Abstract 2857: Metastatic site and response to pembrolizumab (anti-PD1 antibody) in melanoma

Abstract

Abstract Therapies that block the PD-1/PD-L1 axis have shown significant clinical activity in melanoma and other cancers. Recent evidence has shown that pre-existing CD8 T cells infiltrates at the invasive tumor margin of metastatic melanoma are associated with the presence of the PD-1/PD-L1 immune axis and may predict response to therapy. We examined the relationship between site of metastatic disease, local immune response, and treatment outcome in patients with advanced melanoma treated with pembrolizumab. We studied patients enrolled in the pembrolizumab Phase I clinical trial in the intention to treat (ITT, N = 112) and full analysis set (FAS) cohorts (N = 96). Using quantitative immunohistochemistry and multi-parameter flow cytometry we analyzed the local immune response in pre-treatment metastatic samples according to organ site of metastasis and treatment outcome. The overall response rate was 40% with a median progression-free survival (PFS) of 5.58 months. The presence of melanoma metastatic to the liver (liver metastasis group) had an objective response rate (ORR) of 16% and median PFS of 2.79 months. The presence of melanoma metastatic to the lung (lung metastasis group) had an ORR of 64% and median PFS of 14.48 months. Preliminary analysis of samples obtained from patients with liver metastases showed reduced tumor infiltrating CD8+ T cells (TILs), PD-1 expression, and tumor PD-L1 expression in distant metastases. Phenotypic and functional analysis of TILs showed reduced percentages of partially exhausted PD-1+CTLA-4+CD8+ cells, which correlated with progression and with liver metastasis. These cells were shown to make IFNγ but not TNF or IL-2. Additionally, the presence of liver metastasis in melanoma patients prior to starting anti-PD1 therapy correlated with treatment failure. Liver metastasis was associated with fewer PD-1+ CTLA-4+ TILs in distant tumors. These preliminary results warrant further investigation into determining whether site of metastasis modulates the systemic immune response to PD-1/PD-L1 blocking therapies. Citation Format: Paul Camille Tumeh*, Michael Rosenblum*, Nathan Handley, Katy Tsai, Robert Rodriguez S. Rodriguez, Niharika Khurana, Christina Harview, Marko Spasic, Phillip J. Sanchez, Jeremy Chang, I. Peter Shintaku, Emma Taylor, Bartosz Chmielowski, Tristan Grogan, David A. Elashoff, Robert H. Pierce, Adil Daud. Metastatic site and response to pembrolizumab (anti-PD1 antibody) in melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2857. doi:10.1158/1538-7445.AM2015-2857