Patrick A Ott1, Anna C Pavlick2, Douglas B Johnson3, Lowell L Hart4, Jeffrey R Infante5, Jason J Luke6, Jose Lutzky7, Neal E Rothschild8, Lynn E Spitler9, C Lance Cowey10, Aaron R Alizadeh11, April K Salama12, Yi He13, Thomas R Hawthorne13, Rebecca G Bagley13, Joshua Zhang13, Christopher D Turner13, Omid Hamid14. 1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. 2. Department of Medical Oncology, New York University School of Medicine, New York, New York. 3. Department of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. 4. Florida Cancer Specialists and Research Institute, Fort Myers, Florida. 5. Tennessee Oncology, PLLC, Nashville, Tennessee. 6. Department of Hematology/Oncology, University of Chicago Medical Center, Chicago, Illinois. 7. Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida. 8. Florida Cancer Specialists, West Palm Beach, Florida. 9. St. Mary's Medical Center, San Francisco, California. 10. Northern California Melanoma Center, Baylor University Medical Center, Dallas, Texas. 11. Northside Hospital Cancer Institute, Decatur, Georgia. 12. Department of Medical Oncology, Duke University, Durham, North Carolina. 13. Celldex Therapeutics, Inc, Hampton, New Jersey. 14. The Angeles Clinic and Research Institute, Los Angeles, California.
Abstract
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.
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.
Authors: M Liguori; E Digifico; A Vacchini; R Avigni; F S Colombo; E M Borroni; F M Farina; S Milanesi; A Castagna; L Mannarino; I Craparotta; S Marchini; E Erba; N Panini; M Tamborini; V Rimoldi; P Allavena; C Belgiovine Journal: Cell Mol Immunol Date: 2020-07-29 Impact factor: 11.530
Authors: Marco Biondini; Alex Kiepas; Leeanna El-Houjeiri; Matthew G Annis; Brian E Hsu; Anne-Marie Fortier; Geneviève Morin; José A Martina; Isabelle Sirois; Adriana Aguilar-Mahecha; Tina Gruosso; Shawn McGuirk; April A N Rose; Unal M Tokat; Radia M Johnson; Ozgur Sahin; Eric Bareke; Julie St-Pierre; Morag Park; Mark Basik; Jacek Majewski; Rosa Puertollano; Arnim Pause; Sidong Huang; Tibor Keler; Peter M Siegel Journal: Oncogene Date: 2022-02-02 Impact factor: 8.756