Dermatologic side effects associated with the epidermal growth factor receptor inhibitors

Agero, Anna Liza C.; Dusza, Stephen W.; Benvenuto-Andrade, Cristiane; Busam, Klaus J.; Myskowski, Patricia L.; Halpern, Allan C.

doi:10.1016/j.jaad.2005.10.010

Cited by 332 publications

(319 citation statements)

References 42 publications

(125 reference statements)

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“…It is important that the antibody exhibit specific and efficient binding to the antigen on tumor cells with little to no binding on normal cells. Both the monoclonal antibody targeting EGFR (depatux) and the ADC in which it is used (depatux‐m) demonstrated minimal binding in normal tissues and did not lead to the other toxicities5, 6, 14 usually associated with EGFR‐targeted therapies 7, 15. The linker is less likely to drive toxicity, although its stability can influence the toxicity derived from the payloads,11 which are highly active because of their effects on cellular processes necessary for survival.…”

Section: Discussionmentioning

confidence: 99%

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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: 99%

“…This EGFR epitope is largely inaccessible when EGFR is expressed normally, contributing to limited binding of depatux in normal tissues 5. An initial phase 1 study demonstrated that depatux had high tumor specificity,6 with no dose‐limiting acneiform skin rashes or diarrhea that commonly occur with EGFR‐directed therapies 7…”

Section: Introductionmentioning

confidence: 99%

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 skin reactions are fully reversible within a couple of weeks after cessation of therapy (Robert et al, 2005). There are no evidence-based recommendations for treatment of cutaneous side effects, but systemic antibiotics like tetracycline or steroids, topical retinoids and vitamin K have been used successfully on an empirical basis (Yamamoto et al, 2004;Agero et al, 2006;Perez-Soler et al, 2006).…”

Section: Role Of Antibody Therapy P Pfeiffer Et Almentioning

confidence: 99%

Current role of antibody therapy in patients with metastatic colorectal cancer

2007

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“…Moreover, impaired sorting of pro-EGF at the basolateral membrane of the tubular epithelial cells was shown to disturb this mechanism and resulted in renal magnesium loss [377]. Supporting the link between EGF-TRPM6-Mg 2+ -itch, several studies reported itch as a common side effect of cetuximab, a chemotherapeutic monoclonal antibody which inhibits the EGF-receptor [378][379][380].…”

Section: Mg 2+ Homeostasis In Itch -Possible Roles Of Trpm6 and Trpm7mentioning

confidence: 98%

TRP Channels and Pruritus

Tóth¹,

Bı́ró²

2013

TOPAINJ

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Itch (pruritus) is one of the most often seen sensory phenomena in clinical practice. Recent neurophysiological findings proposed the existence of a novel pruriceptive system which includes a multitude of pruritogenic (itch-inducing) peripheral mediators, itch-selective pruriceptors, sensory afferent networks, spinal cord neurons, and certain central nervous system regions. In this review, we first introduce major features of the pruriceptive system. We then focus on defining the roles of transient receptor potential (TRP) ion channels in skin-coupled itch and provide compelling evidence that certain thermosensitive TRP channels (especially TRPV1, TRPV3, TRPV4, and TRPA1) are indeed key players in pruritus pathogenesis. Finally, we propose TRP-centered future experimental directions towards the therapeutic targeting of TRP channels in the clinical management of itch.

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Dermatologic side effects associated with the epidermal growth factor receptor inhibitors

Cited by 332 publications

References 42 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

Current role of antibody therapy in patients with metastatic colorectal cancer

TRP Channels and Pruritus

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