Peripheral neuropathy associated with monomethyl auristatin E-based antibody-drug conjugates

Fu, Zhiwen; Gao, Chen; Wu, Tingting; Wang, Lulu; Li, Shijun; Zhang, Yu; Shi, Chen

doi:10.1016/j.isci.2023.107778

Cited by 9 publications

(2 citation statements)

References 118 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is important to emphasize that the platinum eligibility criteria will be less and less used in clinical practice after the widespread adoption of enfortumab vedotin + pembrolizumab in the first-line setting, and this categorisation will be considered for the choice of the subsequent lines of therapy. Another aspect that needs to be considered is the long-term safety profile of this combination; despite a lower percentage of grade 3-4 adverse events compared to platinum-based chemotherapy, peripheral sensory neuropathy associated with enfortumab vedotin could have a negative impact on quality of life [23], given the expected high number of cycles of this drug administered in the first-line setting. Long-term safety data and patient-reported outcomes will help to clarify this issue (24,25).…”

Section: Discussionmentioning

confidence: 99%

A Head-to-Head Comparison of the First-Line Treatments for Locally Advanced or Metastatic Urothelial Cancer: Has Chemotherapy Still a Role?

Gasperoni,

Del Bono,

Ossato

et al. 2024

Preprint

View full text Add to dashboard Cite

Background: Patients with locally advanced/metastatic urothelial cancer have been conventionally treated with platinum-based chemotherapy. Recently, numerous new treatments have been proposed to improve overall survival (OS) and reduce adverse effects, but no head-to-head direct comparison is available. Methods: We considered: a) monotherapy with immune checkpoint inhibitors (ICI); b) combinations of an ICI with chemotherapy; c) combinations of an ICI with other drugs. An indirect comparison was performed to identify the regimens most effective in prolonging OS compared to each other and to chemotherapy. Results: A total of 6 articles were included. In our final analysis, nivolumab plus chemotherapy showed better OS compared to chemotherapy (HR= 0.70, 95%CI: .59-0.82); while durvalumab plus tremelimumab showed no OS benefit (HR=0.95, 95%CI 0.82-1.11). More interestingly, enfortumab vedotin plus pembrolizumab significantly prolonged OS compared to both chemotherapy alone (HR=0.53, 95%CI 0.45-0.63) and nivolumab plus chemotherapy (HR= 0.76, 95%CI 0.60-0.97). Discussion and conclusion: Among new treatments for locally advanced and metastatic urothelial cancer, enfortumab vedotin + pembrolizumab showed the best efficacy in terms of OS. Our results support the use of this combination as first-line treatment in this setting.

show abstract

Section: Discussionmentioning

confidence: 99%

A Head-to-Head Comparison of the First-Line Treatments for Locally Advanced or Metastatic Urothelial Cancer: Has Chemotherapy Still a Role?

Gasperoni,

Del Bono,

Ossato

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Microtubule-targeted chemotherapy agents (vinca alkaloids and taxanes) commonly cause peripheral neuropathy, and neuropathy is a toxicity common to FDA-approved ADCs with microtubule-targeted toxins (MMAE, DM1, DM4; refs. 40 – 42 ). The high rate of axonal transport in neurons requires constant mobilization by tubules, which can explain their sensitivity to microtubule inhibitors ( 36 , 43 ).…”

Section: Discussionmentioning

confidence: 99%

Bystander Effects, Pharmacokinetics, and Linker-Payload Stability of EGFR-Targeting Antibody-Drug Conjugates Losatuxizumab Vedotin and Depatux-M in Glioblastoma Models

Jain,

Griffith,

Porath

et al. 2024

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Antibody-drug conjugates (ADCs) are targeted therapies with robust efficacy in solid cancers, and there is intense interest in using EGFR-specific ADCs to target EGFR-amplified glioblastoma (GBM). Given the molecular heterogeneity of GBM, bystander activity of ADCs may be important for determining treatment efficacy. In this study, the activity and toxicity of two EGFR-targeted ADCs, Losatuxizumab vedotin (ABBV-221) and Depatuxizumab mafodotin (Depatux-M), with similar auristatin toxins, were compared in GBM patient-derived xenografts (PDXs) and normal murine brain following direct infusion by convection enhanced delivery (CED). Methods: EGFRviii-amplified and non-amplified GBM PDXs were used to determine in vitro cytotoxicity, in vivo efficacy, and bystander activities of ABBV-221 and Depatux-M. Non-tumor bearing mice were used to evaluate pharmacokinetics and toxicity of ADCs using LC-MS/MS and immunohistochemistry. Results: CED improved intracranial efficacy of Depatux-M and ABBV-221 in three EGFRviii-amplified GBM PDX models (Median survival: 125 to >300 days vs 20-49 days with isotype-control AB095). Both ADCs had comparable in vitro and in vivo efficacy. However, neuronal toxicity and CD68+ microglia/macrophage infiltration were significantly higher in brains infused with ABBV-221, with the cell-permeable MMAE, as compared to Depatux-M, with the cell-impermeant MMAF. CED infusion of ABBV-221 into brain or incubation of ABBV-221 with normal brain homogenate resulted in significant release of MMAE, which is consistent with linker instability in the brain microenvironment. Conclusion: EGFR-targeting ADCs are promising therapeutic options for GBM when delivered intra-tumorally by CED. However, the linker and payload for the ADC must be carefully considered to maximize the therapeutic window.

show abstract

Dual immunostimulatory CD73 antibody-polymeric cytotoxic drug complex for triple negative breast cancer therapy

Xie,

Yang,

Wei

et al. 2024

Acta Biomaterialia

View full text Add to dashboard Cite

Peripheral neuropathy associated with monomethyl auristatin E-based antibody-drug conjugates

Cited by 9 publications

References 118 publications

A Head-to-Head Comparison of the First-Line Treatments for Locally Advanced or Metastatic Urothelial Cancer: Has Chemotherapy Still a Role?

A Head-to-Head Comparison of the First-Line Treatments for Locally Advanced or Metastatic Urothelial Cancer: Has Chemotherapy Still a Role?

Bystander Effects, Pharmacokinetics, and Linker-Payload Stability of EGFR-Targeting Antibody-Drug Conjugates Losatuxizumab Vedotin and Depatux-M in Glioblastoma Models

Dual immunostimulatory CD73 antibody-polymeric cytotoxic drug complex for triple negative breast cancer therapy

Contact Info

Product

Resources

About