Antibody Mixture for Treatment-Resistant Colorectal Cancer

Antibody Mixture for Treatment-Resistant Colorectal Cancer

May 11, 2015

A mixture of antibodies against the epidermal growth factor receptor (EGFR) known as Sym004 (Symphogen), is clinically active in advanced colorectal cancer patients who are resistant to available anti-EGFR antibody therapies, according to the results of a study published in Cancer Discovery.

A mixture of antibodies against the epidermal growth factor receptor (EGFR) known as Sym004 (Symphogen), is clinically active in advanced colorectal cancer patients who are resistant to available anti-EGFR antibody therapies, according to the results of a study published in Cancer Discovery. The activity of this compound suggests that tumors continue to rely on EGFR signaling even upon acquiring resistance to other EGFR-directed therapies.1, 2

Thirteen percent of the patients had a partial response to therapy and 44% of patients overall had some tumor shrinkage upon treatment with Sym004. The disease control rate among the 39 patients evaluated, including partial response and stable disease, was 67%.

Sym004 is a one-to-one mixture of two recombinant human-mouse chimeric monoclonal antibodies against two distinct extracellular epitopes on the EGFR. The antibody mix is able to induce internalization of EGFR in cells, and has shown better tumor regression compared with other EGFR-targeted antibodies as well as activity against tumors that have resistance to cetuximab (Erbitux), a monoclonal antibody against EGFR that is approved by the US Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer that is KRAS wild-type.

Patients with metastatic colorectal cancer initially benefit from EGFR-targeted therapy if their tumors are wild-type for KRAS and NRAS. Preclinical studies show that tumors that acquire resistance to EGFR therapy still rely on EGFR signaling, even if the acquired resistance mutation is in a RAS gene.

Josep Tabernero, MD, PhD, head of the medical oncology department at Vall d’Hebron University Hospital and director of the Vall d’Hebron Institute of Oncology in Barcelona, Spain, and colleagues first demonstrated that the novel antibody mix has enhanced activity in vitro compared to cetuximab. According to Tabernero, Sym004 results in better EGFR internalization and degradation inside the cell compared to the two FDA-approved EGFR-targeting antibodies, cetuximab and panitumumab (Vectibix).

“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 Tabernero in a statement.

The current, first-in-human phase I study enrolled 62 patients, including 20 with solid tumors who took part in the dose-escalation portion of the trial, and 42 colorectal cancer patients previously treated with EGFR therapy who were part of the dose-expansion phase of the study. All 42 patients had previously responded to the EGFR-directed therapy followed by progression of advanced disease.

The safety profile for Sym0004 was similar that that seen for other anti-EGFR therapies currently used to treat colorectal patients, according to Tabernero. The most common adverse events that were drug related were rash (69%), dry skin (45%), hypomagnesemia (53%), pruritus (39%), mucosal inflammation (31%), and diarrhea (27%). Serious adverse events related to Sym004 occurred in 31% (11 of 36) patients.

Skin toxicity of at least grade 3 occurred in 50% of patients, and hypomagnesemia of at least grade 3 occurred in 21% of the patients. Both of these toxicities could be supported with topical and systemic antibiotics, steroids, as well as delays in doses and dose reductions.

“In this trial, we validated the EGFR pathway as an important target for therapeutic intervention in wild-type, KRAS-refractory metastatic colorectal cancer, even beyond cetuximab/panitumumab,” concluded the study authors.

Two additional trials are underway to assess the optimal dose and dosing schedule of Sym004 in patients with colorectal cancer.

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