Ahmad A. Tarhini, MD, PhD
Assistant Professor of Medicine
Clinical and Translational Science
John M. Kirkwood, MD
Professor of Medicine, Dermatology & Translational Science
Department of Medicine
Division of Hematology/Oncology
University of Pittsburgh Cancer Institute
To date, immunotherapy has been associated with the only long-term durable clinical benefits for patients with high-risk or advanced melanoma. Until recently, the only immunotherapy treatments approved by the US Food and Drug Administration (FDA) were adjuvant therapy with high-dose interferon-alpha2b (IFNα2b), approved in 1996 for high-risk resected melanoma, and high-dose interleukin-2 (IL-2), approved in 1998 for patients with metastatic disease. In 2011, however, two new immune agents received regulatory approval: ipilimumab, aka YervoyTM (for metastatic unresectable melanoma), and pegylated interferon-alfa 2b (Peg-IFN), aka Sylatron,TM for adjuvant therapy of node-positive resected melanoma.
The Significance of Marshaling the Immune Response
This progress has emerged from the continually increasing understanding of immune processes and their relationship to melanoma. Over the years, the significance of host immunity in melanoma therapy had been suggested by reports of spontaneous regression of disease and pathological evidence of lymphoid infiltrates in primary melanoma associated with tumor regression. In addition, T cell infiltrates have been suggested to be of prognostic value in primary melanoma,1,2and in regional nodal metastases have been associated with clinical benefits in patients treated with neoadjuvant IFNα2b.3,4,5 Moreover, the use of immunotherapy in the adjuvant disease-free setting is supported by the observation that host immune responses differ qualitatively (Th1 effector T cell versus Th2 tolerant T cell) between early and advanced disease settings. Patients in the adjuvant setting exhibit Th1-polarized immune responses that may be more susceptible to immunologic interventions.6,7 Notably, while IFNα at high dosage has shown a limited clinical impact in the management of metastatic disease, it demonstrated the first significant impact upon melanoma relapse and survival in the adjuvant therapy setting.
The High-Dose IFNα2b Regimen
Adjuvant therapy with high-dose IFNα2b (HDI) for surgically resected high-risk cutaneous melanoma has been tested in three phase III US national cooperative group studies (E1684, E1690, and E1694, all focused upon resected AJCC stage IIB and III melanoma) and one Eastern Cooperative Oncology Group (ECOG) randomized phase II trial (E2696, focusing upon resected AJCC stages IIB, III, and IV). The HDI regimen consists of an induction phase administered intravenously at 20 MU/ m²/d for five consecutive days out of seven every week for four weeks followed by a maintenance phase given subcutaneously at 10 MU/m²/d every other day three times each week for 48 weeks.
E1684 and E1694 demonstrated significant survival prolongation for the HDI regimen compared with observation or a vaccine that proved to be ineffective. E1684 showed median relapse-free survival [RFS] of 1.72 years in the HDI arm versus 0.98 in the observation arm [stratified log-rank one sided p-value (P1)=0.0023], and median overall survival [OS] of 3.82 years in the HDI arm versus 2.78 [P1=0.0237] for observation only.8
The HDI regimen also demonstrated prolonged survival compared to the GMK vaccine that was selected as the most promising vaccine candidate at the time (E1694 in 1995).9 In E1694, significant differences emerged in both trial efficacy endpoints at a median followup interval of 16 months where HDI provided significant RFS benefit (hazard ratio [HR]=1.47; P1 = 0.0015) and OS benefit (HR=1.52; P1=0.009) compared with GMK. A similar benefit was observed in the intent-to-treat analysis of RFS (HR=1.49) and OS (HR=1.38).9
The second cooperative group trial testing HDI, E1690, has provoked more questions than other trials: E1690 was conducted in part before and in part after FDA approval of HDI (based on E1684 results), and was associated with consistent crossover of patients from the observation-assigned arm to treatment with HDI at nodal relapse. This trial showed differences in terms of RFS but not OS. In the intent-to-treat analysis of RFS, treatment with HDI was associated with a statistically significant benefit compared with observation (HR=1.28; P1=0.025).10 Observation patients who crossed over to HDI at regional nodal recurrence (stage IIB patients) had not been required to undergo lymphadenectomy prior to study entry as in E1684, and analysis of the post-relapse impact of HDI demonstrated a large benefit that could have confounded the survival analysis.10 The analysis of each of these studies was updated in a pooled analysis of survival and relapse-free outcomes up to April 2001.11 The pooled analysis demonstrated that IFNα2b prevents relapse up to intervals of 20 years, although this analysis (which included the observation-controlled trials E1684 and E1690 but not E1694) did not yield compelling evidence of an impact upon OS, despite the positive survival results of the two randomized US Cooperative Group and Intergroup studies (E1684 and E1694). This is not surprising, given that the larger of the two observation controlled trials included in the pooled analysis (E1690) did not show an OS benefit for HDI.
A meta-analysis of 12 randomized trials of adjuvant IFNα in high-risk melanoma patients estimated a highly significant reduction in the odds of recurrence in treated patients compared to observation only patients. Further, it demonstrated evidence of increased benefit with increasing IFN dose and a trend toward increased benefit with increasing total dose. However, it found no statistically significant OS benefit.12 A subsequent larger meta-analysis of 13 randomized trials reported that IFNα reduced the risk of recurrence or death by 13 percent (OR 0.87, 95% CI 0.81–0.93 for RFS; p<0.0001) and the risk of death by 10 percent (OR 0.90, 0.84–0.97 for OS; p=0.008) compared with observation or vaccination. It did not define an optimal (high, intermediate, or low) dose of interferon.13 The latest and largest meta-analysis of 14 adjuvant randomized clinical trials estimated that IFNα therapy was associated with a significant improvement in disease-free survival (HR for disease recurrence: 0.82; 95% CI: 0.77-0.87; P < .001) and improved OS (HR for death: 0.89; 95% CI: 0.83-0.96; P = .002). However, this meta-analysis again did not clarify an optimal dose or duration for IFNα.14
The covalent attachment of polyethylene glycol (PEG) polymer chains to a drug or therapeutic protein can mask the agent from the host's immune system, reducing immunogenicity and antigenicity, and thereby increasing the size in solution of the agent, which prolongs its circulatory time by reducing renal clearance. The EORTC (European Organization for Research and Treatment of Cancer) 18991 trial that is the pivotal study of Peg-IFN theorized that prolonged treatment may be necessary for the anti-angiogenic benefits of IFN, citing prior studies (EORTC 18952 and French Melanoma COG) where the authors concluded that the effects of IFN on RFS are rapidly lost after discontinuation of treatment.15,16 The 18991 trial authors hypothesized that prolonged weekly self-administered adjuvant pegylated IFN might improve the benefit-toxicity ratio for patients with resected stage III melanoma. This study compared observation with treatment utilizing maximally tolerable doses of pegylated IFNα2b (Peg-IFNα) for an intended five years in patients with resected stage III melanoma (TxN1–2M0).17
Peg-IFNα was administered at six μg/kg/week during the first eight weeks, followed by three μg/kg/week maintenance therapy for up to five years. This trial showed significant benefit in the primary endpoint of RFS, with a median RFS of 34.8 months for peg- IFNα compared with 25.5 months for the observation only group (HR: 0.82; P = .011). No significant improvement was found in either OS or distant metastasis-free survival (DMFS), which had originally been the primary endpoint of this EORTC trial; RFS was adopted as the primary regulatory endpoint at the request of the US FDA.
Subset analysis showed that the RFS benefits were confined to the group of patients without gross nodal disease (sentinel node-positivity). In this subset of patients with the lowest tumor burden (n=382), peg-IFNα significantly improved RFS and DMFS, though not OS, compared with observation. While this trial was designed to test five years of therapy, the median duration of treatment was a little more than one year. Therefore, the question of whether longer therapy achieves more significant antitumor effects remains unanswered.
Based on these data, peg-IFNα has been approved by the FDA for the adjuvant treatment of patients with melanoma and microscopic or palpable nodal involvement within 12 weeks of surgical resection. Updated data from this study were presented at the 2011 American Society of Clinical Oncology annual meeting after a median followup of 7.6 years.18 The overall RFS benefit has now eroded to an HR of 0.87 (95% CI: 0.76-1.00). There were no significant differences versus observation in DMFS overall, unlike what was seen at initial presentation when median follow-up was only 3.8 years. No overall OS benefit was seen, similar to the first report. Subset analysis again showed the greatest benefit in patients with microscopic nodal disease (N1) who have an ulcerated primary tumor: RFS (HR: 0.72; 99% CI: 0.46-1.13) and OS (HR: 0.59; 99% CI: 0.35-0.97). A prospective EORTC 18081 trial plans to compare Peg-IFNα with observation in patients with ulcerated primary tumors > 1 mm. Patients with stage III N2 disease showed no benefit from adjuvant peg-IFNα in any endpoint.
There is now wide overall agreement that RFS is significantly improved with IFNα2b as reported in all three US Cooperative Group trials testing HDI (E1684, E1690, E1694) and in the multiple lower-dose IFN trials summarized in the three aforementioned meta-analyses. OS benefits have been significant only in the independent observation controlled and vaccine-controlled trials of HDI (E1684 and E1694). An OS benefit was also noted in the two largest meta-analyses, by Wheatley, et al13 and Mocellin, et al.14 For peg-IFNα as tested in EORTC 18991, patients with gross nodal metastases (N2) derive no benefit. Therapeutic benefits appear to be confined to the N1 population with microscopic nodal disease and greatest in patients with microscopic nodal disease who have an ulcerated primary tumor. The prolonged regimen of up to five years of treatment as originally planned is hard to achieve, and the median duration of therapy as reported in the EORTC 18991 trial was little over one year. On the other hand, peg-IFNα has a weekly, relatively convenient dosing schedule requiring less frequent administration that may be attractive to patients unwilling to receive the standard high-dose regimen.
The future direction of melanoma adjuvant therapy is to identify biomarkers that define the subpopulations of patients who benefit from IFN, and to build on recent successes with CTLA4-blocking antibodies ipilimumab [BMS-Medarex]), which have shown promising durable clinical activity as monotherapy in patients with metastatic melanoma.19,20 Randomized controlled trials are currently under way testing ipilimumab versus placebo (EORTC 18071) and versus standard HDI (US Intergroup E1609) in the adjuvant arena for melanoma, but no data are expected for several years. MAGE-A3 (melanoma-associated antigen A3) vaccine as adjuvant therapy is under evaluation, following promising EORTC phase I-II studies in which the expression of MAGE-A3 has been found in 66 percent of patients with melanoma. MAGE-A3 is given with a potent TLR-9 (toll-like receptor 9) agonist vaccine adjuvant (CpG). The trial requires the expression of the vaccine antigen in the tumor tissue, and employs the evaluation of a predictive gene signature that may be associated with antitumor efficacy of the vaccine.21,22 The high-risk surgically resected stages provide a great opportunity for curing melanoma by targeting microscopic residual disease at an earlier stage and in a less compromised host. The future of adjuvant therapy appears very promising, building upon unprecedented advances in the management of metastatic disease derived from continuously deepening understanding of melanoma molecular biology and host immunity.
- Clemente CG, Mihm MC Jr, Bufalino R, et al. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 1996; 77(7):1303-10.
- Rao UN, Lee SJ, Luo W, Mihm MC Jr, Kirkwood JM. Presence of tumor-infiltrating lymphocytes and a dominant nodule within primary melanoma are prognostic factors for relapse-free survival of patients with thick (t4) primary melanoma: pathologic analysis of the e1690 and e1694 intergroup trials.Am J Clin Pathol 2010 Apr; 133(4):646-53.
- Mihm MC, Jr., Clemente CG, Cascinelli N. Tumor infiltrating lymphocytes in lymph node melanoma metastases: a histopathologic prognostic indicator and an expression of local immune response. Lab Invest 1996; 74(1):43-7.
- Håkansson A, Gustafsson B, Krysander L, Håkansson L. Tumour-infiltrating lymphocytes in metastatic malignant melanoma and response to interferon alpha treatment. Br J Cancer 1996; 74(5):670-6.
- Moschos SJ, Edington HD, Land SR, et al. Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses. J Clin Oncol 2006; 24(19):3164-71.
- Tatsumi T, Kierstead LS, Ranieri E, et al. Diseaseassociated bias in T helper type 1 (Th1)/Th2 CD4(+) T cell responses against MAGE-6 in HLADRB10401(+) patients with renal cell carcinoma or melanoma. J Exp Med 2002; 196(5):619-28.
- Tatsumi T, Herrem CJ, Olson WC, et al. Disease stage variation in CD4+ and CD8+ T-cell reactivity to the receptor tyrosine kinase EphA2 in patients with renal cell carcinoma. Cancer Res 2003; 63(15):4481-9.
- Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of highrisk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996; 14(1):7-17.
- Kirkwood JM, Ibrahim JG, Sosman JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol 2001; 19(9):2370-80.
- Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 2000; 18(12):2444-58.
- Kirkwood JM, Manola J, Ibrahim J, et al. A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res 2004; 10(5):1670-7.
- Wheatley K, Ives N, Hancock B, et al. Does adjuvant interferon-alpha for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomized trials. Cancer Treat Rev 2003; 29(4):241-52.
- Wheatley K, Ives N, Eggermont A, Kirkwood J, et al. Interferon-α as adjuvant therapy for melanoma: an individual patient data meta-analysis of randomised trials. J Clin Oncol 2007 ASCO Annual Meeting Proceedings 25:18S, 2007 (abs 8526).
- Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 2010; 102(7):493-501.
- Eggermont AM, Suciu S, MacKie R, et al. Postsurgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet 2005;366(9492):1189-96.
- Grob JJ, Dreno B, de la Salmonière P, et al. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases.French Cooperative Group on Melanoma. Lancet 1998; 351(9120):1905-10.
- Eggermont AM, Suciu S, Santinami M, et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomized phase III trial. Lancet 2008; 372(9633):117-26.
- Eggermont AM, Suciu S, Santinami M, et al. EORTC 18991 phase III trial: Long-term adjuvant pegylated interferon-α2b (PEG-IFN) versus observation in resected stage III melanoma: Long-term results at7.6-years follow-up. J Clin Oncol 2011; 29:(suppl;abstr 8506b)
- Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010 Aug 19; 363(8):711-23.
- Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011 Jun 30; 364(26):2517-26.
- Kruit WH, Suciu S, Dreno B, et al. Immunization with recombinant MAGE-A3 protein combined with adjuvant systems AS15 or AS02B in patients with unresectable and progressive metastatic cutaneous melanoma: A randomized open-label phase II study of the EORTC Melanoma Group (16032-18031). J Clin Oncol 26; 2008 (May 20 suppl; abstr 9065).
- Louahed J, Gruselle O, Gaulis S, et al. Expression of defined genes identified by pretreatment tumor profiling: Association with clinical responses to the GSK MAGE-A3 immunotherapeutic in metastatic melanoma patients (EORTC 16032-18031). J Clin Oncol 26: 2008 (May 20 suppl; abstr 9045).