Volume 12 Supplement 1

Melanoma Bridge 2013: Poster and Oral Presentations

Open Access

Peripheral and tumor immune correlates in patients with advanced melanoma treated with nivolumab (anti-PD-1, BMS-936558, ONO-4538) monotherapy or in combination with ipilimumab

  • Michael A Postow1Email author,
  • Diana M Cardona2,
  • Janis M Taube3,
  • Robert A Anders3,
  • Clive R Taylor4,
  • Jedd D Wolchok1,
  • Margaret K Callahan1,
  • Michael A Curran1,
  • Alexander M Lesokhin1,
  • Joseph F Grosso5,
  • Christine E Horak5,
  • John Cogswell5,
  • Jason S Simon5,
  • Ashok K Gupta5 and
  • Mario Sznol6
Journal of Translational Medicine201412(Suppl 1):O8

https://doi.org/10.1186/1479-5876-12-S1-O8

Published: 6 May 2014

Background

The fully human monoclonal antibodies nivolumab (Nivo) and ipilimumab (Ipi) block the interaction between the immune checkpoint receptors programmed death-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4), respectively, and their cognate ligands, restoring antitumor immune response. Phase 1 studies of Nivo monotherapy (CA209-003; NCT00730639) or Nivo+Ipi combination therapy (CA209-004; NCT01024231) demonstrated durable clinical activity and objective response rates (ORRs) of 31% to 40%, respectively, in patients with advanced melanoma (MEL). Evaluation of PD-L1 expression using immunohistochemistry (IHC) suggested a correlation between pretreatment tumor PD-L1 expression and clinical response to Nivo monotherapy [1]. Identification of predictive markers of response would be valuable to guide effective use of Nivo and Ipi.

Materials and methods

MEL patients received Nivo monotherapy (n=107) or Nivo+Ipi combination therapy (N=86; concurrent regimen: n=53; sequenced regimen: n=33). Tumor and tumor infiltrating lymphocyte (TIL) surface programmed death ligand 1 (PD-L1) expression in formalin-fixed, paraffin-embedded (FFPE) tumor tissue was evaluated by IHC with an automated assay (Dako) using the 28-8 Ab. Tumor PD-L1 positivity (PD-L1+) was defined as ≥5% cell membrane staining of any intensity; any expression on TILs was considered positive. Absolute lymphocyte counts (ALC) were measured in serial peripheral blood samples and lymphocyte subsets were evaluated using flow cytometry.

Results

Tumor PD-L1-positive expression was observed in 45% and 37% of samples from the 003 and 004 studies, respectively. In 003, inclusion of any immune cell staining increased PD-L1 positivity to 92%. A numerically higher ORR was observed in MEL patients with PD-L1+ tumors with Nivo monotherapy or with sequential but not concurrent combination therapy. Neither study demonstrated an obvious change in ALC; however, phenotypic changes in T-cell subsets, including increases in the percentage of CD4 and CD8 expressing HLA-DR, ICOS and/or Ki67, were seen with combination therapy. In both studies, responses were observed irrespective of tumor PD-L1 or ALC status. In an exploratory analysis low pretreatment myeloid derived suppressor cells (MDSC) correlated with higher ORR with combination therapy (P< 0.05).

Conclusions

PD-L1 positivity is associated with tumor response with Nivo monotherapy; however, some responses were observed independent of PD-L1 or ALC status. No correlation between response and PD-L1 or ALC status was seen with combination therapy. MDSC levels may correlate with response to combination therapy. Future phase 3 randomized studies will explore these markers and other phenotypic changes in immune cell populations that might predict activity of Nivo in patients with MEL and other advanced cancers.

Authors’ Affiliations

(1)
Memorial Sloan-Kettering Cancer Center
(2)
Duke University School of Medicine
(3)
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
(4)
Keck School of Medicine, University of Southern California
(5)
Bristol-Myers Squibb
(6)
Yale University School of Medicine and Yale Cancer Center

References

  1. Topalian S, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wiggington JM, Sznol M: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012, 366 (26): 2443-2454. 10.1056/NEJMoa1200690.PubMed CentralView ArticlePubMedGoogle Scholar

Copyright

© Postow et al; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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