Neoadjuvant ipilimumab in patients with stage IIIB/C melanoma: Immunogenicity and biomarker analysis.

Abstract

8536 Background: Regional lymph node metastasis from melanoma has a high relapse and mortality risk. Neoadjuvant ipilimumab (ipi) may improve the clinical outcome and through access to tumor before and after ipi may allow new insight into the biologic and immunologic response. Methods: Pts (stage IIIB-C melanoma) were treated with ipi (10 mg/kg IV q3weeks x2doses) as preoperative induction followed by lymphadenectomy (at week ≥ 6) and 2 additional doses of maintenance ipi (3 weeks apart). Tissue samples were obtained at baseline and at definitive surgery and blood (serum/PBMC) collected at baseline, 6 weeks, 3, 6, 9, 12 months and/or progression for immunologic/mechanistic studies comparing pre- and post-treatment tumor and blood features. Results: Seventeen pts (14 M, 3 F), age 44-87 have been enrolled since Feb/2010 (14 cutaneous primary and 3 mucosal). Two had stage IIIB (1N2b, 1N2c) and 15 IIIC (N3) melanoma. Seven pts had recurred after receiving adjuvant IFN. Fifty three cycles have been delivered (median 4). Grade 3 (worst) toxicities include diarrhea/colitis (6 pts; 35%), hepatic enzyme elevations (1; 5%), rash (1; 5%), lipase (1; 5%), all manageable. Among 16 evaluable pts (surgery is pending for1), median follow-up is 7.9 months and 13 pts (81%) continue disease free. The probability of 6 and 12 months PFS is 84.4% (95% CI=0.50, 0.95) and 63.3% (95% CI=0.17, 0.88) respectively. There is significant increase in the frequency of circulating T-regulatory cells (CD4+CD25hi+ Foxp3+; p=0.009. CD4+CD25hi+CD39+; p=0.011) from baseline to 6 wks. In parallel there is significant decrease in circulating MDSCs: (1) monocytic: lin1neg/HLA-DRneg/ CD33+/CD11b+; p=0.038, (2) other monocytic: HLA-DR+/low/CD14+; p<0.0001 and less significant for (3) lymphoid: Lin1neg/HLA-DR-/CD33+/CD11b+; p=0.067. Immune monitoring comparing baseline and 6 wk tumor samples is ongoing. Conclusions: Our preliminary results show that neoadjuvant ipilimumab is clinically promising and immunologically appears to significantly modulate host immune responses. Ongoing functional and tissue biomarker studies will seek correlations between systemic findings and the tissue impact of ipilimumab that are uniquely assailable using the neoadjuvant model.