An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab — which blocks cytotoxic T-lymphocyte–associated antigen 4 to potentiate an antitumor T-cell response — administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma.

Regulatory pathways that limit the immune response to cancer are becoming increasingly well characterized. Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) is an immune checkpoint molecule that down-regulates pathways of T-cell activation. Ipilimumab, a fully human monoclonal antibody (IgG1) that blocks CTLA-4 to promote antitumor immunity,has shown activity in patients with metastatic melanoma when it has been used as monotherapy in phase 2 studies. Ipilimumab has also shown activity when combined with other agents, including cancer vaccines. One well-studied cancer vaccine comprises HLA-A*0201–restricted peptides derived from the melanosomal protein, glycoprotein 100 (gp100). Monotherapy with this vaccine induces immune responses but has limited antitumor activity However, the results of a recent study suggest that gp100 may improve the efficacy of high-dose interleukin-2 in patients with metastatic melanoma.With no accepted standard of care, gp100 was used as an active control for our phase 3 study, which evaluated whether ipilimumab with or without gp100 improves overall survival, as compared with gp100 alone, among patients with metastatic melanoma who had undergone previous treatment.

Methods A total of 676 HLA-A*0201–positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival.

Results The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events.

Discussion

This phase 3 study showed that ipilimumab, either alone or with gp100, improved overall survival as compared with gp100 alone in patients with metastatic melanoma who had undergone previous treatment. More than 70% of the patients had M1c disease (presence of visceral metastases) and more than 36% had elevated lactate dehydrogenase levels, both of which are associated with very poor survival.The eligibility criteria for patients in this study included HLA-A*0201–positive status, on the basis of the mechanism of action of gp100. However, CTLA-4 blockade by ipilimumab is independent of HLA status, as indicated by efficacy and safety outcomes in earlier clinical trials that were similar between HLA-A*0201–positive and HLA-A*0201–negative patients (and unpublished data).

In our study, the efficacy of ipilimumab was not improved by the addition of gp100. It is unlikely that this is due to a lack of gp100 expression in the tumors, because differentiation antigens have been shown to be strongly expressed in more than 90% of melanoma tumors, regardless of stage. Some studies of adjuvant therapy for melanoma showed that patients who were administered non–gp100 vaccines had shorter survival than did patients in the control groups. In contrast, phase 3 trials showed that in subgroups of patients with melanoma, vaccines had clinical activity when used as either adjuvant therapy or therapy for metastatic disease. Cumulative data show that gp100-based vaccines have immunologic activity, although clinical activity is minimal when gp100 vaccines are administered as monotherapy. In a randomized, phase 3 study involving patients with metastatic melanoma, a significant improvement in progression-free survival and response rate, and a nonsignificant improvement in overall survival, were seen with gp100-plus-high-dose interleukin-2, as compared with interleukin-2 alone. Although gp100 appeared to attenuate ipilimumab responses in our study, it is important to consider the fact that some radiographic responses of immunotherapeutic agents are not captured by standard response criteria.Regardless, such effects of gp100 did not translate into a difference in overall survival between the two ipilimumab groups.

The data in this study are consistent with the results of phase 2 trials of ipilimumab monotherapy in the same patient population. The data from phase 2 studies suggest that there is a long-term survival effect of ipilimumab monotherapy; ipilimumab monotherapy at a dose of 3 mg per kilogram resulted in 1-year and 2-year survival rates of 39.3% and 24.2%, respectively. The long-term effect of ipilimumab in our study is shown by survival analyses at late time points, which showed 1-year and 2-year survival rates of 45.6% and 23.5%, respectively. In recent, randomized, phase 3 trials involving patients with unresectable stage III or IV melanoma who had received previous treatment, 1-year survival rates were reported to be 22% to 38% with various treatment regimens.The median overall survival in these studies ranged from 5.9 to 9.7 months. Neither these nor other randomized, controlled trials had shown a significant improvement in overall survival.

The adverse-event profile of ipilimumab in this study is consistent with that reported in phase 2 trials,with the majority of adverse events being immune-related and consistent with the proposed mechanism of action of ipilimumab.As shown in phase 2 studies, prompt medical attention and early administration of corticosteroids are critical to the management of immune-related adverse events. Management guidelines (algorithms) for immune-related adverse events involve close patient follow-up and the administration of high-dose systemic corticosteroids — which were used as necessary in our study — for grade 3 or 4 events.In conclusion, this randomized, controlled trial showed that there was a significant improvement in overall survival among patients with metastatic melanoma. In some patients, side effects can be life-threatening and may be treatment-limiting. Reinduction with ipilimumab at the time of disease progression can result in further clinical benefit. Overall, our findings suggest that the T-cell potentiator ipilimumab may be useful as a treatment for patients with metastatic melanoma whose disease progressed while they were receiving one or more previous therapies.