECIST response (P > 0.1).

The conclusion was that this combination regimen had limited efficacy in uveal melanoma and that octreotide scans did not predict tumor response in this small cohort.

However, Dr Shoushtari emphasized that he "absolutely does believe that select patients would derive some benefit" from this regimen.

"We saw a trend towards more growth stability in individual tumors that were octreotide-avid, suggesting that some tumors may be more susceptible to inhibiting this pathway than others," he explained.

The major shortcoming was the tolerability of the combination, he said. Because the combination was difficult to tolerate and did not cause significant shrinkage and only stability, this approach is not currently moving forward, Dr Shoushtari noted. "This is to our knowledge the first trial to try to combine two pathway inhibitors in uveal melanoma, and it is another real-world embodiment of the concept that side effects from individual medicines can get worse when you combine them," he added.

Targeting the MAPK Pathway

In the second study, Srinath Sundararajan, MD, from the University of Arizona Cancer Center, in Tucson, and colleagues noted that trametinib has proven efficacy in treating cutaneous melanoma, but the data are limited regarding its activity in uveal melanoma.

"Uveal melanoma does not harbor the targetable BRAF mutation that we see with cutaneous melanoma," he told Medscape Medical News. "Metastatic uveal melanoma still does not have a systemic treatment with meaningful response rates and improvement in survival, and the average survival is a few months."

Studies have shown that the MAPK kinase pathway is overactive in about 80% of patients with uveal melanoma, and using a MEK inhibitor to target this pathway might yield clinical responses in this population, the researchers reasoned. With that in mind, Dr Sundararajan and his team reviewed the University of Arizona's experience with trametinib and identified five patients with uveal melanoma who had been treated with this agent.

The median age of the patients was 55 years (range, 42 - 64 years), 80% were women, 80% had liver metastases, and 80% had elevated lactate dehydrogenase levels. In addition, two of the patients had received adjuvant systemic therapy after being treated for their primary tumor prior to receiving a diagnosis of metastatic disease.

The five patients had received treatment with trametinib for a median of 10 weeks (range, 6 - 49 weeks).

Median progression-free survival was 10 weeks, and median overall survial was 31 weeks.

"One patient experienced prolonged stable disease to 34 weeks, which is almost 8 months," said Dr Sundararajan. "This indicates that there is heterogeneity in disease response, and some patients may do better than others with this drug."

Gastrointestinal and cutaneous adverse effects were most commonly observed, with one patient developing a grade 3 rash that necessitated drug discontinuation and hospitalization.

Historical data show overall poor response to treatment in this population, so although trametinib showed only modest efficacy in this small retrospective study, there are plans for future evaluation. "This needs to be further explored and validated in a prospective trial," he explained. "The vacuum in treatment options for metastatic uveal melanoma warrants newer targeted and immunotherapies to be evaluated in this otherwise fatal disease."

Dr Sundararajan pointed out that an ongoing phase 2 study is currently evaluating trametinib in combination with GSK2141795 in MUM.

There is also an ongoing phase 3 placebo-controlled trial in uveal melanoma, he noted ― the SUMIT trial, which is evaluating selumetinib, another MEK inhibitor (under development by AstraZeneca), in comparison with chemotherapy with dacarbazine (DTIC-Dome, Bayer HealthCare Pharmaceuticals), and results are awaited.

An earlier phase 2 trial of selumetinib showed modest benefit, with an improvement in tumor response and progression-free survival, but not overall survival, but this was accompanied by a high rate of adverse events.

"Our understanding of the biology of uveal melanoma has led to the development of a number of rational mechanistic-based therapeutic hypotheses, including targeting the MAPK pathway, the PI3K/mTOR pathway, and the somatostatin receptor pathway," commented Richard D. Carvajal, MD, director of experimental therapeutics and director of the Melanoma Service at Columbia University Medical Center, in New York City.

"Unfortunately, the development of effective therapies in this disease has proven challenging," said Dr Carvajal, who was approached by Medscape Medical News for an independent comment. "The efficacy of combined everolimus and pasireotide as well as single-agent trametinib in this disease, as demonstrated by these two studies, is modest, with notable toxicity observed with everolimus and pasireotide."

He added that a randomized phase 2 trial of trametinib alone or in combination with GSK2141795 in uveal melanoma is ongoing and will provide prospective data regarding the findings presented by Dr Sundararajan and his team.


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