An exploratory, open-label, randomized, multicenter study to investigate the pharmacodynamics of a glycoengineered antibody (imgatuzumab) and cetuximab in patients with operable head and neck squamous cell carcinoma

S Temam, J Spicer, F Farzaneh, J C Soria, D Oppenheim, M McGurk, A Hollebecque, J Sarini, K Hussain, S Soehrman Brossard, L Manenti, S Evers, P Delmar, L Di Scala, C Mancao, F Feuerhake, L Andries, M G Ott, A Passioukov, J P Delord

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

Background: In addition to inhibiting epidermal growth factor receptor (EGFR) signaling, anti-EGFR antibodies of the IgG1 subtype can induce a complementary therapeutic effect through the induction of antibody-dependent cell-mediated cytotoxicity (ADCC). Glycoengineering of therapeutic antibodies increases the affinity for the Fc-gamma receptor, thereby enhancing ADCC.

Patients and methods: We investigated the changes in immune effector cells and EGFR pathway biomarkers in 44 patients with operable, advanced stage head and neck squamous cell carcinoma treated with two pre-operative doses of either glycoengineered imgatuzumab (GA201; 700 or 1400 mg) or cetuximab (standard dosing) in a neoadjuvant setting with paired pre- and post-treatment tumor biopsies.

Results: Significant anti-tumor activity was observed with both antibodies after just two infusions. Metabolic responses were seen in 23 (59.0%) patients overall. One imgatuzumab-treated patient (700 mg) achieved a pathological complete response. An immediate and sustained decrease in peripheral natural killer (NK) cells was consistently observed with the first imgatuzumab infusion but not with cetuximab. The functionality of the remaining peripheral NK cells was maintained. Similarly, a pronounced increase in circulating cytokines was seen following the first infusion of imgatuzumab but not cetuximab. Overall, tumor-infiltrating CD3+ cell counts increased following treatment with both antibodies. A significant increase from baseline in CD3+/perforin+ cytotoxic T-cells occurred only in the 700 mg imgatuzumab group (median 95% increase, p < 0.05). The most prominent decrease of EGFR-expressing cells was recorded after treatment with imgatuzumab (700 mg: –34.6%; 1400 mg: –41.8%). The post-treatment inflammatory tumor microenvironment was strongly related to baseline tumor-infiltrating immune cell density, and baseline levels of EGFR and pERK in tumor cells most strongly predicted therapeutic response.

Conclusions: These pharmacodynamic observations and relationship with efficacy are consistent with the proposed mode of action of imgatuzumab combining efficient EGFR pathway inhibition with ADCC-related immune anti-tumor effects.

Clinical trial registration number: NCT01046266 (ClinicalTrials.gov).

Original languageEnglish
Pages (from-to)2827-2835
JournalAnnals of oncology : official journal of the European Society for Medical Oncology / ESMO
Volume28
Issue number11
Early online date11 Sept 2017
DOIs
Publication statusPublished - 1 Nov 2017

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