美国FDA于2011年3月25日批准ipilimumab（商标名称为Yervoy）用于治疗晚期黑色素瘤。

黑色素瘤是最危险的一种皮肤癌，也是最主要的一种致死性皮肤病。据美国国立癌症研究院统计，2010年全美国总共诊断出68130例黑色素瘤新病例，全年有8700人死于该病。

据FDA相关主管官员介绍，晚期黑色素瘤具有毁灭性，治疗药物极少，而且无一能有效延长患者寿命。Yervoy是FDA批准的第一种确实能延长患者寿命的治疗晚期黑色素瘤药物。

Yervoy是一种单克隆抗体，能有效阻滞一种叫做细胞毒性T细胞抗原-4（CTLA-4）的分子。CTLA-4会影响人体的免疫系统，削弱其杀死癌细胞的能力。Yervoy的作用机制可能是帮助人体免疫系统识别、瞄准并攻击黑色素瘤癌细胞。其给药方式是静脉注射。
Yervoy的安全性与有效性经过一项单一的国际性研究得到验证。该项研究有676名黑色素瘤患者参加，所有的受试对象都对常用治疗药物无反应，并且癌细胞已经扩散或者无法通过手术予以切除。

该研究的主要目的是确定患者的生存期限，即开始服药至患者死亡的时间。受试患者被随机分成三组：第一组服用Yervoy加一种叫做gp100的试验性癌症疫苗；第二组单独服用Yervoy；第三组单独服用gp100。

试验结果是：同时服用Yervoy和gp100的患者及单独服用Yervoy的患者平均可生存大约10个月，而且单独服用gp100的串者平均生存期限只有6.5个月。

Yervoy的常见副作用（主要因自身免疫反应而引致）包括：疲乏、腹泻、皮肤红疹、内分泌不足、肠道炎症（结肠炎）等。12.9%的受试患者会发生致命性的自身免疫反应。一旦发生严重副作用，则立即停止服用Yervoy并使用皮质类固醇进行治疗，但此措施并不是对所有病人有效。由于Yervoy具有上述非同寻常且极严重的副作用，FDA要求医护人员及患者都应对此严重风险有足够的认识。
Yervoy由位于纽约市的布迈施贵宝公司（Bristol-Myers Squibb）销售

FDA NEWS RELEASE

FDA approves new treatment for a type of late-stage skin cancer

Melanoma patients lived longer with treatment

The U.S. Food and Drug Administration today approved Yervoy (ipilimumab) to treat patients with late-stage (metastatic) melanoma, the most dangerous type of skin cancer.

Melanoma is the leading cause of death from skin disease. An estimated 68,130 new cases of melanoma were diagnosed in the United States during 2010 and about 8,700 people died from the disease, according to the National Cancer Institute.
 
“Late-stage melanoma is devastating, with very few treatment options for patients, none of which previously prolonged a patient’s life,” said Richard Pazdur, M.D., director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research. "Yervoy is the first therapy approved by the FDA to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment."

Yervoy is a monoclonal antibody that blocks a molecule known as cytotoxic T-lymphocyte antigen or CTLA-4. CTLA-4 may play a role in slowing down or turning off the body’s immune system, affecting its ability to fight off cancerous cells. Yervoy may work by allowing the body’s immune system to recognize, target, and attack cells in melanoma tumors. The drug is administered intravenously.

Yervoy’s safety and effectiveness were established in a single international study of 676 patients with melanoma. All patients in the study had stopped responding to other FDA-approved or commonly used treatments for melanoma. In addition, participants had disease that had spread or that could not be surgically removed.

The study was designed to measure overall survival, the length of time from when this treatment started until a patient's death. The randomly assigned patients received Yervoy plus an experimental tumor vaccine called gp100, Yervoy alone, or the vaccine alone.

Those who received the combination of Yervoy plus the vaccine or Yervoy alone lived an average of about 10 months, while those who received only the experimental vaccine lived an average of 6.5 months.

Common side effects that can result from autoimmune reactions associated with Yervoy use include fatigue, diarrhea, skin rash, endocrine deficiencies (gland or hormone), and inflammation of the intestines (colitis). Severe to fatal autoimmune reactions were seen in 12.9 percent of patients treated with Yervoy. When severe side effects occurred, Yervoy was stopped and corticosteroid treatment was started. Not all patients responded to this treatment. Patients who did respond in some cases did not see any improvement for several weeks.

Due to the unusual and severe side effects associated with Yervoy, the therapy is being approved with a Risk Evaluation and Mitigation Strategy to inform health care professionals about these serious risks. A medication guide will also be provided to patients to inform them about the therapy's potential side effects.

Yervoy is marketed by New York City-based Bristol-Myers Squibb.
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MEDSCAPE
FDA Approves Ipilimumab for Advanced Melanoma
Nick Mulcahy

March 25, 2011 — The US Food and Drug Administration (FDA) announced today the approval of ipilimumab (Yervoy, Bristol-Myers Squibb) for the treatment of advanced melanoma as a second-line therapy.

Ipilimumab is the first agent ever proven to improve survival in advanced melanoma. Its Biologics License Application was granted priority review designation in August 2010.

Melanoma is the leading cause of death from skin disease. An estimated 68,130 new cases of melanoma were diagnosed in the United States during 2010, and about 8700 people died from the disease, according to the National Cancer Institute.

"Late-stage melanoma is devastating, with very few treatment options for patients, none of which previously prolonged a patient's life," said Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research. Ipilimumab "is the first therapy approved by the FDA to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment."

The pivotal study of ipilimumab, known as 020, was conducted in previously treated unresectable stage III or stage IV melanoma patients. Results from this study made headline news when they were presented at last year's meeting of the American Society of Clinical Oncology (ASCO) and then published in full (N Engl J Med. 2010:363;711-723), as previously reported by Medscape Medical News.

In that study, patients receiving ipilimumab plus a peptide vaccine (glycoprotein 100) had a median survival of 10 months, compared with 6.4 months for patients receiving the vaccine alone (P < .001). Patients receiving ipilimumab alone had a nearly identical median survival — 10.1 months — in the 3-group clinical trial (P < .003).

The response to ipilimumab can be "dramatic," said Patrick Hwu, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, in an editorial that accompanied the study (N Engl J Med. 2010;363:779-781).

Follow-up from the earliest cohort of patients who received ipilimumab "shows that ongoing complete responses in some patients with metastatic melanoma can continue past 6 years," said Dr. Hwu wrote.

However, on the downside of the data from the 676-patient study, the "best overall response rate" (patients with a complete or partial response) was limited to 10.9% of the ipilimumab recipients. In other words, a minority of patients respond to the new drug.

Nevertheless, experts have predicted great patient demand for the new drug, as reported by Medscape Medical News.

Bristol-Myers Squibb announced on March 21 that ipilimumab is also effective in previously untreated patients with metastatic melanoma.

In the new study, designated 024, ipilimumab met the primary end point of improving overall survival in these patients, according to the company. The study compared ipilimumab in combination with chemotherapy (dacarbazine) and chemotherapy alone.

An abstract of the 024 data will be submitted for potential presentation at the annual ASCO meeting in June, the company reports.

New Class of Drug

Ipilimumab is another targeted therapy for cancer, but represents a new class of drug, known as a targeted T cell antibody, said Steven O'Day, MD, one of the study authors, when the study was first presented last year. Ipilimumab is directed against an antigen on the surface of T cells. The antigen, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), acts as a brake on the T cell, explained Dr. O'Day, who is from the University of Southern California Keck School of Medicine in Los Angeles. By blocking the brake, the T cell goes into attack mode and kills cancer cells.

In the pivotal study, treatment with ipilimumab, which is administered intravenously, included some severe adverse events, including 14 deaths.

"This is a powerful drug," said Dr. O'Day, who noted that 10% to 15% of immune-related adverse effects were grade 3 or 4 and required immunosuppressive therapy with steroids.

"Steroids were quite successful in the vast majority of patients," said Dr. O'Day, "and they did not affect efficacy."

The "serious potentially life-threatening complications" with ipilimumab require a committed multidisciplinary team to manage them, explained Vernon Sondak, MD, from the H. Lee Moffitt Cancer Center in Tampa, Florida, who acted as a discussant of the study at ASCO in 2010.

The FDA noted in its approval announcement that the common adverse effects that can result from autoimmune reactions associated with ipilimumab use include fatigue, diarrhea, skin rash, endocrine deficiencies (gland or hormone), and inflammation of the intestines (colitis). Severe to fatal autoimmune reactions were seen in 12.9% of patients treated with ipilimumab. When severe adverse effects occurred, the drug was stopped and corticosteroid treatment was started. Not all patients responded to this treatment. Patients who did respond in some cases did not see any improvement for several weeks.

Because of the unusual and severe adverse effects associated with ipilimumab, the therapy is being approved with a Risk Evaluation and Mitigation Strategy to inform healthcare professionals about these serious risks. A medication guide will also be provided to patients to inform them about the therapy's potential adverse effects.