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A phase 2 study of glembatumumab vedotin, an antibody‐drug conjugate targeting glycoprotein NMB, in patients with advanced melanoma
Author(s) -
Ott Patrick A.,
Pavlick Anna C.,
Johnson Douglas B.,
Hart Lowell L.,
Infante Jeffrey R.,
Luke Jason J.,
Lutzky Jose,
Rothschild Neal E.,
Spitler Lynn E.,
Cowey C. Lance,
Alizadeh Aaron R.,
Salama April K.,
He Yi,
Hawthorne Thomas R.,
Bagley Rebecca G.,
Zhang Joshua,
Turner Christopher D.,
Hamid Omid
Publication year - 2019
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.31892
Subject(s) - medicine , hazard ratio , melanoma , response evaluation criteria in solid tumors , antibody drug conjugate , phases of clinical research , oncology , rash , clinical endpoint , gastroenterology , pharmacology , confidence interval , clinical trial , antibody , immunology , cancer research , monoclonal antibody
Background Glembatumumab vedotin is an antibody‐drug conjugate that produced preliminary clinical activity against advanced melanoma in a phase 1 dose‐escalation trial. The objective of the current study was to investigate further the antitumor activity of glembatumumab vedotin at the recommended phase 2 dose in heavily pretreated patients with melanoma. Methods This single‐arm, phase 2 study enrolled patients with stage IV melanoma who were refractory to checkpoint inhibition and to B‐raf proto‐oncogene, serine/threonine kinase (BRAF)/mitogen‐activated protein kinase kinase (MEK) inhibition (in the presence of a BRAF valine mutation at codon 600). Patients received 1.9 mg/kg glembatumumab vedotin intravenously every 3 weeks until they developed disease progression or intolerance. The primary endpoint was objective response rate (ORR), which was determined according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression‐free survival (PFS), duration of response, overall survival (OS), safety, and clinical efficacy versus tumor glycoprotein NMB (gpNMB) expression. Tumor expression of gpNMB was assessed using immunohistochemistry. Results In total, 62 patients received treatment. The ORR was 11% and the median response duration was 6.0 months (95% confidence interval [CI], 4.1 months to not reached). The median PFS was 4.4 months (95% CI, 2.6‐5.5 months), and the median OS was 9.0 months (95% CI, 6.1‐11.7 months). For patients who developed rash during the first cycle versus those who did not, the ORR was 21% versus 7%, respectively, and there was an overall improvement in PFS (hazard ratio, 0.43; P = .013) and OS (hazard ratio, 0.43; P = .017). The most frequent adverse events were alopecia, neuropathy, rash, fatigue, and neutropenia. With one exception, all evaluable tumors were positive for gpNMB, and 46 of 59 tumors (76%) had 100% gpNMB‐positive epithelial cells. Conclusions Glembatumumab vedotin had modest activity and an acceptable safety profile in patients with advanced melanoma who were refractory to checkpoint inhibitors and MEK/BRAF inhibition. Treatment‐related rash may be associated with response.