Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR -amplified, recurrent glioblastoma: Results from an international phase I multicenter trial

Andrew B. Lassman; Martin J. Van Den Bent; Hui K. Gan; David A. Reardon; Priya Kumthekar; Nicholas Butowski; Zarnie Lwin; Tom Mikkelsen; Louis B. Nabors; Kyriakos P. Papadopoulos; Marta Penas-Prado; John Simes; Helen Wheeler; Tobias Walbert; Andrew M. Scott; Erica Gomez; Ho Jin Lee; Lisa Roberts-Rapp; Hao Xiong; Peter J. Ansell; Earle Bain; Kyle D. Holen; David Maag; Ryan Merrell

doi:10.1093/neuonc/noy091

Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR -amplified, recurrent glioblastoma: Results from an international phase I multicenter trial

Andrew B. Lassman^*, Martin J. Van Den Bent, Hui K. Gan, David A. Reardon, Priya Kumthekar, Nicholas Butowski, Zarnie Lwin, Tom Mikkelsen, Louis B. Nabors, Kyriakos P. Papadopoulos, Marta Penas-Prado, John Simes, Helen Wheeler, Tobias Walbert, Andrew M. Scott, Erica Gomez, Ho Jin Lee, Lisa Roberts-Rapp, Hao Xiong, Peter J. AnsellEarle Bain, Kyle D. Holen, David Maag, Ryan Merrell

^*Corresponding author for this work

Neurology

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

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Abstract

Background Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM. Methods M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5-1.5 mg/kg) on days 1 and 15, and TMZ (150-200 mg/m 2) on days 1-5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve. Results There were 60 patients, median age 56 years (range, 20-79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%. Conclusions Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).

Original language	English
Pages (from-to)	106-114
Number of pages	9
Journal	Neuro-Oncology
Volume	21
Issue number	1
DOIs	https://doi.org/10.1093/neuonc/noy091
Publication status	Published - Jan 2019

Bibliographical note

Funding Information:
ing or advisory role with Abbvie, Bristol Myers Squibb, Cavion, Celldex, Inovio, Merck, Novartis, Roche/Genentech, Amgen, Novocure, Oxigene, Regeneron and Stemline Therapeutics; is involved in speakers’ bureaus with Roche and Merck; received research funding from Incyte, Midatech and Celldex Priya Kumthekar: Advisory fees from AbbVie, Angiochem, Orbus Therapeutics; investigator for AbbVie Nicholas Butowski: Received honoraria from and has a consulting or advisory role with Roche/Genentech, Medicenna, VBL Theraputics, Omniox; is involved in speakers’ bureaus with Roche and Merck; received research funding from Insys Zarnie Lwin: Has served on AbbVie Scientific Advisory Board and received honoraria Louis B. Nabors: Serves on a Scientific Advisory Board for Cavion, Merck, and BMS; investigator for AbbVie Kyriakos P. Papadopoulos: Received research funding from AbbVie, MedImmune, Daiichi Sankyo, GlaxoSmithKline, Onyx, Sanofi, Novartis John Simes: Received research funding for an investigator-initiated trial from AbbVie Helen Wheeler: Investigator for AbbVie Tobias Walbert: Serves on a Scientific Advisory Board for AbbVie and Tocagen Andrew M. Scott: Received research funding and travel support from AbbVie; received research funding from Daiichi-Sankyo; consultant for and has stock in Life Science Pharmaceuticals; affiliated with the Ludwig Institute for Cancer Research Erica Gomez, Ho-Jin Lee, Lisa Roberts-Rapp, Hao Xiong, Peter J. Ansell, Earle Bain, Kyle D. Holen, David Maag: Employees of AbbVie and may own stock or options Ryan Merrell: Serves on a Scientific Advisory Board for AbbVie

Funding Information:
2 years, received: honoraria from prIME Oncology, WebMD, Italian Association for Cancer Research, American Academy of Neurology, American Society of Clinical Oncology; consulting/advisory role for Bioclinica, Celgene, Sapience, AbbVie, Cortice, Kadmon, Novocure, AstraZeneca, Genentech; research support (to institution) from AbbVie. Martin J. van den Bent: Received honoraria from Roche, AbbVie, Celldex, Merck Ag, Cavion, Actelion, BMS, Blue Earth Diagnostics and Novartis; received research funding from AbbVie Hui K. Gan: Consulting/advisory role for AbbVie; speakers’ bureau for Ignyta, Bristol-Myers Squibb; research funding from AbbVie; travel, accommodations, expenses from Ignyta; affiliated with the Ludwig Institute for Cancer Research

Publisher Copyright:
© The Author(s) 2018.

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Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR-amplified, recurrent glioblastoma results from an international phase I multicenter trialFinal published version, 433 KBLicence: CC BY-NC

Cite this

Lassman, A. B., Van Den Bent, M. J., Gan, H. K., Reardon, D. A., Kumthekar, P., Butowski, N., Lwin, Z., Mikkelsen, T., Nabors, L. B., Papadopoulos, K. P., Penas-Prado, M., Simes, J., Wheeler, H., Walbert, T., Scott, A. M., Gomez, E., Lee, H. J., Roberts-Rapp, L., Xiong, H., ... Merrell, R. (2019). Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR -amplified, recurrent glioblastoma: Results from an international phase I multicenter trial. Neuro-Oncology, 21(1), 106-114. https://doi.org/10.1093/neuonc/noy091

@article{a6d634d2cf7741a885f899e93079ff3f,

title = "Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR -amplified, recurrent glioblastoma: Results from an international phase I multicenter trial",

abstract = "Background Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM. Methods M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5-1.5 mg/kg) on days 1 and 15, and TMZ (150-200 mg/m 2) on days 1-5 in a 28-day cycle. Patients were bevacizumab and nitrosourea na{\"i}ve. Results There were 60 patients, median age 56 years (range, 20-79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%. Conclusions Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).",

author = "Lassman, {Andrew B.} and {Van Den Bent}, {Martin J.} and Gan, {Hui K.} and Reardon, {David A.} and Priya Kumthekar and Nicholas Butowski and Zarnie Lwin and Tom Mikkelsen and Nabors, {Louis B.} and Papadopoulos, {Kyriakos P.} and Marta Penas-Prado and John Simes and Helen Wheeler and Tobias Walbert and Scott, {Andrew M.} and Erica Gomez and Lee, {Ho Jin} and Lisa Roberts-Rapp and Hao Xiong and Ansell, {Peter J.} and Earle Bain and Holen, {Kyle D.} and David Maag and Ryan Merrell",

note = "Funding Information: ing or advisory role with Abbvie, Bristol Myers Squibb, Cavion, Celldex, Inovio, Merck, Novartis, Roche/Genentech, Amgen, Novocure, Oxigene, Regeneron and Stemline Therapeutics; is involved in speakers{\textquoteright} bureaus with Roche and Merck; received research funding from Incyte, Midatech and Celldex Priya Kumthekar: Advisory fees from AbbVie, Angiochem, Orbus Therapeutics; investigator for AbbVie Nicholas Butowski: Received honoraria from and has a consulting or advisory role with Roche/Genentech, Medicenna, VBL Theraputics, Omniox; is involved in speakers{\textquoteright} bureaus with Roche and Merck; received research funding from Insys Zarnie Lwin: Has served on AbbVie Scientific Advisory Board and received honoraria Louis B. Nabors: Serves on a Scientific Advisory Board for Cavion, Merck, and BMS; investigator for AbbVie Kyriakos P. Papadopoulos: Received research funding from AbbVie, MedImmune, Daiichi Sankyo, GlaxoSmithKline, Onyx, Sanofi, Novartis John Simes: Received research funding for an investigator-initiated trial from AbbVie Helen Wheeler: Investigator for AbbVie Tobias Walbert: Serves on a Scientific Advisory Board for AbbVie and Tocagen Andrew M. Scott: Received research funding and travel support from AbbVie; received research funding from Daiichi-Sankyo; consultant for and has stock in Life Science Pharmaceuticals; affiliated with the Ludwig Institute for Cancer Research Erica Gomez, Ho-Jin Lee, Lisa Roberts-Rapp, Hao Xiong, Peter J. Ansell, Earle Bain, Kyle D. Holen, David Maag: Employees of AbbVie and may own stock or options Ryan Merrell: Serves on a Scientific Advisory Board for AbbVie Funding Information: 2 years, received: honoraria from prIME Oncology, WebMD, Italian Association for Cancer Research, American Academy of Neurology, American Society of Clinical Oncology; consulting/advisory role for Bioclinica, Celgene, Sapience, AbbVie, Cortice, Kadmon, Novocure, AstraZeneca, Genentech; research support (to institution) from AbbVie. Martin J. van den Bent: Received honoraria from Roche, AbbVie, Celldex, Merck Ag, Cavion, Actelion, BMS, Blue Earth Diagnostics and Novartis; received research funding from AbbVie Hui K. Gan: Consulting/advisory role for AbbVie; speakers{\textquoteright} bureau for Ignyta, Bristol-Myers Squibb; research funding from AbbVie; travel, accommodations, expenses from Ignyta; affiliated with the Ludwig Institute for Cancer Research Publisher Copyright: {\textcopyright} The Author(s) 2018.",

year = "2019",

month = jan,

doi = "10.1093/neuonc/noy091",

language = "English",

volume = "21",

pages = "106--114",

journal = "Neuro-Oncology",

issn = "1522-8517",

publisher = "Oxford University Press",

number = "1",

}

Lassman, AB, Van Den Bent, MJ, Gan, HK, Reardon, DA, Kumthekar, P, Butowski, N, Lwin, Z, Mikkelsen, T, Nabors, LB, Papadopoulos, KP, Penas-Prado, M, Simes, J, Wheeler, H, Walbert, T, Scott, AM, Gomez, E, Lee, HJ, Roberts-Rapp, L, Xiong, H, Ansell, PJ, Bain, E, Holen, KD, Maag, D & Merrell, R 2019, 'Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR -amplified, recurrent glioblastoma: Results from an international phase I multicenter trial', Neuro-Oncology, vol. 21, no. 1, pp. 106-114. https://doi.org/10.1093/neuonc/noy091

Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR -amplified, recurrent glioblastoma: Results from an international phase I multicenter trial. / Lassman, Andrew B.; Van Den Bent, Martin J.; Gan, Hui K. et al.
In: Neuro-Oncology, Vol. 21, No. 1, 01.2019, p. 106-114.

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

TY - JOUR

T1 - Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR -amplified, recurrent glioblastoma

T2 - Results from an international phase I multicenter trial

AU - Lassman, Andrew B.

AU - Van Den Bent, Martin J.

AU - Gan, Hui K.

AU - Reardon, David A.

AU - Kumthekar, Priya

AU - Butowski, Nicholas

AU - Lwin, Zarnie

AU - Mikkelsen, Tom

AU - Nabors, Louis B.

AU - Papadopoulos, Kyriakos P.

AU - Penas-Prado, Marta

AU - Simes, John

AU - Wheeler, Helen

AU - Walbert, Tobias

AU - Scott, Andrew M.

AU - Gomez, Erica

AU - Lee, Ho Jin

AU - Roberts-Rapp, Lisa

AU - Xiong, Hao

AU - Ansell, Peter J.

AU - Bain, Earle

AU - Holen, Kyle D.

AU - Maag, David

AU - Merrell, Ryan

N1 - Funding Information: ing or advisory role with Abbvie, Bristol Myers Squibb, Cavion, Celldex, Inovio, Merck, Novartis, Roche/Genentech, Amgen, Novocure, Oxigene, Regeneron and Stemline Therapeutics; is involved in speakers’ bureaus with Roche and Merck; received research funding from Incyte, Midatech and Celldex Priya Kumthekar: Advisory fees from AbbVie, Angiochem, Orbus Therapeutics; investigator for AbbVie Nicholas Butowski: Received honoraria from and has a consulting or advisory role with Roche/Genentech, Medicenna, VBL Theraputics, Omniox; is involved in speakers’ bureaus with Roche and Merck; received research funding from Insys Zarnie Lwin: Has served on AbbVie Scientific Advisory Board and received honoraria Louis B. Nabors: Serves on a Scientific Advisory Board for Cavion, Merck, and BMS; investigator for AbbVie Kyriakos P. Papadopoulos: Received research funding from AbbVie, MedImmune, Daiichi Sankyo, GlaxoSmithKline, Onyx, Sanofi, Novartis John Simes: Received research funding for an investigator-initiated trial from AbbVie Helen Wheeler: Investigator for AbbVie Tobias Walbert: Serves on a Scientific Advisory Board for AbbVie and Tocagen Andrew M. Scott: Received research funding and travel support from AbbVie; received research funding from Daiichi-Sankyo; consultant for and has stock in Life Science Pharmaceuticals; affiliated with the Ludwig Institute for Cancer Research Erica Gomez, Ho-Jin Lee, Lisa Roberts-Rapp, Hao Xiong, Peter J. Ansell, Earle Bain, Kyle D. Holen, David Maag: Employees of AbbVie and may own stock or options Ryan Merrell: Serves on a Scientific Advisory Board for AbbVie Funding Information: 2 years, received: honoraria from prIME Oncology, WebMD, Italian Association for Cancer Research, American Academy of Neurology, American Society of Clinical Oncology; consulting/advisory role for Bioclinica, Celgene, Sapience, AbbVie, Cortice, Kadmon, Novocure, AstraZeneca, Genentech; research support (to institution) from AbbVie. Martin J. van den Bent: Received honoraria from Roche, AbbVie, Celldex, Merck Ag, Cavion, Actelion, BMS, Blue Earth Diagnostics and Novartis; received research funding from AbbVie Hui K. Gan: Consulting/advisory role for AbbVie; speakers’ bureau for Ignyta, Bristol-Myers Squibb; research funding from AbbVie; travel, accommodations, expenses from Ignyta; affiliated with the Ludwig Institute for Cancer Research Publisher Copyright: © The Author(s) 2018.

PY - 2019/1

Y1 - 2019/1

N2 - Background Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM. Methods M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5-1.5 mg/kg) on days 1 and 15, and TMZ (150-200 mg/m 2) on days 1-5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve. Results There were 60 patients, median age 56 years (range, 20-79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%. Conclusions Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).

AB - Background Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM. Methods M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5-1.5 mg/kg) on days 1 and 15, and TMZ (150-200 mg/m 2) on days 1-5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve. Results There were 60 patients, median age 56 years (range, 20-79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%. Conclusions Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).

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U2 - 10.1093/neuonc/noy091

DO - 10.1093/neuonc/noy091

M3 - Article

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AN - SCOPUS:85059226044

SN - 1522-8517

VL - 21

SP - 106

EP - 114

JO - Neuro-Oncology

JF - Neuro-Oncology

IS - 1

ER -

Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR -amplified, recurrent glioblastoma: Results from an international phase I multicenter trial

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