Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial

Abstract

Importance: Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation.

Objective: To assess the efficacy of selumetinib, a selective, non-adenosine triphosphate competitive inhibitor of MEK1 and MEK2, in uveal melanoma.

Design, setting, and participants: Randomized, open-label, phase 2 clinical trial comparing selumetinib vs chemotherapy conducted from August 2010 through December 2013 among 120 patients with metastatic uveal melanoma at 15 academic oncology centers in the United States and Canada.

Interventions: One hundred one patients were randomized in a 1:1 ratio to receive 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 dacarbazine, 1000 mg/m2 intravenously every 21 days [investigator choice]; n = 51) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression.

Main outcomes and measures: Progression-free survival, the primary end point, was assessed as of April 22, 2013. Additional end points, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013.

Results: Median progression-free survival among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) and among those randomized to selumetinib was 15.9 weeks (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < .001). Median overall survival time was 9.1 months (95% CI, 6.1-11.1 months) with chemotherapy and 11.8 months (95% CI, 9.8-15.7 months) with selumetinib (hazard ratio, 0.66; 95% CI, 0.41-1.06; P = .09). No objective responses were observed with chemotherapy. Forty-nine percent 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% of patients treated with selumetinib, with 37% requiring at least 1 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 rate of adverse events.

Trial registration: clinicaltrials.gov Identifier: NCT01143402.

Figure 1

Consolidated Standard for the Reporting of Trials (CONSORT) diagram for the 98 patients randomized to either chemotherapy (n=50) or selumetinib (n=48) as of April 22, 2013. *Of the 148 patients who provided informed consent for mutational analysis of tumor, 50 did not proceed to the therapeutic portion of the protocol. Data regarding why patients did not proceed to the therapeutic portion of the protocol were not collected.

Figure 2. Progression-free Survival

Kaplan-Meier estimates of progression-free survival in all evaluable patients (n=96; Panel A) and in patients with tumor harboring mutations in exon 5 of GNAQ or GNA11 (n=80; Panel B) treated as of as of April 22, 2013 are shown. The vertical lines indicate that patients’ data were censored. The median progression-free survival was 7 weeks (95% confidence interval (CI), 4.3–8.4) and 15.9 weeks (95% CI, 8.4–21.1) for all evaluable patients randomized to chemotherapy (n=49) and selumetinib (n=47), respectively. The hazard ratio for progression-free survival in all evaluable patients was 0.46 (95% CI, 0.30 – 0.71; p < 0.001) in favor of selumetinib (Panel A). When limiting analysis to the 80 patients with tumor harboring a mutation treated with chemotherapy (n=42) and selumetinib (n=38), the hazard ratio was 0.55 (95% CI, 0.34 – 0.87; p = 0.01) in favor of selumetinib (Panel B).

Figure 3. Best Tumor Response for Each Patient

Data regarding the best tumor response observed as of December 31, 2013 are shown for the 47 patients evaluable for response in the chemotherapy group (Panel A) and the 49 patients evaluable for response in the selumetinib group (Panel B) who had undergone at least one tumor assessment after treatment before the clinical cutoff date on December 31, 2013. Each marker represents data for an individual patient. The specific markers indicate the mutational status for GNAQ and GNA11. The percentage change from baseline in the sum of the diameters of the target lesions is shown on the y-axis. Negative values indicate tumor shrinkage. The dotted horizontal lines indicate 20% tumor enlargement consistent with progression of disease by RECIST criteria and 30% tumor shrinkage consistent with a partial response by RECIST criteria. Five patients with tumors wild-type for exon 5 of GNAQ and GNA11 were tested for exon 4 mutations in GNAQ and GNA111 and are indicated by asterisks and triangles.