CetuGEX and cetuximab in recurrent/metastatic squamous cell carcinoma of the head and neck (RM-HNSCC): PK/PD results from the phase II RESGEX study.

Abstract

61 Background: Standard treatment for RM-HNSCC is a combination of cisplatin (P), 5-FU (F), and the EGFR blocking monoclonal antibody (mAb) cetuximab (C). The mAb CetuGEX (CG) shares with cetuximab the identical EGFR-binding domain, but harbors a defucosylated glycan at the Fc part to increase antibody dependent cellular cytotoxicity (ADCC) by improved binding at the Fcγ receptors IIIa (FcγRIIIa). Methods: 240 pts with RM-HNSCC were randomized in 34 European centers, of which 123 received C and 117 CG, in combination with P (100 mg/m2) and F (4 x 1000 mg/m2/24hrs) for the first 6 cycles. Initial dose of C was 400mg/m2, followed by weekly 250 mg/m2. CG was administered once 990 mg, followed by weekly infusions of 720 mg. After completion of combination treatment, pts received single agent mAb maintenance until disease progression or intolerable toxicity. The tumor tissues were analyzed for EGFR and p16 expression by IHC staining. Blood samples were withdrawn to analyze the FcγRIIIa phenotypes V/V, V/F and F/F and the FcγRIIa phenotypes R/R, H/R and R/R of each patient. The cellular immune status was analyzed in a subset of about 20 pts per arm before 1st and 5th infusion and 28 days after last infusion (Safety Visit) by flow cytometry. Serum CG concentrations were measured before and after the first ten infusions and for a subset of about 20 pts 5 h, 7 h, 24 h, 48 h, 72 h, and 168 h after the first and 10th infusion. The occurrence of anti-drug antibodies (ADA) was determined before 1st, 2nd, 4th and 10th infusion of CG and at the Safety Visit. Efficacy and safety parameters will be looked at in relation to the biomarkers. Results: While most analyses did not show any difference between CG and C, the subgroup of p16+ pts (N=32) is characterized by a significantly longer overall survival (HR 0.52; 95%-CI 0.29 – 0.86; p=0.009) than that of p16- pts, which remains significant under CG (17 pts; HR 0.43; 95%-CI 0.18 – 0.88; p=0.02) but not C treatment (15 pts), probably due to differences in pts immune status. Conclusion: The RESGEX study is the first head-to-head comparison of an ADCC-optimized to a conventional anti-EGFR mAb. The biomarker assessment may help to understand differences between the two mAbs. Clinical trial information: NCT02052960.