depatuxizumab mafodotin (ABT-414) / AbbVie - LARVOL DELTA

Depatuxizumab mafodotin in glioblastoma: A systematic review of efficacy, safety, pharmacokinetics and biomarker stratification. (PubMed, J Oncol Pharm Pract) - "Pharmacokinetic data showed linear, predictable exposure with low potential for drug-drug interactions, notably with temozolomide (TMZ). Its clinical benefit remains limited, underscoring the disease's heterogeneity and therapeutic resistance. The findings support the continued investigation of biomarker-guided ADC therapy and highlight the critical need for future clinical trials to integrate comprehensive molecular profiling for optimal patient selection."

Biomarker • Journal • PK/PD data • Review • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • EGFR

7MeERT Enhances Antibody-Drug Conjugate Efficacy in Glioblastoma by Inducing AMPK-p38MAPK-Mediated Non-Canonical Endocytosis of EGFRvIII. (PubMed, Anticancer Agents Med Chem) - "7MeERT enhances EGFRvIII-targeting ADC efficacy in glioblastoma by inducing metabolic stress and triggering AMPK-p38MAPK-mediated non-canonical endocytosis. This strategy may improve ADC delivery in tumors with impaired receptor internalization."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • AMPK • EGFR

Efficacy and safety of targeted therapies for glioblastoma: a systematic review and network meta-analysis. (PubMed, BMC Cancer) - "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."

Journal • Retrospective data • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • MGMT

Erratum to: Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial. (PubMed, Neuro Oncol) - No abstract available

Clinical • P3 data • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • EGFR

Consideration of spatial companion biomarkers for targeted therapeutics in cancer: depatuxizumab mafodotin in glioblastoma. (PubMed, JCI Insight) - No abstract available

Biomarker • Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

The efficacy of combination therapy versus monotherapy in patients with glioblastoma with abnormal epidermal growth factor receptor (EGFR) genes, a systematic review and network meta-analysis. (PubMed, Neuroscience) - "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."

Journal • Monotherapy • Retrospective data • Review • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • EGFR

Drug and single-cell gene expression integration identifies sensitive and resistant glioblastoma cell populations. (PubMed, Nat Commun) - "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."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • OLIG2

Lost in translation: Do preclinical studies predict clinical failure in GBM? (SNO 2025) - "For the trials evaluated, no preclinical brain:plasma (B/P) data were reported for enzastaurin, cilengitide, nimotuzumab, Depatux-M, or bevacizumab, although IgG typically has a B/P ≈1%...The best response for each drug compared to relevant control (relative increase in median survival) was 22% (nimotuzumab), 31% (marizomib), 36% (sunitinib CD) / 5% (sunitinib PD), 63% (bevacizumab/temozolomide), 140% (imatinib), 157% (Depatux-M), 220% (veliparib/temozolomide), 300% (cediranib); median survival was not reached for cilengitide...The stunning lack of clinical progress in GBM is deeply discouraging, but is consistent with underwhelming preclinical testing and the contextual interpretation of those results. Acknowledging multifaceted reasons for failed clinical trials, a more rigorous and critical approach should be used in preclinical studies, coupled with follow-up surgical window of opportunity studies, to identify and promote only the most promising therapies into..."

Preclinical • Brain Cancer • CNS Disorders • Glioblastoma • Solid Tumor

Lost in translation: Do preclinical studies predict clinical failure in GBM? (SNO 2025) - "For the trials evaluated, no preclinical brain:plasma (B/P) data were reported for enzastaurin, cilengitide, nimotuzumab, Depatux-M, or bevacizumab, although IgG typically has a B/P ≈1%...The best response for each drug compared to relevant control (relative increase in median survival) was 22% (nimotuzumab), 31% (marizomib), 36% (sunitinib CD) / 5% (sunitinib PD), 63% (bevacizumab/temozolomide), 140% (imatinib), 157% (Depatux-M), 220% (veliparib/temozolomide), 300% (cediranib); median survival was not reached for cilengitide...The stunning lack of clinical progress in GBM is deeply discouraging, but is consistent with underwhelming preclinical testing and the contextual interpretation of those results. Acknowledging multifaceted reasons for failed clinical trials, a more rigorous and critical approach should be used in preclinical studies, coupled with follow-up surgical window of opportunity studies, to identify and promote only the most promising therapies into..."

Preclinical • Brain Cancer • CNS Disorders • Glioblastoma • Solid Tumor

Lost in translation: Do preclinical studies predict clinical failure in GBM? (WFNOS 2025) - "For the trials evaluated, no preclinical brain:plasma (B/P) data were reported for enzastaurin, cilengitide, nimotuzumab, Depatux-M, or bevacizumab, although IgG typically has a B/P ≈1%...The best response for each drug compared to relevant control (relative increase in median survival) was 22% (nimotuzumab), 31% (marizomib), 36% (sunitinib CD) / 5% (sunitinib PD), 63% (bevacizumab/temozolomide), 140% (imatinib), 157% (Depatux-M), 220% (veliparib/temozolomide), 300% (cediranib); median survival was not reached for cilengitide...The stunning lack of clinical progress in GBM is deeply discouraging, but is consistent with underwhelming preclinical testing and the contextual interpretation of those results. Acknowledging multifaceted reasons for failed clinical trials, a more rigorous and critical approach should be used in preclinical studies, coupled with follow-up surgical window of opportunity studies, to identify and promote only the most promising therapies into..."

Preclinical • Brain Cancer • CNS Disorders • Glioblastoma • Oncology • Solid Tumor

Lost in translation: Do preclinical studies predict clinical failure in GBM? (WFNOS 2025) - "For the trials evaluated, no preclinical brain:plasma (B/P) data were reported for enzastaurin, cilengitide, nimotuzumab, Depatux-M, or bevacizumab, although IgG typically has a B/P ≈1%...The best response for each drug compared to relevant control (relative increase in median survival) was 22% (nimotuzumab), 31% (marizomib), 36% (sunitinib CD) / 5% (sunitinib PD), 63% (bevacizumab/temozolomide), 140% (imatinib), 157% (Depatux-M), 220% (veliparib/temozolomide), 300% (cediranib); median survival was not reached for cilengitide...The stunning lack of clinical progress in GBM is deeply discouraging, but is consistent with underwhelming preclinical testing and the contextual interpretation of those results. Acknowledging multifaceted reasons for failed clinical trials, a more rigorous and critical approach should be used in preclinical studies, coupled with follow-up surgical window of opportunity studies, to identify and promote only the most promising therapies into..."

Preclinical • Brain Cancer • CNS Disorders • Glioblastoma • Glioma • Oncology • Solid Tumor

Safety and efficacy of depatuxizumab mafodotin monotherapy or in combination with temozolomide in patients with/without EGFR-amplified recurrent glioblastoma: a systematic review. (PubMed, Ann Med Surg (Lond)) - "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."

Journal • Monotherapy • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • EGFR

Glioblastoma resistance to EGFR antibody-drug conjugate is driven by transcriptional reprogramming and TEK-induced EGFR suppression. (PubMed, J Transl Med) - "Our findings demonstrate that resistance to ABT-414 arises through both adaptive transcriptional remodeling and newly acquired genetic alterations. TEK-mediated suppression of EGFR represents a previously unrecognized mechanism of resistance, with potential implications for overcoming antibody-drug conjugate failure in GBM."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • TEK

Efficacy and safety of depatuxizumab mafodotin (ABT-414) in EGFR-amplified glioblastoma: A systematic review and Bayesian network meta-analysis. (ASCO 2025) - "Trials evaluating Depatux-M as monotherapy or combined with temozolomide (TMZ) and/or radiotherapy (RT) were included. Depatuxizumab mafodotin offers limited survival benefits in EGFR-amplified GBM, with monotherapy showing the most favorable PFS. However, significant safety concerns, particularly keratitis, warrant further research to optimize its therapeutic potential and identify more tolerable regimens. Efficacy and safety outcomes of depatuxizumab mafodotin in EGFR-amplified glioblastoma."

Retrospective data • Review • Brain Cancer • CNS Tumor • Glioblastoma • Keratitis • Ocular Inflammation • Oncology • Ophthalmology • Solid Tumor • EGFR

Drug and Single-Cell Gene Expression Integration Identifies Sensitive and Resistant Glioblastoma Cell Populations. (PubMed, bioRxiv) - "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."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • OLIG2

Targeted agents in patients with progressive glioblastoma-A systematic meta-analysis of randomized clinical trials. (PubMed, Cancer Med) - "The aim of this systematic meta-analysis was to establish evidence for the use of targeted therapies in progressive GB. While some studies demonstrated benefits for OS and/or PFS, those results have to be interpreted with caution as most studies had major methodological weaknesses, including potential differences in sample size, trial design, or the initial distribution of prognostic factors."

Clinical • Journal • Retrospective data • Review • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Tumour volumes predict prognosis and response to treatment with Depatuxizumab Mafadotin (SNO 2024) - "We investigated the impact of tumor volumes on outcomes with Depatux-M in the EORTC randomized phase 2 Intellance 2 study on recurrent glioblastoma (NeuroOncol 22(5):684). 260 patients were randomized to Depatux-M, Depatux-M with temozolomide, or control treatment (lomustine/temozolomide). Tumor volumes are an important prognostic variable in recurrent glioblastoma and modulate survival to large molecules like Depatux-M."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Clinical and translational advances in primary brain tumor therapy with a focus on glioblastoma-A comprehensive review of the literature. (PubMed, World Neurosurg ) - "Phase 3 trials indicate the efficacy of DCVax-L in improving survival rates and depatux-m in prolonging progression-free survival. These findings emphasize the importance of personalized treatment approaches and continued exploration of targeted therapies, immunotherapies, and tumor biology understanding in shaping the future of glioblastoma treatment."

Journal • Review • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Infectious Disease • Oncology • Solid Tumor

Efficacy and safety of depatuxizumab mafodotin and temozolomide combination in glioblastoma patients with epidermal growth factor receptor expression alteration: A comprehensive review and meta analysis (KSMO 2024) - No abstract available

Retrospective data • Review • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • EGFR

Bystander effects, pharmacokinetics, and linker-payload stability of EGFR-targeting antibody-drug conjugates Losatuxizumab vedotin and Depatux-M in glioblastoma models. (PubMed, Clin Cancer Res) - "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."

Journal • PK/PD data • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CD68

Efficacy of Depatuxizumab Mafodotin (ABT-414) in preclinical models of head and neck cancer. (PubMed, Carcinogenesis) - "ABT-414 treatment yielded antitumor activity in FaDu tumors, but not in UMSCC47, highlighting the potential for ABT-414 efficacy in high EGFR-expressing tumors. While ABT-414-IRDye800 localized tumors in both cell lines, the differing antitumor responses highlight the need for further investigation into the role of the tumor microenvironment in drug delivery."

Journal • Preclinical • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

A Phase 3b Study for Management of Ocular Side Effects in Patients with EGFR-Amplified Glioblastoma Receiving Depatuxizumab Mafodotin. (PubMed, Ophthalmic Res) - P3b | "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."

Adverse events • Journal • P3 data • Brain Cancer • CNS Tumor • Glioblastoma • Gliosarcoma • Oncology • Sarcoma • Solid Tumor • EGFR

Intellance1: A Study of ABT-414 in Participants With Newly Diagnosed Glioblastoma (GBM) With Epidermal Growth Factor Receptor (EGFR) Amplification (clinicaltrials.gov) - P3 | N=691 | Completed | Sponsor: AbbVie | Phase classification: P2/3 ➔ P3

Phase classification • Brain Cancer • CNS Tumor • Glioblastoma • Gliosarcoma • Oncology • Sarcoma • Solid Tumor • EGFR • MGMT

Understanding the activity of antibody-drug conjugates in primary and secondary brain tumours. (PubMed, Nat Rev Clin Oncol) - "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..."

Journal • Review • Brain Cancer • Breast Cancer • CNS Tumor • Glioblastoma • Glioma • Hematological Malignancies • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • EGFR • HER-2

A series of patients (pts) with recurrent GBM (rGBM) treated with ABT-414, bevacizumab (Bev) and CCNU (SNO 2019) - "ABT-414 with Bev and CCNU was tolerable in this selected small series of pts with EGFR-amplified rGBM, and may have potential activity in selected patients, with 4 out of 6 pts (three MGMT-unmethylated) achieving a PFS greater than 27 wk (range 27 – 64). Despite the outcome of Intellance 1, there may be a subgroup of relapsed pts who benefit from this combination. Further studies are warranted to identify and analyse this group."

Clinical • Oncology • EGFR