Advances and perspectives in immunotherapy of melanoma

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1 Annals of Oncology 23 (Supplement 10): x104 x108, 2012 doi: /annonc/mds321 Advances and perspectives in immunotherapy of melanoma D. Schadendorf*, J. Vaubel, E. Livingstone & L. Zimmer Department of Dermatology, Skin Cancer Centre, University Hospital Essen, Essen, Germany symposium article Immunotherapy using unspecific modulators has a long tradition in the adjuvant treatment of stage II/III melanoma. Interferon has shown a consistent effect on relapse-free survival independent of interferon dosage and duration. The results of the American Joint Committee on Cancer (AJCC) Melanoma Staging Database analysis led to a strict inclusion of additional prognostic risk factors such as ulceration of the primary and microscopic lymph node involvement explored by the sentinel node biopsy in the revised 2009 AJCC classification. These factors are now being increasingly included as stratification factors into clinical trials and yield a new hypothesis that primarily patients with both characteristics benefit from adjuvant interferon treatment. In the metastatic situation, interleukin-2 is the only immunotherapeutic agent approved by the Food and Drug Administration. In combination with interferon and/or with various chemotherapeutic agents, IL-2 is associated with substantial toxic effect and poor efficacy that does not improve overall survival (OS). Ipilimumab is a fully human, monoclonal antibody that blocks the cytotoxic T-lymphocyte antigen-4 and has recently been approved for metastatic melanoma based on two independent randomized phase III studies both demonstrating an improved OS rate after 1, 2, and 3 years compared with the control group. Based on this major step in treating metastatic melanoma, novel adjuvant strategies in stage III and combination therapies with targeted agents in stage IV are currently being explored. Key words: interferon, interleukin-2, ipilimumab, tremelimumab, unspecific immunotherapy introduction Malignant melanoma is one of the most aggressive cancers [1]. About 20% of all primary melanomas will spread. The likelihood of metastatic behavior correlates with prognostic factors such as tumor thickness, mitotic index, presence of ulceration, lymphocytic infiltration, age, gender, and anatomic site [2]. Immunotherapies are being used for melanoma patients in stage II III patients in the adjuvant setting, where only a fraction of patients have widespread (microscopic) disease with the aim to prevent relapse of disease, prolong relapse-free survival (RFS) and, ideally, to prolong overall survival (OS). In patients with stage IV disease, there is a need for adequate systemic therapies as median OS for this patient group is only 6 9 months [3]. Dissemination to distant visceral organs is, with the exception of rare cases eligible for surgery for oligometastatic disease, almost invariably a sign of incurable disease. For the first time in >30 years, prospective randomized trials in patients with distant metastatic melanoma demonstrated an OS benefit [4]. Innovative systemic treatments including immunotherapy have focused on metastatic melanoma and are being tested with an increasing intensity. The term immunotherapy is used for non-specific *Correspondence to: Prof. D. Schadendorf, Department of Dermatology, University Hospital Essen, Hufelandstr. 55, D Essen, Germany. Tel: ; Fax: ; dirk.schadendorf@uk-essen.de and specific immunomodulation that encompasses a number of different approaches summarized below. adjuvant immunotherapy in stage II and III disease interferon-α in the adjuvant setting Interferon-α (IFN-α) has been approved in the adjuvant setting for the treatment of high-risk melanoma based on clinical trials in the early 1990s [5 7]. Over the last two decades, prognostic lymph node staging using the sentinel node biopsy has been implemented in most countries, and the AJCC classification has changed twice. Both factors have led to a different definition of high-risk melanoma which does not fit the registration label of IFN anymore. Many review articles, systematic reviews, metaanalyses, and pooled analyses have been published on the subject [8 14]. Taken together, the data show that, with the exception of ultra-low-dose IFN-α therapy of 1 miu [15], IFN-α given at miu (flat dose), and when given at high doses (20 miu/m 2 induction and 10 miu/m 2 maintenance), has an substantial impact on RFS but no or only a marginal effect on OS. Highdose IFN therapy was approved in both the United States and the Europe for stage IIB to III, but not universally established in Europe. Low-dose IFN-α (3 miu, thrice weekly, s.c.) was approved in Europe only. In meta-analyses, no IFN-dose regimen proved to be superior [13 14]. In 2008, long-term adjuvant therapy (5 years) with pegylated IFN-α 2β was The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please journals.permissions@oup.com.

2 Annals of Oncology reported to have a substantial and sustained effect on RFS in stage III melanoma [16]. Interestingly, in this EORTC trial, the efficacy was evident only in the sentinel node-positive stage III patients but not in patients with macroscopically involved lymph nodes. The same observation had also been made with regular IFN-α in the intermediate dose IFN-α trial (EORTC 18952) in stage IIB to III patients [17]. Thus, in the two largest adjuvant trials in melanoma, IFN-α was most beneficial in patients with less advanced disease. This is in line with the positive results of the trials with low-dose IFN-α in stage II patients before sentinel node staging was practiced and where results were mainly driven by the supposedly sentinel node-positive patients inside these stage II trials [5 6]. The identification of patients who are IFN-α sensitive is clearly the priority to achieve a more selective use of IFN-α and subsequently to improve the outcome. Unfortunately, in the absence of predictive factors, selective use of IFN-α still needs investigation. In the EORTC trials and 18991, it was noted that IFN-α sensitivity was higher in patients with ulcerated primaries. This was confirmed in a recent post hoc meta-analysis of both trials [13]. This observation led to the decision to perform the EORTC trial in patients with ulcerated primaries thicker than 1 mm with sentinel node involvement comparing pegylated IFN-α 2b to observation, which will be activated in the second half of 2012 (NCT ). other options including GM2 vaccine and IL-2 Gangliosides are the essential components of membranes and also essential for various biological effects. Early clinical results indicated that the immunization of melanoma patients with the ganglioside GM2 reduced the risk of relapse in stage III melanoma patients who were free of disease after surgical resection and who had no preexisting anti-gm2 antibodies [18]. In stage IIA patients (T3N0M0) with a moderate risk of micrometastatic disease (35% 40%), the EORTC trial compared observation with ganglioside GM2 vaccination. This trial enrolled 1314 patients between March 2002 and December The second interim analysis was carried out when 267 RFS events were reported. For the primary end point, RFS, the criteria for stopping for futility were met and for distant metastasis-free survival and OS, there was a trend favoring the observation group leading to the recommendation to stop the vaccination by the safety board. The authors concluded that adjuvant GM2-KLH/QS-21 vaccination was ineffective and could even be detrimental in stage II melanoma patients [19]. Since low-dose IFN-α showed some limited effects in the adjuvant treatment of patients with intermediate- and highrisk primary melanoma, the idea end of the 1990s was to test a combination regimen of IFN with low-dose interleukin-2 (IL- 2) to improve survival in these patients (pt3-4, cn0, M0). Two hundred and twenty-five patients were randomly assigned to receive either subcutaneous low-dose IFN-α plus IL-2 (9 miu/ m 2 /days, days 1 4, week 2 of each cycle) for 48 weeks, or observation alone. After a median follow-up time of 79 months, 5-year RFS was 70.1% for the IFN-α and IL-2 combination compared with 69.9% in those receiving surgery and observation alone [20]. Similarly other unspecific symposium article immunomodulatory approaches including BCG, levamisol, and thymosin did not affect the disease outcome of tumor-free melanoma patients in stages II and/or III successful in any prospective clinical trial. immunotherapy in stage IV melanoma interferon-α IFN-α is the first recombinant cytokine evaluated for its effects on metastatic melanoma, which showed response rates of 5% 15% in phase II independent of dose or schedule [21]. In randomized trials, where IFN-α was added to chemotherapeutic regimens, its superiority could not be demonstrated over chemotherapy alone, as is summarized in Schadendorf et al [22]. Thus, IFN-α has not been approved for application in stage IV melanoma. Yet, it is frequently used in various schedules for which evidence is lacking. Pegylated IFN-α, an IFN-α formulation with increased bioavailability, showed dosedependent response rates in the range of 6% 12% in a recent trial of stage IV melanoma patients [23]. interleukin-2 The analysis of eight clinical trials of high-dose IL-2 in 270 patients reported a 16% overall response rate [24]. Complete responses occurred in 6% of patients and were long lasting (>5 years) in 4% of patients. IL-2 was approved by the Food and Drug Administration (FDA) in 1998 for the US and Canada for stage IV disease based on a series of phase II studies, but not by the European Medicines Agency (EMA) for Europe because of the absence of phase III trial data. The most effective treatment regimens are the high-dose bolus and highdose continuous infusion regimens that are associated with serious toxicity, limiting its use to patients in good condition to be treated in specialized centers [24]. IL-2 is frequently claimed to have curative potential in the treatment of metastatic melanoma; however, a retrospective analysis [25] and also prospective randomized clinical trials did not confirm this assumption [26]. Objective response rates have been improved using cytokines combined with chemotherapy, but this has not translated into an improvement in OS [27]. ipilimumab and tremelimumab A recently advocated immunotherapeutic approach for advanced melanoma involves targeting the cytotoxic T- lymphocyte antigen-4 (CTLA-4) [28 30], which is expressed on the surface of activated CD4 + and CD8 + T cells to induce inhibitory signals [31]. Thus, CTLA-4 blockade may increase the function of effector CD4 + and CD8 + T cells by removing a key checkpoint mechanism [31]. Studies in murine models demonstrate that the antibody blockade of CTLA-4 enhances immune responses which result in tumor regression [32 33]. Ipilimumab is a fully human, anti-ctla-4 monoclonal antibody currently undergoing clinical testing in various tumor entities. Recently, ipilimumab gained clinical approval across the world for metastatic melanoma therapy. Early clinical results using ipilimumab in patients with advanced melanoma showed its potent antitumour activity [34]. Based on this and Volume 23 Supplement 10 September 2012 doi: /annonc/mds321 x105

3 other supporting evidence, a prospective randomized, placebocontrolled phase III study was started. Earlier clinical end points such as progression-free survival and response rate were changed during the study to make OS pivotal for registration. A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg/kg body weight, was administered with or without gp100 every 3 weeks for up to four treatments [4]. The median OS was 10.0 months among patients receiving ipilimumab plus gp100, when compared with 6.4 months among patients receiving gp100 alone. In accordance, the median OS with ipilimumab alone was 10.1 months. One-year survival rate for both ipilimumab arms was 46% compared with 25% receiving the peptide only and after 2 years 24% of ipilimumab-treated patients were still alive compared with 14% treated with the gp100 peptide [4]. These data led to approval by the FDA in 2010 and EMA approval in Ipilimumab is now marketed as Yervoy. Grade 3/4 toxic effect occurred twice as often ( 20%) in both ipilimumab arms with immune-related adverse reactions being the most frequently reported. At the dosage of 3 mg/kg body weight, skin-related adverse reactions occurred in 40% of all patients, immune-related gastrointestinal adverse reactions occurred in roughly one-third of all ipilimumab-treated patients (all grades) followed by immune-related endocrinopathies in 5% and immune-related hepatotoxic effects in 3% of patients [4]. The overall adverse event profile of ipilimumab in this study is consistent with previous findings and with its immune-based mechanism of action. irars differ from the adverse events commonly reported with cytotoxic agents. Concomitantly, in a second registration trial, a combination treatment using ipilimumab with dacarbazine (DTIC) (Detimedac, medac GmbH, Hamburg, Germany and Bayer AG, Leverkusen, Germany) was tested. In this clinical trial, 502 patients with previously untreated metastatic melanoma were randomly assigned in a 1:1 ratio, to ipilimumab to a doseintensified 10 mg/kg body weight regimen plus DTIC or DTIC plus placebo. Here, treatment was not stopped after four infusions as in the previous study design but continued if patients demonstrated stable disease or an objective response and no dose-limiting toxic effects. In this case, ipilimumab or placebo was continued every 12 weeks thereafter as a maintenance therapy. The primary end point was OS, which was improved in the ipilimumab/dtic combination arm by 2 months in comparison with DTIC only [35]. Interestingly, again survival rates were improved by around 10% after 1 (47.3% versus 36.3%), 2 (28.5% versus 17.9%), and 3 years (20.8% versus 12.2%) [35]. Furthermore, the adverse events profile of ipilimumab was substantially changed with the addition of DTIC. Adverse events grade 3/4 occurred in roughly 50% of patients and 40% experienced hepatic adverse events [35]. This strongly emphasizes that chemotherapeutic toxic effects can be increased due to the immune-related mechanisms of ipilimumab, which makes a careful evaluation of those combinations in clinical trials mandatory. Furthermore, effective clinical management pathways for the treatment of ipilimumab-induced, immune-related adverse reactions have been developed and should strictly be adhered to when taking care of ipilimumab-treated patients [36]. To date, no randomized clinical studies have evaluated the dose-responsiveness of ipilimumab. Objective responses have been reported with ipilimumab at doses of 3 or 10 mg/kg in previous studies. In an extended clinical phase II study, 217 patients with advanced melanoma were assessed for antitumour efficacy, pharmacokinetics, pharmacodynamics, OS, and safety of ipilimumab monotherapy at doses of 0.3, 3, and 10 mg/kg. The primary objective of the study was to determine the dose response relationship of ipilimumab based on the end point of the best overall response rate in patients with advanced melanoma [37]. The best overall response rate was 11.1% for 10 mg/kg, 4.2% for 3 mg/kg, and 0% for 0.3 mg/kg ipilimumab, which was highly statistically different (P = ; trend test). The number of irar increased correspondingly. Currently, it is not clear which dose and regimen of ipilimumab (3 mg/kg for four infusions in a 3-week interval or a more dose-intense regimen of an induction phase of 10 mg/kg for four infusion followed by a maintenance every 12 weeks) is the clinically most effective strategy with the best efficacy toxicity ratio. This will be tested in a randomized trial with a head-to-head comparison starting in mid-2012 (NCT ). Tremelimumab, another fully human anti-ctla-4 antibody, was tested in different phase I/II studies, and a dosage of 15 mg/kg every 90 days was defined (reviewed in [38]) and subsequently investigated in a phase III trial versus chemotherapy (DTIC or temozolomide) [39]. Differences in OS in the phase III trial were not statistically substantial with 11.7 months in the tremelimumab arm versus 10.7 months in the control arm, and further clinical evaluation of tremelimumab was stopped prematurely. Interestingly, new patterns of response to ipilimumab were observed, and the immune-related response criteria were used to track the total tumor burden [40]. These patterns include a response in the presence of new lesions and a decline in total tumor burden after progressive disease as characterized by modified WHO criteria. The latter includes stable disease (SD), which in some patients is followed by a slow, steady decline in total tumor burden. Most importantly, patients who achieve SD have a favorable survival outcome, which is similar to those patients who achieve an objective response [37]. perspective Annals of Oncology Currently, the results of two phase III trials in stage III melanoma using a MAGE-A3 vaccination and ipilimumab (both compared with placebo) are awaited which both could alter the standard of treatment in the adjuvant setting. In stage IV melanoma, ipilimumab has been established as a new standard therapy and a cornerstone in future strategies. Similar principles such as antibodies targeting PD-1 or PD-1L are in advanced development stages. Studies with allogeneic and autologous vaccines have demonstrated no clinical benefit, and some randomized trials even showed a detrimental effect in the vaccine arm. Adoptive immunotherapy, which represents a promising although technically challenging direction, is still in an experimental stage. x106 Schadendorf et al. Volume 23 Supplement 10 September 2012

4 Annals of Oncology disclosures DS: member of speaker boards and advisory boards of several companies including BMS, Roche, GSK, MSD, Amgen; EL: honoraria and travel expenses AMGEN GmbH, Cephalon GmbH, Boehringer Ingelheim Pharma GmbH & Co KG, Essex Pharma GmbH, Bristol-Myers Squibb GmbH & Co KG, Merck KGaA, MSD; LZ: honoraria and travel expenses Boehringer Ingelheim Pharma GmbH & Co KG, Essex Pharma GmbH, Bristol-Myers Squibb GmbH & Co KG; JV: honoraria and travel expenses Amgen GmbH, Cephalon GmbH, Boehringer Ingelheim Pharma GmbH & Co KG, Essex Pharma GmbH, Roche GmbH, Bristol-Myers-Squibb GmbH & Co KG; DS: honoraria and advisory board Roche GmbH, GSK, Bristol-Myers-Squibb GmbH & Co KG, Genetech, Amagen GmbH, Boehringer Ingelheim Pharma GmbH & Co KG, MSD and Astra Zenaca. references 1. Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med 2004; 351: Balch CM, Gershenwald JE, Soong SJ et al. Final version of 2009 AJCC melanoma staging and classification. 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