Immunological and biological changes during ipilimumab (Ipi) treatment and their correlation with clinical response and survival.
8573 Background: Ipilimumab (Ipi) is approved in the US as first and second line therapy in patients with metastatic melanoma (MM) and in MM patients with previous therapy in the EU, based on an overall survival benefit shown in a phase III study (Hodi, NEJM 2010). To date, no clinical parameter has been found to be predictive for response to treatment and only few immunologic changes have been identified as potential candidates. Methods: From June 2010 to November 2011 we treated in the Expanded Access Program with Ipi at 3 mg/kg, 95 pre-treated metastatic melanoma patients. The median age was 58 yrs (range 17-84); 10 pts (10,5%) were stage IIIc inoperable, 2 pts (2,1%) stage M1a, 4 pts (4,2%) stage M1b, and 79 pts (83,2%) stage M1c. 30/95 pts had brain metastases and 1/95 spinal cord metastases. All 95 patients were evaluable for response (DCR = CR+PR+SD according the irRC), overall survival, safety, including changes in LDH, CRP (C-reactive protein) and lymphocyte populations (CD4+,CD4CD25+,FOXP3/T-Reg cells). PBMC and sera were collected at week 0, 4, 7, 10 and 12. Results: We found a statistical significant decrease of LDH, CRP and FOXP3/T-Reg cells (p<0.0001; χ2 and Mann-Whitney), and an increase of lymphocyte count (p<.0001) in the responders group. These differences were also correlated to survival (log-rank test). No differences were observed for CD4+ and CD4+CD25+ between responders and non-responders (p=0.39;p=0.83; Mann-Whitney). An ORR of 22.1% (1CR+20PR; 95% CI 13.8-30.4) and a DCR at week 24 of 37.9% (36/95; 28.1-47.6, 95% CI) were observed. Median overall survival was estimated of 7.8 months (95%CI:5.0-10.6), with a p value not evaluable at the moment of the analysis due to insufficient follow-up because of long-term survival. Adverse events were registered in 40% (38/95) of patients and the most frequent were of grade 1 and 2 (pruritus 57.9%; rash 5.3%; thyroditis 5.3%). Conclusions: The decrease of LDH, CRP and T-Reg cells during Ipi treatment suggest these parameters should be further explored as potential predictive markers for response and survival. Given the potential clinical utility of these findings, these data warrants further prospective validation in a randomized trial.