Oncogene-targeted therapy is a major component of precision oncology, and although patients with metastatic melanoma have experienced improved outcomes with this strategy, there are a number of potential therapeutic targets currently under study that may further increase the drug armamentarium for this patient population. In this review, we discuss the landscape of targeted therapies for patients with advanced melanoma, focusing on oncogene mutation-specific targets. In patients with typical BRAF V600-mutant melanoma, combination BRAF and MEK inhibition has surpassed outcomes compared with monotherapy with BRAF or MEK inhibition alone, and current strategies seek to address inevitable resistance mechanisms. For patients with NRAS-mutant melanoma, MEK inhibitor monotherapy and combined MEK and CDK4/6 inhibition are burgeoning strategies; for patients with KIT-mutant melanoma, tyrosine kinase inhibition is being leveraged, and for NF-1-mutant melanoma, mTOR and MEK inhibition is being actively evaluated. In patients with atypical, non-V600 BRAF-mutant melanoma, MEK inhibitor monotherapy is the potential novel targeted approach on the horizon. For advanced uveal melanoma, novel targets such as IMCgp100 and glembatumumab have shown activity in early studies. We review additional strategies that remain in the preclinical and early clinical pipeline, so there is much hope for the future of targeted agents for distinct molecular cohorts of patients with advanced melanoma.

01 Jan 2016·Pediatric Blood & CancerQ3 · MEDICINE

Targeting Glycoprotein NMB With Antibody‐Drug Conjugate, Glembatumumab Vedotin, for the Treatment of Osteosarcoma

Q3 · MEDICINE

Article

Author: Houghton, Peter ; Geller, David ; Everts, Stephanie ; Gorlick, Richard ; Gill, Jonathan ; Barris, David M. ; Kolb, E. Anders ; Roth, Michael ; Piperdi, Sajida ; Hawthorne, Thomas ; Kuo, Vicky

BackgroundCure rates for children and young adults with osteosarcoma have remained stagnant over the past three decades. Targeting glycoprotein non‐metastatic b (GPNMB) with the antibody‐drug conjugate glembatumumab vedotin has improved outcomes for patients with melanoma and breast cancer. The potential utility of targeting GPNMB in osteosarcoma was explored.MethodsGPNMB protein expression was evaluated by immunohistochemistry in human osteosarcoma tumor samples and by enzyme‐linked immunosorbent assay (ELISA) in osteosarcoma cell lines. mRNA expression was measured by quantitative PCR in primary osteosarcoma samples and cell lines. Surface GPNMB expression was evaluated by flow cytometry and correlated with in vitro and in vivo cytotoxicity of glembatumumab vedotin.ResultsSixty seven human osteosarcoma samples were evaluated by immunohistochemistry, including 12 samples from initial biopsy, 38 samples from definitive surgery, and 17 from the time of disease recurrence. GPNMB was expressed in 92.5% (62/67) of osteosarcoma samples. All primary osteosarcoma samples expressed high levels of GPNMB mRNA. Glembatumumab induced cytotoxic effects in 74% (14/19) of osteosarcoma cell lines, and GPNMB protein levels correlated with glembatumumab in vitro cytotoxicity (r = −0.46, P = 0.04). All osteosarcoma cell lines demonstrated surface GPNMB expression.ConclusionsGPNMB is expressed in osteosarcoma and targeting GPNMB with the antibody‐drug conjugate glembatumumab vedotin demonstrates osteosarcoma cytotoxic activity. Clinical trials are indicated to assess the efficacy of targeting GPNMB in patients with osteosarcoma. Pediatr Blood Cancer 2015; 9999:1–7 © 2015 Wiley Periodicals, Inc.

01 Jun 2014·BioDrugsQ3 · MEDICINE

Management of Metastatic Breast Cancer with Second-Generation Antibody–Drug Conjugates: Focus on Glembatumumab Vedotin (CDX-011, CR011-vcMMAE)

Q3 · MEDICINE

Review

Author: Christos Vaklavas ; Andres Forero

Exploiting the highly targeted nature of monoclonal antibodies to deliver selectively to tumor cells a cytotoxic payload is an attractive concept and the successful precedents of the recent past set the stage for broader applications in the future. Antibody-drug conjugates may currently hold an unprecedented potential; however, there are multiple unique challenges in their development, and the recent successes have come hand in hand with significant technologic advances in their chemistry and manufacturing. Over the years, multiple factors have been identified to affect the pharmacokinetic and pharmacodynamic properties of an antibody-drug conjugate, but many important details remain to be further investigated. These factors pertain to the target antigen, antibody, conjugate, linker, as well as the nature of the malignancy under treatment. Glembatumumab vedotin is an antibody-drug conjugate targeting glycoprotein non-metastatic B (GPNMB) expressed in multiple malignancies, including breast cancer. The expression of this protein has been associated with an aggressive malignant phenotype, invasive growth, angiogenesis, and generation of skeletal metastases. Glembatumumab vedotin is currently in early stages of clinical development in melanoma and breast cancer. Although in unselected patients with metastatic breast cancer glembatumumab vedotin was not superior to other agents, by virtue of its target being frequently and highly expressed in triple-negative breast cancer, its activity was particularly promising in this subset of patients. Results from the clinical studies in breast cancer as well as companion studies in melanoma indicate that a biomarker-informed approach is the optimal pathway for the future development of this drug.

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASCO2009	Phase 1/2	Locally advanced breast cancer	10	CR011-vcMMAE 1.0 mg/kg	bpnfynqpgg(nkpvzkndrc) = gitwqmuaqt nyhzknwxca (dndigqeavl )	-	20 May 2009

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