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
- 450 Downloads
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.
KeywordsBreast cancer Cancer immunotherapeutic HER2 antigen Vaccine
Clinical benefit rate
Common Terminology Criteria for Adverse Events
Eastern Cooperative Oncology Group
Enzyme-linked immunosorbent assays
Geometric mean concentrations
Human epidermal growth factor receptor 2
Left ventricular ejection fraction
Metastatic breast cancer
Peripheral blood mononuclear cells
Response evaluation criteria in solid tumors
Serious adverse event
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.
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.
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).
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.
Compliance with ethical standards
Conflict of interest
Giuseppe Curigliano, Lionel Duck, Célia Roemer-Becuwe, Mario Roselli, Silvia Neciosup, Thierry Dorval declare that they have no conflict of interest.
- 1.Zardavas D, Cameron D, Krop I et al (2013) Beyond trastuzumab and lapatinib: New options for HER2-positive breast cancer. Am Soc Clin Oncol Educ Book e2-e11Google Scholar
- 3.Andersson M, Lidbrink E, Bjerre K et al (2011) Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol 29:264–271CrossRefPubMedGoogle Scholar
- 20.Limentani SA, Campone M, Dorval T, et al: A non-randomized dose-escalation Phase I trial of a protein-based immunotherapeutic for the treatment of breast cancer patients with HER2-overexpressing tumors. Breast Cancer Res Treat, manuscript submitted in parallelGoogle Scholar
- 22.Kruit WH, Suciu S, Dreno B et al (2013) Selection of immunostimulant AS15 for active immunization with MAGE-A3 protein: results of a randomized phase II study of the European Organization for Research and Treatment of Cancer Melanoma Group in metastatic melanoma. J Clin Oncol 31:2413–2420CrossRefPubMedGoogle Scholar
- 27.Garcia B, Neninger E, de la Torre A et al (2008) Effective inhibition of the epidermal growth factor/epidermal growth factor receptor binding by anti-epidermal growth factor antibodies is related to better survival in advanced non-small-cell lung cancer patients treated with the epidermal growth factor cancer vaccine. Clin Cancer Res 14:840–846CrossRefPubMedGoogle Scholar