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Poster display session

4747 - Pharmacokinetics (PK) and Pharmacodynamics (PD) of cergutuzumab amunaleukin (CA), a carcinoembryonic antigen (CEA)-targeted interleukin 2 variant (IL2v) with abolished binding to CD25

Date

10 Sep 2017

Session

Poster display session

Topics

Cancers in Adolescents and Young Adults (AYA);  Immunotherapy

Presenters

Emilie van Brummelen

Citation

Annals of Oncology (2017) 28 (suppl_5): v403-v427. 10.1093/annonc/mdx376

Authors

E. van Brummelen1, U. Lassen2, I. Melero3, J. Tabernero4, K. Homicsko5, E. Angevin6, V. Teichgräber7, L. Jukofsky8, E. Rossmann9, G. Babitzki10, A. Patricia Silva9, M. Canamero10, C. Boetsch9, S. Evers7, J. Charo7, G. Argiles4

Author affiliations

  • 1 Dept. Of Clinical Pharmacology, The Netherlands Cancer Institute, 1066 CX - Amsterdam/NL
  • 2 Dept. Of Oncology, Phase 1 Unit, Rigshospitalet, 2100   - Copenhagen/DK
  • 3 Laboratory Of Immunology, Clinica Universitaria de Navarra, 31008 - Pamplona/ES
  • 4 Medical Oncology, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 5 Département D'oncologie, Centre Multidisciplinaire d'Oncologie-CePo, 1011 - Lausanne/CH
  • 6 Drug Development Department (ditep), Gustave Roussy Institut de Cancérologie, 94805 - Villejuif/FR
  • 7 Roche Innovation Center Zurich, F. Hoffmann-La Roche AG - Switzerland, 8952 - Schlieren/CH
  • 8 Roche Innovation Center New York, F. Hoffmann-La Roche AG - Switzerland, 10016 - New York/US
  • 9 Roche Innovation Center Basel, F. Hoffmann-La Roche AG - Switzerland, 4070 - Basel/CH
  • 10 Roche Innoavtion Center Munich, F. Hoffmann-La Roche AG - Switzerland, 82377 - Penzberg/DE
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Resources

Abstract 4747

Background

CA is a CEA-specific antibody fused to IL2v with abolished CD25 binding. Compared to wildtype (wt) IL-2, CA was designed to preferentially expand natural killer (NK) and CD8 T cells but not T regulatory cells (Tregs), to be retained within CEA+ tumors, and for improved PK.

Methods

In this FIH phase I study, PK/PD analyses were performed using samples from solid tumor patients treated weekly (QW) or biweekly (Q2W) with 6 – 40 mg CA monotherapy IV. Methods: PK - population modeling; PD analysis of baseline (BL) and on-treatment (OT) samples; flow cytometry of peripheral blood monocytes (PBMCs); immunohistochemistry (IHC) on tumor biopsies; PD-L1 expression using SP142 assay; measurement of plasma cytokines and sCD25.

Results

During cycle 1, CA exhibited prolonged exposure (8-fold) vs. wt IL2. Following multiple cycles, serum exposure showed typical target-mediated drug disposition kinetics, likely due to clearance by IL-2 receptor-expressing cells. In PBMCs from patients treated QW x 4, a significant increase in the absolute number of NK cells and CD8 T cells was seen (median of 13- and 2.3-fold, respectively). By contrast, moderate or no increase was seen in the absolute number of CD4 T or Tregs (median of 1.5- and 1.2-fold). Similar but less prominent changes were observed in patients treated Q2W. Treatment was accompanied by upregulation of the activation marker CD314 (NKG2D), which was undetectable on more than 20% of NK cells in 9 of 39 patients at BL, suggesting increased functional activity of NK cells in the affected patients. A transient increase in the level of various cytokines was seen, peaking 24 hours after administration. Changes in the level of sCD25 correlated with drug exposure. OT biopsies showed an increase in the number of infiltrating Ki67+ CD8 T cells and PD-L1+ immune cells (median of 3.5- and 3-fold, n = 11).

Conclusions

PK data confirmed that CA has longer exposure than wt IL2. PD data demonstrated preferential expansion and reinvigoration of NK and CD8+ T cells in both PBMCs and tumors. This data suggest that CA can be a potent combination partner for cancer immunotherapies targeting CEA+ solid tumors.

Clinical trial identification

NCT02004106

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd

Funding

F. Hoffmann-La Roche Ltd

Disclosure

I. Melero: Advisory board: Bristol-Myers, Roche-genentech, AstraZeneca, Lilly, Merck Serono, Bayer, Genmab, Alligator, Bioncotech, Tusk Grants from: Roche-Genetech, Bristol Myers, Bioncotech. J. Tabernero: Advisory boards for Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Genentech, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho, and Takeda. V. Teichgräber: A permanent employee of F Hoffmann La Roche Ltd. With stock options L. Jukofsky: A Roche employee with stocks options. E. Rossmann: A permanent Roche employee with stocks options. G. Babitzki: A Roche employee. A. Patricia Silva: F.Hoffman-La Roche employee. M. Canamero: Roche employee with stock options. C. Boetsch: An employee of Roche with stock options. S. Evers: An employee and shareholder of Roche. J. Charo: The author is an employee and stockholder of Roche. All other authors have declared no conflicts of interest.

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