New Monoclonal Antibody Shows Robust Efficacy onMany Advanced Solid Tumors
A Research in Its First Phase I Clinical Trial in Humans Have Demonstrated Its Encouraging Effect on Many Advanced Tumor Patients
Recently a new research results were reported at the24th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Dublin, Ireland on Nov. 7. It was about a newly developed antibody targeting a signaling pathway that was frequently active in solid tumors. The compound was a monoclonal antibody known as RG7212.The research has shown encouraging signs of efficacy in its first trial in humans.
The scientific chair of the EORTC-NCI-AACR Symposium, Professor Stefan Sleijfer commented, "Fn14 is a novel target for treatment in cancer. In view of their data, this drug certainly deserves further studies in Fn14 expressing tumors."
The new monoclonal antibody—RG7212 targets a soluble protein in the blood called TWEAK (Tumor Necrosis Factor (TNF)-like weak inducer of apoptosis. TWEAK binds to the receptor Fn14 (fibroblast growth factor-inducible 14) on the cell membrane, and this is the signal for a cascade of subsequent events, including activation of multiple cancer-promoting pathways. TWEAK and Fn14 are a pair of cell signaling molecules that are part of the large family of TNF that play various roles in the development of cancer. The Fn14-receptor will have over-expression in at least 30% of solid tumors, including pancreatic cancer, breast cancer, non-small cell lung cancer and malignant melanoma and signaling through TWEAK-Fn14 enhances multiple processes associated with malignancy.Researchers wanted to know whether blocking of TWEAK-Fn14 signaling with RG7212 would reduce activation of these pathways.
Preclinical data have shown that the RG7212 monoclonal antibody successfully targeted and blocked the action of TWEAK and that it worked most effectively in tumor cells where there was increased Fn14 expression. Therefore, researchers expected that using RG7212 to block TWEAK signaling in patients whose tumors express Fn14 might prevent cancer cells from growing and proliferating.
From July 2011, Dr. Lassen, the head of oncology clinical unit, and his colleagues recruited 38 patients with treatment-refractory solid tumors to the phase I trial, including NSCLC, melanoma, mesothelioma, breast cancer, renal cell carcinoma, and biliary tract cancer. All patients had tumors expressing the Fn14 receptor. They received an intravenous dose of RG7212 either once weekly or once every three weeks, with a dose range of 200 to 3600 mg. A patient with advanced malignant melanoma has shown signs of tumor shrinkage and has been receiving treatment for more than 30 weeks without any serious adverse side-effects. A patient with heavily pre-treated, metastatic melanoma with no mutation in the BRAF gene has shown evidence of tumor regression when scanned using computerized tomography (CT) and remains on study after more than 30 weeks of treatment. Four other patients have had partial metabolic responses confirmed by positron emission tomography (PET) scans.Prolonged stable disease has been seen in several patients. Overall, 11 of the 38 patients (29%) have received more than 12 weeks of study treatment, with several receiving 18 or more weeks of RG7212 therapy.
&Dr Lassen said, “We have gained the encouraging pharmacodynamics data, including durable inhibition of TWEAK, inhibition of signaling pathways controlled by Fn14, and inhibition of tumor cell proliferation.We found that RG7212 has an excellent safety profile across a broad dose range on each schedule. We saw no dose-limiting toxicities and no patient discontinued study treatments for treatment-related adverse side-effects. The phase I data show that RG7212 is quite safe for multi-cycle administration in patients with advanced cancer. Results from tests of blood and tumor samples suggest that it would be feasible to administer the drug over a prolonged period of time. These results are encouraging and support additional studies of RG7212 in combination with other treatments.”
Now the study investigators from four leading cancer research centers in Denmark, The Netherlands and Canada are recruiting patients to the trial, particularly those with advanced metastatic melanoma expressing Fn14.
Tags: Monoclonal Antibody, Signaling Pathway, Tumor Growth, Fn14, RG7212