CHICAGO—The first prospective randomized trial to demonstrate improved clinical outcome with any systemic therapy in patients with metastatic uveal melanoma found tumor shrinkage was achieved in a significant portion of those treated with selumetinib, a non-ATP competitive inhibitor of MEK1/2, according to results presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting.
“Selumetinib could be considered a new standard for patients with advanced uveal melanoma and provides a platform for the development of new combinatorial therapeutic approaches,” said Richard D. Carvajal, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York, NY.
Currently, no known effective systemic therapy exists for metastatic uveal melanoma, which is considered rare, with only 2,000 cases diagnosed annually in the United States.
The 16-center study randomly assigned 98 patients with metastatic uveal melanoma with exon 5 Gnaq/11 mutation who had not received prior treatment with a MEK inhibitor, temozolomide, or dacarbazine to selumetinib 75 mg twice daily (n=48) or temozolomide 150 mg/m2 per day (n=50) for 5 days. Select patients underwent tumor biopsies at baseline and after 14 days (± 3 days) of selumetinib. Radiographic assessments were performed at week 4, week 8, and then every 8 weeks.
Patients were stratified by mutation (Gq vs G11), stage (M1a/b vs M1c), and number of prior therapies (0 vs. >1). Primary end point was progression-free survival (PFS); secondary end points were response rate and overall survival (OS).
In the selumetinib arm, median patient age was 62 years (range, 32–86 years); 52% were male; 44% had Gna11 mutation (exon 5); 96% were M1c; and median prior treatments were 0 (range, 0–3); 17% had received prior ipilimumab. In the temozolomide arm, median age was 61 years (range, 34–86 years); 62% were male; 50% had Gna11 (exon 5) mutation; 94% were M1c; and median prior treatments was 0 (range, 0–2); 22% had received prior ipilimumab. In both arms, median Eastern Cooperative Oncology Group (ECOG) performance status was 0 (range, 0–1).
Of the 50 patients in the temozolomide arm, 40 (80%) crossed-over to the selumetinib arm. Tumor regression with selumetinib occurred less frequently after the cross-over, he noted; 50% of those initially treated with selumetinib had tumor regression compared with 23% in the cross-over arm.
In the overall population, MEK inhibition with selumetinib resulted in a median progression-free survival (PFS) double that achieved with chemotherapy, 15.9 compared with 7 weeks (HR 0.46; P=0.0005), Dr. Carvajal reported. In patients who were exon 5 Gq/11 mutation positive, PFS was 15.4 weeks in the selumetinib arm versus 7.0 weeks in the temozolomide arm (hazard ratio [HR], 0.55; P=0.011). PFS rates were 43.1% at 4 months and 22.9% at 6 months in the selumetinib arm, and 8.5% and 5.7% in the temozolomide arm, respectively.
A total of 35 (76%) of 46 patients achieved stable disease and another seven patients (15%) achieved a RECIST (Response Evaluation Criteria in Solid Tumors) response, with median duration of response of 23 weeks (range, 7.9–40.3 weeks). However, no significant effect on survival was observed between the two treatment arms: in the overall population, OS was 10.8 months in the selumetinib arm and 9.5 months in the temozolomide arm (HR, 0.79; P=0.4).
Grade 3 treatment-related hematologic toxicities were lymphopenia (6%) in the selumetinib arm and lymphopenia (2%) and neutropenia (2%) in the temozolomide arm. Grade 3 nonhematologic toxicities that occurred only in the selumetinib arm included rash (2%), creatine phosphokinase elevation (13%), AST/ALT elevation (15%), edema (2%), and dyspnea (2%).
The trial proved that “inhibiting the MAPK pathway in this unique molecular subset of melanoma, which is commonly characterized by mutations in Gnaq and Gna11, is effective, more than doubling progression-free survival,” Dr. Carvajal said. “While we are hopeful an agent like selumetinib will be commercially available in the near future, in the meantime we must continue to steer patients towards clinical trials.” He noted that patients previously treated with chemotherapy may be less likely to respond to selumetinib.
This study was supported in part by a Conquer Cancer Foundation of ASCO Career Development Award, the National Institutes of Health, Cycle for Survival, and the Fund for Ophthalmic Knowledge.