PMID- 29533458 OWN - NLM STAT- MEDLINE DCOM- 20190911 LR - 20190911 IS - 1097-0142 (Electronic) IS - 0008-543X (Print) IS - 0008-543X (Linking) VI - 124 IP - 10 DP - 2018 May 15 TI - Efficacy and safety results of depatuxizumab mafodotin (ABT-414) in patients with advanced solid tumors likely to overexpress epidermal growth factor receptor. PG - 2174-2183 LID - 10.1002/cncr.31304 [doi] AB - 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. Cancer 2018;124:2174-83. (c) 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. CI - (c) 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. FAU - Goss, Glenwood D AU - Goss GD AUID- ORCID: 0000-0002-5316-1022 AD - The Ottawa Hospital Research Institute and the University of Ottawa, Ottawa, Ontario, Canada. FAU - Vokes, Everett E AU - Vokes EE AD - Department of Medicine, University of Chicago, Chicago, Illinois. FAU - Gordon, Michael S AU - Gordon MS AD - HonorHealth Research Institute, Scottsdale, Arizona. FAU - Gandhi, Leena AU - Gandhi L AD - New York University Perlmutter Cancer Center, NYU Health, New York, New York. FAU - Papadopoulos, Kyriakos P AU - Papadopoulos KP AD - South Texas Accelerated Research Therapeutics, San Antonio, Texas. FAU - Rasco, Drew W AU - Rasco DW AD - South Texas Accelerated Research Therapeutics, San Antonio, Texas. FAU - Fischer, JuDee S AU - Fischer JS AD - AbbVie, Inc, North Chicago, Illinois. FAU - Chu, Katharine L AU - Chu KL AD - AbbVie, Inc, North Chicago, Illinois. FAU - Ames, William W AU - Ames WW AD - AbbVie, Inc, North Chicago, Illinois. FAU - Mittapalli, Rajendar K AU - Mittapalli RK AD - AbbVie, Inc, North Chicago, Illinois. FAU - Lee, Ho-Jin AU - Lee HJ AD - AbbVie, Inc, North Chicago, Illinois. FAU - Zeng, Jiewei AU - Zeng J AD - AbbVie, Inc, North Chicago, Illinois. FAU - Roberts-Rapp, Lisa A AU - Roberts-Rapp LA AD - AbbVie, Inc, North Chicago, Illinois. FAU - Loberg, Lise I AU - Loberg LI AD - AbbVie, Inc, North Chicago, Illinois. FAU - Ansell, Peter J AU - Ansell PJ AD - AbbVie, Inc, North Chicago, Illinois. FAU - Reilly, Edward B AU - Reilly EB AD - AbbVie, Inc, North Chicago, Illinois. FAU - Ocampo, Christopher J AU - Ocampo CJ AD - AbbVie, Inc, North Chicago, Illinois. FAU - Holen, Kyle D AU - Holen KD AD - AbbVie, Inc, North Chicago, Illinois. FAU - Tolcher, Anthony W AU - Tolcher AW AD - South Texas Accelerated Research Therapeutics, San Antonio, Texas. LA - eng SI - ClinicalTrials.gov/NCT01800695 PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180313 PL - United States TA - Cancer JT - Cancer JID - 0374236 RN - 0 (ABT-414) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Immunoconjugates) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Adult MH - Antibodies, Monoclonal, Humanized/*administration & dosage/adverse effects/pharmacokinetics MH - Dose-Response Relationship, Drug MH - Drug Administration Schedule MH - ErbB Receptors/antagonists & inhibitors/genetics/metabolism MH - Fatigue/chemically induced/*epidemiology MH - Female MH - Follow-Up Studies MH - Gene Amplification MH - Humans MH - Immunoconjugates/*administration & dosage/adverse effects/pharmacokinetics MH - Infusions, Intravenous MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Neoplasm Staging MH - Neoplasms/*drug therapy/genetics/pathology MH - Treatment Outcome MH - Vision Disorders/chemically induced/*epidemiology PMC - PMC5969257 OTO - NOTNLM OT - ABT-414 OT - antibody-drug conjugate OT - depatuxizumab mafodotin (depatux-m) OT - epidermal growth factor receptor (EGFR) EDAT- 2018/03/14 06:00 MHDA- 2019/09/12 06:00 PMCR- 2018/05/25 CRDT- 2018/03/14 06:00 PHST- 2017/11/28 00:00 [received] PHST- 2018/01/29 00:00 [revised] PHST- 2018/01/31 00:00 [accepted] PHST- 2018/03/14 06:00 [pubmed] PHST- 2019/09/12 06:00 [medline] PHST- 2018/03/14 06:00 [entrez] PHST- 2018/05/25 00:00 [pmc-release] AID - CNCR31304 [pii] AID - 10.1002/cncr.31304 [doi] PST - ppublish SO - Cancer. 2018 May 15;124(10):2174-2183. doi: 10.1002/cncr.31304. Epub 2018 Mar 13.