A phase 2 study of glembatumumab vedotin, an antibody‐drug conjugate targeting glycoprotein NMB, in patients with advanced melanoma

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.

Role of the kringle‐like domain in glycoprotein NMB for its tumorigenic potential

“…Glembatumumab vedotin, or CDX‐011, an Ab against GPNMB conjugated with an anticancer drug, has been developed to treat GPNMB‐expressing cancers and is in clinical trials for breast cancer and melanoma patients . This suggests the potential of GPNMB as a therapeutic target.…”

“…Glembatumumab vedotin, or CDX-011, an Ab against GPNMB conjugated with an anticancer drug, has been developed to treat GPNMB-expressing cancers and is in clinical trials for breast cancer and melanoma patients. 5,[40][41][42][43] This suggests the potential of GPNMB as a therapeutic target. From the findings of this study, we propose that specifically targeting the KLD in the ECD of GPNMB is a possible therapeutic target.…”

Patient Selection Strategies to Maximize Therapeutic Index of Antibody–Drug Conjugates: Prior Approaches and Future Directions

“…13-38; M. Williams, Table 3; refs. [39][40][41][42][43][44][45][46][47][48][49][50]. A positive association between target expression and clinical activity (target-response relationship; TRR) was based on findings where there was higher frequency of objective response rates (ORRs) in target-expressing patients.…”

A Novel Antibody-Drug Conjugate (ADC) Delivering a DNA Mono-Alkylating Payload to Chondroitin Sulfate Proteoglycan (CSPG4)-Expressing Melanoma

“…Although monoclonal antibodies recognizing T cell checkpoint ligands and receptors have significantly improved patient outcomes [8][9][10], treatments are often accompanied by high toxicities, and half of patients either do not respond or develop resistance [11,12]. Previous efforts to develop anti-melanoma ADCs include DEDN6526A (Seattle Genetics/Genentech) [13] targeted to the endothelin B receptor (ETBR) and glembatumumab vedotin (Celldex) [14] recognizing the transmembrane glycoprotein NMB (GPNMB), both carrying the antimitotic payload monomethyl auristatin E (MMAE, vedotin). These were not progressed beyond Phase I and Phase II trials, respectively [13][14][15], although other ADCs carrying MMAE payloads (e.g., brentuximab vedotin [Adcetris ® , Seattle Genetics] [16] and polatuzumab vedotin [Polivy © , Genentech] [17]) are approved to treat lymphomas.…”

“…Previous efforts to develop anti-melanoma ADCs include DEDN6526A (Seattle Genetics/Genentech) [13] targeted to the endothelin B receptor (ETBR) and glembatumumab vedotin (Celldex) [14] recognizing the transmembrane glycoprotein NMB (GPNMB), both carrying the antimitotic payload monomethyl auristatin E (MMAE, vedotin). These were not progressed beyond Phase I and Phase II trials, respectively [13][14][15], although other ADCs carrying MMAE payloads (e.g., brentuximab vedotin [Adcetris ® , Seattle Genetics] [16] and polatuzumab vedotin [Polivy © , Genentech] [17]) are approved to treat lymphomas. An ADC designed to target drug-resistant melanomas expressing the receptor tyrosine kinase AXL conjugated to MMAE (AXL-107-MMAE, Genmab) showed cooperative inhibition of melanoma growth when combined with BRAF/MEK inhibitors [18], highlighting the importance of targeting tumor vulnerabilities when designing ADCs.…”