Date: 2014-09-30
Type of information: Publication of results in a medical journal
phase: 1,2
Announcement: publication of results in the Journal of Clinical Oncology (JCO)
Company: Celldex Therapeutics (USA - NJ)
Product: glembatumumab vedotin
Action
mechanism: Glembatumumab vedotin (CDX-011) is a fully-human monoclonal antibody-drug conjugate (ADC) that targets glycoprotein NMB (gpNMB), a transmembrane protein that is expressed in subcellular compartments and on the surface of multiple cell types. A number of cancers, including breast cancer, cutaneous and uveal melanoma, small cell lung cancer, osteosarcoma, renal cell cancer and glioblastoma overexpress gpNMB relative to normal tissue. Overexpression of gpNMB has been shown to promote the invasion and metastasis of hepatocellular carcinoma, glioma and breast cancer cells, decrease tumor cell apoptosis and promote angiogenesis in preclinical models. gpNMB expression has also been associated with poor clinical outcomes in small cell lung cancer, renal cell cancer, glioblastoma and breast cancer. Glembatumumab vedotin is produced by covalently linking a fully human immunoglobulin G2 monoclonal antibody against gpNMB (CR011) to monomethyl auristatin E (MMAE), a potent mitotic spindle formation inhibitor. Glembatumumab vedotin binds to gpNMB on tumor cells and, after internalization, releases MMAE, which, in turn, inhibits mitosis, leading to cell death and apoptosis. The MMAE toxin may also be released by dying cells into the tumor microenvironment, resulting in the "bystander effect" of killing neighboring tumor cells.
Disease: breast cancer
Therapeutic area: Cancer - Oncology
Country:
Trial details:
Latest
news: * On September 30, 2014, Celldex Therapeutics announced the publication of a paper highlighting early studies of glembatumumab vedotin in breast cancer in the Journal of Clinical Oncology (JCO). The paper "A Phase 1/2 Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Patients with Locally Advanced or Metastatic Breast Cancer" has been published as Early Release Articles on JCO's website and will appear in a future print edition. The article, "A Phase 1/2 Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Patients with Locally Advanced or Metastatic Breast Cancer," presents results from a Phase 1 dose escalation study and an open-label Phase 2 expansion study. The primary objectives of the study were to evaluate safety and determine the recommended Phase 2 dose in locally advanced and metastatic breast cancer. The primary efficacy endpoint of the study was progression-free survival of greater than or equal to 30% at twelve weeks (PFS12). A total of 42 patients were enrolled, including 34 patients (six in dose escalation; 28 in expansion) treated at the 1.88 mg/kg dose (the "Phase 2 dose"), which was the pre-defined maximum dose, based on the experience in melanoma. Fatigue, rash, nausea, peripheral sensory neuropathy and neutropenia were the most frequent adverse events. Patients were heavily pretreated (median of seven prior anti-cancer regimens). PFS12 was 33% for the 27 evaluable patients treated in the Phase 2 expansion cohort. For secondary efficacy analyses, these 27 patients were pooled with the six additional patients treated at the Phase 2 dose (1.88 mg/kg) in the dose-escalation study portion. For all 33 evaluable patients treated at the Phase 2 dose, PFS12 was 36% and ORR was 12% (6% confirmed). Analyses of gpNMB expression was performed for 15 patients treated at the Phase 2 dose. Because this was the first clinical investigation targeting gpNMB in breast cancer, a positive result was defined by using a standard threshold of greater than or equal to 5% of epithelial or stromal cells expressing gpNMB. In this small sample, 80% were considered positive. All showed predominately stromal expression of gpNMB. Four patients had tumors with gpNMB expression in the epithelial compartment as well, although all had expression in less than 20% of epithelial cells. No responses were seen in the three patients with gpNMB-negative samples. Two patients who were gpNMB-positive experienced a confirmed durable PR. Expression of gpNMB was not assessed for an additional two patients that experienced a transient response. Ten evaluable patients treated at the Phase 2 dose had triple negative breast cancer (TNBC), as determined by local testing. In this population the ORR was 20% (10% confirmed), and PFS12 was 60%. All four patients who had both TNBC and gpNMB-positive tumors remained progression-free at 12 weeks. At the Phase 2 dose, median PFS was 9.1 weeks for all patients, 17.9 weeks for patients with TNBC, and 18.0 weeks for patients with gpNMB-positive tumors. Subsequent Development in Breast Cancer:
After completing the Phase 1/2 study, a randomized Phase 2 study (EMERGE) was conducted in patients with advanced, gpNMB-expressing, heavily pretreated breast cancer to confirm and better characterize glembatumumab vedotin's activity in relation to distribution and intensity of gpNMB expression. Subgroup analyses in EMERGE suggested the greatest benefit from glembatumumab vedotin in patients whose tumors overexpressed gpNMB in 25% of epithelial cells, informing the threshold of 25% or greater gpNMB overexpression for future studies in breast cancer. Improved response rate and overall survival in patients with TNBC was also observed. A pivotal Phase 2 trial, the METRIC Study, is currently underway in patients (n=300) with metastatic, gpNMB overexpressing TNBC. These patients are randomly assigned (2:1) to receive glembatumumab vedotin or capecitabine.
