depatuxizumab mafodotin (ABT-414)

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.

Interim analysis demonstrated no OS benefit for depatux-m in treating EGFR-amp newly diagnosed GBM. No new important safety risks were identified.

P2/3, N=655, Completed, AbbVie | Active, not recruiting --> Completed

A third HER2-directed ADC, disitamab vedotin (RC48), has been approved for locally advanced or metastatic gastric or gastroesophageal junction cancer by the NMPA (National Medical Products Administration) of China in 2021. In this review article, we summarize the three approved ADCs (T-DM1, DS-8201a and RC48), together with the investigational EGFR-directed ADCs (ABT-414, MRG003 and M1231), HER2-directed ADCs (SYD985, ARX-788, A166, MRG002, ALT-P7, GQ1001 and SBT6050) and HER3-directed ADC (U3-1402). Lastly, we discuss the major challenges associated with the development of ADCs, and highlight the possible future directions to tackle these challenges.