Sym004, a novel strategy to target EGFR with an antibody mixture, in patients with advanced SCCHN progressing after anti-EGFR monoclonal antibody: A proof of concept study.

Abstract

6002 Background: Sym004 is a first-in-class drug mixture of two mAbs targeting non-overlapping epitopes on the EGFR. In preclinical models, Sym004 exhibited more pronounced EGFR internalization, degradation and tumor growth inhibition than cetuximab. Sym004 was investigated as monotherapy in palliative squamous cell carcinoma of the head and neck (SCCHN) patients (pts). Methods: SCCHN pts progressing after anti-EGFR mAbs for palliation were eligible. Documented clinical benefit (PR, CR or SD for at least 8 weeks according to RECIST) on an anti-EGFR mAb-containing regimen followed by disease progression during or within 12 weeks after treatment cessation was required. The primary endpoint of this multicentre single arm trial was centrally evaluated progression-free survival (PFS), estimated by median PFS and 24 week progression free rate. Secondary endpoints included objective tumor response, safety, biomarkers and pharmacokinetics. Pts received weekly iv infusions of 12 mg/kg Sym004 until disease progression. Tumor evaluation was performed week 6, 12 and every 8 weeks thereafter. Results: Based on the statistical hypothesis, 26 pts were included, of whom 23 had progressed while on anti-EGFR mAb treatment. One of 19 evaluable pts was HPV positive and no EGFRvIII mutation was detected in 21 evaluable pts. No anti-drug antibodies were detected. Independent central review of CT/MRI scans from 20 evaluable pts showed tumor shrinkage in 8 pts (% decrease in sum of the largest diameters: 6.5, 7.1, 9.6, 10.2, 11.3, 13.6, 16.7, 27.1) and 14 pts had SD as best overall response. Median PFS was 82 days (95% CI: 41, 140) and 24 week progression free rate was 12% (95% CI: 1, 39). During treatment 25/26 (96%) pts developed skin rash with ≥ grade 3 reported in 11/26 (42%) pts. Hypomagnesemia ≥ grade 3 was reported in 10/26 (38%) pts. Sym004 treatment resulted in a marked down regulation of EGFR in centrally reviewed biopsies from skin and tumors. Conclusions: Sym004 demonstrated clinical activity in heavily pretreated, predominately HPV negative pts with advanced SCCHN previously progressing on or after anti-EGFR mAbs. No unexpected toxicities were reported. Clinical trial information: NCT01417936.