New standard care of Advanced Melanoma presented in ASCO 2010 annual meeting

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June 6, 2010 (Chicago, Illinois) — An experimental therapy for advanced melanoma has been shown to improve overall survival in patients, and is "on the road" to becoming the "new standard of care," said one of its investigators here at the American Society of Clinical Oncology (ASCO) 2010 Annual Meeting.

Patients receiving ipilimumab (Bristol-Myers Squibb) plus a peptide vaccine had a median survival of 10 months, compared with 6.4 months for patients receiving the vaccine alone (P < .001).

Ipilimumab also showed, compared with the peptide vaccine, a near doubling of the rates of survival at 12 months (46% vs 25%) and 24 months (24% vs 14%).

Everyone in the 676-patient study had undergone previous treatment for the disease

It is the first time that a therapy has been shown to improve survival in a phase 3 randomized controlled trial in this setting, said investigator Steven O'Day, MD, from the University of Southern California Keck School of Medicine in Los Angeles. Dr. O'Day spoke at a press conference at the meeting.

"This is a really significant finding," said Lynn Schucter, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, who moderated the press conference. "When melanoma is advanced, we have very little in the way of effective therapies." Dr. Schucter expects a big response from patients to this news about ipilimumab.

"Our advanced melanoma patients are all going to be asking to go on this drug," she said. The drug is not approved yet, but is being made available in a compassionate-use clinical trial. Treatment with ipilimumab, which is administered intravenously, included some severe adverse events, including 14 deaths, half of which were immune related, according to study data presented here and published simultaneously online June 5 in the New England Journal of Medicine.

"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."

Ipilimumab is a targeted T-cell antibody, a new class of drugs, said Dr. O'Day. It 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. By blocking the brake, the T cell goes into attack mode and kills cancer cells.

Ipilimumab can also overstimulate the immune system and produce a T-cell attack on normal tissue, usually the skin and colon and less commonly the liver and pituitary gland, Dr. O'Day noted. "These are different side effects than what we are used to," he said.

Ipilimumab is not the first immunotherapy for advanced melanoma. However, interleukin (IL)-2, which is approved by the US Food and Drug Administration, does not produce any response in most patients and has not been proven to improve survival, said Dr. Schucter.

"Finally melanoma doctors are able to manipulate the immune system in a meaningful way for the treatment of advanced melanoma," said Douglas Blayney, MD, about ipilimumab, to Medscape Oncology. Dr. Blayney is outgoing president of ASCO and professor of internal medicine at the University of Michigan Medical School in Ann Arbor. This is not the first news of ipilimumab's effectiveness in the treatment of melanoma at ASCO; excitement was generated when data from several phase 2 clinical trials were presented at ASCO 2008, as reported at the time by Medscape Oncology. Since then, the drug has shown activity in prostate cancer that was described as "dramatic," but the report was based on only 2 patients.

Compassionate-Use Study Is Only in the United States
"Patients are going to have a lot of hope about going on this drug," said Dr. Schucter. Bristol-Myers Squibb has adequate supplies of the drug available for patients who are eligible for its compassionate-use trial, reported Dr. O'Day.

Bristol-Myers Squibb is marketing ipilimumab and cosponsored the new study, along with Medarex, the company that developed the agent and that was eventually bought by Bristol-Myers Squibb.

The compassionate-use study of ipilimumab is ongoing but is limited to 75 centers in the United States. The phase 3 trial reported on by Dr. O'Day at ASCO was a multicenter international trial.

May Be Combined With Targeted Therapy
Approximately 20% to 30% of advanced melanoma patients will receive a benefit from ipilimumab, said Dr. O'Day.

Dr. Schucter said that the "next step" in improving treatment outcomes in the setting might be found by combining ipilimumab, a targeted T-cell antibody, with the investigational PLX4032 (Plexxicon Inc), which is a molecularly targeted therapy and was first reported on at ASCO in 2009. PLX4032 is an oral agent that targets the oncogenic BRAF gene mutation known as V600E, which occurs in about 40% of malignant melanoma patients, Dr. Schucter explained.

Overall survival data are not yet available for PLX4032, but will likely be published soon in the New England Journal of Medicine. PLX4032 has "unbelievably dramatic responses in terms of tumor shrinkage," said Dr. Schucter.

Dr. Schucter said that the Melanoma Research Foundation is in the planning stages of a study that combines ipilimumab and PLX4032 in patients with metastatic melanoma. She also said that there will be other possible combinations as more agents are evaluated, including the investigative agent tremelimumab (Pfizer); like PLX4032, it targets BRAF mutations.

Study Details
The new study involved centers from 13 countries in North America, South America, Europe, Asia, and Africa, and enrolled patients between 2004 and 2008.

Patients with unresectable advanced (stage 3/4) melanoma were randomized to 3 treatment groups in a 1:3:1 ratio: ipilimumab plus placebo (n = 137), ipilimumab plus the gp100 vaccine (n = 403), and the gp100 vaccine plus placebo (n = 136). The gp100 vaccine, an experimental melanoma peptide vaccine also designed to stimulate T cells to attack melanoma cells, was used as a comparison group after previous studies showed that it has modest anticancer activity and is superior to IL-2.

To be eligible, patients had to be HLA-A0201-positive because only those patient types are responsive to the gp100 vaccine. Dr. O'Day said that the study results with ipilimumab apply to all patients with melanoma and are not restricted to HLA-A0201-positive patients.

Ipilimumab, at a dose of 3 mg/kg of body weight, was administered with or without gp100 every 3 weeks for up to 4 treatments (induction). Dr. O'Day said that no difference was detected in survival between the 2 ipilimumab treatment groups — both were about 10 months.

In addition to providing better survival than the vaccine, ipilimumab provided better disease control; after 6 months, the melanoma did not progress in nearly 30% of those receiving ipilimumab, compared with 11% with the vaccine alone. Ipilimumab was generally well tolerated, but the study authors noted that the "side effects can be life-threatening and may be treatment limiting."

The most common immune-related adverse event was diarrhea (any grade; 27% to 31% of the 2 ipilimumab groups). The problem resolved in about 2 weeks after the administration of corticosteroids, reported the authors.

Reinduction Works Too
Reinduction with ipilimumab at the time of disease progression can also lead to clinical benefit, report the study authors. Reinduction was allowed within 28 days of documented progression. A total of 32 patients were reinduced per protocol: 8 with ipilimumab, 23 with combination therapy, and 1 with gp100 (6.1%, 7.3%, and 0.8%, respectively, of the total who received initial therapy with each).]

Upon reinduction, a partial or complete response or stable disease was achieved by 65% to 75% of patients in the ipilimumab groups and 0% in the gp100 group, according to the investigators.

Steven O'Day reports playing a consultant or advisory role for and receiving honoraria and research funding from Bristol-Meyers Squibb, and receiving research funding from Medarex. Dr. Blayney reports uncompensated consulting relationships with Allos, Cephalon, and BMS; and receiving research funding from Blue Cross Blue Shield of Michigan and the National Comprehensive Cancer Network.

American Society of Clinical Oncology (ASCO) 2010 Annual Meeting: Abstract 4, presented June 6, 2010; abstract 8509, presented June 5, 2010.


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