CTLA-4 Blockade with Ipilimumab: Long-term Follow-up of 177 Patients with Metastatic Melanoma

Abstract

PURPOSE Treatment with ipilimumab can cause objective tumor responses in patients with metastatic melanoma. We have treated 177 evaluable patients in three clinical trials and have long-term follow-up to evaluate the durability of responses. PATIENTS AND METHODS Patients with metastatic melanoma were treated in three trials from 2002 to 2005: In Protocol 1, fifty-six patients received ipilimumab with gp100 peptides. In Protocol 2, thirty-six patients received ipilimumab with interleukin-2. In Protocol 3, eighty-five patients received ipilimumab with intra-patient dose escalation and were randomized to receive gp100 peptides. We have analyzed their long-term follow-up and survival data. RESULTS With median follow-up for Protocols 1, 2, and 3 being 92, 84, and 71 months, median survival was 14, 16, and 13 months with five-year survival being 13%, 25%, and 23%, respectively. Patients in Protocol 2 had a 17% complete response (CR) rate, compared to 7% in Protocol 1 and 6% in Protocol 3. These CR rates are higher than previously reported for the same trials because some patients who eventually became CRs had continual tumor regression months to years after therapy. All but one of the 15 complete responders are ongoing at 54+ to 99+ months. CONCLUSIONS This report provides the longest follow-up of melanoma patients treated with ipilimumab and shows that ipilimumab can induce durable, potentially curative tumor regression in a small percentage of patients with metastatic melanoma. The combination of ipilimumab and IL-2 appears to have an increased CR rate, but this needs to be tested in a randomized trial.

Location, location, location: functional and phenotypic heterogeneity between tumor-infiltrating and non-infiltrating myeloid-derived suppressor cells

“…Another possible explanation is that the accumulation of MDSCs is less evident in an immunogenic tumor, such as melanoma, capable of responding to immunotherapy. [70][71][72] These data suggest that the contribution of MDSCs to the inhibition of Tcell proliferation in patients with metastatic melanoma may be less important than what was suggested by data obtained in murine tumor models. However, these are results from only a single study and more research will be needed in order to unravel the immunological relevance and the importance of MDSCs during tumor progression in cancer patients.…”

Re-defining response and treatment effects for neuro-oncology immunotherapy clinical trials

“…Of note in both of these studies, median PFS did not differ between treatment arms although the PFS hazard ratio was reduced for ipilimumab receiving patients. Furthermore, long-term follow-up of 177 advanced melanoma patients treated with ipilimumab revealed a median duration of tumor response of 7.3 years and an unprecedented 5 year survival rate of approximately 20 % [19].…”

The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma

“…The mechanism of action for most immunotherapeutic agents remains incompletely understood, but these treatments are notable for their ability to produce a durable benefit in a subset of patients. 7,8 Ipilimumab has been associated with significant improvement in overall survival in the metastatic setting. 5,9 Immunotherapy requires special attention to several caveats.…”

“…Although therapeutic benefits can be durable, only a subset of patients respond. 7,8 In addition, unique adverse effects of immunotherapy, many of which relate to the induction of autoimmunity and pro-inflammatory-like states, 10 might limit eligibility or become challenges in clinical management. Recent studies suggest immunotherapy, particularly with ipilimu mab and related agents, might result in tumour regression over a prolonged time, based on the kinetics of establishing an effective host anti tumour immune response.…”