Effect of Selumetinib vs Chemotherapy on Progression-Free Survival in Uveal Melanoma

Abstract

Importance Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in MAPK pathway activation. Objective To assess the efficacy of selumetinib, a selective, non-ATP competitive inhibitor of MEK1 and MEK2, in uveal melanoma. Design Randomized open-label phase II clinical trial comparing selumetinib versus chemotherapy. Those receiving chemotherapy could receive selumetinib at the time of radiographic progression. Setting Fifteen academic oncology centers. Participants 120 patients with metastatic uveal melanoma. Interventions 101 patients were randomized on a 1:1 ratio to selumetinib 75 mg orally twice daily on a continual basis (n=50) or chemotherapy (temozolomide 150 mg/m2 orally daily for 5 of every 28 days or DTIC 1000 mg/m2 intravenously every 21 days; investigator choice; n=51) until disease progression, death, intolerable toxicity, or withdrawal of consent. Following primary outcome analysis, enrollment continued in a non-randomized fashion to the superior therapy. Main Outcomes Final analysis of progression-free survival, the primary endpoint, was assessed as of April 22, 2013. Additional endpoints, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013. Results Median progression-free survival for those randomized to chemotherapy and selumetinib was 7 (95% CI, 4.3 – 8.4; median treatment duration of 8 weeks (IQR, 4.3–16)) and 15.9 weeks (95% CI, 8.4 – 21.1; median treatment duration of 16.1 weeks (IQR, 8.1–25.3)), respectively (hazard ratio 0.46; 95% CI, 0.30 – 0.71; p < 0.001). Median overall survival was 9.1 (95% CI, 6.1 – 11.1) and 11.8 months (95% CI, 9.8 – 15.7) for those randomized to chemotherapy and selumetinib, respectively (hazard ratio 0.66; 95% CI, 0.41–1.06; p=0.09). No objective responses were observed with chemotherapy. 49% of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% patients treated with selumetinib, with 37% requiring at least one dose reduction. Conclusions and Relevance 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 adverse event rate.

Management of Uveal Melanoma: A Consensus-Based Provincial Clinical Practice Guideline

“…More than 80% of primary uveal melanomas carry active mutations in the GNAQ or GNA11 genes, which encode for G protein alpha subunits, leading to activation of the mek pathway. Several targeted agents, including the mek inhibitors selumetinib and trametinib, and the C-kit (CD117) inhibitor sunitinib, have demonstrated modest activity in patients with uveal melanoma 88,89 . Invariably, resistance to those agents develops within months of therapy initiation.…”

MEK inhibitor-associated retinopathy (MEKAR) in metastatic melanoma: Long-term ophthalmic effects

“…Sensitivity to MEK inhibitors has been demonstrated as monotherapy or in combination in different cancer types. Moreover, tumour control in patients has been shown in clinical studies [2][3][4][5][6][7]. The introduction of novel treatment strategies such as targeted therapy and immunomodulation have prolonged patient survival in metastatic melanoma [8][9][10][11].…”

Ipilimumab Activity in Advanced Uveal Melanoma: A Pooled Analysis

“…More recently, there have been studies with anti-programmed cell death protein 1 antibody (anti-PD1) monotherapy and targeted therapy with MEK inhibitors that have demonstrated some activity [23][24][25]. Although at least one small series has observed activity with pembrolizumab, more extensive experience suggests that responses and clinical benefit are much more limited than with advanced cutaneous melanoma [23,24].…”

“…Although at least one small series has observed activity with pembrolizumab, more extensive experience suggests that responses and clinical benefit are much more limited than with advanced cutaneous melanoma [23,24]. The role of the newer agents in the treatment landscape for advanced UM needs to be determined and clinically justified bearing in mind the toxicity seen especially with targeted therapy [25].…”