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

Abstract

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.

Evaluation of Prophylactic Corticosteroid Eye Drop Use in the Management of Corneal Abnormalities Induced by the Antibody–Drug Conjugate Mirvetuximab Soravtansine

“…Prophylactic use of steroid eye drops is another approach that has been reported to be successful in reducing the frequency and severity of ocular events in trials of other ADCs, such as ABT-414 and SGN-CD19A (both of which utilize MMAF as their cytotoxic payload; refs. [28][29][30]. The actual mechanism(s) by which steroids can reduce ADC-induced keratopathy remain poorly defined and, as supported by our preclinical modeling, there appears to be no inflammatory component underlying the etiology of the corneal toxicity observed with mirvetuximab soravtansine.…”

“…The more modest effects on blurred vision suggest that additional mechanisms, less influenced by steroid prophylaxis, are likely contributing to this symptom in patients. Of interest, in the ADC studies where steroid prophylaxis has been shown to be effective, the ocular AEs were more severe at onset (grades 3 or 4) and were subsequently reduced to grade 1/2 events (27)(28)(29)(30), comparable with the baseline levels seen with mirvetuximab soravtansine. Prophylactic steroid eye drop use as a mitigation strategy has not eliminated ADC-induced keratopathy, and it is reasonable to suggest that there is a role for additional strategies to further optimize ADC-related ocular AE profiles.…”

EGFRvIII: An Oncogene with Ambiguous Role

“…As a result of deletion, EGFR vIII is unable to bind known ligands and shows enhanced stability in cell membrane. [116] extracellular vesicles (EVs), the fact that extrachromosomal amplicons may be transported between cells is gaining importance [120]. erefore, in such a context, the role of amplicons is not to increase oncogene mRNA levels, but rather to enable more flexible regulation of gene expression as well as transfer of mutated gene to cells initially lacking such alteration.…”

Bispecific Antibodies and Antibody–Drug Conjugates for Cancer Therapy: Technological Considerations

“…Depatuxizumab mafodotin is an anti-EGFR ADC targeting a tumor-selective cryptic epitope on the CR1 domain of EGFR [98]. Probably as a result of the tumor selectivity, depatuxizumab mafodotin did not cause dose-limiting dermatological adverse events or diarrhea characteristic of other anti-EGFR therapies, even though EGFR is broadly expressed in normal tissues [99]. Similar to the cases of the anti-HER2 ADCs, the development of the anti-EGFR ADC suggests that the technical hurdles associated with ADC targets may be overcome by taking advantage of the target biology in the context of cancer cells.…”