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

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. WefelClemens 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

Neuro-Oncology

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

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.

Original language	English (US)
Pages (from-to)	339-350
Number of pages	12
Journal	Neuro-oncology
Volume	25
Issue number	2
DOIs	https://doi.org/10.1093/neuonc/noac173
State	Published - Feb 1 2023

Keywords

antibody drug conjugate
depatuxizumab mafodotin
EGFR
glioblastoma
phase III

ASJC Scopus subject areas

Oncology
Clinical Neurology
Cancer Research

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10.1093/neuonc/noac173

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Lassman, A. B., Pugh, S. L., Wang, T. J. C., Aldape, K., Gan, H. K., Preusser, M., Vogelbaum, M. A., Sulman, E. P., Won, M., Zhang, P., Moazami, G., MacSai, M. S., Gilbert, M. R., Bain, E. E., Blot, V., Ansell, P. J., Samanta, S., Kundu, M. G., Armstrong, T. S., ... Mehta, M. P. (2023). Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial. Neuro-oncology, 25(2), 339-350. https://doi.org/10.1093/neuonc/noac173

Lassman, AB, Pugh, SL, Wang, TJC, Aldape, K, Gan, HK, Preusser, M, Vogelbaum, MA, Sulman, EP, Won, M, Zhang, P, Moazami, G, MacSai, MS, Gilbert, MR, Bain, EE, Blot, V, Ansell, PJ, Samanta, S, Kundu, MG, Armstrong, TS, Wefel, JS, Seidel, C, De Vos, FY, Hsu, S, Cardona, AF, Lombardi, G, Bentsion, D, Peterson, RA, Gedye, C, Bourg, V, Wick, A, Curran, WJ & Mehta, MP 2023, 'Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial', Neuro-oncology, vol. 25, no. 2, pp. 339-350. https://doi.org/10.1093/neuonc/noac173

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

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 = "antibody drug conjugate, depatuxizumab mafodotin, EGFR, glioblastoma, phase III",

author = "Lassman, {Andrew B.} and Pugh, {Stephanie L.} and Wang, {Tony J.C.} and Kenneth Aldape and Gan, {Hui K.} and Matthias Preusser and Vogelbaum, {Michael A.} and Sulman, {Erik P.} and Minhee Won and Peixin Zhang and Golnaz Moazami and MacSai, {Marian S.} and Gilbert, {Mark R.} and Bain, {Earle E.} and Vincent Blot and Ansell, {Peter J.} and Suvajit Samanta and Kundu, {Madan G.} and Armstrong, {Terri S.} and Wefel, {Jeffrey S.} and Clemens Seidel and {De Vos}, {Filip Y.} and Sigmund Hsu and Cardona, {Andr{\'e}s F.} and Giuseppe Lombardi and Dmitry Bentsion and Peterson, {Richard A.} and Craig Gedye and V{\'e}ronique Bourg and Antje Wick and Curran, {Walter J.} and Mehta, {Minesh P.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s). Published by Oxford University Press on behalf of the Society for Neuro-Oncology.",

year = "2023",

month = feb,

day = "1",

doi = "10.1093/neuonc/noac173",

language = "English (US)",

volume = "25",

pages = "339--350",

journal = "Neuro-oncology",

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TY - JOUR

T1 - Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma

T2 - A phase III randomized clinical trial

AU - Lassman, Andrew B.

AU - Pugh, Stephanie L.

AU - Wang, Tony J.C.

AU - Aldape, Kenneth

AU - Gan, Hui K.

AU - Preusser, Matthias

AU - Vogelbaum, Michael A.

AU - Sulman, Erik P.

AU - Won, Minhee

AU - Zhang, Peixin

AU - Moazami, Golnaz

AU - MacSai, Marian S.

AU - Gilbert, Mark R.

AU - Bain, Earle E.

AU - Blot, Vincent

AU - Ansell, Peter J.

AU - Samanta, Suvajit

AU - Kundu, Madan G.

AU - Armstrong, Terri S.

AU - Wefel, Jeffrey S.

AU - Seidel, Clemens

AU - De Vos, Filip Y.

AU - Hsu, Sigmund

AU - Cardona, Andrés F.

AU - Lombardi, Giuseppe

AU - Bentsion, Dmitry

AU - Peterson, Richard A.

AU - Gedye, Craig

AU - Bourg, Véronique

AU - Wick, Antje

AU - Curran, Walter J.

AU - Mehta, Minesh P.

PY - 2023/2/1

Y1 - 2023/2/1

N2 - 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.

AB - 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.

KW - antibody drug conjugate

KW - depatuxizumab mafodotin

KW - EGFR

KW - glioblastoma

KW - phase III

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

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