PMID- 29075855 OWN - NLM STAT- MEDLINE DCOM- 20171201 LR - 20210109 IS - 1432-0843 (Electronic) IS - 0344-5704 (Print) IS - 0344-5704 (Linking) VI - 80 IP - 6 DP - 2017 Dec TI - Efficacy of depatuxizumab mafodotin (ABT-414) monotherapy in patients with EGFR-amplified, recurrent glioblastoma: results from a multi-center, international study. PG - 1209-1217 LID - 10.1007/s00280-017-3451-1 [doi] AB - PURPOSE: Patients with recurrent glioblastoma (rGBM) have a poor prognosis. Epidermal growth factor receptor (EGFR) gene amplification is present in ~ 50% of glioblastomas (GBMs). Depatuxizumab mafodotin (depatux-m), formerly ABT-414, is an antibody-drug conjugate that preferentially binds cells with EGFR amplification, is internalized and releases a potent antimicrotubule agent, monomethyl auristatin F (MMAF). Here we report the safety, pharmacokinetics, and efficacy of depatux-m monotherapy at the recommended Phase 2 dose (RPTD) in patients with EGFR-amplified, rGBM. METHODS: M12-356 (NCT01800695) is an open-label study with three escalation and expansion cohorts. Sixty-six patients with EGFR-amplified, rGBM were treated with depatux-m monotherapy at 1.25 mg/kg intravenously every 2 weeks. Adults with measurable rGBM, who were bevacizumab-naive, with EGFR amplification were eligible. RESULTS: Among 66 patients, median age was 58 years (range 35-80). All patients were previously treated with radiotherapy/temozolomide. The most common adverse events (AEs) were eye related (91%), including blurred vision (65%), dry eye (29%), keratitis, and photophobia (27% each). Grade 3/4 AEs occurred in 42% of all patients, and ocular Grade 3/4 AEs occurred in 33% of patients overall. One patient (2%) had a Grade 4 ocular AE. Ocular AEs were manageable and usually resolved once treatment with depatux-m ceased. The objective response rate was 6.8%, the 6-month progression-free survival rate was 28.8%, and the 6-month overall survival rate was 72.5%. CONCLUSION: Depatux-m monotherapy displayed frequent but mostly Grade 1/2 ocular toxicities. A PFS6 of 28.8% was observed in this rGBM population, warranting further study. FAU - van den Bent, Martin AU - van den Bent M AD - Brain Tumor Center, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA, Rotterdam, the Netherlands. m.vandenbent@erasmusmc.nl. FAU - Gan, Hui K AU - Gan HK AD - School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia. AD - Department of Medicine, University of Melbourne, Melbourne, VIC, Australia. FAU - Lassman, Andrew B AU - Lassman AB AD - Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA. FAU - Kumthekar, Priya AU - Kumthekar P AD - Northwestern University, Chicago, IL, USA. FAU - Merrell, Ryan AU - Merrell R AD - NorthShore University Health System, Evanston, IL, USA. FAU - Butowski, Nicholas AU - Butowski N AD - Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. FAU - Lwin, Zarnie AU - Lwin Z AD - Department of Medical Oncology, School of Medicine, University of Queensland, Royal Brisbane and Women's Hospital, Brisbane, Australia. FAU - Mikkelsen, Tom AU - Mikkelsen T AD - Henry Ford Health System, Detroit, MI, USA. FAU - Nabors, Louis B AU - Nabors LB AD - University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Papadopoulos, Kyriakos P AU - Papadopoulos KP AD - South Texas Accelerated Research Therapeutics (START), San Antonio, TX, USA. FAU - Penas-Prado, Marta AU - Penas-Prado M AD - The University of Texas MD Anderson Cancer Center, Houston, TX, USA. FAU - Simes, John AU - Simes J AD - NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia. FAU - Wheeler, Helen AU - Wheeler H AD - Medical Oncology, Royal North Shore Hospital, Sydney, NSW, Australia. FAU - Walbert, Tobias AU - Walbert T AD - Henry Ford Health System, Detroit, MI, USA. FAU - Scott, Andrew M AU - Scott AM AD - School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia. AD - Department of Medicine, University of Melbourne, Melbourne, VIC, Australia. FAU - Gomez, Erica AU - Gomez E AD - AbbVie Inc., North Chicago, IL, USA. FAU - Lee, Ho-Jin AU - Lee HJ AD - AbbVie Inc., North Chicago, IL, USA. FAU - Roberts-Rapp, Lisa AU - Roberts-Rapp L AD - AbbVie Inc., North Chicago, IL, USA. FAU - Xiong, Hao AU - Xiong H AD - AbbVie Inc., North Chicago, IL, USA. FAU - Bain, Earle AU - Bain E AD - AbbVie Inc., North Chicago, IL, USA. FAU - Ansell, Peter J AU - Ansell PJ AD - AbbVie Inc., North Chicago, IL, USA. FAU - Holen, Kyle D AU - Holen KD AD - AbbVie Inc., North Chicago, IL, USA. FAU - Maag, David AU - Maag D AD - AbbVie Inc., North Chicago, IL, USA. FAU - Reardon, David A AU - Reardon DA AD - Dana-Farber Cancer Institute, Boston, MA, USA. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study DEP - 20171026 PL - Germany TA - Cancer Chemother Pharmacol JT - Cancer chemotherapy and pharmacology JID - 7806519 RN - 0 (ABT-414) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Immunoconjugates) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Antibodies, Monoclonal, Humanized/*therapeutic use MH - ErbB Receptors/genetics MH - Female MH - Glioblastoma/*drug therapy/pathology MH - Humans MH - Immunoconjugates/*therapeutic use MH - Male MH - Middle Aged PMC - PMC5686264 OTO - NOTNLM OT - ABT-414 OT - Antibody-drug conjugate OT - Depatuxizumab mafodotin OT - EGFR OT - Recurrent glioblastoma COIS- FUNDING: AbbVie provided financial support for this study (NCT01800695) and participated in the design, study conduct, analysis and interpretation of the data, as well as the writing, review, and approval of the manuscript. All authors were involved in the data gathering, analysis, review, interpretation and manuscript preparation and approval. CONFLICT OF INTEREST: Martin van den Bent: received honoraria from Roche, AbbVie, Celldex, Merck Ag, Cavion, Actelion, BMS, Blue Earth Diagnostics and Novartis; received research funding from AbbVie. Hui K. Gan: has an investigator-initiated study with AbbVie; received travel support and research funding from AbbVie; received honoraria from Pfizer, BMS, and Merck Serono; affiliated with the Ludwig Institute for Cancer Research. Andrew B. Lassman: in the last 12 months received personal compensation from WebMD, Sapience Therapeutics, Genentech, Italian Association for Cancer Research, AbbVie, AstraZeneca, Novocure, and Kadmon; additional travel support from Karyopharm, AstraZeneca, Abbvie, Bioclinica, Genentech, and VBI Vaccines; and research support from RTOG Foundation, Genentech, Amgen, AbbVie, Novartis, Karyopharm, Celldex, NW Biotherapeutics, Plexxicon, Pfizer, Agenus, Medimmune, Boehringer Ingelheim, Angiochem, Novocure, Stemline, E-Therapeutics, Millennium. Priya Kumthekar: Consultant for AbbVie. Ryan Merrell: Serves on a Scientific Advisory Board for AbbVie. Nicholas Butowski: Received honoraria from and has a consulting or advisory role with, Roche/Genentech, Medicenna, VBL Theraputics, Omniox; is involved in speakers' bureaus with Roche and Merck; received research funding from Insys. Zarnie Lwin: Has served on Abbvie Scientific Advisory Board and received honoraria. Tom Mikkelsen: No potential conflicts of interest to disclose. Louis B. Nabors: Serves on a Scientific Advisory Board for Cavion, Merck, and BMS; investigator for AbbVie. Kyriakos P. Papadopoulos: Received research funding from AbbVie, MedImmune, Daiichi Sankyo, GlaxoSmithKline, Onyx, Sanofi, Novartis. Marta Penas-Prado: No potential conflicts of interest to disclose. John Simes: Received research funding for an investigator-initiated trial from AbbVie. Helen Wheeler: Investigator for AbbVie. Tobias Walbert: Serves on a Scientific Advisory Board for Novocure. Andrew M. Scott: Received research funding and travel support from AbbVie; received research funding from Daiichi-Sankyo; is a consultant and has stock in Life Science Pharmaceuticals; is affiliated with the Ludwig Institute for Cancer Research. Erica Gomez, Ho-Jin Lee, Lisa Roberts-Rapp, Hao Xiong, Earle Bain, Peter J. Ansell, Kyle D. Holen, David Maag: Employees of AbbVie and may own stock. David A. Reardon: Received honoraria from and has a consulting or advisory role with Abbvie, Bristol Myers Squibb, Cavion, Celldex, Inovio, Merck, Novartis, Roche/Genentech, Amgen, Novocure, Oxigene, Regeneron and Stemline Therapeutics; is involved in speakers' bureaus with Roche and Merck; received research funding from Incyte, Midatech and Celldex. ETHICAL APPROVAL: This article does not contain any study with animals performed by any of the authors. HUMAN RIGHTS AND ANIMAL STATEMENT: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. INFORMED CONSENT: Informed consent was obtained from all individual participants included in the study. EDAT- 2017/10/28 06:00 MHDA- 2017/12/02 06:00 PMCR- 2017/10/26 CRDT- 2017/10/28 06:00 PHST- 2017/08/14 00:00 [received] PHST- 2017/10/07 00:00 [accepted] PHST- 2017/10/28 06:00 [pubmed] PHST- 2017/12/02 06:00 [medline] PHST- 2017/10/28 06:00 [entrez] PHST- 2017/10/26 00:00 [pmc-release] AID - 10.1007/s00280-017-3451-1 [pii] AID - 3451 [pii] AID - 10.1007/s00280-017-3451-1 [doi] PST - ppublish SO - Cancer Chemother Pharmacol. 2017 Dec;80(6):1209-1217. doi: 10.1007/s00280-017-3451-1. Epub 2017 Oct 26.