Clinical Therapeutics/Volume 37, Number 4, 2015
Review Article
Cytotoxic T-Lymphocyte Antigen-4 Blockade in Melanoma Elizabeth I. Buchbinder, MD1; and David F. McDermott, MD2 1
Division of Oncology, Dana Farber Cancer Institute, Boston, Massachusetts; and 2Division of Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
ABSTRACT Purpose: Melanoma is an aggressive malignancy that has a complex relationship with the host immune system. Immunotherapies have long been a mainstay of melanoma therapy, and advanced therapies continue to be effective in treating this disease. Immune checkpoint blockade has proven to be a novel target in melanoma, with the approval of cytotoxic T-lymphocyte antigen-4 (CTLA-4)–targeted therapy. This review evaluates the role of CTLA-4–targeted therapies in the treatment of metastatic melanoma, with a focus on mechanisms, efficacy, toxicity, and future directions of this therapy. Methods: A search was performed in PubMed to identify relevant clinical studies that explored the clinical experience with CTLA-4–targeted therapy in melanoma. Findings: Signaling through CTLA-4 causes deactivation of T cells after the initial stimulatory signals. Therapies that block CTLA-4 lead to increased T-cell function and an antitumor response in patients with metastatic melanoma. The adverse event profile of these agents is different from that seen with more traditional cancer therapies and consists of dermatitis, colitis, and other autoimmune toxicities. In addition, the pattern of response is different from that seen with traditional cytotoxic therapies, with some patients experiencing initial progression followed by response and some patients having long-term durable responses. Implications: Extensive clinical evidence supports the use of CTLA-4–targeted agents in the treatment of metastatic melanoma. The durability of response seen in patients receiving these agents has changed the landscape for patients with melanoma. Combination Accepted for publication February 3, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.02.003 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
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therapies and other agents with similar mechanisms warrant further exploration for the treatment of metastatic melanoma. (Clin Ther. 2015;37:755– 763) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: autoimmunity, checkpoint inhibitor, CTLA4, ipilimumab.
INTRODUCTION Melanoma has proven to be 1 of the most immunologic malignancies based on documented cases of spontaneous regression and its higher prevalence in immunocompromised patients. Although melanoma is the ninth most common malignancy, it is the second in terms of potential life lost. The incidence of melanoma has been on the rise, with an estimated 76,100 new cases and 9710 deaths due to melanoma in 2014.1 Manipulation of the patient’s immune system in the treatment of malignancies has been a goal of melanoma investigators for decades.2 Cytokines, including interferon and interleukin-2 (IL-2), are used in the treatment of this disease. However, the effects of these agents are limited to a small proportion of those treated, and toxicity is high. Efforts to increase efficacy and decrease toxicity led to the exploration of alternate mechanisms to activate the immune system and subsequently checkpoint blockade. This review evaluated the role of cytotoxic T-lymphocyte antigen 4 (CTLA-4)–targeted therapies in the treatment of metastatic melanoma, with a focus on mechanisms, efficacy, toxicity, and future directions of this therapy. Scan the QR Code with your phone to obtain FREE ACCESS to the articles featured in the Clinical Therapeutics topical updates or text GS2C65 to 64842. To scan QR Codes your phone must have a QR Code reader installed.
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MATERIALS AND METHODS PubMed was searched by using the search terms CTLA-4 and melanoma, ipilimumab and melanoma, and tremelimumab and melanoma. Only Englishlanguage clinical trials in humans and systematic reviews published between 1970 and December 12, 2014, and additional trials and reviews referenced in published articles were included.
RESULTS A total of 233 publications were identified; 52 clinical trials were categorized as having relevant data exploring the use of ipilimumab and tremelimumab in the treatment of metastatic melanoma. A total of 21 key clinical trials were analyzed and are summarized in the current systematic review.
CTLA-4’s Role in the Immune System The immune system is continually being exposed to foreign antigens and self-antigens. An intricate system is in place to induce the immune system that involves both T-cell receptor engagement and costimulatory signaling.3,4 Antigens are presented by major histocompatibility class I or II on an antigen-presenting cell to the T-cell receptor complex, which initiates the signal within the T cell. Costimulatory molecules work to amplify or counteract signals provided by
T-cell Activation
the T-cell receptor complex.5,6 Typically, CD28 binds to B7-1/B7-2 on the T cell, leading to activation. CTLA-4 is a costimulatory molecule that competes with CD28 and inhibits T-cell proliferation and signaling. CTLA-4 is member of the CD28 superfamily and is not constitutively expressed on T cells but is induced after CD28 binding and activation.7 The ligands for CTLA-4, B7-1 and B7-2, are the same as for CD28 but with higher affinity.8 CTLA-4 engagement on activated T cells inhibits IL-2 transcription as well as progression through the cell cycle.9 Thus, its signaling has a direct effect on the T-cell proliferation beyond blocking signaling through CD28, (Figure 1). CTLA-4 has been shown to play a role in human disease. According to genetic mapping of patients with autoimmune disease, the CTLA-4 gene is a locus of susceptibility to disease.10 In addition, CTLA-4 gene polymorphisms have been associated with numerous autoimmune conditions, including diabetes and inflammatory bowel disease.11 Tumors utilize local and systemic mechanisms to suppress the immune system. These mechanisms include increasing regulatory T cells, inducing myeloid suppressor cells to suppress T-cell proliferation, local accumulation of tumor-associated macrophages, upregulation of programmed death ligand-1 (which
T-cell Inhibition
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T-cell remains activated
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CD28 CTLA4 TCR CD28 B7
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Figure 1. T-cell activation requires costimulation through the TCR and CD28. Binding of B7 to CTLA4 inhibits T-cell function. Anti-CTLA4 antibodies block CTLA4 binding and prevent inhibition of T-cell function.
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E.I. Buchbinder and D.F. McDermott inhibits T-cell function), and production of factors associated with immunosuppression.12 The inability of immunotherapy to induce sufficient tumor-specific T-cell responses to more consistently eradicate tumors is due to many of these factors. In addition, the immune system receives insufficient costimulation by tumor cells when an antigen is presented. Tumor cells that were transfected with B7-1 were rejected when placed into mice, and subsequent attempts at tumor growth in these mice were unsuccessful, suggesting an activation of tumor immunity. This research led to the notion that inhibition of CTLA-4 would be a potential target in the treatment of malignancy.13 Because CTLA-4 inhibition turned off a checkpoint on the immune system, targeting this and similar signaling interactions is referred to as checkpoint blockade.
Discovery of CTLA-4–Targeted Therapies Researchers (led by Jim Allison) at the University of California, Berkeley, discovered the CTLA-4 pathway and were responsible for the initial use of CTLA-4– blocking antibodies as a cancer therapeutic agent.8,14,15 Antibodies against CTLA-4 were injected into mice concurrent with tumor cells, and a lack of growth was observed. CTLA-4 antibodies were also used as treatment in mice with pre-established tumors, with rejection of the tumor.1 These mouse experiments were expanded into prostate cancer, melanoma, and other malignancies.16,17 In some malignancies, the efficacy of CTLA-4 blockade required coadministration with a vaccine. 17 Researchers at Medarex (led by Alan Korman) then developed human monoclonal immunoglobulin G1κ antibodies that block CTLA-4 by using a transgenic mouse with human immunoglobulin genes. Studies in cynomolgus macaques demonstrated that the antibody could augment a vaccine response, but no increase in observable autoimmunity was noted.18 This finding paved the way for use of this antibody, then named MDX-010 and subsequently named ipilimumab, in human clinical trials. Concurrently, scientists at Pfizer developed CP-675 (tremelimumab), an immunoglobulin G2 antibody targeting CTLA-4; tremelimumab then entered clinical development.
Initial Studies of CTLA-4–Targeted Agents in Solid Malignancies The initial use of CTLA-4–targeted therapy with ipilimumab was in a small pilot study of patients with prostate cancer; a decline in prostate-specific antigen
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levels by Z50% in 2 of 14 patients was reported.19 In addition, a cohort of previously vaccinated patients with melanoma and ovarian carcinoma were treated with CTLA-4 antibody blockade, with reduced tumor markers and evidence of tumor necrosis.20 A Phase I trial of ipilimumab in melanoma demonstrated partial responses in 2 of 17 patients.21 This early indication of clinical activity led to more intensive exploration of ipilimumab, particularly in patients with metastatic melanoma. Trials in metastatic melanoma showed early evidence of response to CTLA-4 blockade. A Phase I/II study of ipilimumab in patients with advanced melanoma reported a disease control rate of 39%.22 An intrapatient dose escalation study found that elevating the dose from 3 to 9 mg/kg increased autoimmune toxicity with no increase in the objective response rate.23 However, a double-blind, dose-ranging study found a dose-dependent effect on efficacy, with an 11.1% response rate in patients receiving ipilimumab 10 mg/kg.24 As Phase II trials progressed, the dosing of ipilimumab was refined. A multicenter, Phase II trial used ipilimumab 10 mg/kg every 3 weeks for 4 treatments followed by maintenance therapy every 3 months.25 This trial reported a disease control rate of 35% when immune-related response criteria were used. Both the 3-mg/kg and the 10-mg/kg dosing regimens were used in stage III testing. Tremelimumab was similarly successful in initial testing. Two dosages of this agent were tested: 15 mg/ kg every 90 days and 10 mg/kg every month. Initial results from the Phase I/II testing of these doses found a 10% objective tumor response rate; these responses were durable. Serious AEs were less frequently observed in the treatment arm of 15 mg/kg every 3 months (13% vs 27%); based on this finding, the less frequent dosing regimen was chosen for further clinical testing.26 A prospective, randomized, Phase II trial found an association between response to ipilimumab and immune-related tumor biomarkers and posttreatment tumor-infiltrating lymphocytes.27 Ipilimumab targets the immune system, as opposed to the tumor, by several mechanisms. Blockade of CTLA-4 can cause proliferation or increased activity of effector T cells. T-regulatory cells (T-regs) inhibit effector T-cell function. T-regs express CTLA-4, and intratumoral T-regs were depleted by CTLA-4–targeted antibodies in preclinical experiments.12 This depletion reportedly
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Clinical Therapeutics occurs by an Fc-dependent mechanism.28,29 Both the T-cell activation and T-reg depletion may contribute to the antitumor activity of CTLA-4–targeted antibodies. The exact mechanism of action of CTLA-4 blockade is an area of active investigation.
Response Patterns to CTLA-4 It was discovered that some patients who initially had progressive disease with CTLA-4 blockade went on to respond after treatment was stopped, even if their initial disease had met the criteria for progression. The tumor growth seen in these patients was believed to be due to immune infiltration into the tumors. This observation illustrated that the conventional Response Evaluation Criteria in Solid Tumors would not be an effective method of monitoring responses in all patients, and alternative criteria, termed immune-related response criteria, were proposed. These proposed criteria consider total tumor burden regardless of the growth of new disease, with higher maximum tumor growth allowed within the bounds of stable disease.30,31 Patterns of response to CTLA-4 blockade include: (1) regression of baseline lesions with no new lesions; (2) stable disease followed by a slow, steady decline in tumor burden; (3) delayed response after an initial increase in tumor burden; and (4) response after the appearance of new lesions. Given these irregular patterns of response, it is recommended that no imaging be obtained until the end of the induction period (12 weeks) and the findings confirmed with a scan at least 4 weeks later.30 The other important lesson from these early-phase trials was the identification of immune-related AEs (irAEs) as the most common toxicities associated with CTLA-4 blockade. These toxicities were shown to be manageable in most cases and were often reversible with appropriate therapy.32 They are discussed in more depth later in this review.
Phase III Trials of CTLA-4–Targeted Agents in Melanoma The initial Phase III trial of ipilimumab explored its activity at a dosage of 3 mg/kg every 3 weeks for up to 4 treatments. The patients were randomized to receive ipilimumab combined with glycoprotein 100 (gp100) peptide vaccine, ipilimumab alone, or gp100 alone. No difference in survival was detected between the ipilimumab groups. However, an overall survival benefit was seen when the groups receiving
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ipilimumab plus gp100 and ipilimumab alone were compared with the group receiving gp100 alone. The overall survival rates were 10.0 months, 10.1 months, and 6.4 months, respectively, with a hazard ratio for death between the 2 gp100 arms of 0.68 (P o 0.001).33 Grade 3 or 4 irAEs occurred in 10% to 15% of patients treated with ipilimumab; of the 676 patients, 14 deaths were attributed to study drugs. In addition, previous treatment with IL-2 did not preclude a response to ipilimumab. The results of this study were the basis for the approval of ipilimumab for the treatment of advanced melanoma. The dosing used in this study (3 mg/kg every 3 weeks for 4 doses) became the approved dose for treatment-naive or previously treated patients with metastatic melanoma. A second Phase III trial compared ipilimumab plus dacarbazine versus dacarbazine in previously untreated patients with metastatic melanoma.34 This trial used a higher dose of ipilimumab: 10 mg/kg every 3 weeks for 4 doses followed by maintenance therapy every 12 weeks. The overall survival was significantly longer in the ipilimumab group compared with dacarbazine alone (11.2 vs 9.1 months, with a hazard ratio for death of 0.72; P o 0.0001). In this trial, adding ipilimumab to dacarbazine led to 28.8% more episodes of grade 3 to 4 toxicity (56.3% vs 27.5%), but there were no deaths associated with ipilimumab despite the higher dose being used. Despite promising Phase I/II trial results for tremelimumab, its Phase III results were disappointing. A Phase III trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma found an overall survival of 12.6 months in the tremelimumab arm and 10.7 months in the chemotherapy arm.35 This result failed to meet statistical significance, with a hazard ratio of 0.88 (P ¼ 0.127). It was believed that patient selection, dosing regimen, and use of ipilimumab as salvage therapy for patients in this trial likely led to the lack of a statistically significant difference between the 2 arms. Patients with high lactate dehydrogenase levels were excluded, leading to a healthier patient population overall. At least 16% of patients within the control arm went on to receive ipilimumab, which would have blunted any survival difference between the arms.
Melanoma Patients with Brain Metastasis Previous immunotherapies have not had particular success controlling brain metastasis in patients with
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E.I. Buchbinder and D.F. McDermott melanoma. Patients who have responses to IL-2 therapy can go on to develop brain metastasis despite good systemic control of their disease. This population of patients is in need of better systemic therapies that also control their central nervous system disease. An open-label Phase II trial of ipilimumab in patients with brain metastasis enrolled patients both on and off corticosteroids.36 In those patients off steroids, there was an 18% disease control rate with a 24% brain-alone disease control rate. In patients on steroids, the control rate was lower, with only 1 patient of 21 exhibiting disease control and 2 exhibiting brain-alone disease control. This study demonstrated that ipilimumab has some activity in patients with brain metastasis from melanoma, particularly those with asymptomatic disease not requiring corticosteroid therapy. These findings suggest that the blood–brain barrier does not restrict ipilimumab’s activity.
irAEs Associated with CTLA-4 Blockade CTLA-4 blockade induces drug-related adverse events that are believed to be related to immune effects and are classified as irAEs. The most common toxicity observed comprised gastrointestinal, skin, endocrine, or liver toxicities. Hypophysitis, pancreatitis, iridocyclitis, lymphadenopathy, neuropathies, and nephritis have also been reported with ipilimumab. Early diagnosis, vigilant follow-up, and prompt use of systemic high-dose corticosteroids are essential to minimizing toxicity and death from these events.29 An analysis of patients treated in the Phase III trial of ipilimumab found that the majority of these irAEs developed within 12 weeks of initial dosing and resolved within 12 weeks of onset.37 Skin rash was the most prevalent toxicity, with 47% to 66% of patients experiencing a pruritic maculopapular rash. Topical steroids are often effective, and holding of the drug is rarely required. Rare cases of toxic epidermal necrolysis and Stevens-Johnson syndrome, which have led to death, have also been reported.31 Ipilimumab should be discontinued in patients with severe rash, and systemic steroids should be initiated. Diarrhea was observed in 44% of patients receiving ipilimumab 10 mg/kg, and severe diarrhea (grade 3 or 4) was reported in 18%.37 The overall rate of bowel perforation is o1%; however, deaths related to ipilimumab due to this toxicity have been reported. An algorithm to treat the diarrhea was developed and
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published; it involves early initiation of corticosteroids and infliximab in patients who have steroid-refractory diarrhea. A randomized Phase II study compared the efficacy of ipilimumab with or without prophylactic budesonide to determine if this regimen would decrease diarrhea.38 No change in the rate of grade 2 or higher diarrhea was noted between the 2 arms. Hepatotoxicity was observed in 3% to 9% of patients receiving anti–CTLA-4 antibodies, often reported as asymptomatic elevation of liver enzyme levels. For severe hepatotoxicity, systemic steroids are recommended, and if serum transaminase levels do not decrease within 48 hours of the start of systemic steroids, oral mycophenolate mofetil 500 mg every 12 hours should be initiated.31 A rare but potentially long-term adverse effect of CTLA-4 blockade is hypophysitis. This condition occurs in 1% to 9% of patients treated with 3 or 10 mg/kg of ipilimumab, on average 6 weeks after initiation of therapy. Symptoms can include headache, double vision, nausea, weakness, and fatigue. Results of blood tests typically reveal low levels of thyroid, adrenal, and gonadal hormones. A brain magnetic resonance imaging scan may show pituitary swelling/ enlargement. Patients with evidence of hypophysitis should be started on intravenous steroids; these patients often require very slow tapering of these steroids. Although some patients reportedly are able to regain pituitary function, many require long-term hormone replacement.31,39 Some data suggest that patients with irAEs are more likely to achieve a clinical benefit from ipilimumab. In 139 ipilimumab-treated patients with metastatic melanoma among 86 patients experiencing any grade of irAE, 22 (26%) were objective responders, compared with 2% (1 of 53) of patients who did not have any irAE.40 Development of an irAE was significantly associated with likelihood of response (P ¼ 0.0004). Analysis of patient data from other studies has supported this finding thus far. A randomized trial of ipilimumab with and without granulocyte-macrophage colony-stimulating factor (GM-CSF) found a trend toward improved tolerability in the GM-CSF arm over ipilimumab alone.41 Final analysis of this trial may support using this regimen to decrease the toxicity of ipilimumab.
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Long Term Survival with Ipilimumab The largest benefit seen with previous immune therapies, particularly IL-2, is the durability of response when treatment is discontinued. Data are now available regarding a similar durability of response in ipilimumab-patients who have melanoma. Five-year survival rates in various studies have been reported to be between 16.5% and 25%. Of interest, some of these patients displayed no objective response to ipilimumab.42 Survival curves show a plateau at 3 years that is ongoing. Initial reports suggest that similar findings will be seen with analysis of the larger Phase III trials.43,44
Patient Selection for CTLA-4 Blockade Because only a subset of patients treated with CTLA-4 blockade exhibit a long-term benefit from therapy, it would be advantageous to identify those patients most likely to respond. To date, however, no clear predictive biomarker has been developed for the selection of these patients. Some retrospective markers that reflect immune activation in responders include absolute lymphocyte count, up-regulation of the T-cell activation marker–inducible costimulator, and the development of a polyfunctional T-cell response to the tumor antigen NY-ESO-1.45 High baseline expression levels of immune-related genes predicted response to ipilimumab treatment in a cohort of 45 patients.46 Some promising mechanisms being explored include analyzing genetic factors within the tumor itself or the host. According to some data, the tumor mutation volume may help predict activity of immune checkpoint blockade.47 There may also be host factors that predict response, and genes such as CCR2/CCRL2/CCR5 are being explored.48 There is clearly some association between immune system function and response to ipilimumab, as noted in the increased irAEs seen among responders. However, further study to determine what those factors are and prospective validation of any proposed, predictive biomarker will be required before we are able to better target CLTA-4 antibody treatment.
Adjuvant Therapy The ultimate goal in melanoma therapy would be to find an agent that not only successfully treats patients who have metastatic disease but can also work to prevent recurrence in patients with high-risk
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early-stage disease. Iplimumab’s success in the metastatic melanoma setting led to its testing in resected stage III patients at high risk of recurrence. A study of the European Organisation for Research and Treatment of Cancer randomized 951 patients to receive placebo or ipilimumab at 10 mg/kg every 3 weeks for 4 doses, then every 3 months out to 3 years.49 This trial reported a recurrence-free survival of 26.1 months in the ipilimumab arm compared with 17.1 months, with a hazard ratio of 0.75 (P ¼ 0.0013). Unfortunately, 5 deaths caused by ipilimumab-related immune toxicity occurred during the trial (3 due to colitis, 1 due to myocarditis, and 1 due to GuillainBarré syndrome). Although the European Organisation for Research and Treatment of Cancer trial used placebo as a control, high-dose interferon-α2b is approved by the US Food and Drug Administration for use in this setting and has previously demonstrated benefit.50 Based on this finding, the Eastern Cooperative Oncology Group is currently enrolling patients in a study comparing high-dose interferon-α2b versus ipilimumab at 3 mg/kg and 10 mg/kg. Results of this trial will be helpful in defining therapy for this high-risk population.
Combination Therapies There are many very interesting clinical trials assessing the combination of ipilimumab and tremelimumab versus conventional cytotoxic chemotherapy, radiation therapy, targeted therapy, traditional immune therapy, and other checkpoint blockade agents. Combination therapies need to be chosen in a rational way by which other therapies either lead to increased release of antigens from tumors or change the immune milieu. Evidence suggests that radiation therapy may activate the immune system and thus prime it for greater activation by immunotherapy. The abscopal effect, by which local radiation therapy causes tumor regression at a distant site, may be mediated by immune response.51 Studies to further explore this scenario are being performed. Bevacizumab is a vascular endothelial growth factor–targeted agent that is also known to play a role in dendritic cell maturation and lymphocyte endothelial trafficking. A study of 46 patients treated with a combination of ipilimumab and bevacizumab reported a disease control rate of 67.4%.52 Based on these results, a Phase III trial of this combination is
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E.I. Buchbinder and D.F. McDermott currently enrolling patients. The combination of IL-2 and ipilimumab has shown an overall response rate of 22%, with 3 complete responses.53 Further exploration of this combination is also planned. GM-CSF is known to enhance dendritic cell activation and potentiate antitumor T- and B-cell responses and is hypothesized to synergize with CTLA-4 blockade. The Eastern Cooperative Oncology Group performed a randomized trial of ipilimumab with and without GM-CSF.41 The trial reported an overall survival benefit to adding GM-CSF and showed a trend toward improved tolerability in the GM-CSF arm over ipilimumab alone. The most promising combination therapies at this time are with other checkpoint blockade agents. Nivolumab is a novel antibody targeting the programmed death-1 receptor. It has demonstrated single-agent activity in melanoma. In combination with ipilimumab, evidence of clinical activity was observed in 65% of 53 patients, and many of those patients had a reduction in tumor volume of Z80%.54 Survival updates for these patients exhibited 1- and 2-year overall survival rates of 82% and 75%, respectively. The complete response rate in this subsequent analysis was 17%, and the median duration of response was not reached, indicting ongoing responses for many patients.55 Trials are underway to determine if the benefit is greater if ipilimumab and nivolumab are given concurrently or if they could be given sequentially, with similar long-term benefits.
CONCLUSIONS CTLA-4 blockade is an effective new therapy in the treatment of metastatic melanoma. It has demonstrated a survival benefit compared with currently available therapies. In addition, the responses are often durable, which is changing long-term survival for this disease. Unfortunately, the number of patients responding is still limited. Research is ongoing to better select patients likely to benefit from CTLA-4 blockade. In addition, novel agents are being added to this therapy, with early results suggesting an increase in the number of overall responders. CTLA-4 blockade has paved the way for a new generation of immunotherapy.
CONFLICTS OF INTEREST Dr. McDermott serves on an advisory board for Bristol-Myers Squibb and is a Drug Safety Monitoring Board member for Pfizer. The authors have indicated
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that they have no other conflicts of interest regarding the content of this article.
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phase II study. Ann Oncol. 2010;21: 1712–1717. Camacho LH, Antonia S, Sosman J, et al. Phase I/II trial of tremelimumab in patients with metastatic melanoma. J Clin Oncol. 2009;27: 1075–1081. Hamid O, Schmidt H, Nissan A, et al. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med. 2011;9:204. Simpson TR, Li F, Montalvo-Ortiz W, et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA4 therapy against melanoma. J Exp Med. 2013;210:1695–1710. Selby MJ, Engelhardt JJ, Quigley KA, et al. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol Res. 2013;1:32–42. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin?Cancer Res. 2009;15:7412–7420. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012; 30:2691–2697. Wolchok JD, Hodi SF, Weber JS, et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci. 2013; 1291:1–13. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363:711–723. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364: 2517–2526.
35. Ribas A, Kefford R, Marshall MA, et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013;31:616–622. 36. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastasis: an open-label, phase II trial. Lancet Oncol. 2012;13:459–465. 37. Weber JS, Dummer R, de Pril V, et al. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer. 2013; 119:1675–1682. 38. Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15:5591–5598. 39. Blansfield JA, Beck KE, Tran K, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother. 2005;28: 593–598. 40. Downey SG, Klapper JA, Smith FO, et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res. 2007;13:6681–6688. 41. Hodi FS, Lee SJ, McDermott DF, et al. Multicenter randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus Ipi alone in metastatic melanoma: E1608. J Clin Oncol. 2013:31 (suppl; abstr CRA 9007). 42. Prieto PA, Jang JC, Sherry RM, et al. CTLA-4 blockade with ipilimumab: long-term follow-up for 177 patients with metastatic melanoma. Clin Cancer Res. 2012;18:2039–2047.
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E.I. Buchbinder and D.F. McDermott 43. McDermott D, Haanen J, Chen TT, et al. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol. 2013; 24:2694–2698. 44. McDermott D, Lebbe C, Hodi FS, et al. Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. Cancer Treat Rev. 2014;40: 1056–1064. 45. Callahan MK, Postow MA, Wolchok JD. Immunomodulatory therapy for melanoma: Ipilimumab and beyond. Clin in Derm. 2013;31:191–199. 46. Ji RR, Chasalow SD, Wang L, et al. An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol Immunother. 2012;61:1019–1031. 47. Charen AS, Makarov V, Merghoub T, et al. The neoantigen landscape underlying clinical response to ipilimumab. J Clin Oncol. 2014;32:5s (suppl; abstr 3003). 48. Adaniel C, Rendleman J, Polsky D, et al. Germline genetic determinants of immunotherapy response in metastatic melanoma. J Clin Oncol. 2014;32:5s (suppl; abstr 3004). 49. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Ipilimumab versus placebo after complete resection of stage II melanoma: initial efficacy and safety results from EORTC 18071 phase III trial. J Clin Oncol. 2014;32:5s (suppl; abstr LBA9008). 50. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14:7–17. 51. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366: 925–931. 52. Hodi FS, Lawrence D, Lezcano C, et al. Bevacizumab plus ipilimumab in
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patients with metastatic melanoma. Cancer Immunol Res. 2014;2:632–642. 53. Maker AV, Phan GQ, Attia P, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol. 2005;12: 1005–1016. 54. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab pulse ipilimumab in
advanced melanoma. N Engl J Med. 2013;369:122–133. 55. Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, antiPD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). J Clin Oncol. 2014;32:5s (suppl; abstr LBA9003̂ ).
Address correspondence to: Elizabeth I. Buchbinder, Division of Oncology, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215. E-mail: [email protected]
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Review Article
Cytotoxic T-Lymphocyte Antigen-4 Blockade in Melanoma Elizabeth I. Buchbinder, MD1; and David F. McDermott, MD2 1
Division of Oncology, Dana Farber Cancer Institute, Boston, Massachusetts; and 2Division of Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
ABSTRACT Purpose: Melanoma is an aggressive malignancy that has a complex relationship with the host immune system. Immunotherapies have long been a mainstay of melanoma therapy, and advanced therapies continue to be effective in treating this disease. Immune checkpoint blockade has proven to be a novel target in melanoma, with the approval of cytotoxic T-lymphocyte antigen-4 (CTLA-4)–targeted therapy. This review evaluates the role of CTLA-4–targeted therapies in the treatment of metastatic melanoma, with a focus on mechanisms, efficacy, toxicity, and future directions of this therapy. Methods: A search was performed in PubMed to identify relevant clinical studies that explored the clinical experience with CTLA-4–targeted therapy in melanoma. Findings: Signaling through CTLA-4 causes deactivation of T cells after the initial stimulatory signals. Therapies that block CTLA-4 lead to increased T-cell function and an antitumor response in patients with metastatic melanoma. The adverse event profile of these agents is different from that seen with more traditional cancer therapies and consists of dermatitis, colitis, and other autoimmune toxicities. In addition, the pattern of response is different from that seen with traditional cytotoxic therapies, with some patients experiencing initial progression followed by response and some patients having long-term durable responses. Implications: Extensive clinical evidence supports the use of CTLA-4–targeted agents in the treatment of metastatic melanoma. The durability of response seen in patients receiving these agents has changed the landscape for patients with melanoma. Combination Accepted for publication February 3, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.02.003 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
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therapies and other agents with similar mechanisms warrant further exploration for the treatment of metastatic melanoma. (Clin Ther. 2015;37:755– 763) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: autoimmunity, checkpoint inhibitor, CTLA4, ipilimumab.
INTRODUCTION Melanoma has proven to be 1 of the most immunologic malignancies based on documented cases of spontaneous regression and its higher prevalence in immunocompromised patients. Although melanoma is the ninth most common malignancy, it is the second in terms of potential life lost. The incidence of melanoma has been on the rise, with an estimated 76,100 new cases and 9710 deaths due to melanoma in 2014.1 Manipulation of the patient’s immune system in the treatment of malignancies has been a goal of melanoma investigators for decades.2 Cytokines, including interferon and interleukin-2 (IL-2), are used in the treatment of this disease. However, the effects of these agents are limited to a small proportion of those treated, and toxicity is high. Efforts to increase efficacy and decrease toxicity led to the exploration of alternate mechanisms to activate the immune system and subsequently checkpoint blockade. This review evaluated the role of cytotoxic T-lymphocyte antigen 4 (CTLA-4)–targeted therapies in the treatment of metastatic melanoma, with a focus on mechanisms, efficacy, toxicity, and future directions of this therapy. Scan the QR Code with your phone to obtain FREE ACCESS to the articles featured in the Clinical Therapeutics topical updates or text GS2C65 to 64842. To scan QR Codes your phone must have a QR Code reader installed.
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MATERIALS AND METHODS PubMed was searched by using the search terms CTLA-4 and melanoma, ipilimumab and melanoma, and tremelimumab and melanoma. Only Englishlanguage clinical trials in humans and systematic reviews published between 1970 and December 12, 2014, and additional trials and reviews referenced in published articles were included.
RESULTS A total of 233 publications were identified; 52 clinical trials were categorized as having relevant data exploring the use of ipilimumab and tremelimumab in the treatment of metastatic melanoma. A total of 21 key clinical trials were analyzed and are summarized in the current systematic review.
CTLA-4’s Role in the Immune System The immune system is continually being exposed to foreign antigens and self-antigens. An intricate system is in place to induce the immune system that involves both T-cell receptor engagement and costimulatory signaling.3,4 Antigens are presented by major histocompatibility class I or II on an antigen-presenting cell to the T-cell receptor complex, which initiates the signal within the T cell. Costimulatory molecules work to amplify or counteract signals provided by
T-cell Activation
the T-cell receptor complex.5,6 Typically, CD28 binds to B7-1/B7-2 on the T cell, leading to activation. CTLA-4 is a costimulatory molecule that competes with CD28 and inhibits T-cell proliferation and signaling. CTLA-4 is member of the CD28 superfamily and is not constitutively expressed on T cells but is induced after CD28 binding and activation.7 The ligands for CTLA-4, B7-1 and B7-2, are the same as for CD28 but with higher affinity.8 CTLA-4 engagement on activated T cells inhibits IL-2 transcription as well as progression through the cell cycle.9 Thus, its signaling has a direct effect on the T-cell proliferation beyond blocking signaling through CD28, (Figure 1). CTLA-4 has been shown to play a role in human disease. According to genetic mapping of patients with autoimmune disease, the CTLA-4 gene is a locus of susceptibility to disease.10 In addition, CTLA-4 gene polymorphisms have been associated with numerous autoimmune conditions, including diabetes and inflammatory bowel disease.11 Tumors utilize local and systemic mechanisms to suppress the immune system. These mechanisms include increasing regulatory T cells, inducing myeloid suppressor cells to suppress T-cell proliferation, local accumulation of tumor-associated macrophages, upregulation of programmed death ligand-1 (which
T-cell Inhibition
T-cell
T-cell remains activated
T-cell
T-cell
CD28 CTLA4 TCR CD28 B7
MHC
APC
CTLA4
CTLA4
TCR
B7
MHC
APC
TCR
CD28
MHC
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Anti-CTLA4 Ab
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Figure 1. T-cell activation requires costimulation through the TCR and CD28. Binding of B7 to CTLA4 inhibits T-cell function. Anti-CTLA4 antibodies block CTLA4 binding and prevent inhibition of T-cell function.
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E.I. Buchbinder and D.F. McDermott inhibits T-cell function), and production of factors associated with immunosuppression.12 The inability of immunotherapy to induce sufficient tumor-specific T-cell responses to more consistently eradicate tumors is due to many of these factors. In addition, the immune system receives insufficient costimulation by tumor cells when an antigen is presented. Tumor cells that were transfected with B7-1 were rejected when placed into mice, and subsequent attempts at tumor growth in these mice were unsuccessful, suggesting an activation of tumor immunity. This research led to the notion that inhibition of CTLA-4 would be a potential target in the treatment of malignancy.13 Because CTLA-4 inhibition turned off a checkpoint on the immune system, targeting this and similar signaling interactions is referred to as checkpoint blockade.
Discovery of CTLA-4–Targeted Therapies Researchers (led by Jim Allison) at the University of California, Berkeley, discovered the CTLA-4 pathway and were responsible for the initial use of CTLA-4– blocking antibodies as a cancer therapeutic agent.8,14,15 Antibodies against CTLA-4 were injected into mice concurrent with tumor cells, and a lack of growth was observed. CTLA-4 antibodies were also used as treatment in mice with pre-established tumors, with rejection of the tumor.1 These mouse experiments were expanded into prostate cancer, melanoma, and other malignancies.16,17 In some malignancies, the efficacy of CTLA-4 blockade required coadministration with a vaccine. 17 Researchers at Medarex (led by Alan Korman) then developed human monoclonal immunoglobulin G1κ antibodies that block CTLA-4 by using a transgenic mouse with human immunoglobulin genes. Studies in cynomolgus macaques demonstrated that the antibody could augment a vaccine response, but no increase in observable autoimmunity was noted.18 This finding paved the way for use of this antibody, then named MDX-010 and subsequently named ipilimumab, in human clinical trials. Concurrently, scientists at Pfizer developed CP-675 (tremelimumab), an immunoglobulin G2 antibody targeting CTLA-4; tremelimumab then entered clinical development.
Initial Studies of CTLA-4–Targeted Agents in Solid Malignancies The initial use of CTLA-4–targeted therapy with ipilimumab was in a small pilot study of patients with prostate cancer; a decline in prostate-specific antigen
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levels by Z50% in 2 of 14 patients was reported.19 In addition, a cohort of previously vaccinated patients with melanoma and ovarian carcinoma were treated with CTLA-4 antibody blockade, with reduced tumor markers and evidence of tumor necrosis.20 A Phase I trial of ipilimumab in melanoma demonstrated partial responses in 2 of 17 patients.21 This early indication of clinical activity led to more intensive exploration of ipilimumab, particularly in patients with metastatic melanoma. Trials in metastatic melanoma showed early evidence of response to CTLA-4 blockade. A Phase I/II study of ipilimumab in patients with advanced melanoma reported a disease control rate of 39%.22 An intrapatient dose escalation study found that elevating the dose from 3 to 9 mg/kg increased autoimmune toxicity with no increase in the objective response rate.23 However, a double-blind, dose-ranging study found a dose-dependent effect on efficacy, with an 11.1% response rate in patients receiving ipilimumab 10 mg/kg.24 As Phase II trials progressed, the dosing of ipilimumab was refined. A multicenter, Phase II trial used ipilimumab 10 mg/kg every 3 weeks for 4 treatments followed by maintenance therapy every 3 months.25 This trial reported a disease control rate of 35% when immune-related response criteria were used. Both the 3-mg/kg and the 10-mg/kg dosing regimens were used in stage III testing. Tremelimumab was similarly successful in initial testing. Two dosages of this agent were tested: 15 mg/ kg every 90 days and 10 mg/kg every month. Initial results from the Phase I/II testing of these doses found a 10% objective tumor response rate; these responses were durable. Serious AEs were less frequently observed in the treatment arm of 15 mg/kg every 3 months (13% vs 27%); based on this finding, the less frequent dosing regimen was chosen for further clinical testing.26 A prospective, randomized, Phase II trial found an association between response to ipilimumab and immune-related tumor biomarkers and posttreatment tumor-infiltrating lymphocytes.27 Ipilimumab targets the immune system, as opposed to the tumor, by several mechanisms. Blockade of CTLA-4 can cause proliferation or increased activity of effector T cells. T-regulatory cells (T-regs) inhibit effector T-cell function. T-regs express CTLA-4, and intratumoral T-regs were depleted by CTLA-4–targeted antibodies in preclinical experiments.12 This depletion reportedly
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Clinical Therapeutics occurs by an Fc-dependent mechanism.28,29 Both the T-cell activation and T-reg depletion may contribute to the antitumor activity of CTLA-4–targeted antibodies. The exact mechanism of action of CTLA-4 blockade is an area of active investigation.
Response Patterns to CTLA-4 It was discovered that some patients who initially had progressive disease with CTLA-4 blockade went on to respond after treatment was stopped, even if their initial disease had met the criteria for progression. The tumor growth seen in these patients was believed to be due to immune infiltration into the tumors. This observation illustrated that the conventional Response Evaluation Criteria in Solid Tumors would not be an effective method of monitoring responses in all patients, and alternative criteria, termed immune-related response criteria, were proposed. These proposed criteria consider total tumor burden regardless of the growth of new disease, with higher maximum tumor growth allowed within the bounds of stable disease.30,31 Patterns of response to CTLA-4 blockade include: (1) regression of baseline lesions with no new lesions; (2) stable disease followed by a slow, steady decline in tumor burden; (3) delayed response after an initial increase in tumor burden; and (4) response after the appearance of new lesions. Given these irregular patterns of response, it is recommended that no imaging be obtained until the end of the induction period (12 weeks) and the findings confirmed with a scan at least 4 weeks later.30 The other important lesson from these early-phase trials was the identification of immune-related AEs (irAEs) as the most common toxicities associated with CTLA-4 blockade. These toxicities were shown to be manageable in most cases and were often reversible with appropriate therapy.32 They are discussed in more depth later in this review.
Phase III Trials of CTLA-4–Targeted Agents in Melanoma The initial Phase III trial of ipilimumab explored its activity at a dosage of 3 mg/kg every 3 weeks for up to 4 treatments. The patients were randomized to receive ipilimumab combined with glycoprotein 100 (gp100) peptide vaccine, ipilimumab alone, or gp100 alone. No difference in survival was detected between the ipilimumab groups. However, an overall survival benefit was seen when the groups receiving
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ipilimumab plus gp100 and ipilimumab alone were compared with the group receiving gp100 alone. The overall survival rates were 10.0 months, 10.1 months, and 6.4 months, respectively, with a hazard ratio for death between the 2 gp100 arms of 0.68 (P o 0.001).33 Grade 3 or 4 irAEs occurred in 10% to 15% of patients treated with ipilimumab; of the 676 patients, 14 deaths were attributed to study drugs. In addition, previous treatment with IL-2 did not preclude a response to ipilimumab. The results of this study were the basis for the approval of ipilimumab for the treatment of advanced melanoma. The dosing used in this study (3 mg/kg every 3 weeks for 4 doses) became the approved dose for treatment-naive or previously treated patients with metastatic melanoma. A second Phase III trial compared ipilimumab plus dacarbazine versus dacarbazine in previously untreated patients with metastatic melanoma.34 This trial used a higher dose of ipilimumab: 10 mg/kg every 3 weeks for 4 doses followed by maintenance therapy every 12 weeks. The overall survival was significantly longer in the ipilimumab group compared with dacarbazine alone (11.2 vs 9.1 months, with a hazard ratio for death of 0.72; P o 0.0001). In this trial, adding ipilimumab to dacarbazine led to 28.8% more episodes of grade 3 to 4 toxicity (56.3% vs 27.5%), but there were no deaths associated with ipilimumab despite the higher dose being used. Despite promising Phase I/II trial results for tremelimumab, its Phase III results were disappointing. A Phase III trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma found an overall survival of 12.6 months in the tremelimumab arm and 10.7 months in the chemotherapy arm.35 This result failed to meet statistical significance, with a hazard ratio of 0.88 (P ¼ 0.127). It was believed that patient selection, dosing regimen, and use of ipilimumab as salvage therapy for patients in this trial likely led to the lack of a statistically significant difference between the 2 arms. Patients with high lactate dehydrogenase levels were excluded, leading to a healthier patient population overall. At least 16% of patients within the control arm went on to receive ipilimumab, which would have blunted any survival difference between the arms.
Melanoma Patients with Brain Metastasis Previous immunotherapies have not had particular success controlling brain metastasis in patients with
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E.I. Buchbinder and D.F. McDermott melanoma. Patients who have responses to IL-2 therapy can go on to develop brain metastasis despite good systemic control of their disease. This population of patients is in need of better systemic therapies that also control their central nervous system disease. An open-label Phase II trial of ipilimumab in patients with brain metastasis enrolled patients both on and off corticosteroids.36 In those patients off steroids, there was an 18% disease control rate with a 24% brain-alone disease control rate. In patients on steroids, the control rate was lower, with only 1 patient of 21 exhibiting disease control and 2 exhibiting brain-alone disease control. This study demonstrated that ipilimumab has some activity in patients with brain metastasis from melanoma, particularly those with asymptomatic disease not requiring corticosteroid therapy. These findings suggest that the blood–brain barrier does not restrict ipilimumab’s activity.
irAEs Associated with CTLA-4 Blockade CTLA-4 blockade induces drug-related adverse events that are believed to be related to immune effects and are classified as irAEs. The most common toxicity observed comprised gastrointestinal, skin, endocrine, or liver toxicities. Hypophysitis, pancreatitis, iridocyclitis, lymphadenopathy, neuropathies, and nephritis have also been reported with ipilimumab. Early diagnosis, vigilant follow-up, and prompt use of systemic high-dose corticosteroids are essential to minimizing toxicity and death from these events.29 An analysis of patients treated in the Phase III trial of ipilimumab found that the majority of these irAEs developed within 12 weeks of initial dosing and resolved within 12 weeks of onset.37 Skin rash was the most prevalent toxicity, with 47% to 66% of patients experiencing a pruritic maculopapular rash. Topical steroids are often effective, and holding of the drug is rarely required. Rare cases of toxic epidermal necrolysis and Stevens-Johnson syndrome, which have led to death, have also been reported.31 Ipilimumab should be discontinued in patients with severe rash, and systemic steroids should be initiated. Diarrhea was observed in 44% of patients receiving ipilimumab 10 mg/kg, and severe diarrhea (grade 3 or 4) was reported in 18%.37 The overall rate of bowel perforation is o1%; however, deaths related to ipilimumab due to this toxicity have been reported. An algorithm to treat the diarrhea was developed and
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published; it involves early initiation of corticosteroids and infliximab in patients who have steroid-refractory diarrhea. A randomized Phase II study compared the efficacy of ipilimumab with or without prophylactic budesonide to determine if this regimen would decrease diarrhea.38 No change in the rate of grade 2 or higher diarrhea was noted between the 2 arms. Hepatotoxicity was observed in 3% to 9% of patients receiving anti–CTLA-4 antibodies, often reported as asymptomatic elevation of liver enzyme levels. For severe hepatotoxicity, systemic steroids are recommended, and if serum transaminase levels do not decrease within 48 hours of the start of systemic steroids, oral mycophenolate mofetil 500 mg every 12 hours should be initiated.31 A rare but potentially long-term adverse effect of CTLA-4 blockade is hypophysitis. This condition occurs in 1% to 9% of patients treated with 3 or 10 mg/kg of ipilimumab, on average 6 weeks after initiation of therapy. Symptoms can include headache, double vision, nausea, weakness, and fatigue. Results of blood tests typically reveal low levels of thyroid, adrenal, and gonadal hormones. A brain magnetic resonance imaging scan may show pituitary swelling/ enlargement. Patients with evidence of hypophysitis should be started on intravenous steroids; these patients often require very slow tapering of these steroids. Although some patients reportedly are able to regain pituitary function, many require long-term hormone replacement.31,39 Some data suggest that patients with irAEs are more likely to achieve a clinical benefit from ipilimumab. In 139 ipilimumab-treated patients with metastatic melanoma among 86 patients experiencing any grade of irAE, 22 (26%) were objective responders, compared with 2% (1 of 53) of patients who did not have any irAE.40 Development of an irAE was significantly associated with likelihood of response (P ¼ 0.0004). Analysis of patient data from other studies has supported this finding thus far. A randomized trial of ipilimumab with and without granulocyte-macrophage colony-stimulating factor (GM-CSF) found a trend toward improved tolerability in the GM-CSF arm over ipilimumab alone.41 Final analysis of this trial may support using this regimen to decrease the toxicity of ipilimumab.
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Long Term Survival with Ipilimumab The largest benefit seen with previous immune therapies, particularly IL-2, is the durability of response when treatment is discontinued. Data are now available regarding a similar durability of response in ipilimumab-patients who have melanoma. Five-year survival rates in various studies have been reported to be between 16.5% and 25%. Of interest, some of these patients displayed no objective response to ipilimumab.42 Survival curves show a plateau at 3 years that is ongoing. Initial reports suggest that similar findings will be seen with analysis of the larger Phase III trials.43,44
Patient Selection for CTLA-4 Blockade Because only a subset of patients treated with CTLA-4 blockade exhibit a long-term benefit from therapy, it would be advantageous to identify those patients most likely to respond. To date, however, no clear predictive biomarker has been developed for the selection of these patients. Some retrospective markers that reflect immune activation in responders include absolute lymphocyte count, up-regulation of the T-cell activation marker–inducible costimulator, and the development of a polyfunctional T-cell response to the tumor antigen NY-ESO-1.45 High baseline expression levels of immune-related genes predicted response to ipilimumab treatment in a cohort of 45 patients.46 Some promising mechanisms being explored include analyzing genetic factors within the tumor itself or the host. According to some data, the tumor mutation volume may help predict activity of immune checkpoint blockade.47 There may also be host factors that predict response, and genes such as CCR2/CCRL2/CCR5 are being explored.48 There is clearly some association between immune system function and response to ipilimumab, as noted in the increased irAEs seen among responders. However, further study to determine what those factors are and prospective validation of any proposed, predictive biomarker will be required before we are able to better target CLTA-4 antibody treatment.
Adjuvant Therapy The ultimate goal in melanoma therapy would be to find an agent that not only successfully treats patients who have metastatic disease but can also work to prevent recurrence in patients with high-risk
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early-stage disease. Iplimumab’s success in the metastatic melanoma setting led to its testing in resected stage III patients at high risk of recurrence. A study of the European Organisation for Research and Treatment of Cancer randomized 951 patients to receive placebo or ipilimumab at 10 mg/kg every 3 weeks for 4 doses, then every 3 months out to 3 years.49 This trial reported a recurrence-free survival of 26.1 months in the ipilimumab arm compared with 17.1 months, with a hazard ratio of 0.75 (P ¼ 0.0013). Unfortunately, 5 deaths caused by ipilimumab-related immune toxicity occurred during the trial (3 due to colitis, 1 due to myocarditis, and 1 due to GuillainBarré syndrome). Although the European Organisation for Research and Treatment of Cancer trial used placebo as a control, high-dose interferon-α2b is approved by the US Food and Drug Administration for use in this setting and has previously demonstrated benefit.50 Based on this finding, the Eastern Cooperative Oncology Group is currently enrolling patients in a study comparing high-dose interferon-α2b versus ipilimumab at 3 mg/kg and 10 mg/kg. Results of this trial will be helpful in defining therapy for this high-risk population.
Combination Therapies There are many very interesting clinical trials assessing the combination of ipilimumab and tremelimumab versus conventional cytotoxic chemotherapy, radiation therapy, targeted therapy, traditional immune therapy, and other checkpoint blockade agents. Combination therapies need to be chosen in a rational way by which other therapies either lead to increased release of antigens from tumors or change the immune milieu. Evidence suggests that radiation therapy may activate the immune system and thus prime it for greater activation by immunotherapy. The abscopal effect, by which local radiation therapy causes tumor regression at a distant site, may be mediated by immune response.51 Studies to further explore this scenario are being performed. Bevacizumab is a vascular endothelial growth factor–targeted agent that is also known to play a role in dendritic cell maturation and lymphocyte endothelial trafficking. A study of 46 patients treated with a combination of ipilimumab and bevacizumab reported a disease control rate of 67.4%.52 Based on these results, a Phase III trial of this combination is
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E.I. Buchbinder and D.F. McDermott currently enrolling patients. The combination of IL-2 and ipilimumab has shown an overall response rate of 22%, with 3 complete responses.53 Further exploration of this combination is also planned. GM-CSF is known to enhance dendritic cell activation and potentiate antitumor T- and B-cell responses and is hypothesized to synergize with CTLA-4 blockade. The Eastern Cooperative Oncology Group performed a randomized trial of ipilimumab with and without GM-CSF.41 The trial reported an overall survival benefit to adding GM-CSF and showed a trend toward improved tolerability in the GM-CSF arm over ipilimumab alone. The most promising combination therapies at this time are with other checkpoint blockade agents. Nivolumab is a novel antibody targeting the programmed death-1 receptor. It has demonstrated single-agent activity in melanoma. In combination with ipilimumab, evidence of clinical activity was observed in 65% of 53 patients, and many of those patients had a reduction in tumor volume of Z80%.54 Survival updates for these patients exhibited 1- and 2-year overall survival rates of 82% and 75%, respectively. The complete response rate in this subsequent analysis was 17%, and the median duration of response was not reached, indicting ongoing responses for many patients.55 Trials are underway to determine if the benefit is greater if ipilimumab and nivolumab are given concurrently or if they could be given sequentially, with similar long-term benefits.
CONCLUSIONS CTLA-4 blockade is an effective new therapy in the treatment of metastatic melanoma. It has demonstrated a survival benefit compared with currently available therapies. In addition, the responses are often durable, which is changing long-term survival for this disease. Unfortunately, the number of patients responding is still limited. Research is ongoing to better select patients likely to benefit from CTLA-4 blockade. In addition, novel agents are being added to this therapy, with early results suggesting an increase in the number of overall responders. CTLA-4 blockade has paved the way for a new generation of immunotherapy.
CONFLICTS OF INTEREST Dr. McDermott serves on an advisory board for Bristol-Myers Squibb and is a Drug Safety Monitoring Board member for Pfizer. The authors have indicated
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that they have no other conflicts of interest regarding the content of this article.
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Address correspondence to: Elizabeth I. Buchbinder, Division of Oncology, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215. E-mail: [email protected]
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