Testing Adjuvant Ipilimumab in Advanced Melanoma
Name of the Trial
Phase III Randomized Study of Adjuvant Ipilimumab versus High-Dose Recombinant Interferon Alfa-2b in Patients with High-Risk Stage IIIB, IIIC, or IV (M1a, M1b) Melanoma (ECOG-E1609). See the protocol summary.
Dr. Ahmad Tarhini, Eastern Cooperative Oncology Group
Why This Trial Is Important
Melanoma, the most deadly form of skin cancer, begins in melanocytes, which are cells that produce a dark pigment known as melanin. In its early stages, melanoma can often be cured by surgery alone. However, in patients with more advanced disease, even after full resection, relapses occur frequently and few systemic therapies have demonstrated any benefit in terms of delaying recurrences or prolonging life.
Nevertheless, there has been progress in treating patients with advanced melanoma. Recent reports of phase III clinical trials of new treatments have demonstrated that some of them can help improve the survival of patients with inoperable, metastatic disease. One of these new treatments, an antibody called ipilimumab, was shown to extend overall survival by more than 3 months compared to treatment with an experimental vaccine.
Ipilimumab is a type of cancer immunotherapy, meaning it helps a patient's immune system attack tumor cells. Preclinical, clinical, and observational research has shown that the immune system can mount a powerful response against melanoma tumors, including completely eradicating tumors in some patients. For the immune system to mount an effective anti-tumor response, however, it must be stimulated to recognize and attack melanoma cells. Unfortunately, activation of an antigen called CTLA-4 on cytotoxic T lymphocytes, the very cells known to kill melanoma cells, suppresses the stimulation of these killer cells, effectively putting the brakes on anti-tumor immune responses. Normally, activation of CTLA-4 is beneficial. It helps control the intensity and duration of immune responses and reduces the chance that immune cells will attack normal tissues. In terms of fighting cancer, however, activation of CTLA-4 is not helpful, so ipilumumab was designed to bind to this antigen and prevent it from suppressing the immune system's ability to attack tumors.
Now doctors want to know if ipilimumab treatment following surgical removal of advanced melanoma tumors will help improve patient outcomes.
In this clinical trial, patients with stage III or stage IV melanoma that has been completely resected will be randomly assigned to receive adjuvant (post-surgical) treatment with either ipilimumab or high-dose interferon alfa-2b, the current standard of care for patients with resected stage III or IV melanoma. (Eligible patients will have been diagnosed with stage IIIB, IIIC, IV M1a, or IV M1b disease and will have had complete resection of all tumors within the previous 12 weeks.)
"We know that patient immunity is relevant to disease outcome in patients with melanoma. Spontaneous tumor regression has been reported in melanoma, suggesting a role for host immunity, indirectly supported by the presence of lymphoid infiltrates in primary melanoma tumors associated with tumor regression," said Dr. Tarhini. "T-cell infiltrates in the original primary tumor are prognostic of disease outcome, and T-cell infiltrates within regional lymph node metastases from melanoma predict benefit from interferon alfa-2b therapy. In addition, the quality of the patient's immune response seems to differ between earlier and more advanced disease settings, suggesting that these patients are more likely to benefit from immunotherapy in earlier, operable disease stages."
"What these [immunotherapy] drugs do is stimulate the immune system by stimulating an antitumor immune response, breaking the immune system's tolerance of the tumor, or releasing the brake on existing activated anti-tumor T cells, allowing them to have prolonged activation and increased proliferation," Dr. Tarhini added.
Doctors will determine whether adjuvant ipilimumab improves recurrence-free survival and overall survival compared to adjuvant therapy with high-dose interferon alfa. They will also compare the tolerability of the drugs as well as the quality of life of patients in each arm of the study and will attempt to identify other markers that may predict benefit from ipilimumab treatment.