Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma

Reardon, David A.; Lassman, Andrew B.; Bent, Martin J. van den; Kumthekar, Priya; Merrell, Ryan; Scott, Andrew M.; Fichtel, Lisa; Sulman, Erik P.; Gomez, Erica; Fischer, JuDee; Lee, Ho Jin; Munasinghe, Wijith; Xiong, Hao; Mandich, Helen; Roberts-Rapp, Lisa; Ansell, Peter; Holen, Kyle D.; Gan, Hui

doi:10.1093/neuonc/now257

Cited by 89 publications

(123 citation statements)

References 48 publications

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“…However, the majority resolved or improved upon administration of steroid eye drops or when patients entirely stopped taking the mafodotin‐conjugated ADCs 12. Resolution and/or improvement of ocular AEs were observed in this and other depatux‐m trials 21, 22, 23, 24. However, calculating the median time to resolution has been unreliable because of limited patient numbers in this first‐in‐human study.…”

Section: Discussionmentioning

confidence: 80%

“…This encouraging result provided evidence that depatux‐m may be highly specific for tumor types with EGFR amplification, leading to further study of depatux‐m in glioblastoma, in which nearly 50% of patients have EGFR amplification 13. Encouraging efficacy of depatux‐m has been observed in a phase 1 trial of patients with newly diagnosed and recurrent glioblastoma 21, 22, 23, 24. In addition, preliminary efficacy results from a large phase 2 trial of patients with recurrent glioblastoma (http://clinicaltrials.gov identifier NCT02343406) further support its development as a novel, targeted therapy that may improve outcomes for patients with EGFR amplification in a disease with very few treatment options 25.…”

Section: Discussionmentioning

confidence: 81%

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Efficacy and safety results of depatuxizumab mafodotin (ABT‐414) in patients with advanced solid tumors likely to overexpress epidermal growth factor receptor

Goss

Vokes

Gordon

et al. 2018

Cancer

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BACKGROUNDEpidermal 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.METHODSThis 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.RESULTSFifty‐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.CONCLUSIONSDepatux‐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. © 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.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 81%

Efficacy and safety results of depatuxizumab mafodotin (ABT‐414) in patients with advanced solid tumors likely to overexpress epidermal growth factor receptor

Goss

Vokes

Gordon

et al. 2018

Cancer

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“…The antibody-drug conjugate ABT-414, which specifically recognizes EGFRvIII and WT EGFR when expressed at amplified levels, has shown promise in phase I/II clinical trials for GBM patients (Gan et al, 2017; Phillips et al, 2016; Reardon et al, 2017). Previously, we have proposed that certain mutations such as EGFR A289V could bind and respond to mAb806 based on simulations (Orellana et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

“…More effective therapies are needed to improve patient outcomes. Following promising results indicating safety, efficacy studies are currently underway for ABT-414, which specifically targets tumor cells expressing aberrant EGFR (Reardon et al, 2017). Here we examined the prospects of using ABT-414 against GBMs containing the EGFR A289V missense mutant by assessing the efficacy of its non-conjugated precursor, mAb806, in subcutaneous and orthotopic animal models.…”

Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Receptor Extracellular Domain Mutations in Glioblastoma Present Opportunities for Clinical Imaging and Therapeutic Development

et al. 2018

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We explored the clinical and pathological impact of epidermal growth factor receptor (EGFR) extracellular domain missense mutations. Retrospective assessment of 260 de novo glioblastoma patients revealed a significant reduction in overall survival of patients having tumors with EGFR mutations at alanine 289 (EGFR). Quantitative multi-parametric magnetic resonance imaging analyses indicated increased tumor invasion for EGFR mutants, corroborated in mice bearing intracranial tumors expressing EGFR and dependent on ERK-mediated expression of matrix metalloproteinase-1. EGFR tumor growth was attenuated with an antibody against a cryptic epitope, based on in silico simulation. The findings of this study indicate a highly invasive phenotype associated with the EGFR mutation in glioblastoma, postulating EGFR as a molecular marker for responsiveness to therapy with EGFR-targeting antibodies.

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“…For example, ABT-414 is an antibody-drug conjugate that can target either EGFR or EGFRvIII and when attached to a cell can deliver a potent anti-microtubule toxin. Current phase I studies for ABT-414 for newly diagnosed GBM patients have elicited a median progression free survival of 6.1 months and a 6-month progression free survival of 25.3% for recurrent GBM [105,106]. …”

Section: Current Therapiesmentioning

confidence: 99%

Engineering challenges for brain tumor immunotherapy

Lyon

Mokarram

Saxena

et al. 2017

Advanced Drug Delivery Reviews

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Malignant brain tumors represent one of the most devastating forms of cancer with abject survival rates that have not changed in the past 60 years. This is partly because the brain is a critical organ, and poses unique anatomical, physiological, and immunological barriers. The unique interplay of these barriers also provides an opportunity for creative engineering solutions. Cancer immunotherapy, a means of harnessing the host immune system for anti-tumor efficacy, is becoming a standard approach for treating many cancers. However, its use in brain tumors is not widespread. This review discusses the current approaches, and hurdles to these approaches in treating brain tumors, with a focus on immunotherapies. We identify critical barriers to immunoengineering brain tumor therapies and discuss possible solutions to these challenges.

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Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma

Abstract: ABT-414 plus chemoradiation demonstrated an acceptable safety and pharmacokinetic profile in newly diagnosed glioblastoma. Randomized studies are ongoing to determine efficacy in newly diagnosed (NCT02573324) and recurrent glioblastoma (NCT02343406).

Cited by 89 publications

References 48 publications

Efficacy and safety results of depatuxizumab mafodotin (ABT‐414) in patients with advanced solid tumors likely to overexpress epidermal growth factor receptor

Efficacy and safety results of depatuxizumab mafodotin (ABT‐414) in patients with advanced solid tumors likely to overexpress epidermal growth factor receptor

Epidermal Growth Factor Receptor Extracellular Domain Mutations in Glioblastoma Present Opportunities for Clinical Imaging and Therapeutic Development

Engineering challenges for brain tumor immunotherapy

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