Safety and Efficacy of Crizotinib in Combination with Temozolomide and Radiotherapy in Patients with Newly Diagnosed Glioblastoma: Phase Ib GEINO 1402 Trial

Simple Summary Most patients with glioblastoma, the most frequent primary brain tumor in adults, develop resistance to standard first-line treatment combining temozolomide and radiotherapy. Signaling through the hepatocyte growth factor receptor (c-MET) and the midkine (ALK ligand) promotes gliomage...

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Authors: Martínez García, María, Velasco, Guillermo, Pineda, Estela, Gil Gil, Miguel, Alameda, Francesc, Capellades, Jaume, Martín Soberón, Mari Cruz, López Valero, Israel, Tovar Ambel, Elena, Foro, Palmira, Taus, Álvaro, Arumi, Montserrat, Hernández Laín, Aurelio, Sepúlveda Sánchez, Juan Manuel
Format: article
Status:Published version
Publication Date:2022
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/187067
Online Access:https://hdl.handle.net/2445/187067
Access Level:Open access
Keyword:Radioteràpia
Glioma
Radiotherapy
Gliomas
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spelling Safety and Efficacy of Crizotinib in Combination with Temozolomide and Radiotherapy in Patients with Newly Diagnosed Glioblastoma: Phase Ib GEINO 1402 TrialMartínez García, MaríaVelasco, GuillermoPineda, EstelaGil Gil, MiguelAlameda, FrancescCapellades, JaumeMartín Soberón, Mari CruzLópez Valero, IsraelTovar Ambel, ElenaForo, PalmiraTaus, ÁlvaroArumi, MontserratHernández Laín, AurelioSepúlveda Sánchez, Juan ManuelRadioteràpiaGliomaRadiotherapyGliomasSimple Summary Most patients with glioblastoma, the most frequent primary brain tumor in adults, develop resistance to standard first-line treatment combining temozolomide and radiotherapy. Signaling through the hepatocyte growth factor receptor (c-MET) and the midkine (ALK ligand) promotes gliomagenesis and glioma stem cell maintenance, contributing to the resistance of glioma cells to anticancer therapies. This trial reports for the first time that the addition of crizotinib, an ALK, ROS1, and c-MET inhibitor, to standard RT and TMZ is safe and resulted in a promising efficacy for newly diagnosed patients with glioblastoma. Background: MET-signaling and midkine (ALK ligand) promote glioma cell maintenance and resistance against anticancer therapies. ALK and c-MET inhibition with crizotinib have a preclinical therapeutic rationale to be tested in newly diagnosed GBM. Methods: Eligible patients received crizotinib with standard radiotherapy (RT)/temozolomide (TMZ) followed by maintenance with crizotinib. The primary objective was to determine the recommended phase 2 dose (RP2D) in a 3 + 3 dose escalation (DE) strategy and safety evaluation in the expansion cohort (EC). Secondary objectives included progression-free (PFS) and overall survival (OS) and exploratory biomarker analysis. Results: The study enrolled 38 patients. The median age was 52 years (33-76), 44% were male, 44% were MGMT methylated, and three patients had IDH1/2 mutation. In DE, DLTs were reported in 1/6 in the second cohort (250 mg/QD), declaring 250 mg/QD of crizotinib as the RP2D for the EC. In the EC, 9/25 patients (32%) presented grade >= 3 adverse events. The median follow up was 18.7 months (m) and the median PFS was 10.7 m (95% CI, 7.7-13.8), with a 6 m PFS and 12 m PFS of 71.5% and 38.8%, respectively. At the time of this analysis, 1 died without progression and 24 had progressed. The median OS was 22.6 m (95% CI, 14.1-31.1) with a 24 m OS of 44.5%. Molecular biomarkers showed no correlation with efficacy. Conclusions: The addition of crizotinib to standard RT and TMZ for newly diagnosed GBM was safe and the efficacy was encouraging, warranting prospective validation in an adequately powered, randomized controlled study.MDPI2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/187067Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.3390/cancers14102393Cancers, 2022, vol. 14, num. 10https://doi.org/10.3390/cancers14102393cc by (c) Martínez García, María et al, 2022http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1870672026-05-27T06:46:51Z
dc.title.none.fl_str_mv Safety and Efficacy of Crizotinib in Combination with Temozolomide and Radiotherapy in Patients with Newly Diagnosed Glioblastoma: Phase Ib GEINO 1402 Trial
title Safety and Efficacy of Crizotinib in Combination with Temozolomide and Radiotherapy in Patients with Newly Diagnosed Glioblastoma: Phase Ib GEINO 1402 Trial
spellingShingle Safety and Efficacy of Crizotinib in Combination with Temozolomide and Radiotherapy in Patients with Newly Diagnosed Glioblastoma: Phase Ib GEINO 1402 Trial
Martínez García, María
Radioteràpia
Glioma
Radiotherapy
Gliomas
title_short Safety and Efficacy of Crizotinib in Combination with Temozolomide and Radiotherapy in Patients with Newly Diagnosed Glioblastoma: Phase Ib GEINO 1402 Trial
title_full Safety and Efficacy of Crizotinib in Combination with Temozolomide and Radiotherapy in Patients with Newly Diagnosed Glioblastoma: Phase Ib GEINO 1402 Trial
title_fullStr Safety and Efficacy of Crizotinib in Combination with Temozolomide and Radiotherapy in Patients with Newly Diagnosed Glioblastoma: Phase Ib GEINO 1402 Trial
title_full_unstemmed Safety and Efficacy of Crizotinib in Combination with Temozolomide and Radiotherapy in Patients with Newly Diagnosed Glioblastoma: Phase Ib GEINO 1402 Trial
title_sort Safety and Efficacy of Crizotinib in Combination with Temozolomide and Radiotherapy in Patients with Newly Diagnosed Glioblastoma: Phase Ib GEINO 1402 Trial
dc.creator.none.fl_str_mv Martínez García, María
Velasco, Guillermo
Pineda, Estela
Gil Gil, Miguel
Alameda, Francesc
Capellades, Jaume
Martín Soberón, Mari Cruz
López Valero, Israel
Tovar Ambel, Elena
Foro, Palmira
Taus, Álvaro
Arumi, Montserrat
Hernández Laín, Aurelio
Sepúlveda Sánchez, Juan Manuel
author Martínez García, María
author_facet Martínez García, María
Velasco, Guillermo
Pineda, Estela
Gil Gil, Miguel
Alameda, Francesc
Capellades, Jaume
Martín Soberón, Mari Cruz
López Valero, Israel
Tovar Ambel, Elena
Foro, Palmira
Taus, Álvaro
Arumi, Montserrat
Hernández Laín, Aurelio
Sepúlveda Sánchez, Juan Manuel
author_role author
author2 Velasco, Guillermo
Pineda, Estela
Gil Gil, Miguel
Alameda, Francesc
Capellades, Jaume
Martín Soberón, Mari Cruz
López Valero, Israel
Tovar Ambel, Elena
Foro, Palmira
Taus, Álvaro
Arumi, Montserrat
Hernández Laín, Aurelio
Sepúlveda Sánchez, Juan Manuel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Radioteràpia
Glioma
Radiotherapy
Gliomas
topic Radioteràpia
Glioma
Radiotherapy
Gliomas
description Simple Summary Most patients with glioblastoma, the most frequent primary brain tumor in adults, develop resistance to standard first-line treatment combining temozolomide and radiotherapy. Signaling through the hepatocyte growth factor receptor (c-MET) and the midkine (ALK ligand) promotes gliomagenesis and glioma stem cell maintenance, contributing to the resistance of glioma cells to anticancer therapies. This trial reports for the first time that the addition of crizotinib, an ALK, ROS1, and c-MET inhibitor, to standard RT and TMZ is safe and resulted in a promising efficacy for newly diagnosed patients with glioblastoma. Background: MET-signaling and midkine (ALK ligand) promote glioma cell maintenance and resistance against anticancer therapies. ALK and c-MET inhibition with crizotinib have a preclinical therapeutic rationale to be tested in newly diagnosed GBM. Methods: Eligible patients received crizotinib with standard radiotherapy (RT)/temozolomide (TMZ) followed by maintenance with crizotinib. The primary objective was to determine the recommended phase 2 dose (RP2D) in a 3 + 3 dose escalation (DE) strategy and safety evaluation in the expansion cohort (EC). Secondary objectives included progression-free (PFS) and overall survival (OS) and exploratory biomarker analysis. Results: The study enrolled 38 patients. The median age was 52 years (33-76), 44% were male, 44% were MGMT methylated, and three patients had IDH1/2 mutation. In DE, DLTs were reported in 1/6 in the second cohort (250 mg/QD), declaring 250 mg/QD of crizotinib as the RP2D for the EC. In the EC, 9/25 patients (32%) presented grade >= 3 adverse events. The median follow up was 18.7 months (m) and the median PFS was 10.7 m (95% CI, 7.7-13.8), with a 6 m PFS and 12 m PFS of 71.5% and 38.8%, respectively. At the time of this analysis, 1 died without progression and 24 had progressed. The median OS was 22.6 m (95% CI, 14.1-31.1) with a 24 m OS of 44.5%. Molecular biomarkers showed no correlation with efficacy. Conclusions: The addition of crizotinib to standard RT and TMZ for newly diagnosed GBM was safe and the efficacy was encouraging, warranting prospective validation in an adequately powered, randomized controlled study.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/187067
url https://hdl.handle.net/2445/187067
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3390/cancers14102393
Cancers, 2022, vol. 14, num. 10
https://doi.org/10.3390/cancers14102393
dc.rights.none.fl_str_mv cc by (c) Martínez García, María et al, 2022
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Martínez García, María et al, 2022
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300724

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