Ipilimumab—an antibody against cytotoxic T-lymphocyte-associated protein 4—was the first systemic treatment in unresectable metastatic melanoma to be proven to extend overall survival. No previous phase 3 trial had shown any significant survival benefit for systemic treatments in melanoma. 1 Eigentler TK Caroli UM Radny P Garbe C Palliative therapy of disseminated malignant melanoma: a systematic review of 41 randomised clinical trials. Lancet Oncol. 2003; 4: 748-759 Summary Full Text Full Text PDF PubMed Scopus (277) Google Scholar , 2 Garbe C Eigentler TK Keilholz U Hauschild A Kirkwood JM Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist. 2011; 16: 5-24 Crossref PubMed Scopus (397) Google Scholar Two phase 3 clinical trials (one comparing ipilimumab with gp100 vaccination 3 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 Crossref PubMed Scopus (10776) Google Scholar and one ipilimumab plus dacarbazine versus dacarbazine alone 4 Robert C Thomas L Bondarenko I et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011; 364: 2517-2526 Crossref PubMed Scopus (3462) Google Scholar ) showed a significant improvement of 10% in overall survival after 2–4 years. In these two trials, different doses of 3 and 10 mg/kg were used. 3 mg/kg ipilimumab every 3 weeks for four treatment cycles has been approved in Europe and the USA for treatment of unresectable metastatic melanoma. However, the two previous trials 3 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 Crossref PubMed Scopus (10776) Google Scholar , 4 Robert C Thomas L Bondarenko I et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011; 364: 2517-2526 Crossref PubMed Scopus (3462) Google Scholar raised questions about whether this immunotherapy should be combined with cytotoxic drugs and whether increased doses and reinduction or maintenance treatment would increase effectiveness. Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an open-label, single-arm phase 2 trialThe combination of ipilimumab plus fotemustine has clinical activity in patients with metastatic melanoma, including those with brain metastases. Full-Text PDF