A phase 2 study of glembatumumab vedotin, an antibody-drug conjugate targeting glycoprotein NMB, in patients with advanced melanoma
| Autor: | Lowell L. Hart, Lynn E. Spitler, April K.S. Salama, Omid Hamid, Neal Evan Rothschild, Yi He, Christopher D. Turner, Joshua Zhang, Jose Lutzky, Anna C. Pavlick, Jason J. Luke, Douglas B. Johnson, Patrick A. Ott, Jeffrey R. Infante, C. Lance Cowey, Rebecca G. Bagley, Aaron R. Alizadeh, Thomas Hawthorne |
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| Rok vydání: | 2018 |
| Předmět: |
Oncology
Adult Male Cancer Research medicine.medical_specialty Antibody-drug conjugate Immunoconjugates Skin Neoplasms Phases of clinical research Neutropenia Proto-Oncogene Mas 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Antineoplastic Agents Immunological Internal medicine Medicine Humans 030212 general & internal medicine Melanoma Aged Neoplasm Staging Proportional Hazards Models Aged 80 and over GPNMB Membrane Glycoproteins business.industry Antibodies Monoclonal Middle Aged medicine.disease Rash Progression-Free Survival Treatment Outcome chemistry Response Evaluation Criteria in Solid Tumors 030220 oncology & carcinogenesis Female medicine.symptom business Glembatumumab vedotin |
| Zdroj: | Cancer. 125(7) |
| ISSN: | 1097-0142 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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