Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial

doi:10.1093/neuonc/noac173

Clinical Trial

. 2023 Feb 14;25(2):339-350.

doi: 10.1093/neuonc/noac173.

Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial

Andrew B Lassman^{1

2}, Stephanie L Pugh³, Tony J C Wang^{4

2}, Kenneth Aldape⁵, Hui K Gan^{6

7

8}, Matthias Preusser⁹, Michael A Vogelbaum¹⁰, Erik P Sulman^{11

12}, Minhee Won³, Peixin Zhang³, Golnaz Moazami¹³, Marian S Macsai¹⁴, Mark R Gilbert¹⁵, Earle E Bain¹⁶, Vincent Blot¹⁶, Peter J Ansell¹⁶, Suvajit Samanta¹⁶, Madan G Kundu¹⁶, Terri S Armstrong¹⁷, Jeffrey S Wefel¹⁸, Clemens Seidel¹⁹, Filip Y de Vos²⁰, Sigmund Hsu²¹, Andrés F Cardona²², Giuseppe Lombardi²³, Dmitry Bentsion²⁴, Richard A Peterson²⁵, Craig Gedye²⁶, Véronique Bourg²⁷, Antje Wick²⁸, Walter J Curran²⁹, Minesh P Mehta³⁰

Affiliations

¹ Division of Neuro-Oncology, Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons and New York-Presbyterian Hospital, New York, New York, USA.
² Herbert Irving Comprehensive Cancer Center, New York, New York, USA.
³ RTOG Foundation Statistics and Data Management Center, American College of Radiology, Philadelphia, Pennsylvania.
⁴ Department of Radiation Oncology (in Neurological Surgery), Columbia University Vagelos College of Physicians and Surgeons and New York-Presbyterian Hospital, New York, New York, USA.
⁵ Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
⁶ Cancer Therapies and Biology Group, Centre of Research Excellence in Brain Tumours, Olivia Newton-John Cancer Wellness and Research Centre, Austin Hospital, Heidelberg, Melbourne, Australia.
⁷ La Trobe University School of Cancer Medicine, Heidelberg, Victoria, Australia.
⁸ Department of Medicine, University of Melbourne, Heidelberg, Victoria, Australia.
⁹ Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria.
¹⁰ Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, Florida, USA.
¹¹ Department of Radiation Oncology, New York University, Grossman School of Medicine, New York, New York, USA.
¹² Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA.
¹³ Department of Ophthalmology, Columbia University Vagelos College of Physicians and Surgeons and New York-Presbyterian Hospital, New York, New York, USA.
¹⁴ NorthShore University HealthSystem, Department of Ophthalmology, University of Chicago Pritzker School of Medicine, Evanston, Illinois, USA.
¹⁵ Neuro-Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
¹⁶ Abbvie, Inc., North Chicago, Illinois, USA.
¹⁷ Neuro-Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
¹⁸ Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
¹⁹ University Hospital Leipzig, Leipzig, Germany.
²⁰ University Medical Center Utrecht, Cancer Center, Utrecht, The Netherlands.
²¹ Department of Neurosurgery, University of Texas Health Sciences Center, McGovern School of Medicine, Houston, Texas, USA.
²² Foundation for Clinical and Applied Cancer Research-FICMAC/Clinical and Translational Oncology Group, Brain Tumor Section, Bogotá, Colombia.
²³ Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
²⁴ Sverdlovsk Regional Oncology Center, Ekaterinburg, Russia.
²⁵ Metro Minnesota NCORP, Saint Paul, Minnesota, USA.
²⁶ Calvary Mater Newcastle, Waratah, New South Wales, Australia.
²⁷ Department of Neurology, Côte d'Azur University, Nice, France.
²⁸ Heidelberg University Medical Center, Heidelberg, Germany.
²⁹ Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.
³⁰ Miami Cancer Institute, Baptist Hospital, Miami, Florida, USA.

PMID: 35849035
PMCID: PMC9925712
DOI: 10.1093/neuonc/noac173

Clinical Trial

Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial

Andrew B Lassman et al. Neuro Oncol. 2023.

. 2023 Feb 14;25(2):339-350.

doi: 10.1093/neuonc/noac173.

Authors

Affiliations

¹ Division of Neuro-Oncology, Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons and New York-Presbyterian Hospital, New York, New York, USA.
² Herbert Irving Comprehensive Cancer Center, New York, New York, USA.
³ RTOG Foundation Statistics and Data Management Center, American College of Radiology, Philadelphia, Pennsylvania.
⁴ Department of Radiation Oncology (in Neurological Surgery), Columbia University Vagelos College of Physicians and Surgeons and New York-Presbyterian Hospital, New York, New York, USA.
⁵ Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
⁶ Cancer Therapies and Biology Group, Centre of Research Excellence in Brain Tumours, Olivia Newton-John Cancer Wellness and Research Centre, Austin Hospital, Heidelberg, Melbourne, Australia.
⁷ La Trobe University School of Cancer Medicine, Heidelberg, Victoria, Australia.
⁸ Department of Medicine, University of Melbourne, Heidelberg, Victoria, Australia.
⁹ Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria.
¹⁰ Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, Florida, USA.
¹¹ Department of Radiation Oncology, New York University, Grossman School of Medicine, New York, New York, USA.
¹² Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA.
¹³ Department of Ophthalmology, Columbia University Vagelos College of Physicians and Surgeons and New York-Presbyterian Hospital, New York, New York, USA.
¹⁴ NorthShore University HealthSystem, Department of Ophthalmology, University of Chicago Pritzker School of Medicine, Evanston, Illinois, USA.
¹⁵ Neuro-Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
¹⁶ Abbvie, Inc., North Chicago, Illinois, USA.
¹⁷ Neuro-Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
¹⁸ Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
¹⁹ University Hospital Leipzig, Leipzig, Germany.
²⁰ University Medical Center Utrecht, Cancer Center, Utrecht, The Netherlands.
²¹ Department of Neurosurgery, University of Texas Health Sciences Center, McGovern School of Medicine, Houston, Texas, USA.
²² Foundation for Clinical and Applied Cancer Research-FICMAC/Clinical and Translational Oncology Group, Brain Tumor Section, Bogotá, Colombia.
²³ Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
²⁴ Sverdlovsk Regional Oncology Center, Ekaterinburg, Russia.
²⁵ Metro Minnesota NCORP, Saint Paul, Minnesota, USA.
²⁶ Calvary Mater Newcastle, Waratah, New South Wales, Australia.
²⁷ Department of Neurology, Côte d'Azur University, Nice, France.
²⁸ Heidelberg University Medical Center, Heidelberg, Germany.
²⁹ Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.
³⁰ Miami Cancer Institute, Baptist Hospital, Miami, Florida, USA.

PMID: 35849035
PMCID: PMC9925712
DOI: 10.1093/neuonc/noac173

Abstract

Background: Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene amplification (EGFR-amp). Preclinical and early-phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody-drug conjugate comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule-inhibitor toxin in EGFR-amp GBMs.

Methods: In this phase III trial, adults with centrally confirmed, EGFR-amp newly diagnosed GBM were randomized 1:1 to radiotherapy, temozolomide, and depatux-m/placebo. Corneal epitheliopathy was treated with a combination of protocol-specified prophylactic and supportive measures. There was 85% power to detect a hazard ratio (HR) ≤0.75 for overall survival (OS) at a 2.5% 1-sided significance level (ie traditional two-sided p ≤ 0.05) by log-rank testing.

Results: There were 639 randomized patients (median age 60, range 22-84; 62% men). Prespecified interim analysis found no improvement in OS for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.02, 95% CI 0.82-1.26, 1-sided p = 0.63). Progression-free survival was longer for depatux-m than placebo (median 8.0 vs. 6.3 months; HR 0.84, 95% confidence interval [CI] 0.70-1.01, p = 0.029), particularly among those with EGFRvIII-mutant (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56-0.93, 1-sided p = 0.002) or MGMT unmethylated (HR 0.77, 95% CI 0.61-0.97; 1-sided p = 0.012) tumors but without an OS improvement. Corneal epitheliopathy occurred in 94% of depatux-m-treated patients (61% grade 3-4), causing 12% to discontinue.

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

Keywords: EGFR; antibody drug conjugate; depatuxizumab mafodotin; glioblastoma; phase III.

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Figures

**Fig. 1**
Consolidated Standards of Reporting Trials (CONSORT) diagram of RTOG-F 3508/AbbVie M13-813 (INTELLANCE-1) at the time of preplanned interim analysis.

**Fig. 2**
Overall and progression-free survival. Overall (a) and progression-free survival (b) (by central review) curves by treatment arm among all randomized patients (intent-to-treat). The number of patients at risk over time is shown below the curves. HR, Hazard ratio (with 95% confidence intervals).

**Fig. 3**
Overall and progression-free survival by *EGFRvIII* mutation. Overall (a, c) and progression-free survival (b, d; by central review) by treatment arm for patients with (a, b) or without (c, d) *EGFRvIII* mutation on an intent-to treat basis. The number of patients at risk over time is shown below the curves. HR, Hazard ratio (with 95% confidence intervals).

See this image and copyright information in PMC

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References

1. Libermann TA, Nusbaum HR, Razon N, et al. . Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 1985;313(5998):144–147. - PubMed
1. Lassman AB, Roberts-Rapp L, Sokolova I, et al. . Comparison of biomarker assays for EGFR: implications for precision medicine in patients with Glioblastoma. Clin Cancer Res. 2019;25(11):3259–3265. - PMC - PubMed
1. Gan HK, Cvrljevic AN, Johns TG. The epidermal growth factor receptor variant III (EGFRvIII): where wild things are altered. FEBS J. 2013;280(21):5350–5370. - PubMed
1. Lee A, Arasaratnam M, Chan DLH, et al. . Anti-epidermal growth factor receptor therapy for glioblastoma in adults. Cochrane Database Syst Rev. 2020;5:CD013238. - PMC - PubMed
1. Cleary JM, Reardon DA, Azad N, et al. . A phase 1 study of ABT-806 in subjects with advanced solid tumors. Invest New Drugs. 2015;33(3):671–678. - PubMed

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[1] Libermann TA, Nusbaum HR, Razon N, et al. . Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 1985;313(5998):144–147. - PubMed

[2] Libermann TA, Nusbaum HR, Razon N, et al. . Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 1985;313(5998):144–147. - PubMed

[3] Lassman AB, Roberts-Rapp L, Sokolova I, et al. . Comparison of biomarker assays for EGFR: implications for precision medicine in patients with Glioblastoma. Clin Cancer Res. 2019;25(11):3259–3265. - PMC - PubMed

[4] Lassman AB, Roberts-Rapp L, Sokolova I, et al. . Comparison of biomarker assays for EGFR: implications for precision medicine in patients with Glioblastoma. Clin Cancer Res. 2019;25(11):3259–3265. - PMC - PubMed

[5] Gan HK, Cvrljevic AN, Johns TG. The epidermal growth factor receptor variant III (EGFRvIII): where wild things are altered. FEBS J. 2013;280(21):5350–5370. - PubMed

[6] Gan HK, Cvrljevic AN, Johns TG. The epidermal growth factor receptor variant III (EGFRvIII): where wild things are altered. FEBS J. 2013;280(21):5350–5370. - PubMed

[7] Lee A, Arasaratnam M, Chan DLH, et al. . Anti-epidermal growth factor receptor therapy for glioblastoma in adults. Cochrane Database Syst Rev. 2020;5:CD013238. - PMC - PubMed

[8] Lee A, Arasaratnam M, Chan DLH, et al. . Anti-epidermal growth factor receptor therapy for glioblastoma in adults. Cochrane Database Syst Rev. 2020;5:CD013238. - PMC - PubMed

[9] Cleary JM, Reardon DA, Azad N, et al. . A phase 1 study of ABT-806 in subjects with advanced solid tumors. Invest New Drugs. 2015;33(3):671–678. - PubMed

[10] Cleary JM, Reardon DA, Azad N, et al. . A phase 1 study of ABT-806 in subjects with advanced solid tumors. Invest New Drugs. 2015;33(3):671–678. - PubMed

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Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial

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Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial

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