Cargando…

Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial

BACKGROUND: Availability of checkpoint inhibitors has created a paradigm shift in the management of patients with solid tumors. Despite this, most patients do not respond to immunotherapy, and there is considerable interest in developing combination therapies to improve response rates and outcomes....

Descripción completa

Detalles Bibliográficos
Autores principales: Aggarwal, Charu, Prawira, Amy, Antonia, Scott, Rahma, Osama, Tolcher, Anthony, Cohen, Roger B, Lou, Yanyan, Hauke, Ralph, Vogelzang, Nicholas, P Zandberg, Dan, Kalebasty, Arash Rezazadeh, Atkinson, Victoria, Adjei, Alex A, Seetharam, Mahesh, Birnbaum, Ariel, Weickhardt, Andrew, Ganju, Vinod, Joshua, Anthony M, Cavallo, Rosetta, Peng, Linda, Zhang, Xiaoyu, Kaul, Sanjeev, Baughman, Jan, Bonvini, Ezio, Moore, Paul A, Goldberg, Stacie M, Arnaldez, Fernanda I, Ferris, Robert L, Lakhani, Nehal J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9006844/
https://www.ncbi.nlm.nih.gov/pubmed/35414591
http://dx.doi.org/10.1136/jitc-2021-004424
_version_ 1784686745537740800
author Aggarwal, Charu
Prawira, Amy
Antonia, Scott
Rahma, Osama
Tolcher, Anthony
Cohen, Roger B
Lou, Yanyan
Hauke, Ralph
Vogelzang, Nicholas
P Zandberg, Dan
Kalebasty, Arash Rezazadeh
Atkinson, Victoria
Adjei, Alex A
Seetharam, Mahesh
Birnbaum, Ariel
Weickhardt, Andrew
Ganju, Vinod
Joshua, Anthony M
Cavallo, Rosetta
Peng, Linda
Zhang, Xiaoyu
Kaul, Sanjeev
Baughman, Jan
Bonvini, Ezio
Moore, Paul A
Goldberg, Stacie M
Arnaldez, Fernanda I
Ferris, Robert L
Lakhani, Nehal J
author_facet Aggarwal, Charu
Prawira, Amy
Antonia, Scott
Rahma, Osama
Tolcher, Anthony
Cohen, Roger B
Lou, Yanyan
Hauke, Ralph
Vogelzang, Nicholas
P Zandberg, Dan
Kalebasty, Arash Rezazadeh
Atkinson, Victoria
Adjei, Alex A
Seetharam, Mahesh
Birnbaum, Ariel
Weickhardt, Andrew
Ganju, Vinod
Joshua, Anthony M
Cavallo, Rosetta
Peng, Linda
Zhang, Xiaoyu
Kaul, Sanjeev
Baughman, Jan
Bonvini, Ezio
Moore, Paul A
Goldberg, Stacie M
Arnaldez, Fernanda I
Ferris, Robert L
Lakhani, Nehal J
author_sort Aggarwal, Charu
collection PubMed
description BACKGROUND: Availability of checkpoint inhibitors has created a paradigm shift in the management of patients with solid tumors. Despite this, most patients do not respond to immunotherapy, and there is considerable interest in developing combination therapies to improve response rates and outcomes. B7-H3 (CD276) is a member of the B7 family of cell surface molecules and provides an alternative immune checkpoint molecule to therapeutically target alone or in combination with programmed cell death-1 (PD-1)–targeted therapies. Enoblituzumab, an investigational anti-B7-H3 humanized monoclonal antibody, incorporates an immunoglobulin G1 fragment crystallizable (Fc) domain that enhances Fcγ receptor-mediated antibody-dependent cellular cytotoxicity. Coordinated engagement of innate and adaptive immunity by targeting distinct members of the B7 family (B7-H3 and PD-1) is hypothesized to provide greater antitumor activity than either agent alone. METHODS: In this phase I/II study, patients received intravenous enoblituzumab (3–15 mg/kg) weekly plus intravenous pembrolizumab (2 mg/kg) every 3 weeks during dose-escalation and cohort expansion. Expansion cohorts included non–small cell lung cancer (NSCLC; checkpoint inhibitor [CPI]–naïve and post-CPI, programmed death-ligand 1 [PD-L1] <1%), head and neck squamous cell carcinoma (HNSCC; CPI-naïve), urothelial cancer (post-CPI), and melanoma (post-CPI). Disease was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 after 6 weeks and every 9 weeks thereafter. Safety and pharmacokinetic data were provided for all enrolled patients; efficacy data focused on HNSCC and NSCLC cohorts. RESULTS: Overall, 133 patients were enrolled and received ≥1 dose of study treatment. The maximum tolerated dose of enoblituzumab with pembrolizumab at 2 mg/kg was not reached. Intravenous enoblituzumab (15 mg/kg) every 3 weeks plus pembrolizumab (2 mg/kg) every 3 weeks was recommended for phase II evaluation. Treatment-related adverse events occurred in 116 patients (87.2%) and were grade ≥3 in 28.6%. One treatment-related death occurred (pneumonitis). Objective responses occurred in 6 of 18 (33.3% [95% CI 13.3 to 59.0]) patients with CPI-naïve HNSCC and in 5 of 14 (35.7% [95% CI 12.8 to 64.9]) patients with CPI-naïve NSCLC. CONCLUSIONS: Checkpoint targeting with enoblituzumab and pembrolizumab demonstrated acceptable safety and antitumor activity in patients with CPI-naïve HNSCC and NSCLC. TRIAL REGISTRATION NUMBER: NCT02475213.
format Online
Article
Text
id pubmed-9006844
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher BMJ Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-90068442022-05-02 Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial Aggarwal, Charu Prawira, Amy Antonia, Scott Rahma, Osama Tolcher, Anthony Cohen, Roger B Lou, Yanyan Hauke, Ralph Vogelzang, Nicholas P Zandberg, Dan Kalebasty, Arash Rezazadeh Atkinson, Victoria Adjei, Alex A Seetharam, Mahesh Birnbaum, Ariel Weickhardt, Andrew Ganju, Vinod Joshua, Anthony M Cavallo, Rosetta Peng, Linda Zhang, Xiaoyu Kaul, Sanjeev Baughman, Jan Bonvini, Ezio Moore, Paul A Goldberg, Stacie M Arnaldez, Fernanda I Ferris, Robert L Lakhani, Nehal J J Immunother Cancer Clinical/Translational Cancer Immunotherapy BACKGROUND: Availability of checkpoint inhibitors has created a paradigm shift in the management of patients with solid tumors. Despite this, most patients do not respond to immunotherapy, and there is considerable interest in developing combination therapies to improve response rates and outcomes. B7-H3 (CD276) is a member of the B7 family of cell surface molecules and provides an alternative immune checkpoint molecule to therapeutically target alone or in combination with programmed cell death-1 (PD-1)–targeted therapies. Enoblituzumab, an investigational anti-B7-H3 humanized monoclonal antibody, incorporates an immunoglobulin G1 fragment crystallizable (Fc) domain that enhances Fcγ receptor-mediated antibody-dependent cellular cytotoxicity. Coordinated engagement of innate and adaptive immunity by targeting distinct members of the B7 family (B7-H3 and PD-1) is hypothesized to provide greater antitumor activity than either agent alone. METHODS: In this phase I/II study, patients received intravenous enoblituzumab (3–15 mg/kg) weekly plus intravenous pembrolizumab (2 mg/kg) every 3 weeks during dose-escalation and cohort expansion. Expansion cohorts included non–small cell lung cancer (NSCLC; checkpoint inhibitor [CPI]–naïve and post-CPI, programmed death-ligand 1 [PD-L1] <1%), head and neck squamous cell carcinoma (HNSCC; CPI-naïve), urothelial cancer (post-CPI), and melanoma (post-CPI). Disease was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 after 6 weeks and every 9 weeks thereafter. Safety and pharmacokinetic data were provided for all enrolled patients; efficacy data focused on HNSCC and NSCLC cohorts. RESULTS: Overall, 133 patients were enrolled and received ≥1 dose of study treatment. The maximum tolerated dose of enoblituzumab with pembrolizumab at 2 mg/kg was not reached. Intravenous enoblituzumab (15 mg/kg) every 3 weeks plus pembrolizumab (2 mg/kg) every 3 weeks was recommended for phase II evaluation. Treatment-related adverse events occurred in 116 patients (87.2%) and were grade ≥3 in 28.6%. One treatment-related death occurred (pneumonitis). Objective responses occurred in 6 of 18 (33.3% [95% CI 13.3 to 59.0]) patients with CPI-naïve HNSCC and in 5 of 14 (35.7% [95% CI 12.8 to 64.9]) patients with CPI-naïve NSCLC. CONCLUSIONS: Checkpoint targeting with enoblituzumab and pembrolizumab demonstrated acceptable safety and antitumor activity in patients with CPI-naïve HNSCC and NSCLC. TRIAL REGISTRATION NUMBER: NCT02475213. BMJ Publishing Group 2022-04-12 /pmc/articles/PMC9006844/ /pubmed/35414591 http://dx.doi.org/10.1136/jitc-2021-004424 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.
spellingShingle Clinical/Translational Cancer Immunotherapy
Aggarwal, Charu
Prawira, Amy
Antonia, Scott
Rahma, Osama
Tolcher, Anthony
Cohen, Roger B
Lou, Yanyan
Hauke, Ralph
Vogelzang, Nicholas
P Zandberg, Dan
Kalebasty, Arash Rezazadeh
Atkinson, Victoria
Adjei, Alex A
Seetharam, Mahesh
Birnbaum, Ariel
Weickhardt, Andrew
Ganju, Vinod
Joshua, Anthony M
Cavallo, Rosetta
Peng, Linda
Zhang, Xiaoyu
Kaul, Sanjeev
Baughman, Jan
Bonvini, Ezio
Moore, Paul A
Goldberg, Stacie M
Arnaldez, Fernanda I
Ferris, Robert L
Lakhani, Nehal J
Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial
title Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial
title_full Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial
title_fullStr Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial
title_full_unstemmed Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial
title_short Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial
title_sort dual checkpoint targeting of b7-h3 and pd-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase i/ii trial
topic Clinical/Translational Cancer Immunotherapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9006844/
https://www.ncbi.nlm.nih.gov/pubmed/35414591
http://dx.doi.org/10.1136/jitc-2021-004424
work_keys_str_mv AT aggarwalcharu dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT prawiraamy dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT antoniascott dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT rahmaosama dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT tolcheranthony dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT cohenrogerb dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT louyanyan dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT haukeralph dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT vogelzangnicholas dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT pzandbergdan dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT kalebastyarashrezazadeh dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT atkinsonvictoria dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT adjeialexa dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT seetharammahesh dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT birnbaumariel dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT weickhardtandrew dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT ganjuvinod dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT joshuaanthonym dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT cavallorosetta dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT penglinda dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT zhangxiaoyu dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT kaulsanjeev dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT baughmanjan dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT bonviniezio dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT moorepaula dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT goldbergstaciem dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT arnaldezfernandai dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT ferrisrobertl dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial
AT lakhaninehalj dualcheckpointtargetingofb7h3andpd1withenoblituzumabandpembrolizumabinadvancedsolidtumorsinterimresultsfromamulticenterphaseiiitrial