Chicago—A monoclonal antibody with a unique mechanism of action has become the first drug ever to demonstrate a survival benefit in previously treated advanced melanoma. The benefit of ipilimumab (Bristol-Myers Squibb), achieved with relatively modest toxicity, was demonstrated in a multinational Phase III study presented at the annual meeting of the American Society of Clinical Oncology (ASCO; abstract 4). It is considered a major step forward in a disease that has been notoriously resistant to pharmacologic therapy in dozens of prior controlled studies.

Although the drug increased median overall survival by almost four months in patients relative to controls (10 vs. 6.4 months; P<0.0004), an equally impressive result was that more than 40% of patients were alive at one year and more than 20% at two years. These survival rates are unprecedented in the types of patients who entered the study.

“Finally we are getting some good news in melanoma,” said the senior author of the study, Steven O’Day, MD, chief of research, Angeles Clinic and Research Institute, Los Angeles. Although this drug is a potent agent that poses risks for life-threatening immune-related side effects, it has been generally well tolerated. The longest follow-up in this Phase III study now extends past four years with survival benefit continuing to be documented.

In this multinational study, 676 patients with previously treated, unresectable stage III/IV melanoma were randomized in 3:1:1 ratio to ipilimumab (3 mg/kg every three weeks for four cycles) plus the glycoprotein (gp)100 peptide vaccine in a conventional dose, the same regimen of ipilimumab plus placebo, or gp100 vaccine plus placebo. All patients were HLA-A0201-positive, an entry criterion required because of the inclusion of the gp100 vaccine. Overall survival was the primary end point. The vaccine did not appear to have any influence on the survival advantage of ipilimumab. If anything, the vaccine appeared to diminish the efficacy of ipilimumab on the secondary end points, such as progression-free survival and the rate of objective response.

The drug potentiates T-cell activation by blocking the cytotoxic T-lymphocyte antigen-4 (CTL4) receptor. The efficacy of any agent that controls melanoma by boosting the immune response is somewhat surprising after so many failures with this strategy, including vaccines. The mechanism of blocking the CTLA-4 receptor is based on the role this target plays in turning off T-cell activation. The emergence of this receptor on the surface of the T cell approximately 48 hours after the T cell is activated appears to serve as a barrier to autoimmune diseases by turning off T cells before they begin to attack normal proteins. The anti-tumor effect of ipilimumab is produced by blocking this receptor to keep T cells activated. This explains the risk posed by ipilimumab for autoimmune activity, but it is an activity that may be relevant to cancers other than melanoma.

The efficacy of ipilimumab was characterized by Dr. O’Day as an “exciting advance both for patients with advanced melanoma and for the field of cancer immunology.” The discussant invited by ASCO to provide context for the findings, Vernon K. Sondak, MD, chief of the Department of Cutaneous Oncology at the H. Lee Moffitt Cancer Center, Tampa, Fla., largely agreed. Although the benefit of this mechanism for other tumors remains to be demonstrated, he said the identification of a new treatment for melanoma is a milestone. Dr. Sondak cited a study that compiled a list of 70 negative trials in melanoma over the past 30 years. The last drug to be approved by the FDA for melanoma was more than 10 years ago, and that drug, interleukin-2, is rarely used due to substantial toxicities and low response rates.

“The experience with treatment of melanoma has not just been bad but consistently and monotonously bad,” Dr. Sondak observed. He characterized the experience of conducting melanoma clinical research as being “in a long, dark tunnel.” He indicated that the results of this study provide substantial encouragement that progress will now be made, and he is particularly hopeful that when ipilimumab is combined with other therapies, the potential to extend the survival observed in this trial will be realized. He cautioned, however, that the potential risks associated with this therapy cannot be overlooked.

“The immune-related toxicity of ipilimumab requires a committed multidisciplinary team. This is not your 5-fluorouracil/leucovorin diarrhea,” Dr. Sondak reported. Although he believes that physicians properly trained to manage the immune-related adverse events associated with ipilimumab will permit this drug to be broadly used, he indicated that ipilimumab is not the final answer in melanoma, and that additional work is needed to understand where it exactly fits within routine clinical practice.

Due to the risk for a dysregulated immune system from CTLA-4 receptor inhibition, Dr. O’Day emphasized that patients need to be followed closely so that doctors can intervene early and quickly when this process begins. In the study, T-cell attacks in normal tissue were most commonly observed in the skin, gastrointestinal (GI) tract, endocrine system and liver (Figure 2). The greatest risk for significant morbidity and death was associated with attacks in the GI system. Grade 1 or 2 reactions were generally reversible with dose reductions or drug discontinuation, but high-dose steroids were required for grade 3 or 4 reactions. Approximately 3% of patients receiving ipilimumab had a treatment-related death.

With the exception of immune-related events, however, ipilimumab was generally well tolerated, which is an important attribute for therapies extending survival in advanced disease. Overall, there was a general consensus that this is a breakthrough agent for a notoriously treatment-refractory malignancy. “Ipilimumab represents a new class of T cell potentiators and an important advance for the field of immuno-oncology,” said Dr. O’Day. “Further development of ipilimumab is ongoing. We are very excited to see that it is being applied to other diseases, particularly non-small cell lung cancer and prostate cancer. We are very interested in looking at alternative combinations with this drug, as well as refining its dose and schedule.”