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In a phase III randomized trial, overall survival (OS) was more than 34% longer for patients with advanced melanoma who received the novel agent ipilimumab
In a phase III randomized trial, overall survival (OS) was more than 34% longer for patients with advanced melanoma who received the novel agent ipilimumab (MDX-010) with or without the glycoprotein 100 (gp100) peptide vaccine than for those who received the gp100 vaccine alone. Data for this pivotal trial were presented at ASCO’s Plenary Session.
“Over the past 30 years, randomized clinical trials have repeatedly failed to demonstrate an improvement in OS in patients with advanced melanoma, which is an extremely difficult disease to treat,” said lead researcher Steven O’Day, MD, chief of research and director, Melanoma Clinic, The Angeles Clinic and Research Institute, Los Angeles, California. “These results are an exciting advance, both for patients with advanced melanoma and for the fi eld of cancer immunology.”
Ipilimumab, a fully human monoclonal antibody, targets and blocks the cytotoxic T-lymphocyte— associated antigen 4 (CTLA-4) expressed on the surface of immune system T cells. CTLA-4 suppresses the immune system’s response to disease. Inhibiting this antigen with ipilimumab “triggers the T cells to attack the cancer,” O’Day told Oncology & Biotech News, who noted that the drug can be given on an outpatient basis as a 90-minute infusion. The gp100 vaccine is also an experimental treatment, and it is effective only in patients who are positive for the HLA-A0201 antigen. O’Day said investigators used it as a comparator because previous studies have found it to be more eff ective than the approved drug interleukin-2 (IL-2).
Investigators at 125 centers in 13 countries accrued 676 HLA-A0201—positive patients with previously treated metastatic melanoma for the trial. Patients were randomized 3:1:1 to receive ipilimumab plus gp100 vaccine, ipilimumab alone, or gp100 vaccine alone. Median OS in both ipilimumab arms extended to 10 months compared with 6.4 months in the vaccine-only arm. In addition, patients who received ipilimumab had 1- and 2-year rates of survival that were nearly double those seen in patients treated only with vaccine (Table). O’Day said some ipilimumab-treated patients were still alive at 4.5 years’ follow-up. Combining the gp100 vaccine with ipilimumab appeared to have no eff ect on toxicity or survival.
Ipilimumab’s side eff ects were generally mild to moderate and primarily immune related. However, severe side eff ects were observed in 10% to 15% of patients in the ipilimumab arms, and treatment-related deaths were also reported (2.1% in one ipilimumab group and 3.1% in the other). Approximately 1.5% of these deaths were immune related. “This is a powerful, immune-stimulating drug,” said O’Day. Other preliminary studies have shown that the adverse effects typically appear soon aft er initiating treatment with ipilimumab. The most common are gastrointestinal and skin reactions; less frequently, patients experience hepatitis, inflammation of the pituitary gland, eye inflammation, and nephritis.
It has been more than a decade since the FDA approved a new drug for melanoma. “The only approved drugs are DTIC, which is not very effective at all, and high doses of IL-2, which most community doctors don’t give because of the side effects and the need for hospitalization,” O’Day said. “[Ipilimumab] does have some serious side effects that relate to the T cells attacking normal tissues, and there will be some learning curve for community oncologists since managing these is different fr om managing typical chemotherapy side eff ects.” O’Day added that different algorithms have been set up to help manage severe adverse effects. In most cases, the primary treatment is high-dose steroids, which have been found to reduce many of the severe immunosupressory effects.
“There needs to be good communication between physician and patients about side effects and the need to manage them promptly,” advised O’Day, who said if the drug is approved, guidelines will be developed on how to do this so that the drug can be administered safely in the community setting.
O’Day said another large, international randomized phase III trial has just fi nished investigating ipilimumab as first-line therapy in melanoma and results are anticipated within 6 to 12 months. “We’re also very interested in starting to study ipilimumab in combination with the Plexxikon BRAF drug [PLX4032], which has a very high rate of breaking the tumor up, somewhere in the order of 70% to 80%,” said O’Day. “There’s a lot of hope and interest in the research community about getting these drugs combined because they may be very synergistic together, but first we have to get both drugs on the market,” he added.
Session discussant Vernon K. Sondak, MD, of the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, said he shared O’Day’s optimism about the “dramatic” data but that the study invites several questions. “Is the dose the right one? Has ipilimumab been compared with the right control? In light of these data, can we still be hopeful that ipilimumab can be combined with a vaccine to provide potent immunotherapy for patients?” Sondak said additional research should seek to answer these questions.
This is the first trial to show a survival benefit in metastatic melanoma, and O’Day said he is hopeful that ipilimumab will go through the regulatory process rapidly and become available for patients in 2011. Following the ASCO meeting, the FDA granted priority review for the novel agent, which is manufactured by Bristol-Myers Squibb. Abstract 4.