Logo image
Back
Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial
Journal article   Open access   Peer reviewed

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

Richard D Carvajal, Jeffrey A Sosman, Jorge Fernando Quevedo, Mohammed M Milhem, Anthony M Joshua, Ragini R Kudchadkar, Gerald P Linette, Thomas F Gajewski, Jose Lutzky, David H Lawson, …
JAMA : the journal of the American Medical Association, Vol.311(23), pp.2397-2405
06/18/2014
DOI: 10.1001/jama.2014.6096
PMCID: PMC4249701
PMID: 24938562
url
https://doi.org/10.1001/jama.2014.6096View
Published (Version of record) Open Access

Abstract

Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation. To assess the efficacy of selumetinib, a selective, non-adenosine triphosphate competitive inhibitor of MEK1 and MEK2, in uveal melanoma. 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. 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. 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. 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. 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. clinicaltrials.gov Identifier: NCT01143402.
 Dacarbazine - adverse effects Dacarbazine - therapeutic use Humans Middle Aged Male Treatment Outcome Disease Progression Uveal Neoplasms - drug therapy Antineoplastic Agents, Alkylating - therapeutic use Melanoma - drug therapy Dacarbazine - analogs & derivatives Survival Analysis Aged, 80 and over Adult Female Aged Temozolomide Antineoplastic Agents, Alkylating - adverse effects Benzimidazoles - adverse effects Benzimidazoles - therapeutic use

Details

Metrics

20 Record Views
344 Times Cited - Web of Science
Logo image