Researchers have, in the last decades, made major advances in the development of therapies for breast cancer by identifying key markers known to drive the growth of most of these cancers, include the hormones estrogen(ER+) and progesterone (PR+) and the protein human epidermal growth factor receptor 2 or HER2.
Based on these advances, researchers have successfully developed various targeting therapies specific to those markers. However, none of these markers are found for patients diagnosed with triple negative breast cancer. This makes triple negative beast cancer more difficult to treat. In addition, the disease is also known to be more aggressive and more likely to recur than other subtypes of breast cancer.
Poor prognostic marker
Glycoprotein NMB, also known as gpNMB, is an internalizable transmembrane protein over-expressed by multiple tumor types, including in approximately 20% of breast cancer and melanoma. It is a poor prognostic marker associated with tumor invasion, metastasis, angiogenesis and reduced time to progression and survival. Approximately 40% of triple-negative breast cancer show over-expression of gpNMB.
Glembatumumab vedotin (CDX-11), a novel, gpNMB-targeting, antibody-drug conjugate or ADC is linked to a potent cytotoxic, monomethyl auristatin E (MMAE), a toxin designed to kill cancer. The linker-MMAE technology is the same as the proprietary technology that is successfully used in brentuximab vedotin (Adcetris; Seattle Genetics).
The drug is being investigated for the treatment of patients with a number of solid cancers, including locally advanced or metastatic breast cancer, with an initial focus in triple negative disease, and for the treatment of Stage III and IV melanoma. The drug is being developed by Celldex therapeutics.
The investigational agent is designed to be stable in the bloodstream, but to release monomethyl auristatin E upon internalization into gpNMB-expressing tumor cells, resulting in a targeted cell-killing effect.
In May 2010, the U.S. Food and Drug Administration (FDA) granted Fast Track designation for glembatumumab vedotin.
Data from the phase II EMERGE study, designed to examine whether anti-cancer activity of glembatumumab vedotin is dependent upon distribution and/or intensity of gpNMB expression, presented during the 2012 San Antonio Breast Cancer Symposium (SABCS), confirmed promising activity of glembatumumab vedotin in the treatment of patients with triple-negative breast cancer. These results supported an overall survival benefit in specific sub-groups of breast cancer patients with tumors that over-express gpNMB. Treatment of patients with both triple negative breast cancer and over-expression of gpNMB showed a high overall response rate (ORR) of 33% when treated with glembatumumab vedotin. In comparison, these researchers found no responses in patients with both triple negative breast cancer and over-expression of gpNMB treated with standard chemotherapies.
The data confirmed that glembatumumab vedotin was well-tolerated with the most frequent treatment-related toxicities consisting of rash, neutropenia, and neuropathy.
In additional subset analyses of the EMERGE trial, objective response rate was 30% (7/23) for glembatumumab vedotin vs. 9% (1/11) for investigator’s choice in tumors with gpNMB-overexpression (>25% of tumor epithelium); 18% (5/28) vs. 0% (0/11) in triple-negative breast cancer; and 40% (4/10) vs. 0% (0/6) in gpNMB-overexpressing triple-negative breast cancer for glembatumumab vedotin and IC respectively. This trial also showed apparent improvements in progression-free survival (PFS; hazard ratio (HR) = 0.11) and overall survival (OS; HR = 0.14).
While the EMERGE trial was not powered to demonstrate statistical significance between the arms, beneficial activity in targeted patient populations that highly expressed gpNMB was consistently observed and, in some cases, was statistically significant.
These impressive response rates were uniquely observed in patients with heavily-pretreated metastatic disease, where physicians typically have little expectation of clinical response. The promising results supported initiation of the METRIC study in patients with gpNMB overexpressing triple-negative breast cancer.
Ongoing trials: The METRIC Trial
The METRIC Trial (NCT01997333) is an international, two-arm phase II study in which patients are randomized 2:1 to glembatumumab vedotin (1.88 mg/kg IV q 21 days) or capecitabine, a current standard of care for this population (2,500 mg/m2 daily for d1-14, q21 days) until progression or intolerance. Crossover in trial is not permitted.
To be eligibility to participate in this trial, patients must meet criteria including >25% of tumor epithelium gpNMB+ by central immunohistochemistry (IHC) screening of archival tissue; estrogen receptor and progesterone receptor <10% and HER2 negative [0-1+ IHC, or ISH copy number <4.0/ratio <2.0] by local assessment; ECOG 0-1; taxane resistance; anthracycline exposure (if indicated); <2 chemotherapy regimens for advanced BC; measurable disease; no persistent Grade >2 toxicity.
Statistical methods and target accrual
The trial has 85% power to detect a PFS HR of 0.64 with two sided α = 0.05. The hypothesized median progression-free survival is 4.0 months for capecitabine and 6.25 months for GV. Target accrual is open for 300 patients.
In addition to an ongoing METRIC study in metastatic triple-negative breast cancer overexpressing gpNMB and an ongoing study in advanced melanoma, additional studies are planned in osteosarcoma, uveal melanoma, and squamous cell lung cancer. The study is being conducted at approximately 100 sites in US, Canada, and Australia.
During the 2015 SABCS an review of ongoing clinical trials in targeted therapies included a update of glembatumumab vedotin.