New Antibody Mixture Shows Promise to Treat Advanced Colorectal Cancer

Colorectal cancer remains one of the most deadly cancers in the U.S., and in recent years researchers are making steady progress against this disease. The development of many new drugs allow people with even the most advanced metastatic disease to live longer, but there is still more efforts needed to treat those patients with therapies, resulting in less side effects.

The problem with traditional chemotherapy is that it can’t be focused. The drugs go through the body, affecting both cancerous cells and healthy cells. Targeted therapies are in need, which are expected to affect the specific mechanisms that allow cancer cells to grow. As a result, they may have fewer side effects.Next, in 2004, came targeted therapies. Avastin (bevacizumab) and Erbitux (cetuximab) are monoclonal antibodies, a new generation of cancer drugs that can specifically target cancer tumors.

Anti-EGFR therapies are the most common treatment against colorectal cancer, and those with advanced colorectal tumors without mutations in the RAS genes will benefit a lot from anti-EGFR therapies. However, as Anti-EGFR therapies become the prior and only option for treatment, advanced colorectal cancer that has become resistant to prior anti-EGFR therapies. “Over the last decade, some of the disease mechanisms driving resistance have been identified, but treatment options available for patients have not improved”, said by Tabernero, researcher from American Association for Cancer Research.

According to Tabernero, Sym004 is a 1:1 mixture in the same infusion bag of two antibodies that bind to different regions of the extracellular domain of EGFR. Like anti-EGFR antibodies cetuximab and panitumumab, Sym004 antibodies block EGFR. But the double-targeting ability of EGFR by Sym004 will cause superior EGFR internalization and degradation, which is very likely to provide better outcomes than cetuximab or panitumumab.

Tabernero’ research involved 62 patients to participate in a phase I study. Among them, 20 patients with advanced solid epithelial tumors were enrolled to the dose-escalation phase of the study and received different doses of Sym004 weekly. Other 42 patients with metastatic colorectal cancer, previously treated with anti-EGFR antibodies with brief responses, were enrolled to the dose-expansion phase of the trial.

Result showed that of the patients in the dose-expansion cohort, five had a partial response, and overall, 17 had some degree of tumor shrinkage during treatment with Sym004. The overall disease-control rate, which includes partial responses and stable disease, was 67 percent.

The toxicity profile was consistent with the experience from FDA-approved anti-EGFR antibodies and was controlled with supportive care, dose delays, and reductions, according to Tabernero.

About Anti-EGFR Therapies
Anti-EGFR (epidermal growth factor receptor) therapies, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, demonstrate activity in a variety of tumor types. While both inhibit the EGFR pathway, they act via different mechanisms. Monoclonal antibodies bind to the extracellular domain of EGFR, preventing ligand binding and interrupting the signaling cascade. Tyrosine kinase inhibitors bind to the intracellular domain of EGFR and inhibit the downstream effects of EGFR ligand binding. Both categories of agents have been evaluated in a variety of clinical settings and tumor types, including colorectal cancer, non-small-cell lung cancer (NSCLC), and squamous cell carcinoma of the head and neck (SCCHN). Phase II/III trials in patients with previously treated or untreated metastatic colorectal cancer, including those with documented refractory disease, demonstrate activity of the monoclonal antibody cetuximab (Erbitux) as a single agent or in combination with both irinotecan (Camptosar)- and oxaliplatin (Eloxatin)-based chemotherapy.

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