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JAMA. 2014 Jun 18;311(23):2397-405. doi: 10.1001/jama.2014.6096.

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

Author information

1
Memorial Sloan-Kettering Cancer Center, New York, New York2Weill Medical College of Cornell University, New York, New York.
2
Vanderbilt University Medical Center, Department of Hematology-Oncology, Nashville, Tennessee.
3
Mayo Clinic, Rochester, Minnesota.
4
University of Iowa Hospital and Clinics, Iowa City.
5
Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
6
H. Lee Moffitt Cancer Center, Tampa, Florida.
7
Washington University, St Louis, Missouri.
8
University of Chicago, Chicago, Illinois.
9
Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida.
10
Winship Cancer Institute of Emory University, Atlanta, Georgia.
11
University of Michigan, Ann Arbor.
12
Metro Minnesota Community Clinical Oncology Program, St Louis Park.
13
University of Wisconsin, Madison.
14
Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania.
15
University of Colorado, Aurora.
16
Investigational Drug Branch, National Cancer Institute, Rockville, Maryland.
17
Memorial Sloan-Kettering Cancer Center, New York, New York.

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.

Comment in

PMID:
24938562
PMCID:
PMC4249701
DOI:
10.1001/jama.2014.6096
[Indexed for MEDLINE]
Free PMC Article
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