depatuxizumab mafodotin (ABT-414)

Bevacizumab was associated with improved PFS, but not OS compared to standard therapy and other targeted therapies in newly diagnosed GBM patients. Exploratory subgroup findings suggested that nivolumab may be associated with less favorable OS and PFS estimates in MGMT-unmethylated patients. SUCRA rankings should be interpreted as exploratory because most interventions were supported by limited trial evidence. However, certain targeted drugs exhibit inadequate safety profiles, and careful risk-benefit assessment is required. Future research should further explore safer and more effective multi-targeted combination strategies to overcome GBM's survival bottleneck.

The analysis revealed that combination therapies generally demonstrated superior efficacy compared to the single ones, while monotherapies exhibited greater potency than temozolomide (TMZ). In terms of median progression-free survival (PFS), the combinations of Afatinib plus TMZ (SUCRA: 62.28%), rindopepimut (CDX-110) plus TMZ (SUCRA: 62.27%), and depatuxizumab mafodotin (Depatux M) plus TMZ (SUCRA: 54.4%) ranked among the top tier. For median overall survival (OS), the combinations of CDX-110 plus TMZ (SUCRA: 68.8%), Depatux M plus TMZ (SUCRA: 68.3%), and Nimotuzumab plus TMZ (SUCRA: 52.5%) were positioned in the upper echelon. In terms of prolonging both median PFS and median OS in GB, CDX-110 plus TMZ and Depatux M plus TMZ have shown slightly better than comparable therapies. However, further clinical trials are needed to confirm the effectiveness of other drugs in this respect.

We validate the significance of these findings in vitro, ex vivo, and in vivo, and identify a combination of an OLIG2 inhibitor and Depatux-M for the treatment of GBM. Our studies suggest that scFOCAL identifies cell states that are sensitive and resistant to targeted therapies in GBM using a measure of cell and drug connectivity, which can be applied to identify new synergistic combinations.

This study aimed to assess the safety and efficacy of depatuxizumab mafodotin as a monotherapy or in combination with temozolomide in patients with recurrent epidermal growth factor receptor (EGFR)-amplified glioblastoma multiforme, focusing on overall survival (OS) and progression-free survival (PFS). While depatuxizumab mafodotin shows the potential to improve survival outcomes, the heterogeneity in results highlights the need for further research. Future studies should refine patient selection criteria and explore alternative therapeutic combinations, such as depatuxizumab mafodotin with gemcitabine or cisplatin, to optimize treatment strategies.

We validated the significance of these findings in vitro, ex vivo, and in vivo , and identified a novel combination of an OLIG2 inhibitor and Depatux-M for GBM. Our studies suggest that ISOSCELES identifies cell states sensitive and resistant to targeted therapies in GBM and that it can be applied to identify new synergistic combinations. Integration of GBM single-cell RNA sequencing data with L1000-derived drug response signatures facilitates clustering of tumor cells and small molecules on cell-drug connectivity.Cell-drug connectivity predicts the identities of drug-sensitive and resistant cell states.In silico perturbation analysis using cell-drug connectivity predicts drug-induced changes in the cell-drug connectivity landscape in vivo.In silico perturbation analysis to predict drug-induced changes in the tumor cell-drug connectivity landscape predicts drug combinations that synergize in vivo to extend survival.

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.

The premature cessation of the study precludes definitive conclusions regarding the OSE prophylaxis strategies. No new clinically significant safety findings were noted. Despite these limitations, this study highlights the need for novel assessment tools to better understand and mitigate OSEs associated with ADCs.

Pharmacotherapy of brain tumours can be limited by restricted drug delivery across the blood-brain or blood-tumour barrier, although data from phase II studies of the HER2-targeted ADC trastuzumab deruxtecan indicate clinically relevant intracranial activity in patients with brain metastases from HER2 breast cancer. However, depatuxizumab mafodotin, an ADC targeting wild-type EGFR and EGFR variant III, did not provide a definitive overall survival benefit in patients with newly diagnosed or recurrent EGFR-amplified glioblastoma in phase II and III trials, despite objective radiological responses in some patients. In this Review, we summarize the available data on the central nervous system activity of ADCs from trials involving patients with primary and secondary brain tumours and discuss their clinical implications. Furthermore, we explore pharmacological determinants of intracranial activity and discuss the optimal design of clinical trials to facilitate development of ADCs for the treatment of gliomas and brain metastases.

P3, N=691, Completed, AbbVie | Phase classification: P2/3 --> P3

CED of Depatux-M is well tolerated and results in extended survival in orthotopic GBM PDXs. In contrast, CED of Ser-T was associated with a much narrower therapeutic window.

To pave the way for future efficacy studies for the treatment of GBM with an intra-CSF administered ADC consisting of a conjugate of ABT-806 (or of one of its close analogs), we verified in vivo the binding of ABT-414 to GBM tumor cells implanted in the cisterna magna and collected toxicity data from both the central nervous system (CNS) and peripheral tissues. The current study supports further exploration of harnessing CSF microcirculation as an alternative to systemic delivery to achieve higher brain tissue exposure, while reducing previously reported ocular toxicity with ABT-414.