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


Authors: Carvajal, R. D.; Sosman, J. A.; Quevedo, J. F.; Milhem, M. M.; Joshua, A. M.; Kudchadkar, R. R.; Linette, G. P.; Gajewski, T. F.; Lutzky, J.; Lawson, D. H.; Lao, C. D.; Flynn, P. J.; Albertini, M. R.; Sato, T.; Lewis, K.; Doyle, A.; Ancell, K.; Panageas, K. S.; Bluth, M.; Hedvat, C.; Erinjeri, J.; Ambrosini, G.; Marr, B.; Abramson, D. H.; Dickson, M. A.; Wolchok, J. D.; Chapman, P. B.; Schwartz, G. K.
Article Title: 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, 75mg orally twice daily on a continual basis (n = 50), or chemotherapy (temozolomide, 150mg/m 2 orally daily for 5 of every 28 days, or dacarbazine, 1000 mg/m 2 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 Copyright 2014 American Medical Association. All rights reserved.
Keywords: adult; treatment outcome; aged; aged, 80 and over; middle aged; survival analysis; dacarbazine; melanoma; disease progression; antineoplastic agents, alkylating; uveal neoplasms; benzimidazoles; humans; male; female
Journal Title: JAMA - Journal of the American Medical Association
Volume: 311
Issue: 23
ISSN: 0098-7484
Publisher: American Medical Association  
Date Published: 2014-06-01
Start Page: 2397
End Page: 2405
Language: English
DOI: 10.1001/jama.2014.6096
PROVIDER: scopus
PUBMED: 24938562
PMCID: PMC4249701
DOI/URL:
Notes: JAMA -- Export Date: 8 July 2014 -- CODEN: JAMAA -- Source: Scopus
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MSK Authors
  1. Brian Marr
    111 Marr
  2. Gary Schwartz
    384 Schwartz
  3. Cyrus Hedvat
    125 Hedvat
  4. Jedd D Wolchok
    771 Wolchok
  5. Richard D Carvajal
    147 Carvajal
  6. Mark J Bluth
    13 Bluth
  7. David H Abramson
    287 Abramson
  8. Paul Chapman
    293 Chapman
  9. Katherine S Panageas
    373 Panageas
  10. Joseph Patrick Erinjeri
    113 Erinjeri
  11. Mark Andrew Dickson
    106 Dickson