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Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy by Tumor Mutational Burden in Metastatic Castration-Resistant Prostate Cancer

IMPORTANCE: The most useful biomarkers for clinical decision-making identify patients likely to have improved outcomes with one treatment vs another. OBJECTIVE: To evaluate treatment class-specific outcomes of patients receiving immune checkpoint inhibitor (ICI) vs taxane chemotherapy by tumor mutat...

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Autores principales: Graf, Ryon P., Fisher, Virginia, Weberpals, Janick, Gjoerup, Ole, Tierno, Marni B., Huang, Richard S. P., Sayegh, Nicolas, Lin, Douglas I., Raskina, Kira, Schrock, Alexa B., Severson, Eric, Haberberger, James F., Ross, Jeffrey S., Creeden, James, Levy, Mia A., Alexander, Brian M., Oxnard, Geoffrey R., Agarwal, Neeraj
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Medical Association 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8972027/
https://www.ncbi.nlm.nih.gov/pubmed/35357449
http://dx.doi.org/10.1001/jamanetworkopen.2022.5394
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author Graf, Ryon P.
Fisher, Virginia
Weberpals, Janick
Gjoerup, Ole
Tierno, Marni B.
Huang, Richard S. P.
Sayegh, Nicolas
Lin, Douglas I.
Raskina, Kira
Schrock, Alexa B.
Severson, Eric
Haberberger, James F.
Ross, Jeffrey S.
Creeden, James
Levy, Mia A.
Alexander, Brian M.
Oxnard, Geoffrey R.
Agarwal, Neeraj
author_facet Graf, Ryon P.
Fisher, Virginia
Weberpals, Janick
Gjoerup, Ole
Tierno, Marni B.
Huang, Richard S. P.
Sayegh, Nicolas
Lin, Douglas I.
Raskina, Kira
Schrock, Alexa B.
Severson, Eric
Haberberger, James F.
Ross, Jeffrey S.
Creeden, James
Levy, Mia A.
Alexander, Brian M.
Oxnard, Geoffrey R.
Agarwal, Neeraj
author_sort Graf, Ryon P.
collection PubMed
description IMPORTANCE: The most useful biomarkers for clinical decision-making identify patients likely to have improved outcomes with one treatment vs another. OBJECTIVE: To evaluate treatment class-specific outcomes of patients receiving immune checkpoint inhibitor (ICI) vs taxane chemotherapy by tumor mutational burden (TMB). DESIGN, SETTING, AND PARTICIPANTS: This comparative effectiveness analysis of clinical variables and outcomes used prospectively defined biomarker-stratified genomic data from a deidentified clinicogenomic database. Data included men with previously treated metastatic castration-resistant prostate cancer (mCRPC) receiving ICI or single-agent taxane chemotherapy from January 2011 to April 2021 at approximately 280 US academic or community-based cancer clinics (approximately 800 sites of care). Data were analyzed from July to August 2021. EXPOSURES: Single-agent ICI or single-agent taxanes. Treatments were assigned at discretion of physician and patient without randomization. Imbalances of known factors between treatment groups were adjusted with propensity weighting. MAIN OUTCOMES AND MEASURES: Prostate-specific antigen (PSA) response, time to next therapy (TTNT), and overall survival (OS). RESULTS: A total of 741 men (median [IQR], 70 [64-76] years) with mCRPC received comprehensive genomic profiling and were treated with ICI or single-agent taxane therapy. At baseline, the median (IQR) PSA level was 79.4 (19.0-254) ng/mL, 108 men (18.8%) had Eastern Cooperative Oncology Group Performance Status scores of 2 or greater, and 644 men (86.9%) had received prior systemic treatments for mCRPC. A total of 45 patients (6.1%) received ICI therapy and 696 patients (93.9%) received taxane therapy. Among patients with TMB of fewer than 10 mutations per megabase (mt/Mb) receiving ICI, compared with those receiving taxanes, had worse TTNT (median [IQR], 2.4 [1.1-3.2] months vs 4.1 [2.2-6.3] months; hazard ratio [HR], 2.65; 95% CI, 1.78-3.95; P < .001). In contrast, for patients with TMB of 10 mt/Mb or greater, use of ICIs, compared with use taxanes, was associated with more favorable TTNT (median [IQR], 8.0 [3.4 to unknown] months vs 2.4 [2.4-7.3] months; HR, 0.37, 95% CI, 0.15-0.87; P = .02) and OS (median 19.9 [8.06 to unknown] months vs 4.2 [2.69 – 6.12] months; HR, 0.23; 95% CI, 0.10-0.57; P = .001). Among all 741 patients, 44 (5.9%) had TMB of 10 mt/Mb or greater, 22 (3.0%) had high microsatellite instability, and 20 (2.7%) had both. Treatment interactions with TMB of 10 mt/Mb or greater (TTNT: HR, 0.10; 95% CI, 0.32-0.31; P < .001; OS: HR, 0.25; 95% CI, 0.076-0.81; P = .02) were stronger than high microsatellite instability alone (TTNT: HR, 0.12; 95% CI, 0.03-0.51; P = .004; OS: HR, 0.38; 95% CI, 0.13-1.12; P = .08). CONCLUSIONS AND RELEVANCE: In this comparative effectiveness study, ICIs were more effective than taxanes in patients with mCRPC when TMB was 10 mt/Mb or greater but not when TMB was fewer than 10 mt/Mb. The results add validity to the existing TMB cutoff of 10 mt/Mb for ICI use in later lines of therapy, and suggest that ICIs may be a viable alternative to taxane chemotherapy for patients with mCRPC with high TMB.
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spelling pubmed-89720272022-04-20 Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy by Tumor Mutational Burden in Metastatic Castration-Resistant Prostate Cancer Graf, Ryon P. Fisher, Virginia Weberpals, Janick Gjoerup, Ole Tierno, Marni B. Huang, Richard S. P. Sayegh, Nicolas Lin, Douglas I. Raskina, Kira Schrock, Alexa B. Severson, Eric Haberberger, James F. Ross, Jeffrey S. Creeden, James Levy, Mia A. Alexander, Brian M. Oxnard, Geoffrey R. Agarwal, Neeraj JAMA Netw Open Original Investigation IMPORTANCE: The most useful biomarkers for clinical decision-making identify patients likely to have improved outcomes with one treatment vs another. OBJECTIVE: To evaluate treatment class-specific outcomes of patients receiving immune checkpoint inhibitor (ICI) vs taxane chemotherapy by tumor mutational burden (TMB). DESIGN, SETTING, AND PARTICIPANTS: This comparative effectiveness analysis of clinical variables and outcomes used prospectively defined biomarker-stratified genomic data from a deidentified clinicogenomic database. Data included men with previously treated metastatic castration-resistant prostate cancer (mCRPC) receiving ICI or single-agent taxane chemotherapy from January 2011 to April 2021 at approximately 280 US academic or community-based cancer clinics (approximately 800 sites of care). Data were analyzed from July to August 2021. EXPOSURES: Single-agent ICI or single-agent taxanes. Treatments were assigned at discretion of physician and patient without randomization. Imbalances of known factors between treatment groups were adjusted with propensity weighting. MAIN OUTCOMES AND MEASURES: Prostate-specific antigen (PSA) response, time to next therapy (TTNT), and overall survival (OS). RESULTS: A total of 741 men (median [IQR], 70 [64-76] years) with mCRPC received comprehensive genomic profiling and were treated with ICI or single-agent taxane therapy. At baseline, the median (IQR) PSA level was 79.4 (19.0-254) ng/mL, 108 men (18.8%) had Eastern Cooperative Oncology Group Performance Status scores of 2 or greater, and 644 men (86.9%) had received prior systemic treatments for mCRPC. A total of 45 patients (6.1%) received ICI therapy and 696 patients (93.9%) received taxane therapy. Among patients with TMB of fewer than 10 mutations per megabase (mt/Mb) receiving ICI, compared with those receiving taxanes, had worse TTNT (median [IQR], 2.4 [1.1-3.2] months vs 4.1 [2.2-6.3] months; hazard ratio [HR], 2.65; 95% CI, 1.78-3.95; P < .001). In contrast, for patients with TMB of 10 mt/Mb or greater, use of ICIs, compared with use taxanes, was associated with more favorable TTNT (median [IQR], 8.0 [3.4 to unknown] months vs 2.4 [2.4-7.3] months; HR, 0.37, 95% CI, 0.15-0.87; P = .02) and OS (median 19.9 [8.06 to unknown] months vs 4.2 [2.69 – 6.12] months; HR, 0.23; 95% CI, 0.10-0.57; P = .001). Among all 741 patients, 44 (5.9%) had TMB of 10 mt/Mb or greater, 22 (3.0%) had high microsatellite instability, and 20 (2.7%) had both. Treatment interactions with TMB of 10 mt/Mb or greater (TTNT: HR, 0.10; 95% CI, 0.32-0.31; P < .001; OS: HR, 0.25; 95% CI, 0.076-0.81; P = .02) were stronger than high microsatellite instability alone (TTNT: HR, 0.12; 95% CI, 0.03-0.51; P = .004; OS: HR, 0.38; 95% CI, 0.13-1.12; P = .08). CONCLUSIONS AND RELEVANCE: In this comparative effectiveness study, ICIs were more effective than taxanes in patients with mCRPC when TMB was 10 mt/Mb or greater but not when TMB was fewer than 10 mt/Mb. The results add validity to the existing TMB cutoff of 10 mt/Mb for ICI use in later lines of therapy, and suggest that ICIs may be a viable alternative to taxane chemotherapy for patients with mCRPC with high TMB. American Medical Association 2022-03-31 /pmc/articles/PMC8972027/ /pubmed/35357449 http://dx.doi.org/10.1001/jamanetworkopen.2022.5394 Text en Copyright 2022 Graf RP et al. JAMA Network Open. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the CC-BY-NC-ND License.
spellingShingle Original Investigation
Graf, Ryon P.
Fisher, Virginia
Weberpals, Janick
Gjoerup, Ole
Tierno, Marni B.
Huang, Richard S. P.
Sayegh, Nicolas
Lin, Douglas I.
Raskina, Kira
Schrock, Alexa B.
Severson, Eric
Haberberger, James F.
Ross, Jeffrey S.
Creeden, James
Levy, Mia A.
Alexander, Brian M.
Oxnard, Geoffrey R.
Agarwal, Neeraj
Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy by Tumor Mutational Burden in Metastatic Castration-Resistant Prostate Cancer
title Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy by Tumor Mutational Burden in Metastatic Castration-Resistant Prostate Cancer
title_full Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy by Tumor Mutational Burden in Metastatic Castration-Resistant Prostate Cancer
title_fullStr Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy by Tumor Mutational Burden in Metastatic Castration-Resistant Prostate Cancer
title_full_unstemmed Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy by Tumor Mutational Burden in Metastatic Castration-Resistant Prostate Cancer
title_short Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy by Tumor Mutational Burden in Metastatic Castration-Resistant Prostate Cancer
title_sort comparative effectiveness of immune checkpoint inhibitors vs chemotherapy by tumor mutational burden in metastatic castration-resistant prostate cancer
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8972027/
https://www.ncbi.nlm.nih.gov/pubmed/35357449
http://dx.doi.org/10.1001/jamanetworkopen.2022.5394
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