Philadelphia: Sym004, a 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 study published in Cancer Discovery, a journal of the American Association for Cancer Research.
“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 University Hospital
and director of the Vall d’Hebron Institute of Oncology 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 the RAS genes
derive substantial benefit from anti-EGFR therapies; however, the
disease eventually progresses, leaving these patients with few
alternative therapeutic options, explained Tabernero. 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 U.S. Food
and Drug Administration (FDA)-approved anti-EGFR antibodies cetuximab
and panitumumab, 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 to a phase I study;
20 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.
Of the patients in the dose-expansion cohort, five (13
percent) had a partial response, and overall, 17 (44 percent) had some
degree of tumor shrinkage during treatment with Sym004, according to
Tabernero. The overall disease-control rate, which includes partial
responses and stable disease, was 67 percent.
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 was controlled with supportive care
(topical and systemic antibiotics, and steroids), dose delays, and
reductions.
In this research article, Tabernero and colleagues
also discussed their preclinical experiments which helped them establish
that Sym004 could make colorectal cancer cells overcome acquired
resistance to cetuximab.
This study was funded by Symphogen A/S
and Merck KGaA. Tabernero is a consultant/advisory board member for
Amgen, Imclone, Lilly, Merck KGaA, Millennium, Novartis, Roche, Sanofi,
Celgene, Chugai, Taiho, and Symphogen A/S.