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

Andrew B Lassman; Stephanie L Pugh; Tony J C Wang; Kenneth Aldape; Hui K Gan; Matthias Preusser; Michael A Vogelbaum; Erik P Sulman; Minhee Won; Peixin Zhang; Golnaz Moazami; Marian S Macsai; Mark R Gilbert; Earle E Bain; Vincent Blot; Peter J Ansell; Suvajit Samanta; Madan G Kundu; Terri S Armstrong; Jeffrey S Wefel; Clemens Seidel; Filip Y de Vos; Sigmund Hsu; Andrés F Cardona; Giuseppe Lombardi; Dmitry Bentsion; Richard A Peterson; Craig Gedye; Véronique Bourg; Antje Wick; Walter J Curran; Minesh P Mehta

doi:10.1093/neuonc/noac173

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

Neuro Oncol. 2023 Feb 14;25(2):339-350. doi: 10.1093/neuonc/noac173.

Authors

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.

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.

Publication types

Randomized Controlled Trial
Clinical Trial, Phase III
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Antibodies, Monoclonal, Humanized
Brain Neoplasms* / drug therapy
Brain Neoplasms* / genetics
Brain Neoplasms* / pathology
ErbB Receptors
Female
Glioblastoma* / drug therapy
Glioblastoma* / genetics
Glioblastoma* / metabolism
Humans
Male
Middle Aged
Temozolomide / therapeutic use

Substances

depatuxizumab mafodotin
Antibodies, Monoclonal, Humanized
Temozolomide
ErbB Receptors
EGFR protein, human