Phase I study of tomuzotuximab, a glycoengineered therapeutic antibody against the epidermal growth factor receptor, in patients with advanced carcinomas

Abstract

Background: Changes in glycosylation of the constant domain (Fc) of monoclonal antibodies (mAbs) enhance antibody-dependent cell-mediated cytotoxicity independently of downstream effects following receptor blockade by the antibody, thus extending their indication. We investigated the safety, pharmacokinetics, pharmacodynamics and antitumour activity of tomuzotuximab, an IgG1 glycoengineered mAb against the epidermal growth factor receptor with enhanced tumour cytotoxicity in a phase I dose-escalation study (NTC01222637).

Patients and methods: Forty-one patients with advanced solid tumours refractory to standard therapies received tomuzotuximab weekly (12-1370 mg) or two-weekly (990 mg) on a three-plus-three dose escalation design.

Results: A maximum tolerated dose was not reached. The most frequent treatment-related adverse events were infusion-related reactions in 31 (76%) patients (grade 3, 12%), mainly confined to the first dose, and skin toxicities (grade 1 or 2) in 30 (73%) patients. Hypomagnesaemia was observed in 9 out of 23 evaluable patients (39%). Similar to cetuximab, tomuzotuximab concentrations increased proportionally to dose from doses≥480 mg with a median terminal half life (t½) of 82 hours, range 55-113 hours. Antitumour activity included one complete response ongoing since more than 4.5 years in a patient with non-small-cell lung cancer and one partial response lasting 353 days in a patient with colorectal cancer. Twelve patients achieved stable disease (median, 166 days, range, 71-414 days) and two patients had prolonged control (>1 year) of their non-measurable disease.

Conclusion: Tomuzotuximab was safe and showed promising antitumour activity in heavily pretreated patients with advanced metastatic disease. A phase IIb trial of chemotherapy and weekly tomuzotuximab or cetuximab followed with maintenance therapy with the corresponding mAb in patients with recurrent or metastatic head and neck squamous cell carcinoma is ongoing.

Keywords: egfr; glycoengineered; monoclonal antibody; phase I; tomuzotuximab.

Conflict of interest statement

Competing interests: Employment or leadership position: HB, BD, SG, AZ, AD. Stock ownership: HB, SG, AD. MS was employee of Pharma Brains AG, which received funding for the study from Glycotope GmbH. Other remuneration: WF, Meeting participation to present the data at the American Society of Clinical Oncology 2013 Annual Meeting.

Figures

Figure 1

Concentration-time profiles of repeated weekly infusions of (A) 720 mg and (B) 990 mg tomuzotuximab measured in individual patients before and at the end of infusion. The dotted line indicates the 50 µg/mL trough level. Tomuzotuximab serum levels were above 50 µg/mL 1 week after the second infusion in four out of five patients who received 720 mg and 1 week after the first infusion in all three patients who received 900 mg tomuzotuximab.

Figure 2

Waterfall plot of the best per cent change from baseline in SLD of target lesions in 33 patients. Baseline is defined as the last non-missing value before the first dose of tomuzotuximab. Only patients with valid baseline and postbaseline values are included. Tumour assessment was not performed in six patients because of early withdrawal from the study following clinical deterioration or AE; two patients had no measurable disease according to RECIST1.1 criteria. The dotted lines indicate the cut-off for partial response (−30%) and progressive disease (+20%). *Patients with stable target lesions but progression because of new lesions. †Patient (CRC, dose 1370 mg) had a best change from baseline of 32.2%, unconfirmed 50 days later (change from baseline 29.5%). ¶ Patient is still in complete remission (4.5 years) and received tomuzotuximab for 5.2 years. CRC, colorectal cancer; GCA, gastric cancer; NSCLC, non-small cell lung cancer; OVCA, ovarian cancer; PanC, pancreatic cancer; RCC, renal cell cancer; SLD, sum of longest diameters.