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Original Investigation |

Effect of Selumetinib vs Chemotherapy on Progression-Free Survival in Uveal Melanoma:  A Randomized Clinical Trial

Richard D. Carvajal, MD1,2; Jeffrey A. Sosman, MD3; Jorge Fernando Quevedo, MD4; Mohammed M. Milhem, MD5; Anthony M. Joshua, MBBS, PhD6; Ragini R. Kudchadkar, MD7; Gerald P. Linette, MD, PhD8; Thomas F. Gajewski, MD, PhD9; Jose Lutzky, MD10; David H. Lawson, MD11; Christopher D. Lao, MD12; Patrick J. Flynn, MD13; Mark R. Albertini, MD14; Takami Sato, MD, PhD15; Karl Lewis, MD16; Austin Doyle, MD17; Kristin Ancell, MD3; Katherine S. Panageas, DrPH1; Mark Bluth, MD1; Cyrus Hedvat, MD, PhD1; Joseph Erinjeri, MD, PhD1; Grazia Ambrosini, PhD1; Brian Marr, MD1; David H. Abramson, MD1,2; Mark Andrew Dickson, MD1,2; Jedd D. Wolchok, MD, PhD1,2; Paul B. Chapman, MD1,2; Gary K. Schwartz, MD1,2
[+] Author Affiliations
1Memorial Sloan-Kettering Cancer Center, New York, New York
2Weill Medical College of Cornell University, New York, New York
3Vanderbilt University Medical Center, Department of Hematology-Oncology, Nashville, Tennessee
4Mayo Clinic, Rochester, Minnesota
5University of Iowa Hospital and Clinics, Iowa City
6Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
7H. Lee Moffitt Cancer Center, Tampa, Florida
8Washington University, St Louis, Missouri
9University of Chicago, Chicago, Illinois
10Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida
11Winship Cancer Institute of Emory University, Atlanta, Georgia
12University of Michigan, Ann Arbor
13Metro Minnesota Community Clinical Oncology Program, St Louis Park
14University of Wisconsin, Madison
15Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania
16University of Colorado, Aurora
17Investigational Drug Branch, National Cancer Institute, Rockville, Maryland
JAMA. 2014;311(23):2397-2405. doi:10.1001/jama.2014.6096.
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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

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Figure 1.
Flow of Study Participants

aData regarding why patients did not proceed to the therapeutic portion of the protocol were not collected.bAfter primary outcome analysis, 19 additional patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment.cAs of April 22, 2013.dAs of December 31, 2013.

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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 April 22, 2013, are shown. The median progression-free survival was 7 weeks (95% CI, 4.3-8.4 weeks) among evaluable patients randomized to chemotherapy (n = 49) and 15.9 weeks (95% CI, 8.4-21.1 weeks) for evaluable patients randomized to selumetinib (n = 47). The hazard ratio for progression-free survival in all evaluable patients was 0.46 (95% CI, 0.30-0.71; P < .001) in favor of selumetinib (panel A). When limiting analysis to the 80 patients with tumor harboring a mutation (chemotherapy, n = 42; selumetinib, n = 38), the hazard ratio was 0.55 (95% CI, 0.34-0.87; P = .01) in favor of selumetinib (panel B).

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Figure 3.
Best Tumor Response for Each Patient

Data regarding the best tumor response 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 1 tumor assessment after treatment and before the clinical cutoff date on December 31, 2013. Each marker represents data for an individual patient. The percentage change from baseline in the sum of the diameter of the target lesions is shown on the y-axis. Negative values indicate tumor shrinkage. The horizontal dashed lines indicate 20% tumor enlargement consistent with progression of disease by Response Evaluation Criteria in Solid Tumors (RECIST) and 30% tumor shrinkage consistent with a partial response by RECIST. Five patients with wild-type tumors for exon 5 of GNAQ and GNA11 were tested for exon 4 mutations in GNAQ and GNA11 and are indicated by triangles.

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