色素膜黑色素瘤是一种罕见疾病，美国每年新诊断大约2,000例，其生物学特性与皮肤黑色素瘤不同。治疗包括手术摘除肿瘤或患眼，以及放疗或化疗。大约有一半的病例发生转移，这些患者的生存期为9~12个月。纽约纪念Sloan-Kettering肿瘤中心的Richard D. Carvajal医生在新闻发布会上公布结果时表示：“这是首项确定某种药物可改善晚期眼部黑色素瘤患者临床结局的临床试验。司美替尼是眼色素膜转移性黑色素瘤的新标准治疗。”
Richard D. Carvajal医生
在这项研究之前，尚无证据显示任何一种全身性治疗真正对这种疾病有效。在最近10年内进行的8项临床试验中，157例患者中仅有2例对潜在新治疗产生应答，包括化疗、靶向治疗和免疫治疗。Carvajal医生指出，另一种MEK抑制剂曲美替尼(Mekinist，葛兰素史克)于2013年5月成为首个经美国食品药品管理局(FDA)批准的MEK抑制剂，其适应证为：作为单一口服用药治疗有BRAF V600E 或V600K突变的成人患者的无法切除或转移性黑色素瘤。阿斯利康公司正在Array Biopharma的专利使用权转让协议下对司美替尼开展研究。
By: MARY JO M. DALES, Oncology Practice
CHICAGO – Selumetinib, an investigational MEK 1/2 inhibitor, shrank uveal melanomas in half of all treated patients, with a duration of disease control that was more than twice that achieved with the comparator therapy temozolomide, based on the final analysis of data from 98 patients in a phase II crossover study.
This is the first clinical trial to identify a drug that improves clinical outcome in patients with advanced melanoma of the eye, said Dr. Richard D. Carvajal, who presented the data at the annual meeting of the American Society of Clinical Oncology.
"Selumetinib is a new standard of therapy for uveal metastatic melanoma," he said at a press conference announcing the results. Before this study, there was no evidence that any systemic therapy was truly effective in this disease. In eight different clinical trials conducted in the last decade, 2 of 157 patients have responded to potential new therapies, including chemotherapy, targeted therapy, and immunotherapy.
With about 2,000 cases diagnosed each year in the United States, uveal melanoma is an orphan disease that is biologically distinct from cutaneous melanoma. Treatment consists of surgery to remove the tumor or eye, as well as radiation therapy or chemotherapy. About half of cases metastasize, and survival for these patients is 9-12 months.
In this study, 98 patients with metastatic melanoma of the eye were randomly assigned to receive selumetinib or temozolomide (Temodar), with 48 receiving selumetinib and 50 receiving temozolomide. Based on imaging studies using RECIST (Response Evaluation Criteria in Solid Tumors), patients whose disease worsened on temozolomide were permitted to cross over to selumetinib.
Looking at the response patterns, tumors regressed in 11% (RECIST response, 0%) of 46 evaluable patients in the temozolomide arm and in 50% (RECIST response, 15%) of 46 evaluable patients in the selumetinib arm, for a highly significant hazard ratio of 0.46, reported Dr. Carvajal of Memorial Sloan-Kettering Cancer Center in New York.
Progression-free survival was improved to nearly 16 weeks for selumetinib as compared with 7 weeks for temozolomide. Overall survival was 10.8 months for selumetinib and 9.4 months with temozolomide.
More than 90% of patients in both arms of the study had metastatic liver disease and more than 50% had an elevated lactate dehydrogenase, Dr. Carvajal noted. Further, the study allowed for crossover to selumetinib by temozolomide-treated patients with no evidence of response at 4 weeks; 80% of patients in the temozolomide arm crossed over to selumetinib.
Selumetinib blocks the MEK protein, a key component of the MAPK pathway, which is activated by Gnaq and Gna11 gene mutations, found in 84% of the uveal melanoma patients in the study. Selumetinib also is being investigated for the treatment of cancers of the thyroid and lung, and trials are underway with selumetinib in combination with other drugs.
Dr. Carvajal noted that another MEK inhibitor, trametinib (Mekinist, GlaxoSmithKline), recently became the first MEK inhibitor to be approved by the Food and Drug Administration. Trametinib was approved in May 2013 as a single-agent oral treatment for unresectable or metastatic melanoma in adult patients with BRAF V600E or V600K mutations.
AstraZeneca is developing selumetinib under a licensing agreement with Array Biopharma.
The selumetinib study was supported in part by a Conquer Cancer Foundation of ASCO Career Development Award, the National Institutes of Health, Cycle for Survival, and the Fund for Ophthalmic Knowledge. Dr. Carvajal had no relevant financial disclosures.