The randomized, Phase IIb METRIC Study of glembatumumab vedotin, also known as CDX-011, an antibody-drug conjugate or ADC being developed by Celldex, compared to capecitabine (Xeloda®; Genentech/Roche) in patients with metastatic triple-negative breast cancers that overexpress gpNMB failed to meet its primary endpoint, progression-free survival (PFS) as assessed by an independent, central reading of patient scans (Hazard ratio = 0.95; median PFS: glembatumumab vedotin 2.9 months vs. Xeloda 2.8 months; p=0.76). [1]

Glembatumumab vedotin is a fully human monoclonal antibody-drug conjugate targeting glycoprotein NMB (gpNMB). This protein is overexpressed by multiple tumor types, including breast cancer, melanoma, lung cancer, uveal melanoma and osteosarcoma.

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.

Schematic 1.0: The main purpose of the METRIC study is to see whether  Glembatumumab Vedotin, an antibody-drug conjugate also known as CDX-011, is effective in treating patients who have advanced Triple-Negative Breast Cancer (TNBC), and whose tumor cells make a protein called glycoprotein NMB (gpNMB), which glembatumumab vedotin binds to. The study was also designed to further characterize the safety of CDX-011 treatment in this patient population.

The METRIC study is a randomized Phase IIb study of glembatumumab vedotin in patients with metastatic triple-negative breast cancers that overexpress gpNMB.

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In this indication, overexpression is defined as greater than or equal to 25% of tumor cells testing positive for gpNMB.

In this trial patients were randomized 2 to 1 to either glembatumumab vedotin or to capecitabine, as a comparator. In total, 327 patients were enrolled into METRIC. The primary endpoint of the study is progression-free survival (PFS), which is defined as the time from randomization to the earlier of disease progression, assessed based on an independent, central reading of patient scans, or death due to any cause. The study called for 203 progression events for evaluation of the primary endpoint. The sum of the data, including the secondary endpoints of response rate, overall survival, duration of response and safety, are also important in assessing clinical benefit.

No significant advantage
However, in the trial, researchers did not observe a significant advantage for glembatumumab vedotin in key secondary endpoints, including overall response rate, duration of response and overall survival.

The glembatumumab vedotin safety profile was consistent with prior experience.

“Triple-negative breast cancer is a very difficult disease to treat, and we are extremely disappointed for patients that the METRIC Study was not successful,” said Anthony Marucci, Co-founder, President and Chief Executive Officer of Celldex Therapeutics.

“I want to express our gratitude to the METRIC investigators, patients and families who participated in this study. Based on these results, we have also made the decision to discontinue the glembatumumab vedotin program across all indications and are currently prioritizing our pipeline, which includes five candidates in ongoing clinical studies,” Marucci added.

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