Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma

Abstract

The immunotherapeutic agent ipilimumab has helped address a significant unmet need in the treatment of advanced melanoma. Ipilimumab is a fully human monoclonal antibody that targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), thereby augmenting antitumor immune responses. After decades in which a number of clinical trials were conducted, ipilimumab was the first therapy to improve overall survival in a randomized, controlled phase III trial of patients with advanced melanoma. These results led to the regulatory approval of ipilimumab at 3 mg/kg for the treatment of unresectable or metastatic melanoma. More than 17,000 patients worldwide have received ipilimumab, either as a commercial drug at 3 mg/kg or in clinical trials and expanded access programs at different doses. Consistent with its proposed mechanism of action, the most common toxicities associated with ipilimumab therapy are inflammatory in nature. These immune-related adverse events were mostly reversible when effective treatment guidelines were followed. Importantly, long-term follow-up of patients who received ipilimumab in a phase III trial showed that 24% survived at least two years, and in phase II studies, a proportion of patients survived at least five years. Evaluation of ipilimumab is ongoing in the adjuvant setting for melanoma, and for advanced disease in nonsmall cell lung, small cell lung, prostate, ovarian, and gastric cancers.

Keywords: cytotoxic T-lymphocyte antigen-4; immuno-oncology; immunotherapy; ipilimumab; melanoma; monoclonal antibody.

Figure 1

Key milestones in the development of ipilimumab. Following preclinical studies of CTLA-4 blockade in murine tumor models, ipilimumab was developed as a fully human monoclonal antibody and evaluated in several clinical trials. These trials included two randomized, controlled phase III trials in which ipilimumab demonstrated an improvement in OS. Ipilimumab received approval in 2011 in both the United States and the European Union for the treatment of patients with unresectable or metastatic melanoma. Ongoing evaluation of ipilimumab includes combination studies with other anticancer therapies (e.g., RT, anti-PD-1 antibody), as an adjuvant therapy for stage III melanoma, and its efficacy and safety in several other solid tumors.

Figure 2

Mechanism of action of ipilimumab. Competitive inhibition of CD28-B7.1/B7.2 binding by CTLA-4 suppresses T cell activation and prevents an immune response. Blockade of CTLA-4 with ipilimumab allows continued T cell activation to augment the antitumor response. Other regulatory checkpoints with the potential for modulation include the coinhibitory molecule PD-1 as well as costimulatory molecules OX40 and 4-1BB.

Figure 3

Kaplan–Meier analysis of overall survival in the phase III study MDX010-20. Separation of the Kaplan–Meier survival curves was not observed until three months, at which time an OS benefit of approximately four months was observed with ipilimumab treatment compared with the gp100 control. Survival in the ipilimumab monotherapy group reached a plateau after two years, indicating durable response and long-term survival benefits. The table shows data for the primary endpoint of OS, and secondary endpoints of 1- and 2-year survival rates. Modified, with permission, from Ref. .

Figure 4

Kaplan–Meier analysis of overall survival in the phase III study CA184-024. Survival analysis of OS in treatment-naive patients with advanced melanoma who received ipilimumab at 10 mg/kg plus DTIC or placebo plus DTIC in the phase III trial, CA184-024. The survival curves reach a plateau beginning at approximately three years after initiation of treatment. Continued survival follow-up of more than four years demonstrates a long-term survival benefit that is consistent with the results of other ipilimumab studies. The table shows data for the primary endpoint of OS, with secondary endpoints of 1-, 2-, and 3-year survival rates as originally reported and 4-year survival rates based on recent survival follow-up.