Phase II Trial Shows Improved Progression-Free Survival but Greater Toxicity With Selumetinib vs Chemotherapy in Metastatic Uveal Melanoma
Oncogenic mutations in GNAQ and GNA11, resulting in MAPK pathway activation, are observed in > 80% of uveal melanomas. In a phase II trial reported in JAMA, Carvajal et al found that treatment with the MEK1/MEK2 inhibitor selumetinib significantly prolonged progression-free survival vs chemotherapy in metastatic uveal melanoma, but was associated with substantial excess toxicity.
Study Details
In this open-label trial, 101 patients from 15 centers in the United States and Canada were randomly assigned between August 2010 and December 2013 to receive oral selumetinib at 75 mg continuously (n = 50), or investigator choice of oral temozolomide at 150 mg/m2 daily for 5 of every 28 days or intravenous dacarbazine at 1,000 mg/m2 every 21 days (n = 51).
The primary endpoint was progression-free survival. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression.
The selumetinib and chemotherapy groups were generally balanced for age (median, 62 years in both), sex (52% and 62%), median Eastern Cooperative Oncology Group performance status (0; range, 0–1 in both), disease stage (M1a/b in 4% and 6%, M1c in 96% and 94%), elevated lactate dehydrogenase level (50% and 59%), number of prior systemic treatments (median, 0; range, 0–3 and 0–2, ipilimumab in 16% and 22%), number of prior liver-directed therapies (median, 0; range 0–2 in both, radiofrequency ablation in 10% and 6%, chemoembolization in 8% and 10%, immunoembolization in 2% in both, other in 8% and 4%), and tumor mutations (GNAQ in 40% and 37%, GNA11 in 42% and 49%, wild-type in 18% and 14%).
Prolonged Progression-Free Survival
Median treatment duration was 16.1 weeks in the selumetinib group and 8.0 weeks in the chemotherapy group and. Median progression-free survival was 15.9 vs 7.0 weeks (hazard ratio [HR] = 0.46, P < .001). Similar improvement was observed when analysis was limited to patients with GNAQ or GNA11 mutation (HR = 0.55, P = .01).
Median overall survival was 11.8 vs 9.1 months (HR = 0.66, P = .09), with no significant difference between groups observed when analysis was limited to patients with GNAQ or GNA11 mutation. A total of 42 chemotherapy patients (86%) had disease progression and subsequently received selumetinib. Median progression-free survival after the switch was 8 weeks; tumor regression, but no objective response, was observed in 28% of evaluable patients. Eight patients (16%) initially randomly assigned to chemotherapy did not receive selumetinib after progression because of death or declining performance status.
Tumor Response
Tumor regression was uncommon in the chemotherapy group but was observed in 49% of selumetinib patients, with 0% vs 14% of evaluable patients having partial response. Five selumetinib patients with partial response confirmed by imaging studies had response durations of 23.0 to 40.3 weeks.
Toxicities
Treatment-related adverse events of any grade were observed in 97% of patients receiving selumetinib, with the most common being acneiform rash (75% vs 6% in chemotherapy group), creatine kinase elevation (60% vs 0%), fatigue (57% vs 44%), AST elevation (48% vs 12%), and ALT elevation (42% vs 8%). Patients in the selumetinib group also reported blurred vision (6%) and other visual changes (7%).
Grade 3 or 4 treatment-related adverse events occurred in 37% of selumetinib patients, including creatine kinase elevation in 13%, aspartate aminotransferase elevation in 7%, alanine aminotransferase elevation in 6%, and lymphopenia in 6%; grade 3 or 4 adverse events in the chemotherapy group consisted of lymphopenia and neutropenia in one patient (2%) each. Although most cases of creatine kinase elevation were asymptomatic and clinically insignificant, neck myopathy or myositis occurred in 4% of selumetinib patients. Treatment-related adverse events led to selumetinib dose reduction in 37% of patients and to discontinuation of treatment in 6%.
The investigators concluded, “In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events.”
Richard D. Carvajal, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the JAMA article.
The study was sponsored by the Cancer Therapy Evaluation Program and supported by the National Cancer Institute, Conquer Cancer Foundation, Cycle for Survival, and Fund for Ophthalmic Knowledge. For full disclosures of the study authors, visit jama.jamanetwork.com.
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