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

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 preoperative 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 antitumor 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 cells was consistently observed with the first imgatuzumab infusion but not with cetuximab. The functionality of the remaining peripheral natural killer 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 antitumor effects.

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

Keywords: GA201; antibody-dependent cell cytotoxicity; cetuximab; imgatuzumab; squamous cell carcinoma of the head and neck; tumor-infiltrating lymphocytes.

© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

Waterfall plot showing the change in SUVmax in the head and neck region from baseline to post-mAb therapy per study arm for the safety population patients. The dotted line at –25% represents the EORTC recommended cut-off between the lower level of stable metabolic disease and the upper level of metabolic response. Centrally read PET scans were not available for four patients from the 700-mg imgatuzumab arm, six patients from the 1400-mg imgatuzumab arm, and 10 cetuximab patients. This was due to either missing baseline/post-mAb therapy PET scans, large differences in baseline and post-mAb therapy uptake times, or because the PET scans were done at non-qualified sites. EORTC, European Organization for Research and Treatment of Cancer; mAb, monoclonal antibody; PET, positron emission tomography; SUVmax, maximum standardized uptake value.

Figure 2.

Kinetics of peripheral blood NK (CD3–/CD56+) cells (A) and CD16-dependent killing capacity of peripheral blood NK cells (B) following infusion of imgatuzumab or cetuximab. A dramatic decrease in the number of peripheral NK cells was seen with the first infusion of imgatuzumab (beginning as early as the end of the infusion) but not with cetuximab (A). NK cell numbers recovered to some extent by the time of the second infusion. The functional capacity of the remaining NK cells appeared relatively unchanged (B). BL, baseline; B-i, beginning of infusion; CD, cluster of differentiation; D1/8, day 1/8; E-i, end of infusion; NK, natural killer.

Figure 3.

Immunohistochemistry data showing the change in immune infiltration and EGFR/pERK staining following treatment. Multiple fields of view were assessed for each tumor biopsy. Immunostaining was scored as the median number of positively stained cells per mm2 for infiltrating CD3+ and CD16+ cells and using the H-score system [8] for EGFR and pERK immunohistochemistry. This scoring system combines the total percentage of cells staining with intensities of negative (0), weak (1), intermediate (2), and strong (3) to give a final value ranging from 0 to 300. Orange lines indicate patients in whom marker levels decreased after mAb treatment and blue lines indicate increases. Results show an on-treatment increase in immune infiltration with both antibodies and downregulation of EGFR and pERK. CD, cluster of differentiation; EGFR, epidermal growth factor receptor; mAb, monoclonal antibody; pERK, phosphorylated extracellular signal-regulated kinase.