Glembatumumab vedotin (CDX-011) is a fully-human monoclonal antibody-drug conjugate (ADC) that targets glycoprotein NMB (GPNMB). GPNMB is a protein overexpressed by multiple tumor types, including breast cancer and melanoma. GPNMB has been shown to be associated with the ability of the cancer cell to invade and metastasize and to correlate with reduced time to progression and survival in breast cancer. The GPNMB-targeting antibody, CR011, is linked to a potent cytotoxic, monomethyl auristatin E (MMAE), using Seattle Genetics’ proprietary technology. Glembatumumab vedotin is designed to be stable in the bloodstream, but to release MMAE upon internalization into GPNMB-expressing tumor cells, resulting in a targeted cell-killing effect. Glembatumumab vedotin is in development for the treatment of locally advanced or metastatic breast cancer—with an initial focus in triple negative disease. This program is also in development for the treatment of Stage III and IV melanoma.
Breast Cancers Expressing GPNMB
In late 2012, Celldex completed the Phase 2 EMERGE study in metastatic breast cancer. This exploratory study was prospectively designed to enable the Company to analyze if potential clinical benefit could be linked back to GPNMB expression levels. Final data from the study were presented at the 2012 San Antonio Breast Cancer Symposium and supported a clinical benefit in heavily pre-treated breast cancer patients with tumors that over-express GPNMB, quantified as expression in greater than 25% of tumor cells.
EMERGE: Overall Response Rate and Disease Control Data in Breast Cancer
EMERGE: Overall Survival and Progression Free Survival Data in Breast Cancer
Future Clinical Development: The METRIC Study in Triple Negative Breast Cancer
In December 2013, Celldex initiated a randomized, accelerated approval study (METRIC) evaluating Glembatumumab vedotin (CDX-011) in patients with GPNMB over-expressing triple negative breast cancer. Initial sites are now open to screen patients in the United States. Additional sites in the United States and in Canada and Australia will open in early 2014. The study is expected to include up to 100 sites and will randomize approximately 300 patients (2 to 1) with metastatic triple negative breast cancers that over-express GPNMB and who have previously received anthracyclines and taxanes. The study is a direct comparison of Glembatumumab vedotin versus capecitabine, also known by the trade name Xeloda®. The primary endpoints for this accelerated approval study will be overall response rate and progression free survival. The study is designed to enable Celldex to apply for registration with positive results for either endpoint. An interim analysis (futility assessment) will be conducted after the enrollment of the first 80 patients.
For more information on the Glembatumumab vedotin program, view recent scientific presentations and publications.
Xeloda is a registered trademark of Genentech, a member of the Roche Group.
Melanomas Expressing GPNMB
More than 85% of patients with metastatic melanoma express GPNMB, making it an attractive target for study of Glembatumumab vedotin. In 2010, data from a Phase 2 study of Glembatumumab vedotin were presented at the American Society of Clinical Oncology Annual Meeting which demonstrated significant activity in advanced melanoma patients. In the study, the primary activity endpoint of overall response rate (ORR) was achieved with an ORR of 15% (5/34). Median progression free survival (PFS) was 3.9 months. More frequent dosing schedules were evaluated in two additional, parallel dose-escalation arms in which patients received Glembatumumab vedotin weekly or twice every three weeks. At the maximum tolerated doses in these schedules, the response rate was observed to be 20% (n=15) and 33% (n=6), respectively. Preliminary data suggest an increase in PFS in patients with high tumoral GPNMB expression. The subset of seven patients, whose tumors were found to express high amounts of GPNMB, and who were treated at the maximum tolerated doses across all dosing schedules, demonstrated a median PFS of 4.9 months. The Company is planning to initiate a study evaluating Glembatumumab vedotin in metastatic melanoma in 2014.
In addition to triple negative breast cancer and metastatic melanoma, Celldex plans to evaluate Glembatumumab vedotin in other indications in which GPNMB is highly expressed, including squamous cell lung cancer and osteosarcoma.