Gauging the Long-Term Benefits of Ipilimumab in Melanoma

The long-standing interest in cancer immunotherapy is based on the premise that it could provide responses with long duration that may translate into true cures to patients with metastatic cancers. There are many anecdotal reports of such long-term responders with the first generation of cytokine-based therapies, such as high-dose interleukin-2 (IL-2), which was approved by the US Food and Drug Administration on the basis of a 6% durable complete response rate. This therapy is inherently limited to relatively young patients who could endure the severe physiologic stress induced by this therapy. By using high-dose IL-2 in asymptomatic patients with limited burden of metastatic disease, the fraction of responding patients can be increased but not the absolute number of long-term survivors. The anticytotoxic T-lymphocyte–associated antigen 4 antibody ipilimumab is an immunotherapy agent that inhibits a negative immune regulatory mechanism that limits T-cell activation, thereby inducing T-cell responses to cancer. Starting in 2011, ipilimumab was broadly approved by many drug regulatory agencies for the treatment of patients with metastatic melanoma on the basis of positive results that showed improvement in overall survival in two randomized clinical trials. In both of these studies, response rates in the ipilimumabcontaining arms were in the range of 10% to 15% and typically manifested only after 3 or more months from initiation of therapy. The progression-free and overall survival curves separated after several months and stayed separated by approximately 10% beyond 2 years. In this issue of the Journal of Clinical Oncology, Schadendorf et al report on the follow-up of 1,861 patients treated with ipilimumab in 12 clinical studies to provide more information on the long-term effects of ipilimumab. Patients in these studies had advanced melanoma stage IIIc or IV. The authors document a plateau in the survival curve at 21% starting at 3 years and maintained thereafter, suggesting that patients previously treated with ipilimumab who survive to 3 years are highly likely to have a good long-term outcome. It is this feature that motivates doctors and patients to consider treatment with ipilimumab. Pooled analysis of large numbers of patients treated with a single agent can provide information beyond what can be achieved by individual clinical trials. However, inclusion of many patients treated on uncontrolled trials loses the benefit of the information provided by concurrent control groups to isolate the added benefit from the experimental agent. Schadendorf et al do not provide information on the long-term outcomes of patients in the control arms of the two pivotal phase III trials with ipilimumab; therefore, indirect comparisons need to be done with historical control series. Patients who participated in the ipilimumab trials pooled by Schadendorf et al would be unlikely to have had access to new molecularly targeted and second-generation immunologic therapies. Therefore, it is reasonable to consider that the long-term outcome of patients in the control arm of these ipilimumab trials would mirror that observed for large, well-annotated cohorts from the preceding era. The largest cohort is the one amassed by the American Joint Committee on Cancer (AJCC) Melanoma Staging Database, which draws on major academic medical centers in the United States, Europe, and Australia. Review of the stage IIIc and IV overall survival Kaplan-Meier curves of the 2009 AJCC melanoma classification suggests that these curves may have a plateau in patients not treated with ipilimumab, but this plateau is much later (beyond 8 years). The updated data from the seventh edition of the AJCC melanoma classification provides survival rates of 19%, 13%, and 9% at 3, 5, and 10 years, respectively, for patients with stage IV melanoma. Therefore, an indirect assessment of the long-term benefit of ipilimumab in terms of survival outcome suggests that the survival at 3 years may not be too different from what could be expected, but thereafter it improves by 10% over what could be expected with any other treatment for advanced melanoma that was available at the time when most of these studies were being conducted. Notably, this difference aligns with the percentage of patients who achieve objective responses. A more direct assessment of the long-term benefits attributable to ipilimumab could have been inferred from reporting the number of patients with a durable tumor response. It is notoriously difficult to assess response rate and progression-free survival in patients treated with ipilimumab, because there are well-documented instances of patients who meet the criteria for disease progression early in the course of therapy but can then go on to have a durable tumor response. Furthermore, patients may have determination of response confounded by localized or systemic treatments after ipilimumab that would complicate long-term response evaluation. Despite these caveats, it would have been useful to query this large database of patients followed for a long time after having received ipilimumab to determine how many of the patients in the 21% plateau after 3 years were disease-free or stably maintaining response at that time. This would represent firmer evidence of the long-term benefits of ipilimumab, even if it did overestimate (presumably by a small JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 17 JUNE 1