A phase 2 study of glembatumumab vedotin (GV), an
antibody-drug conjugate (ADC) targeting gpNMB, in
advanced melanoma
P.A. Ott1, A.C. Pavlick2, D.B. Johnson3, L.L. Hart4, J.R. Infante5, J.J. Luke6,
J. Lutzky7, N. Rothschild8, L. Spitler9, C.L. Cowey10, A. Alizadeh11, A. Salama12,
Y. He13, R.G. Bagley14, J. Zhang14, O. Hamid15
1
Melanoma Center & Center for Immuno-Oncology, Dana-Farber Cancer Institute,
Boston, MA, USA, 2
Department of Medicine, New York University School of
Medicine, New York, NY, USA, 3
Department of Medicine, Vanderbilt-Ingram
Cancer Center, Nashville, TN, USA, 4
Hematology/Oncology, Florida Cancer
Specialists, Ft. Myers, FL, USA, 5
Department of Medicine, Tennessee Oncology,
PLLC, Nashville, TN, USA, 6
Hematology/Oncology, University of Chicago,
Chicago, IL, USA, 7
Department of Medicine, Division of Hematology/Oncology,
Mount Sinai Comprehensive Cancer Center, Miami Beach, FL, USA, 8
Department
of Medicine, Florida Cancer Specialists, West Palm Beach, FL, USA, 9
Northern
California Melanoma Center, St. Mary’s Medical Center, San Francisco, CA, USA, 10Baylor Skin Malignancy & Treatment Center, Baylor University Medical Center,
Dallas, TX, USA, 11Central Research, Georgia Cancer Specialists, Decatur, GA,
USA, 12Department of Medicine, Duke University, Durham, NC, USA, 13Biostatistics, Celldex Therapeutics, Inc., Hampton, NJ, USA, 14Clinical Science,
Celldex Therapeutics, Inc., Hampton, NJ, USA, 15Department of Translational
Research/ImmunoOncology, The Angeles Clinic and Research Institute, Los
Angeles, CA, USA
Background: gpNMB is an internalizable transmembrane glycoprotein expressed in
multiple tumor types including melanoma. The ADC GV (CDX-011) delivers the
potent cytotoxin MMAE to gpNMB+ cells. GV has shown promising activity in
advanced melanoma and breast cancer (Ott JCO 2014; Yardley JCO 2015).
Methods: In this Phase 2 single-arm study (CDX011-05), efficacy and safety of GV
(1.9 mg/kg q3w) is assessed in advanced melanoma patients ( pts) with disease
progression after ≤1 chemotherapy, ≥1 checkpoint inhibitor, and if BRAF mutation
≥1 BRAF or MEK + BRAF inhibitor. gpNMB expression is determined retrospectively
by central IHC on archival tumor and/or pre-treatment tumor biopsy. Primary
endpoint is objective response rate (ORR) (RECIST 1.1) with ≥6 responders out of 52
evaluable pts as threshold for determining statistical positive outcome. Additional
endpoints include progression free survival and overall survival (PFS, OS) (95% CI),
duration of response (DOR), safety, pharmacodynamics, pharmacokinetics, and
correlation of outcome with gpNMB expression.
Results: Enrollment (n = 62) completed in April 2016: median age = 67 years; 55%
male; 21% BRAF mutation; 53% >2 lines prior therapy. Preliminary tumor response
data (n = 57 evaluable; 5 pts pending 1st response assessment): 1 complete response
(CR) and 7 partial response (PR [current confirmed ORR = 14%]); 1 single time-point
PR; 26 stable disease (SD) (duration 6-51+ weeks, 11 ongoing). Thus far, 50/51
evaluable pts had gpNMB+ tumors, and 38/51 had 100% of epithelial cells gpNMB+.
Toxicities include rash, alopecia, fatigue, neuropathy, nausea, neutropenia, decreased
appetite and diarrhea; rash may correlate with efficacy.
Conclusions: GV has shown promising activity including induction of partial and
complete responses in patients with heavily pre-treated melanoma. The safety profile is
manageable and consistent with cytotoxic treatment. DOR, PFS, OS, and correlation of
biomarkers with outcome will be analyzed on the mature dataset. An additional cohort
will be treated with GV in combination with varlilumab, an activating anti-CD27
monoclonal antibody, in order to evaluate safety and efficacy of the combination.
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