Abstract
Purpose
The purpose of the trial was to assess the efficacy and tolerability of Sym004, a novel 1:1 mixture of two chimeric monoclonal antibodies (992 and 1024) targeting non-overlapping epitopes of the anti-epidermal growth factor receptor (EGFR), in patients with squamous cell carcinoma of the head and neck (SCCHN).
Methods
Incurable, recurrent and/or metastatic SCCHN patients with acquired resistance to anti-EGFR monoclonal antibody-containing treatment received weekly infusions of 12 mg/kg Sym004 until disease progression or unacceptable toxicity.
Results
Among the 26 patients treated with Sym004, the proportion of patients alive without disease progression at 6 months was 12 % (95 % CI 1–39 %). The median duration of progression-free survival was 82 days (95 % CI 41–140 days). Of 19 patients evaluable for response, eight showed a decrease in the sum of the largest diameter in their target lesions (median 11 %; range 7–27 %). The best overall response was stable disease in 13 patients (50 %). Paired biopsies showed a significant down-regulation of EGFR in both skin and tumors following exposure to Sym004. All patients had EGFR-related adverse events, including grade 3 skin toxicities and grade ≥3 hypomagnesemia reported in 13 (50 %) and 10 (38 %) of 26 patients, respectively. One event fulfilling the protocol-defined criteria for infusion-related reactions (grade 2) was reported. No anti-drug antibodies were detected.
Conclusions
The marked EGFR down-regulation shown in target tissues supports the proposed mechanism of action of Sym004. This trial revealed modest anti-tumor activity of Sym004 in extensively pretreated advanced SCCHN patients.
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Acknowledgments
We thank R. Hald, Symphogen A/S, for developing bioanalytical methods measuring Sym004 in human serum; H. Liedman, TFS, for assistance in the preparation and editing of this manuscript and M. Düring, BioStata ApS, for statistical assistance. This trial was sponsored by Symphogen A/S; Merck KGaA provided financial support for the trial.
Conflict of interest
J.-P. Machiels has advisory board function in MSD (with financial compensation) and has received research grants from Novartis, Bayer and Sanofi. A. Dietz has advisory board function in Merck Serono, Boehringer Ingelheim and Merck MSD and has received speakers honorarium from Merck Serono. T.C. Gauler has advisory board function in Boehringer Ingelheim, Merck Serono, Novartis and Symphogen, has received refunds for presentations and travel from Boehringer Ingelheim and Merck Serono and performs scientific investigations in cooperation with and with financial support by Boehringer Ingelheim and Merck Serono. N.J. Skartved, I.D. Horak, P. Pamperin and S. Braun are employees of and have ownership interests (including warrants) in Symphogen A/S. All remaining authors have declared no conflicts of interest.
Ethical standard
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
Informed consent
Informed consent was obtained from all individual participants included in the study.
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Machiels, JP., Specenier, P., Krauß, J. et al. A proof of concept trial of the anti-EGFR antibody mixture Sym004 in patients with squamous cell carcinoma of the head and neck. Cancer Chemother Pharmacol 76, 13–20 (2015). https://doi.org/10.1007/s00280-015-2761-4
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DOI: https://doi.org/10.1007/s00280-015-2761-4