Glembatumumab vedotin 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 published in the Journal of Clinical Oncology (Yardley 2015) 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 Study in Metastatic Breast Cancer: Efficacy Measures (Intent-to-Treat Population)
The METRIC Study in Triple Negative Breast Cancer
In December 2013, Celldex initiated a randomized study, called METRIC, evaluating glembatumumab vedotin in patients with gpNMB over-expressing triple negative breast cancer. Patients are currently being screened at sites in the United States, European Union, Canada and Australia. Approximately 300 patients are being randomized (2 to 1) with metastatic triple negative breast cancers that over-express gpNMB and who have received standard therapies, including anthracycline, if clinically indicated, and taxane treatments. The study is a direct comparison of glembatumumab vedotin versus capecitabine, also known by the trade name Xeloda®. The primary endpoint for this study is progression free survival. Please visit www.MetricStudy.com or clinicaltrials.gov for more information on this trial.
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 December 2014, the Company initiated an open-label Phase 2 study of glembatumumab vedotin in patients with unresectable Stage III or IV melanoma (n=60) and enrollment has been completed. In May 2016, we amended the protocol to add a second cohort of patients to a glembatumumab vedotin and varlilumab combination arm to assess the potential clinical benefit of the combination and to explore varlilumab’s potential biologic and immunologic effect when combined with an ADC. In November 2016, we amended the protocol again to add a third cohort of patients evaluating glembatumumab vedotin in combination with an approved checkpoint inhibitor (i.e., nivolumab or pembrolizumab) following progression on the checkpoint inhibitor alone. Both additional cohorts are open to enrollment. The primary endpoint for each cohort is ORR. Secondary endpoints include analyses of PFS, duration of response, OS, retrospective investigation of whether the anti-cancer activity of glembatumumab vedotin is dependent upon the degree of gpNMB expression in tumor tissue and safety of both the monotherapy and combination regimens.
We presented data from the single-agent cohort at the European Society for Medical Oncology (ESMO) Congress in October 2016. The cohort enrolled 62 evaluable patients with unresectable stage III (n=1; 2%) or stage IV (n=61; 98%) melanoma. All patients had progressed after checkpoint inhibitor therapy, and almost all patients had received both ipilimumab (n=58; 94%) and anti-PD-1/anti-PDL-1 (n=58; 94%) therapy. Twelve patients presented with BRAF mutation, and eleven had prior treatment with BRAF or BRAF/MEK targeted agents. The primary endpoint of the cohort (6 or more objective responses in the first 52 patients enrolled) was exceeded. Seven of 62 (11%) patients experienced a confirmed response, and an additional three patients also experienced single timepoint responses. The median duration of response was 6.0 months. A 52% disease control rate (patients without progression for greater than three months) was demonstrated and median PFS for all patients was 4.4 months. In addition, patients who experienced rash in the first cycle of treatment had a 20% confirmed response rate and a more prolonged PFS of 5.5 months [p=0.054; hazard rating=0.52 (0.27, 1.02)].
In addition to triple negative breast cancer and metastatic melanoma, glembatumumab vedotin is being evaluated in other indications in which gpNMB is highly expressed, including squamous cell lung cancer and uveal melanoma, through third-party sponsored studies.