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|Ref Type||Journal Article|
|Authors||Carvajal RD, Sosman JA, Quevedo JF, Milhem MM, Joshua AM, Kudchadkar RR, Linette GP, Gajewski TF, Lutzky J, Lawson DH, Lao CD, Flynn PJ, Albertini MR, Sato T, Lewis K, Doyle A, Ancell K, Panageas KS, Bluth M, Hedvat C, Erinjeri J, Ambrosini G, Marr B, Abramson DH, Dickson MA, Wolchok JD, Chapman PB, Schwartz GK|
|Title||Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial.|
|Date||2014 Jun 18|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|GNA11 mutant||uveal melanoma||no benefit||Selumetinib||Phase II||Actionable||In a Phase II trial, Koselugo (selumetinib) did not improved overall survival (10.9 vs 9.1 months, p=0.59) compared to chemotherapy in patients with uveal melanoma harboring GNAQ or GNA11 exon 5 mutations (n=83) (PMID: 24938562; NCT01143402).||24938562|
|GNAQ exon5||uveal melanoma||no benefit||Selumetinib||Phase II||Actionable||In a Phase II trial, Koselugo (selumetinib) did not improved overall survival (10.9 vs 9.1 months, p=0.59) compared to chemotherapy in patients with uveal melanoma harboring GNAQ or GNA11 exon 5 mutations (n=83) (PMID: 24938562; NCT01143402).||24938562|
|Unknown unknown||uveal melanoma||not applicable||Selumetinib||Phase II||Actionable||In a Phase II trial, Koselugo (selumetinib) improved median progression-free survival (15.9 vs 7 weeks, HR=0.46, p<0.001) but not overall survival (11.8 vs 9.1 months, HR=0.66, p=0.09) compared to chemotherapy in patients with uveal melanoma, but also caused high adverse event rate (PMID: 24938562; NCT01143402).||24938562|
|GNA11 Q209L||uveal melanoma||predicted - sensitive||Selumetinib||Case Reports/Case Series||Actionable||In a Phase II trial, Koselugo (selumetinib) treatment resulted in partial response in a patient with uveal melanoma harboring GNA11 Q209L (PMID: 24938562; NCT01143402).||24938562|