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

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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
Pages (from-to)	339-350
Number of pages	12
Journal	Neuro-oncology
Volume	25
Issue number	2
Early online date	15 Jul 2022
DOIs	https://doi.org/10.1093/neuonc/noac173
Publication status	Published - 1 Feb 2023

Keywords

EGFR
antibody drug conjugate
depatuxizumab mafodotin
glioblastoma
phase III

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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

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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 = "EGFR, antibody drug conjugate, depatuxizumab mafodotin, 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",

volume = "25",

pages = "339--350",

journal = "Neuro-oncology",

issn = "1522-8517",

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number = "2",

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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

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 - EGFR

KW - antibody drug conjugate

KW - depatuxizumab mafodotin

KW - glioblastoma

KW - phase III

UR - http://www.scopus.com/inward/record.url?scp=85148113365&partnerID=8YFLogxK

U2 - 10.1093/neuonc/noac173

DO - 10.1093/neuonc/noac173

M3 - Article

C2 - 35849035

SN - 1522-8517

VL - 25

SP - 339

EP - 350

JO - Neuro-oncology

JF - Neuro-oncology

IS - 2

ER -

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

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