Efficacy and safety of ipilimumab in elderly patients with pretreated advanced melanoma treated at Italian centres through the expanded access programme

Journal of Experimental & Clinical Cancer Research

Paola Queirolo⁵  Marco Grosso⁵  Massimo Aglietta²  Gaetana Rinaldi⁷  Giorgio Parmiani^1,14  Barbara Merelli⁶  Riccardo Marconcini^1,12  Michele Guida⁹  Maria Grazia Bernengo^1,17  Emilia Cocorocchio^1,13  Alessandro Testori^1,10  Carmen Nuzzo^1,11  Francesco de Rosa^1,15  Paolo Marchetti³  Lorenza Di Guardo⁸  Michele Maio¹  Antonio Maria Grimaldi⁴  Paolo Antonio Ascierto⁴  Jacopo Pigozzo^1,16  Vanna Chiarion Sileni^1,16 

[1] Medical Oncology and Immunotherapy Division, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy;University of Torino, Turin, Italy;Medical Oncology, Sant'Andrea Hospital, University Sapienza, Rome, Italy;Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori Fondazione “G. Pascale”, Naples, Italy;Medical Oncology A, National Institute for Cancer Research, Genoa, Italy;Department of Oncology and Hematology, Unit of Clinical and Translational Research, “Papa Giovanni XXIII” Hospital, Bergamo, Italy;“Paolo Giaccone” Polyclinic University Hospital, Palermo, Italy;Medical Oncology, National Cancer Institute, Milan, Italy;Medical Oncology Department, National Cancer Research Centre, “Giovanni Paolo II”, Bari, Italy;Divisione melanoma e sarcomi muscolo-cutanei, Istituto Europeo di Oncologia, Milan, Italy;Department of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy;University Hospital Pisa, “Gathered Hospitals of Santa Chiara”, Pisa, Italy;Melanoma Medical Oncology Division, Istituto Europeo di Oncologia, Milan, Italy;Unit of Immuno-Biotherapy of Melanoma, San Raffaele Hospital, Milan, Italy;Immunotherapy Unit, Romagna National Cancer Institute, Meldola, Italy;Melanoma Cancer Unit, Oncology Institute of Veneto IRCCS, Via Gattamelata, 64, 35128 Padua, Italy;University Hospital St John the Baptist, Turin, Italy

关键词: Safety;    Treatment outcome;    Elderly patients;    Expanded access;    Ipilimumab;    Melanoma;   

Others  :  804111
DOI  :  10.1186/1756-9966-33-30

 received in 2013-12-11, accepted in 2014-03-17,  发布年份 2014

【 摘 要 】

Background

Elderly patients with metastatic melanoma have different disease characteristics and a poorer prognosis than younger patients. Data from clinical trials and expanded access programmes (EAPs) suggest ipilimumab confers a consistent survival benefit and has a similar safety profile across different age groups of patients with metastatic melanoma. Here we report the efficacy and safety of ipilimumab 3 mg/kg in elderly patients enrolled in an EAP in Italy.

Methods

Patients aged > 70 years with pretreated melanoma received ipilimumab 3 mg/kg every 3 weeks for four doses through an EAP. Tumour response was evaluated at baseline and after completion of induction therapy using immune-related response criteria and patients were monitored throughout the treatment period for adverse events (AEs), including immune-related AEs.

Results

The immune-related disease control rate among 188 evaluable patients was 38%, including four patients with an immune-related complete response, 24 with an immune-related partial response and 44 with immune-related stable disease. Median progression-free survival (PFS) was 4.0 months and the 1- and 2-year PFS rates were 21% and 12%, respectively. Median overall survival (OS) was 8.9 months; 1- and 2-year OS rates were 38% and 22%, respectively. The safety profile of ipilimumab was consistent with that observed in the general population of the Italian EAP and treatment-related AEs generally resolved within a median of 2 weeks with treatment as per protocol-specific guidelines.

Conclusions

These results suggest ipilimumab is a feasible treatment option in elderly patients with metastatic melanoma. Ipilimumab treatment was generally well tolerated and resulted in clinical benefit and extended survival in elderly patients treated at centres in Italy.

【 授权许可】

   
2014 Chiarion Sileni et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Balch CM, Gershenwald JE, Soong SJ, Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit DG, Ding S, Eggermont AM, Flaherty KT, Gimotty PA, Kirkwood JM, McMasters KM, Mihm MC Jr, Morton DL, Ross MI, Sober AJ, Sondak VK: Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009, 27:6199-6206.
• [2]Korn EL, Liu PY, Lee SJ, Chapman JA, Niedzwiecki D, Suman VJ, Moon J, Sondak VK, Atkins MB, Eisenhauer EA, Parulekar W, Markovic SN, Saxman S, Kirkwood JM: Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol 2008, 26:527-534.
• [3]Bethesda M: SEER Cancer Statistics Review, 1975–2010. National Cancer Institute; 2012. Available at [http://seer.cancer.gov/statfacts/html/melan.html webcite] (1 July 2013, date last accessed)
• [4]Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin 2010, 60:277-300.
• [5]Chao C, Martin RC, Ross MI, Reintgen DS, Edwards MJ, Noyes RD, Hagendoorn LJ, Stromberg AJ, McMasters KM: Correlation between prognostic factors and increasing age in melanoma. Ann Surg Oncol 2004, 11:259-264.
• [6]Conway WC, Faries MB, Nicholl MB, Terando AM, Glass EC, Sim M, Morton DL: Age-related lymphatic dysfunction in melanoma patients. Ann Surg Oncol 2009, 16:1548-1552.
• [7]Macdonald JB, Dueck AC, Gray RJ, Wasif N, Swanson DL, Sekulic A, Pockaj BA: Malignant melanoma in the elderly: different regional disease and poorer prognosis. J Cancer Educ 2011, 2:538-543.
• [8]Hegde UP, Chakraborty N, Kerr P, Grant-Kels JM: Melanoma in the elderly patient: relevance of the aging immune system. Clin Dermatol 2009, 27:537-544.
• [9]Hegde UP, Grant-Kels JM: Metastatic melanoma in the older patient: special considerations. Clin Dermatol 2013, 31:311-316.
• [10]Eggermont AMM, Robert C: New drugs in melanoma: It’s a whole new world. Eur J Cancer 2011, 47:2150-2157.
• [11]Wolchok JD, Hodi FS, Weber JS, Allison JP, Urba WJ, Robert C, O’Day SJ, Hoos A, Humphrey R, Berman DM, Lonberg N, Korman AJ: Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci 2013, 1291:1-13.
• [12]Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010, 363:711-723.
• [13]Robert C, Thomas L, Bondarenko I, O’Day S, JW MD, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011, 364:2517-2526.
• [14]Lebbé C, Weber JS, Maio M, Neyns B, Harmankaya K, Hamid O, O’Day S, Chin KM, Opatt McDowell D, Cykowski L, McHenry B, Wolchok JD: Long-term survival in patients with metastatic melanoma who received ipilimumab in four phase II trials. J Clin Oncol 2013, 31(suppl):abstr 9053.
• [15]Prieto PA, Yang JC, Sherry RM, Hughes MS, Kammula US, White DE, Levy CL, Rosenberg SA, Phan GQ: CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res 2012, 18:2039-2047.
• [16]Lebbé C, McDermott DF, Robert C, Lorigan P, Ottensmeier CH, Wolchok J, Garbe C, Messina M, Hoos A, Weber JS: Ipilimumab improves survival in previously treated advanced melanoma patients with poor prognostic factors: subgroup analysis from a phase III trial. Ann Oncol 2010, 21(suppl 8):abstr 13240.
• [17]Robert C, Ghiringhelli F: What is the role of cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma? Oncologist 2009, 14:848-861.
• [18]Lawrence D, McDermott D, Hamid O, Weber J, Wolchok J, Richards J, Minor D, Pavlick A, Sznol M, Hwu P, Urba W, Amin A, Bennett K, Michener T, Balogh A, Hodi FS: Treatment of Patients (pts) with Stage III or IV Melanoma on an Ipilimumab (Ipi) Expanded Access Program (EAP): Results for 3 mg/kg Cohort. Hollywood, USA: Society for Melanoma Research (SMR) Congress; 2012.
• [19]Lawrence D, McDermott D, Hamid O, Weber J, Wolchok J, Richards J, Amin A, Bennett K, Balogh A, Hodi FS: Ipilimumab (IPI) Expanded Access Program (EAP) for patients (pts) with Stage III/IV melanoma: safety data by subgroups. Ann Oncol 2012, 23(suppl 9):abstr 1129P.
• [20]Lopez Martin JA, Gonzalez Cao M, Sereno M, Mayordomo J, Hidalgo M, Campos B, Cumplido D, Zambrana F, Medina J, Berrocal A: Ipilimumab in older patients: Spanish melanoma multidisciplinary group (GEM) experience in the expanded access programme. Ann Oncol 2012, 23(suppl 9):abstr 3233.
• [21]Del Vecchio M, Di Guardo L, Ascierto PA, Grimaldi AM, Sileni VC, Pigozzo J, Ferraresi V, Nuzzo C, Rinaldi G, Testori A, Ferrucci PF, Marchetti P, De Galitiis F, Queirolo P, Tornari E, Marconcini R, Calabrò L, Maio M: Efficacy and safety of ipilimumab 3mg/kg in patients with pretreated, metastatic, mucosal melanoma. Eur J Cancer 2014, 50:121-127.
• [22]Maio M, Danielli R, Chiarion-Sileni V, Pigozzo J, Parmiani G, Ridolfi R, De Rosa F, Del Vecchio M, Di Guardo L, Queirolo P, Picasso V, Marchetti P, De Galitiis F, Mandalà M, Guida M, Simeone E, Ascierto PA: Efficacy and safety of ipilimumab in patients with pre-treated, uveal melanoma. Ann Oncol 2013, 24:2911-2915.
• [23]Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M, Bohnsack O, Nichol G, Humphrey R, Hodi FS: Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009, 15:7412-7420.
• [24]Queirolo P, Spagnolo F, Altomonte M, Chiarion-Sileni V, Pigozzo J, Del Vecchio M, Di Guardo L, Ridolfi R, Scoppola A, Francesco Ferrucci P, Ferraresi V, Grazia Bernengo M, Guida M, Marconcini R, Mandalà M, Parmiani G, Rinaldi G, Aglietta M, Simeone E, Antonio Ascierto P: Italian cohort of the ipilimumab Expanded Access Programme: efficacy, safety and correlation with mutation status in metastatic melanoma patients. J Clin Oncol 2013, 31(suppl):abstr 9070.
• [25]Aapro MS, Köhne C-H, Cohen HJ, Extermann M: Never too old? Age should not be a barrier to enrollment in cancer clinical trials. Oncologist 2005, 10:198-204.
• [26]Chandra S, Madden KM, Kannan R, Pavlick AC: Evaluating the safety of anti-CTLA-4 therapy in elderly patients with unresectable melanoma. J Clin Oncol 2013, 31(suppl):abstr 9063.
• [27]Balducci L: Geriatric oncology: challenges for the new century. Eur J Cancer 2000, 36:1741-1754.
• [28]Chustecka Z: Older Patients With Cancer Need Geriatric Assessment. MedScape Multispecialty News 2012. Available at [http://www.medscape.com/viewarticle/773479 webcite] (12 February 2014, date last accessed)
• [29]Chapman PB, Hauschild A, Robert C, Larkin JMG, Haanen JBAG, Ribas A, Hogg D, Hamid O, Ascierto PA, Testori A, Lorigan P, Dummer R, Sosman JA, Garbe C, Maio M, Nolop KB, Nelson BJ, Joe AK, Flaherty KT, McArthur GA: Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAF V600E-mutated melanoma. J Clin Oncol 2012, 30(suppl):abstr 8502^.
• [30]Weber JS, Dummer R, de Pril V, Lebbé C, Hodi FS: MDX010-20 Investigators.l. 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.
• [31]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.
• [32]Larkin JMG, Del Vecchio M, Ascierto PA, Schachter J, Garbe C, Neyns B, Mandala M, Lorigan P, Miller WH, Guminski AD, Berking C, Rutkowski P, Queirolo P, Hauschild A, Arance AM, Brown MP, Mitchell L, Veronese ML, Blank CU: Open-label, multicenter safety study of vemurafenib in patients with BRAFV600 mutation–positive metastatic melanoma. J Clin Oncol 2013, 31(suppl):abstr 9046.
• [33]Wu D, Meydani SN: Age-associated changes in immune and inflammatory responses: impact of vitamin E intervention. J Leuk Biol 2008, 84:900-914.
• [34]Yalcin AD, Gorczynski RM, Kahraman MS, Demirel MU, Terzioglu E: CD40, CD45 CTLA-4 levels are elevated in healthy older adults. Clin Lab 2012, 58:449-456.