Sym004: Truly a New Level of Anti-EGFR Treatment?

摘要

Summary: Sym004 is a new antibody mixture to target EGFR in metastatic colorectal cancer. Preclinical data suggest efficacy in anti-EGFR-resistant tumors, but it remains unclear whether a higher toxicity is outweighed by those advantages. Metastatic colorectal cancer is the most frequent gastrointestinal malignancy. During the past two decades, overall survival (OS) times have been prolonged from a median of 12 months to up to 30 months in molecularly defined subgroups (1). These advantages have been possible due to the development and introduction of new chemotherapeutic substances, such as irinotecan and oxaliplatin. For more than a decade, drugs targeting specific pathways important for carcinogen-esis, metastasis, proliferation, and angiogenesis have further increased the outcome of patients with metastatic colorectal cancer. The use of mAbs targeting EGFR is an established strategy to treat patients with metastatic colorectal cancer and has been shown to improve tumor response, progression-free survival (PFS), and OS when added to standard chemotherapy. In first-line treatment of RAS wild-type tumors, cetuximab and panitumumab are approved and established in combination with FOLFOX or FOLFIRI. In this issue of Cancer Discovery, Dienstmann and colleagues (2) publish phase I data of Sym004, a mixture of two chimeric human-mouse antibodies targeting two different epitopes of the extracellular domain of EGFR, for the treatment of patients with metastatic colorectal cancer pretreated with anti-EGFR antibodies. In addition, preclinical data demonstrate a superior antitumor effect of Sym004 in comparison with cetuximab that was specifically evident in cells showing EGFR ligand-dependent growth. However, the underlying mechanism of action is not new, and side effects restricting the use of anti-EGFR treatment, such as acneiform exanthema Common Toxicity Criteria Adverse Events (CTC AE) grade 3, occurred in both of the tested dosages in more than 60% of the patients with no advantage in the lower, 9-mg, dose. A recommended dosage for a potential phase II trial has not been evaluated by the investigators of Sym004.