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First-in-Class Antibody Mixture Shows Clinical Activity Against Treatment-Resistant Colorectal Cancer

Authors report 67% disease-control rate

Sym004 (Symphogen), an investigational mixture of two anti-epidermal growth factor receptor (EGFR) antibodies, was found to be clinically active in patients with advanced colorectal cancer that had become resistant to prior anti-EGFR therapies, according to a new study published in Cancer Discovery.

“This study represents one of the first examples of promising translation from preclinical findings to drug development and clinical activity against anti-EGFR antibody-resistant colorectal cancer,” said Josep Tabernero, MD, PhD, head of the medical oncology department at Vall d'Hebron Hospital in Barcelona, Spain. “The significant antitumor activity of Sym004 in patients whose tumors have become resistant to anti-EGFR therapies suggests that some colorectal cancers that progress after treatment with cetuximab or panitumumab [anti-EGFR therapies] remain dependent on EGFR signaling.”

Patients with advanced colorectal tumors without mutations in RAS genes derive substantial benefit from anti-EGFR therapies; however, the disease eventually progresses, leaving these patients with few alternative therapeutic options, Tabernero explained. Over the last decade, some of the mechanisms driving resistance have been identified, but despite intensive research, treatment options available for patients have not improved, he added.

“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,” Tabernero said.

Like the FDA-approved anti-EGFR antibodies cetuximab (Erbitux, Bristol-Myers Squibb/Eli Lilly) and panitumumab (Vectibix, Amgen), Sym004 antibodies block EGFR. However, the double-targeting of EGFR by Sym004 causes superior EGFR internalization and degradation, which is likely to provide better outcomes than cetuximab or panitumumab, he explained.

Tabernero and colleagues enrolled 62 patients in a  phase I study; 20 patients with advanced solid epithelial tumors entered the dose-escalation phase of the study and received different doses of Sym004 ranging from 0.4 mg/kg to 12 mg/kg, administered weekly. The remaining 42 patients had metastatic colorectal cancer and had previously been treated with anti-EGFR antibodies with brief responses. These patients entered the dose-expansion phase of the trial and received weekly doses of 9 mg/kg or 12 mg/kg of Sym004.

Of the patients in the dose-expansion cohort, five (13%) showed a partial response to treatment with Sym004, and 17 (44%) had some degree of tumor shrinkage, according to Tabernero. The overall disease-control rate, which included partial responses and stable disease, was 67%.

Tabernero said that the toxicity profile of Sym004 was consistent with that of FDA-approved anti-EGFR antibodies (grade-3 skin toxicity and low magnesium levels, among others) and was controlled with supportive care (i.e., topical and systemic antibiotics, and steroids), dose delays, and dose reductions.

In their article, Tabernero and his colleagues also discussed their preclinical experiments, which helped them establish that Sym004 could make colorectal cancer cells overcome acquired resistance to cetuximab.

Sources: AACR; May 11, 2015; and Cancer Discovery; May 11, 2015.

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