First-in-Class Antibody Mixture Shows Clinical Activity Against Treatment-Resistant, Advanced Colorectal Cancer
Patients with advanced colorectal tumors without mutations in the RAS genes derive substantial benefit from anti-EGFR (epidermal growth factor receptor) therapies; however, the disease eventually progresses, leaving these patients with few alternative therapeutic options. Over the past decade, some of the mechanisms driving resistance have been identified, but despite intensive research, treatment options available for patients have not improved. International researchers have found a mixture that may provide hope for these patients, according to a study published by Dienstmann et al in Cancer Discovery.
Study Details
Sym004 is a 1:1 mixture of two antibodies that bind to different regions of the extracellular domain of EGFR, according to lead investigator Josep Tabernero, MD, PhD, of the Vall d'Hebron Institute of Oncology. Like the U.S. Food and Drug Administration–approved anti-EGFR antibodies cetuximab (Erbitux) and panitumumab (Vectibix), Sym004 antibodies block EGFR. However, the double-targeting of EGFR by Sym004 causes superior EGFR internalization and degradation, which may provide better outcomes than cetuximab or panitumumab, he explained.
Dr. Tabernero and colleagues enrolled 62 patients in a phase I study. Twenty patients with advanced solid epithelial tumors were enrolled to 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, and were enrolled to the dose-expansion phase of the trial. Patients in the dose-expansion cohort received weekly doses of 9 mg/kg or 12 mg/kg of Sym004.
Treatment Effectiveness
Of the patients in the dose-expansion cohort, 5 (13%) had a partial response, and overall, 17 (44%) had some degree of tumor shrinkage during treatment with Sym004. The overall disease-control rate was 67%.
Dr. Tabernero said that the toxicity profile was consistent with the experience from FDA-approved anti-EGFR antibodies (grade 3 skin toxicity and low magnesium levels, among others) and that adverse events were controlled with supportive care (topical and systemic antibiotics, and steroids), dose delays, and dose reductions.
Dr. Tabernero said, “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. 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.”
This study was supported by Symphogen A/S and Merck KGaA.
Dr. Tabernero is the corresponding author of the Cancer Discovery article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
