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A phase I/II trial of the safety and clinical activity of a HER2-protein based immunotherapeutic for treating women with HER2-positive metastatic breast cancer

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Abstract

The objectives of this phase I/II study (NCT00140738) were to evaluate the safety and clinical activity of a cancer immunotherapeutic agent (recombinant HER2 protein (dHER2) and the immunostimulant AS15) in patients with HER2-overexpressing metastatic breast cancer (MBC). Forty HER2-positive MBC patients received up to 18 doses (12q2w, 6q3w) of dHER2 immunotherapeutic, as first- or second-line therapy following response to trastuzumab-based treatment as maintenance. Toxicity was graded by the Common Terminology Criteria for Adverse Events (CTCAE) and clinical activity was evaluated by target lesion assessment according to the Response Evaluation Criteria in Solid Tumors (RECIST). Immunogenicity was assessed. The dHER2 immunotherapeutic was well tolerated: grade 1/2 adverse events (AEs) were most common. No cardiac events were observed and one patient experienced an asymptomatic decrease of left ventricular ejection fraction below the normal range (47 %). Both humoral and cellular immunogenicity to the dHER2 antigen was observed. No patient discontinued the immunizations because of AEs but 35/40 withdrew prematurely, 34 because of disease progression (24/34 before or at the tumor assessment after dose 6). One patient achieved a complete response lasting 11 months and one patient had a partial response lasting 3.5 months. Ten patients experienced stable disease ≥26 weeks with 4/10 still in stable disease at the last tumor assessment after 47 weeks. Immunization of MBC patients with the dHER2 immunotherapeutic was associated with minimal toxicity and no cardiac events. Clinical activity was observed with two objective responses and prolonged stable disease for 10/40 patients.

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Abbreviations

Ab:

Antibody

AE:

Adverse events

BC:

Breast cancer

CBR:

Clinical benefit rate

CMI:

Cell-mediated immunogenicity

CR:

Complete response

CTCAE:

Common Terminology Criteria for Adverse Events

ECD:

Extracellular domain

ECOG:

Eastern Cooperative Oncology Group

ELISA:

Enzyme-linked immunosorbent assays

GMC:

Geometric mean concentrations

HER2:

Human epidermal growth factor receptor 2

ICD:

Intracellular domain

LVEF:

Left ventricular ejection fraction

MBC:

Metastatic breast cancer

PBMC:

Peripheral blood mononuclear cells

PR:

Partial response

RECIST:

Response evaluation criteria in solid tumors

SAE:

Serious adverse event

SD:

Stable disease

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Acknowledgments

The authors thank the patients who participated in this study and their families. They also acknowledge the investigators and their clinical teams for their contribution to the study and their support and care of patients, in particular Thomas Bachelot, Henri Roche and Jaak Janssens. The authors thank the global and regional clinical operations and safety teams of GSK for their contribution to the study, the scientific writer for clinical protocol and clinical report writing and the team of statisticians at GSK for the statistical analysis. The authors thank Françoise Cormont, Valentine Wascotte and Anne-Laure Puaux for critical reading of the paper and helpful suggestions. The authors thank Niels Neymark (medical writer on behalf of GSK) for assistance in the manuscript writing, and Sophie Timmery (XPE Pharma & Science) for coordination and editorial assistance.

Author contributions

Study conception and design Vincent Brichard, Frédéric F. Lehmann, Jamila Louahed, Andrea Callegaro. Collection and assembly of data Giuseppe Curigliano, Gilles Romieu, Lionel Duck, Célia Roemer-Becuwe, Mario Roselli, Silvia Neciosup, Jean-Luc Canon. Data analysis and interpretation Vincent Brichard, Frédéric F. Lehmann, Jamila Louahed, Wivine Burny, Giuseppe Curigliano, Pedro Miguel de Sousa Alves, Andrea Callegaro, Lionel Duck, Mario Campone. Provision of study materials or patients Giuseppe Curigliano, Gilles Romieu, Silvia Neciosup, Mario Campone.

Disclosures

Employment Pedro Miguel De Sousa Alves (GSK group of companies); Frédéric F. Lehmann (GSK group of companies); Jamila Louahed (GSK group of companies); Vincent G. Brichard (GSK group of companies); Wivine Burny (GSK group of companies); Andrea Callegaro (GSK group of companies). Stock ownership Frédéric F. Lehmann (GSK group of companies); Jamila Louahed (GSK group of companies); Vincent G. Brichard (GSK group of companies); Pedro Miguel De Sousa Alves (GSK group of companies). Honoraria Mario Campone (Novartis, Servier, Menar). Consultant or advisory role Mario Campone (Novartis, Servier, Menar), Jean-Luc Canon (GSK). Speakers’ bureau Gilles Romieu (GSK, Roche), Mario Campone (Novartis). Research funding Mario Campone’s institution (Novartis). Expert testimony: Gilles Romieu (Roche). Travel, accommodations, expenses Gilles Romieu (Amgen), Mario Campone (Novartis).

Funding

This work was supported by GlaxoSmithKline Biologicals SA that was involved in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals SA also funded all costs associated with the development and the publishing of the present manuscript. All authors had full access to the data and the corresponding author was responsible for submission of the publication.

Author information

Authors and Affiliations

  1. Early Drug Development for Innovative Therapies Division, Istituto Europeo di Oncologica di Milano, Via Ripamonti, 435, 20141, Milan, Italy

    Giuseppe Curigliano

  2. Institut régional du Cancer de Montpellier, Montpellier, France

    Gilles Romieu

  3. Institut de Cancérologie de l’Ouest, Nantes, France

    Mario Campone

  4. Department of Medical Oncology, Institut Curie, Paris, France

    Thierry Dorval

  5. Department of Medical Oncology, Clinique Saint-Pierre, Ottignies, Belgium

    Lionel Duck

  6. Oncology-Hematology Department, Grand Hopital de Charleroi, Charleroi, Belgium

    Jean-Luc Canon

  7. Centre d’Oncologie de Gentilly, Nancy, France

    Celia Roemer-Becuwe

  8. Medical Oncology Unit, ‘Tor Vergata’ University Hospital, Rome, Italy

    Mario Roselli

  9. Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru

    Silvia Neciosup

  10. GSK Vaccines, Rixensart, Belgium

    Wivine Burny, Andrea Callegaro, Pedro Miguel de Sousa Alves, Jamila Louahed, Vincent Brichard & Frédéric F. Lehmann

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  1. Giuseppe Curigliano
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  2. Gilles Romieu
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  12. Pedro Miguel de Sousa Alves
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  15. Frédéric F. Lehmann
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Corresponding author

Correspondence to Giuseppe Curigliano.

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Conflict of interest

Giuseppe Curigliano, Lionel Duck, Célia Roemer-Becuwe, Mario Roselli, Silvia Neciosup, Thierry Dorval declare that they have no conflict of interest.

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Curigliano, G., Romieu, G., Campone, M. et al. A phase I/II trial of the safety and clinical activity of a HER2-protein based immunotherapeutic for treating women with HER2-positive metastatic breast cancer. Breast Cancer Res Treat 156, 301–310 (2016). https://doi.org/10.1007/s10549-016-3750-y

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  • DOI: https://doi.org/10.1007/s10549-016-3750-y

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