BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)

The CTLA-4 receptor on T lymphocytes is a negative regulator of T cell activation that blocks positive stimulatory effects to these cells mediated through their co-stimulatory and antigen specific T cell receptors. The monoclonal antibodies ipilimumab and tremelimumab bind to CTLA-4 and thus prevent this feedback inhibition. Both have been studied in patients with melanoma, with the most extensive data and promising results being observed with ipilimumab.

Ipilimumab was studied in a placebo-controlled phase III trial in which 676 patients with previously treated advanced melanoma were randomly assigned in a 3:1:1 ratio to ipilimumab plus gp100 peptide vaccine, ipilimumab alone or gp100 vaccine alone [94]. Ipilimumab (3 mg/kg) and/or vaccine were given every 3 weeks for four doses. Patients with confirmed partial or complete response or stable disease for 3 months or more after completion of the 12 week induction period were allowed to receive re-induction with their original treatment if they subsequently had disease progression.

In this study, overall survival was significantly increased in the two groups that received ipilimumab (median 10.0 and 10.1 versus 6.4 months, in the ipilimumab plus gp100, ipilimumab alone, and gp100 groups, hazard ratios for death 0.68 and 0.66 versus gp100 alone, respectively). Treatment benefits appeared to be independent of gender, age (= 65 or > 65 years), stage at presentation (M0, M1a, and M1b versus M1c), baseline LDH or prior use of IL-2. Tumor response rate was also significantly improved in both groups of patients treated with ipilimumab compared to gp100 alone (5.7 and 10.9 versus 1.5%, respectively). Further objective partial or complete responses were maintained for at least 2 years in 4 of 23 (17%) patients treated with ipilimumab plus gp100 and 9 of 15 (60%) with ipilimumab alone. Among 31 patients who initially received ipilimumab either alone or with gp100 and then underwent reinduction therapy with ipilimumab, six (21%) had an objective response to retreatment, and 15 (48%) had stable disease. Although this phase III trial limited enrollment to patients who were HLA-A*0201 positive, a retrospective analysis of four phase II trials involving ipilimumab alone showed similar activity regardless of HLA type [96]. Although patients on this trial did not have tumor profiling for BRAF mutations, recent data suggest that the activity of ipilimumab is independent of BRAF mutational status [97]. As a consequence of this study, ipilimumab was approved for the treatment of all patients with advanced melanoma.

Ipilimumab’s presumed mechanism of action is to break down tolerance to tumor-associated antigens in the melanoma. At the same time, this break down of tolerance may result in autoimmune reactions against self antigens. A wide range of immune-mediated adverse events have been observed. The most common serious manifestations include enterocolitis, hepatitis, dermatitis, and endocrinopathies. In this trial using a 3 mg/kg dose of ipilimumab immune-related adverse events occurred in approximately 60% of patients treated with ipilimumab. Grade 3 or 4 toxicity was seen in 10–15% of ipilimumab-treated patients, compared to 3% of those receiving only gp100. These side effects were typically not seen until 6 or more weeks into therapy. A somewhat higher incidence of side effects was observed with a dose of 10 mg/kg every 3 weeks in the randomized phase II trial that assessed the effects of dose on activity and toxicity [98]. Several investigators have suggested that the development of immune related toxicities correlated with benefit from therapy; however, other studies have not confirmed this correlation.

Although patients with untreated brain metastases were excluded from the phase III trial, other studies have observed antitumor activity with ipilimumab treatment in patients with brain metastases [99]. Finally, data from phase II trials suggested that a number of patients (up to 10% of those treated) exhibited apparent disease progression after 12 weeks of ipilimumab (with either larger lesions or new lesions), followed by subsequent disease regression. The overall survival outcome of these patients was similar to those exhibiting a tumor response. This led to the establishment of Immune-related Response Criteria that endeavored to capture these patients in the subset of patients achieving treatment benefit [100].

A second phase III trial involved previously untreated patients who were randomly assigned to dacarbazine plus either ipilimumab or placebo [101]. In this study, overall survival was significantly increased in patients assigned to the dacarbazine plus ipilimumab arm (median 11.2 versus 9.1 months). The overall incidence of grade 3 or 4 toxicity was significantly higher with dacarbazine plus ipilimumab (56 versus 28%). In particular, hepatic toxicity was significantly more common with the combination than with dacarbazine alone or than that previously or subsequently observed with ipilimumab alone. The increase in hepatic toxicity relative to single agent ipilimumab may be due to the fact that dacarbazine is also known to be hepatotoxic. On other hand, the incidence of other immune related toxicities (colitis, rash, hypophysitis) was less than that seen in prior studies with ipilimumab alone, perhaps suggesting that dacarbazine may have blunted and/or the higher incidence of hepatotoxicity may have pre-empted the immune toxicity profile of ipilimumab. Whether this blunting of immune toxicity by dacarbazine might have also blunted the antitumor effect of ipilimumab is a matter of speculation. However, the overall pattern of toxicity and efficacy on this trial do not support the addition of dacarbazine to ipilimumab. The relative value of the use of ipilimumab at the 10 mg/kg dose used this study and in multiple phase II studies vs. the already approved 3 mg/kg dose awaits the completion of an ongoing Phase III trial directly comparing the two doses.

A recent report of long-term survival of patients receiving ipilimumab suggests that death rate for patients followed for more than 3 years declines dramatically and that 20–25% of patients will achieve long term survival [102].

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