Each year, nearly 60,000 new cases of melanoma are reported in the United States. The vast majority of these are cured by surgery. However, 8,000 of these patients are found to have metastatic melanoma beyond the scope of surgical cure—and this number closely approximates the annual number of deaths from this disease. This statistic illustrates the lack of progress that had been made in the treatment of advanced melanoma over the last several decades.
Until recently, immunotherapy utilizing interleukin-2 (IL-2; for metastatic melanoma) and interferon-α (for surgically resected melanoma) have produced the most promising results.[1] It is now well accepted that solid tumors are able to evade detection and destruction by the immune system, despite the fact that many tumors—and especially melanoma—elicit a strong immune response evident in lymphocyte infiltrates of the primary lesion.[2] Tumor immune evasion can be categorized into induction of immune tolerance and resistance to killing by activated immune effector cells.[3] The concept of “immunoediting” holds that tumors manipulate their microenvironment by creating complex local and regional immunosuppressive networks that consist of various tumor-derived cytokines and other soluble factors.[4] By the time melanoma has become clinically detectable, the tumor has already evolved mechanisms to evade the immune response mounted against it by the host.[4]
One of the most promising strategies for enhancing a patient’s antitumor response appears to be the use of antibodies that block the immunoregulatory mechanisms that are able to suppress host responses to tumor-associated antigens (TAAs). One such critical inhibitory checkpoint is the cytotoxic T-lymphocyte antigen 4 (CTLA-4), a molecule that down-regulates T-cell activation via a homeostatic feedback loop designed to prevent unwanted autoimmunity and to establish tolerance to self antigens.[5] Anti-CTLA-4 monoclonal antibodies such as ipilimumab result in the blockade of CTLA-4 signaling, thereby prolonging T-cell activation, restoring T-cell proliferation, and thus amplifying T-cell–mediated immunity, which enhances the patient’s capacity to mount an antitumor immune response.[5,6]
Clinical testing of ipilimumab has now yielded significant new results. In a study (CA184-022) of 217 patients with previously treated unresectable stage III/IV melanoma treated with ipilimumab (0.3 mg/kg, 3 mg/kg, or 10 mg/kg every 3 weeks × 4; maintenance at week 24 assigned blinded dose; patients with progression of disease [PD] able to cross over to 10-mg/kg dose), the best overall response rates were 11.1% (95% confidence interval [CI], 4.9% to 20.7%) at 10 mg/kg, 4.2% (95% CI, 0.9% to 11.7%) at 3 mg/kg, and 0% (95% CI, 0% to 4.9%) at 0.3 mg/kg.[7] Disease control rates (DCR; complete response [CR] + partial response [PR] + stable disease [SD]) at the 0.3-, 3-, and 10-mg/kg dose levels were 13.7%, 26.4%, and 29.2%, respectively. The safety profile for therapy with this antibody was comparable for the 3-mg/kg and 10-mg/kg dose cohorts, with an overall immune-related adverse event (irAE) rate of 70% at 10 mg/kg and 65% at 3 mg/kg. Because these data favored the 10-mg/kg dose, in 2007 the dosage of 10 mg/kg given every 3 weeks for four doses followed by maintenance dosing every 3 months was adopted for subsequent trials. Analysis of the long-term survival of patients who received ipilimumab, 10 mg/kg, during three key phase II trials (CA184-007, CA184-008, and CA184-022) has shown overall survival (OS) ranging from 10.2 months in previously treated patients to 22.5 months in treatment-naïve patients after median follow-ups of between 10.1 months and 16.3 months.[8] The 12-month survival rates across these three studies ranged from 47.2% to 71.4% for previously treated patients; corresponding 18-month survival rates ranged from 34.5% to 39.4%.[9] Long-term survivors included patients with PD by World Health Organization (WHO) criteria. Overall, these data demonstrate durable clinical antitumor activity for ipilimumab in advanced unresectable melanoma across a spectrum of doses and schedules, and they favor the 10-mg/kg dose as the optimal dose tested to date.
Two phase III trials with ipilimumab in advanced inoperable American Joint Committee on Cancer stage III and stage IV melanoma have completed enrollment. One trial is a first-line treatment comparison of combination therapy with ipilimumab and dacarbazine(Drug information on dacarbazine) vs dacarbazine and placebo. Results from this study are currently pending. The second trial tested the combination of ipilimumab with gp100 peptide vaccine vs gp100 vaccine alone and vs ipilimumab monotherapy, in the second-line setting. The impetus for this trial was earlier experimental data suggesting synergy between ipilimumab and vaccines in melanoma.[10] This study randomly assigned 676 pretreated patients to one of the three treatment arms. The inclusion of vaccine arms meant that this second-line trial was restricted to patients with human lymphocytic antigen A2 (HLA-A2)-positive melanoma, and ipilimumab induction therapy was given at a dosage of 3 mg/kg every 3 weeks for four doses without maintenance, with responding patients eligible for re-induction with ipilimumab if they relapsed. The trial’s original primary endpoint was response rate, but when it became apparent from ipilimumab studies that survival was more important than response rate by traditional WHO criteria, the primary endpoint was amended to OS. The 1-year survival rates were 44% (ipilimumab + gp100), 46% (ipilimumab + placebo), and 25% (ipilimumab + placebo); 2-year survival rates were 22% (ipilimumab + gp100), 24% (ipilimumab + placebo), and 14% (gp100 + placebo). The best objective response rates (BORRs) were 5.7% (ipilimumab + gp100), 10.9% (ipilimumab + placebo), and 1.5% (gp100 + placebo). The DCRs were 20.1 % (ipilimumab + gp100), 28.5% (ipilimumab + placebo), and 11% (gp100 + placebo). Median OS increased from 6.4 months to 10.0 months with the addition of ipilimumab to gp100 vaccine (hazard ration [HR], 0.68, P < .0001), and long-term survival rates improved. DCR improved from 11.0% to 20.1% (P = .02). Approximately 20% in the group treated with ipilimumab alone were alive at 4 years.[10] In addition, some patients whose disease progressed after an initial response to ipilimumab induction therapy had objective responses or SD on re-induction with ipilimumab with or without gp100. Overall, 31 patients whose disease progressed after an initial response to ipilimumab induction therapy and who received re-induction with ipilimumab with or without gp100 had an objective response rate of 19%, and an additional 48% had SD.[10] The addition of the gp100 vaccine did not lead to greater improvement than that achieved with ipilimumab alone, although the enhancement of vaccine therapy of tumors in murine models provided the premise for clinical trials of this antibody; in fact, progression-free survival (PFS) was worse in patients treated with ipilimumab and vaccine than it was in patients who received ipilimumab alone (P = .04). Paradoxically, the addition of gp100 to ipilimumab appears to reduce PFS, BORR, and DCR, without any influence on safety or OS. Relevant to these results is another phase III clinical trial that has shown that vaccination with the gp100 peptide improves outcome with high dose IL-2 therapy.[11]
The survival improvement in metastatic melanoma in the ipilimumab/gp100 randomized phase III trial is significant (HR = 0.66, 0.68),[10] but at the same time, this therapeutic strategy presents new challenges in the management of unique drug toxicities. Ongoing therapeutic strategies are building on data obtained from these studies, both to refine the immunotherapeutic strategy to overcome tumor-induced immune suppression and tumor evasion, and to identify biomarkers of prognostic and therapeutic predictive value.[12] Additional approaches for clinical development may include combination strategies with other cytokines and monoclonal antibodies targeting 4-1BB (CD137), PD-1, and CD40, with or without melanoma-specific immunization. Given the emerging understanding of the regulatory pathways that drive melanoma, and the dramatic responses observed with therapies that target the activation of the MAP kinase pathway, these new immunotherapies are reasonable to test in combination with small molecule inhibitors of the specific activating mutations, such as the V600E BRAF mutation, or the less frequent mutations and amplifications in the receptor tyrosine kinase c-kit. The most promising arena for the testing of CTLA-4 blockade may prove to be the earlier setting of adjuvant therapy, where interferon has had its greatest impact. Such testing is ongoing in European Organisation for Research and Treatment of Cancer (EORTC) trial 18071 (ipilimumab vs placebo) and is shortly to be pursued in the US Intergroup E1609 trial (ipilimumab vs high-dose interferon-α). The neoadjuvant setting, in which there is access to tumor tissue before and after neoadjuvant therapy, provides an ideal opportunity to identify immunologic and histologic correlates of tumor response. This is ongoing in a neoadjuvant ipilimumab trial in which the goal is further validation of biomarker data in the context of the E1609 adjuvant trial.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
