Efficacy and Safety Results of Depatuxizumab Mafodotin (ABT-414) in Patients With Advanced Solid Tumors Likely to Overexpress Epidermal Growth Factor Receptor

被引:51
作者
Goss, Glenwood D. [1 ,2 ]
Vokes, Everett E. [3 ]
Gordon, Michael S. [4 ]
Gandhi, Leena [5 ]
Papadopoulos, Kyriakos P. [6 ]
Rasco, Drew W. [6 ]
Fischer, JuDee S. [7 ]
Chu, Katharine L. [7 ]
Ames, William W. [7 ]
Mittapalli, Rajendar K. [7 ]
Lee, Ho-Jin [7 ]
Zeng, Jiewei [7 ]
Roberts-Rapp, Lisa A. [7 ]
Loberg, Lise I. [7 ]
Ansell, Peter J. [7 ]
Reilly, Edward B. [7 ]
Ocampo, Christopher J. [7 ]
Holen, Kyle D. [7 ]
Tolcher, Anthony W. [6 ,8 ]
机构
[1] Ottawa Hosp, Res Inst, Ottawa, ON, Canada
[2] Univ Ottawa, Ottawa, ON, Canada
[3] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA
[4] HonorHlth Res Inst, Scottsdale, AZ USA
[5] NYU, Perlmutter Canc Ctr, NYU Hlth, New York, NY USA
[6] South Texas Accelerated Res Therapeut, San Antonio, TX USA
[7] AbbVie Inc, N Chicago, IL USA
[8] NEXT Oncol, San Antonio, TX USA
关键词
ABT-414; antibody-drug conjugate; epidermal growth factor receptor (EGFR); depatuxizumab mafodotin (depatux-m); ANTIBODY; DRUG; ABT-806;
D O I
10.1002/cncr.31304
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
BACKGROUND: Epidermal growth factor receptor (EGFR) alterations are associated with multiple cancers. Current EGFR-directed therapies have led to increased efficacy but are associated with specific side effects. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) targets EGFR with a monoclonal antibody linked to a cytotoxin, and is highly tumor-specific. METHODS: This phase 1/2 study evaluated the safety, pharmacokinetics, and efficacy of depatux-m in patients who had advanced solid tumors with known wild-type EGFR overexpression, amplification, or mutated EGFR variant III. A 3 + 3 dose escalation was used, and 2 dosing schedules were evaluated. Depatux-m also was manufactured under an alternate process to reduce the drug load and improve the safety profile, and it was tested at the maximum tolerated dose (MTD). In another cohort, prolonged infusion time of depatux-m was evaluated; and a cohort with confirmed EGFR amplification also was evaluated at the MTD. RESULTS: Fifty-six patients were treated. The MTD and the recommended phase 2 dose for depatux-m was 3.0 mg/kg. Common adverse events (AEs) were blurred vision (48%) and fatigue (41%). A majority of patients (66%) experienced 1 or more ocular AEs. Grade 3 or 4 AEs were observed in 43% of patients. One patient with EGFR-amplified, triple-negative breast cancer had a partial response. Stable disease was observed in 23% of patients. Pharmacokinetics revealed that depatux-m exposures were approximately dose-proportional. CONCLUSIONS: Depatux-m resulted in infrequent nonocular AEs but increased ocular AEs. Patient follow-up confirmed that ocular AEs were reversible. Lowering the drug-antibody ratio did not decrease the number of ocular AEs. A partial response in 1 patient with EGFR-amplified disease provides the opportunity to study depatux-m in diseases with a high incidence of EGFR amplification. (C) 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
引用
收藏
页码:2174 / 2183
页数:10
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