Abstract
Introduction: Although frequent in NSCLC, patients with brain metastases (BMs) are often excluded from immune checkpoint inhibitor (ICI) trials. We evaluated BM outcome in a less-selected NSCLC cohort.
Methods: Data from consecutive patients with advanced ICI-treated NSCLC were collected. Active BMs were defined as new and/or growing lesions without any subsequent local treatment before the start of ICI treatment. Objective response rate (ORR), progression-free survival, and overall survival (OS) were evaluated. Multivariate analyses were performed by using a Cox proportional hazards model and logistic regression.
Results: A total of 1025 patients were included; the median follow-up time from start of ICI treatment was 15.8 months. Of these patients, 255 (24.9%) had BMs (39.2% active, 14.3% symptomatic, and 27.4% being treated with steroids). Disease-specific Graded Prognostic Assessment (ds-GPA) score was known for 94.5% of patients (35.7% with a score of 0-1, 58.5% with a score of 1.5-2.5, and 5.8% with a score of 3). The ORRs with BM versus without BM were similar: 20.6% (with BM) versus 22.7% (without BM) (p = 0.484). The intracranial ORR (active BM with follow-up brain imaging [n = 73]) was 27.3%. The median progression-free survival times were 1.7 (95% confidence interval [CI]: 1.5-2.1) and 2.1 (95% CI: 1.9-2.5) months, respectively (p = 0.009). Of the patients with BMs, 12.7% had a dissociated cranial-extracranial response and two (0.8%) had brain pseudoprogression. Brain progression occurred more in active BM than in stable BM (54.2% versus 30% [p <0.001]). The median OS times were 8.6 months (95% CI: 6.8-12.0) with BM and 11.4 months (95% CI: 8.6-13.8) months with no BM (p = 0.035). In the BM subgroup multivariate analysis, corticosteroid use (hazard ratio [HR] = 2.37) was associated with poorer OS, whereas stable BMs (HR = 0.62) and higher ds-GPA classification (HR = 0.48-0.52) were associated with improved OS.
Conclusion: In multivariate analysis BMs are not associated with a poorer survival in patients with ICI-treated NSCLC. Stable patients with BM without baseline corticosteroids and a good ds-GPA classification have the best prognosis. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
| Original language | English |
|---|---|
| Pages (from-to) | 1244-1254 |
| Number of pages | 11 |
| Journal | Journal of Thoracic Oncology |
| Volume | 14 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Jul 2019 |
Keywords
- NSCLC
- Checkpoint inhibition
- Brain metastases
- survival
- Disease specific Graded Prognostic Assessment
- PATIENTS PTS
- OPEN-LABEL
- NIVOLUMAB
- PEMBROLIZUMAB
- DOCETAXEL
- SYSTEM
- EFFICACY
- LIFE
Fingerprint
Dive into the research topics of 'Outcome of Patients with Non-Small Cell Lung Cancer and Brain Metastases Treated with Checkpoint Inhibitors'. Together they form a unique fingerprint.Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: Journal of Thoracic Oncology, Vol. 14, No. 7, 07.2019, p. 1244-1254.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Outcome of Patients with Non-Small Cell Lung Cancer and Brain Metastases Treated with Checkpoint Inhibitors
AU - Hendriks, Lizza E. L.
AU - Henon, Clemence
AU - Auclin, Edouard
AU - Mezquita, Laura
AU - Ferrara, Roberto
AU - Audigier-Valette, Clarisse
AU - Mazieres, Julien
AU - Lefebvre, Corentin
AU - Rabeau, Audrey
AU - Le Moulec, Sylvestre
AU - Cousin, Sophie
AU - Duchemann, Boris
AU - le Pechoux, Cecile
AU - Botticella, Angela
AU - Ammari, Samy
AU - Gazzah, Anas
AU - Caramella, Caroline
AU - Adam, Julien
AU - Lechapt, Emmanuele
AU - Planchard, David
AU - De Ruysscher, Dirk
AU - Dingemans, Anne-Marie
AU - Besse, Benjamin
N1 - Funding Information: Disclosure: Dr. Hendriks reports research funding from Roche and Boehringer Ingelheim (both to her institution), fees for participation in advisory boards of Boehringer Ingelheim (to her institution) and BMS (to her institution and to her personally), travel/conference reimbursement from Roche and BMS (to her personally), participation in a mentorship program with key opinion leaders that was funded by AstraZeneca, and fees for educational webinars from Quadia outside of the submitted work. Dr. Audigier-Valette reports fees for being the principal investigator of industry trials for AstraZeneca, Boehringer Ingelheim, BMS, Novartis, and Roche; fees for service on advisory boards of AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, MSD, Pfizer, Roche; and fees for speaker bureau participation from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, Pfizer, Roche. Dr. Duchemann has received payments for expert testimony from BMS and Roche and reimbursement for travel, accommodations, and expenses from BMS and Roche. Dr. Mazieres has received institutional research funding from Roche, Bristol-Myers Squibb, and AstraZeneca; fees for consulting/advisory roles for Novartis, Roche/Genentech, Pfizer, Bristol-Myers Squibb, Lilly/ImClone, MSD, and AstraZeneca; and reimbursement for travel and accommodation expenses from Pfizer, Roche, and Bristol-Myers Squibb. Dr. Mezquita has received payments from BMS for serving as a speaker and from Roche Diagnostics for advisory board participation. Dr. le Pechoux has received payment from AstraZeneca for advisory board participation outside the submitted work. Dr. Dingemans has received payments from BMS, MSD, Roche, Eli Lilly, Takeda, Pfizer, Boehringer Ingelheim for advisory board participation (all to her institution) and a research grant from BMS (to her institution) outside the submitted work. Dr. Besse has received institutional grants for clinical and translational research from Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, and Tiziana Pharma (all outside the submitted work). Dr. de Ruysscher reports fees for participation on advisory boards of Bristol-Myers-Squibb, Astra Zeneca, Roche/Genentech, Merck/Pfizer and Celgene (all to his institution), as well as research grants from Bristol-Myers Squibb and Boehringer Ingelheim (all to his institution). The remaining authors declare no conflict of interest. Disclosure: Dr. Hendriks reports research funding from Roche and Boehringer Ingelheim (both to her institution), fees for participation in advisory boards of Boehringer Ingelheim (to her institution) and BMS (to her institution and to her personally), travel/conference reimbursement from Roche and BMS (to her personally), participation in a mentorship program with key opinion leaders that was funded by AstraZeneca, and fees for educational webinars from Quadia outside of the submitted work. Dr. Audigier-Valette reports fees for being the principal investigator of industry trials for AstraZeneca, Boehringer Ingelheim, BMS, Novartis, and Roche; fees for service on advisory boards of AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, MSD, Pfizer, Roche; and fees for speaker bureau participation from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, Pfizer, Roche. Dr. Duchemann has received payments for expert testimony from BMS and Roche and reimbursement for travel, accommodations, and expenses from BMS and Roche. Dr. Mazieres has received institutional research funding from Roche, Bristol-Myers Squibb, and AstraZeneca; fees for consulting/advisory roles for Novartis, Roche/Genentech, Pfizer, Bristol-Myers Squibb, Lilly/ImClone, MSD, and AstraZeneca; and reimbursement for travel and accommodation expenses from Pfizer, Roche, and Bristol-Myers Squibb. Dr. Mezquita has received payments from BMS for serving as a speaker and from Roche Diagnostics for advisory board participation. Dr. le Pechoux has received payment from AstraZeneca for advisory board participation outside the submitted work. Dr. Dingemans has received payments from BMS, MSD, Roche, Eli Lilly, Takeda, Pfizer, Boehringer Ingelheim for advisory board participation (all to her institution) and a research grant from BMS (to her institution) outside the submitted work. Dr. Besse has received institutional grants for clinical and translational research from Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, and Tiziana Pharma (all outside the submitted work). Dr. de Ruysscher reports fees for participation on advisory boards of Bristol-Myers-Squibb, Astra Zeneca, Roche/Genentech, Merck/Pfizer and Celgene (all to his institution), as well as research grants from Bristol-Myers Squibb and Boehringer Ingelheim (all to his institution). The remaining authors declare no conflict of interest. Dr. Hendriks was the recipient of a European University Diploma for Translational and Clinical Research in Oncology grant for 2017–2018. Disclosure: Dr. Hendriks reports research funding from Roche and Boehringer Ingelheim (both to her institution), fees for participation in advisory boards of Boehringer Ingelheim (to her institution) and BMS (to her institution and to her personally), travel/conference reimbursement from Roche and BMS (to her personally), participation in a mentorship program with key opinion leaders that was funded by AstraZeneca, and fees for educational webinars from Quadia outside of the submitted work. Dr. Audigier-Valette reports fees for being the principal investigator of industry trials for AstraZeneca, Boehringer Ingelheim, BMS, Novartis, and Roche; fees for service on advisory boards of AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, MSD, Pfizer, Roche; and fees for speaker bureau participation from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, Pfizer, Roche. Dr. Duchemann has received payments for expert testimony from BMS and Roche and reimbursement for travel, accommodations, and expenses from BMS and Roche. Dr. Mazieres has received institutional research funding from Roche, Bristol-Myers Squibb, and AstraZeneca; fees for consulting/advisory roles for Novartis, Roche/Genentech, Pfizer, Bristol-Myers Squibb, Lilly/ImClone, MSD, and AstraZeneca; and reimbursement for travel and accommodation expenses from Pfizer, Roche, and Bristol-Myers Squibb. Dr. Mezquita has received payments from BMS for serving as a speaker and from Roche Diagnostics for advisory board participation. Dr. le Pechoux has received payment from AstraZeneca for advisory board participation outside the submitted work. Dr. Dingemans has received payments from BMS, MSD, Roche, Eli Lilly, Takeda, Pfizer, Boehringer Ingelheim for advisory board participation (all to her institution) and a research grant from BMS (to her institution) outside the submitted work. Dr. Besse has received institutional grants for clinical and translational research from Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, and Tiziana Pharma (all outside the submitted work). Dr. de Ruysscher reports fees for participation on advisory boards of Bristol-Myers-Squibb, Astra Zeneca, Roche/Genentech, Merck/Pfizer and Celgene (all to his institution), as well as research grants from Bristol-Myers Squibb and Boehringer Ingelheim (all to his institution). The remaining authors declare no conflict of interest. Funding Information: Disclosure: Dr. Hendriks reports research funding from Roche and Boehringer Ingelheim (both to her institution), fees for participation in advisory boards of Boehringer Ingelheim (to her institution) and BMS (to her institution and to her personally), travel/conference reimbursement from Roche and BMS (to her personally), participation in a mentorship program with key opinion leaders that was funded by AstraZeneca, and fees for educational webinars from Quadia outside of the submitted work. Dr. Audigier-Valette reports fees for being the principal investigator of industry trials for AstraZeneca, Boehringer Ingelheim, BMS, Novartis, and Roche; fees for service on advisory boards of AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, MSD, Pfizer, Roche; and fees for speaker bureau participation from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, Pfizer, Roche. Dr. Duchemann has received payments for expert testimony from BMS and Roche and reimbursement for travel, accommodations, and expenses from BMS and Roche. Dr. Mazieres has received institutional research funding from Roche, Bristol-Myers Squibb, and AstraZeneca; fees for consulting/advisory roles for Novartis, Roche/Genentech, Pfizer, Bristol-Myers Squibb, Lilly/ImClone, MSD, and AstraZeneca; and reimbursement for travel and accommodation expenses from Pfizer, Roche, and Bristol-Myers Squibb. Dr. Mezquita has received payments from BMS for serving as a speaker and from Roche Diagnostics for advisory board participation. Dr. le Pechoux has received payment from AstraZeneca for advisory board participation outside the submitted work. Dr. Dingemans has received payments from BMS, MSD, Roche, Eli Lilly, Takeda, Pfizer, Boehringer Ingelheim for advisory board participation (all to her institution) and a research grant from BMS (to her institution) outside the submitted work. Dr. Besse has received institutional grants for clinical and translational research from Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, and Tiziana Pharma (all outside the submitted work). Dr. de Ruysscher reports fees for participation on advisory boards of Bristol-Myers-Squibb, Astra Zeneca, Roche/Genentech, Merck/Pfizer and Celgene (all to his institution), as well as research grants from Bristol-Myers Squibb and Boehringer Ingelheim (all to his institution). The remaining authors declare no conflict of interest. Disclosure: Dr. Hendriks reports research funding from Roche and Boehringer Ingelheim (both to her institution), fees for participation in advisory boards of Boehringer Ingelheim (to her institution) and BMS (to her institution and to her personally), travel/conference reimbursement from Roche and BMS (to her personally), participation in a mentorship program with key opinion leaders that was funded by AstraZeneca, and fees for educational webinars from Quadia outside of the submitted work. Dr. Audigier-Valette reports fees for being the principal investigator of industry trials for AstraZeneca, Boehringer Ingelheim, BMS, Novartis, and Roche; fees for service on advisory boards of AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, MSD, Pfizer, Roche; and fees for speaker bureau participation from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, Pfizer, Roche. Dr. Duchemann has received payments for expert testimony from BMS and Roche and reimbursement for travel, accommodations, and expenses from BMS and Roche. Dr. Mazieres has received institutional research funding from Roche, Bristol-Myers Squibb, and AstraZeneca; fees for consulting/advisory roles for Novartis, Roche/Genentech, Pfizer, Bristol-Myers Squibb, Lilly/ImClone, MSD, and AstraZeneca; and reimbursement for travel and accommodation expenses from Pfizer, Roche, and Bristol-Myers Squibb. Dr. Mezquita has received payments from BMS for serving as a speaker and from Roche Diagnostics for advisory board participation. Dr. le Pechoux has received payment from AstraZeneca for advisory board participation outside the submitted work. Dr. Dingemans has received payments from BMS, MSD, Roche, Eli Lilly, Takeda, Pfizer, Boehringer Ingelheim for advisory board participation (all to her institution) and a research grant from BMS (to her institution) outside the submitted work. Dr. Besse has received institutional grants for clinical and translational research from Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, and Tiziana Pharma (all outside the submitted work). Dr. de Ruysscher reports fees for participation on advisory boards of Bristol-Myers-Squibb, Astra Zeneca, Roche/Genentech, Merck/Pfizer and Celgene (all to his institution), as well as research grants from Bristol-Myers Squibb and Boehringer Ingelheim (all to his institution). The remaining authors declare no conflict of interest. Dr. Hendriks was the recipient of a European University Diploma for Translational and Clinical Research in Oncology grant for 2017?2018. Disclosure: Dr. Hendriks reports research funding from Roche and Boehringer Ingelheim (both to her institution), fees for participation in advisory boards of Boehringer Ingelheim (to her institution) and BMS (to her institution and to her personally), travel/conference reimbursement from Roche and BMS (to her personally), participation in a mentorship program with key opinion leaders that was funded by AstraZeneca, and fees for educational webinars from Quadia outside of the submitted work. Dr. Audigier-Valette reports fees for being the principal investigator of industry trials for AstraZeneca, Boehringer Ingelheim, BMS, Novartis, and Roche; fees for service on advisory boards of AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, MSD, Pfizer, Roche; and fees for speaker bureau participation from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, Pfizer, Roche. Dr. Duchemann has received payments for expert testimony from BMS and Roche and reimbursement for travel, accommodations, and expenses from BMS and Roche. Dr. Mazieres has received institutional research funding from Roche, Bristol-Myers Squibb, and AstraZeneca; fees for consulting/advisory roles for Novartis, Roche/Genentech, Pfizer, Bristol-Myers Squibb, Lilly/ImClone, MSD, and AstraZeneca; and reimbursement for travel and accommodation expenses from Pfizer, Roche, and Bristol-Myers Squibb. Dr. Mezquita has received payments from BMS for serving as a speaker and from Roche Diagnostics for advisory board participation. Dr. le Pechoux has received payment from AstraZeneca for advisory board participation outside the submitted work. Dr. Dingemans has received payments from BMS, MSD, Roche, Eli Lilly, Takeda, Pfizer, Boehringer Ingelheim for advisory board participation (all to her institution) and a research grant from BMS (to her institution) outside the submitted work. Dr. Besse has received institutional grants for clinical and translational research from Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, and Tiziana Pharma (all outside the submitted work). Dr. de Ruysscher reports fees for participation on advisory boards of Bristol-Myers-Squibb, Astra Zeneca, Roche/Genentech, Merck/Pfizer and Celgene (all to his institution), as well as research grants from Bristol-Myers Squibb and Boehringer Ingelheim (all to his institution). The remaining authors declare no conflict of interest. Publisher Copyright: © 2019 International Association for the Study of Lung Cancer
PY - 2019/7
Y1 - 2019/7
N2 - Introduction: Although frequent in NSCLC, patients with brain metastases (BMs) are often excluded from immune checkpoint inhibitor (ICI) trials. We evaluated BM outcome in a less-selected NSCLC cohort.Methods: Data from consecutive patients with advanced ICI-treated NSCLC were collected. Active BMs were defined as new and/or growing lesions without any subsequent local treatment before the start of ICI treatment. Objective response rate (ORR), progression-free survival, and overall survival (OS) were evaluated. Multivariate analyses were performed by using a Cox proportional hazards model and logistic regression.Results: A total of 1025 patients were included; the median follow-up time from start of ICI treatment was 15.8 months. Of these patients, 255 (24.9%) had BMs (39.2% active, 14.3% symptomatic, and 27.4% being treated with steroids). Disease-specific Graded Prognostic Assessment (ds-GPA) score was known for 94.5% of patients (35.7% with a score of 0-1, 58.5% with a score of 1.5-2.5, and 5.8% with a score of 3). The ORRs with BM versus without BM were similar: 20.6% (with BM) versus 22.7% (without BM) (p = 0.484). The intracranial ORR (active BM with follow-up brain imaging [n = 73]) was 27.3%. The median progression-free survival times were 1.7 (95% confidence interval [CI]: 1.5-2.1) and 2.1 (95% CI: 1.9-2.5) months, respectively (p = 0.009). Of the patients with BMs, 12.7% had a dissociated cranial-extracranial response and two (0.8%) had brain pseudoprogression. Brain progression occurred more in active BM than in stable BM (54.2% versus 30% [p <0.001]). The median OS times were 8.6 months (95% CI: 6.8-12.0) with BM and 11.4 months (95% CI: 8.6-13.8) months with no BM (p = 0.035). In the BM subgroup multivariate analysis, corticosteroid use (hazard ratio [HR] = 2.37) was associated with poorer OS, whereas stable BMs (HR = 0.62) and higher ds-GPA classification (HR = 0.48-0.52) were associated with improved OS.Conclusion: In multivariate analysis BMs are not associated with a poorer survival in patients with ICI-treated NSCLC. Stable patients with BM without baseline corticosteroids and a good ds-GPA classification have the best prognosis. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
AB - Introduction: Although frequent in NSCLC, patients with brain metastases (BMs) are often excluded from immune checkpoint inhibitor (ICI) trials. We evaluated BM outcome in a less-selected NSCLC cohort.Methods: Data from consecutive patients with advanced ICI-treated NSCLC were collected. Active BMs were defined as new and/or growing lesions without any subsequent local treatment before the start of ICI treatment. Objective response rate (ORR), progression-free survival, and overall survival (OS) were evaluated. Multivariate analyses were performed by using a Cox proportional hazards model and logistic regression.Results: A total of 1025 patients were included; the median follow-up time from start of ICI treatment was 15.8 months. Of these patients, 255 (24.9%) had BMs (39.2% active, 14.3% symptomatic, and 27.4% being treated with steroids). Disease-specific Graded Prognostic Assessment (ds-GPA) score was known for 94.5% of patients (35.7% with a score of 0-1, 58.5% with a score of 1.5-2.5, and 5.8% with a score of 3). The ORRs with BM versus without BM were similar: 20.6% (with BM) versus 22.7% (without BM) (p = 0.484). The intracranial ORR (active BM with follow-up brain imaging [n = 73]) was 27.3%. The median progression-free survival times were 1.7 (95% confidence interval [CI]: 1.5-2.1) and 2.1 (95% CI: 1.9-2.5) months, respectively (p = 0.009). Of the patients with BMs, 12.7% had a dissociated cranial-extracranial response and two (0.8%) had brain pseudoprogression. Brain progression occurred more in active BM than in stable BM (54.2% versus 30% [p <0.001]). The median OS times were 8.6 months (95% CI: 6.8-12.0) with BM and 11.4 months (95% CI: 8.6-13.8) months with no BM (p = 0.035). In the BM subgroup multivariate analysis, corticosteroid use (hazard ratio [HR] = 2.37) was associated with poorer OS, whereas stable BMs (HR = 0.62) and higher ds-GPA classification (HR = 0.48-0.52) were associated with improved OS.Conclusion: In multivariate analysis BMs are not associated with a poorer survival in patients with ICI-treated NSCLC. Stable patients with BM without baseline corticosteroids and a good ds-GPA classification have the best prognosis. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
KW - NSCLC
KW - Checkpoint inhibition
KW - Brain metastases
KW - survival
KW - Disease specific Graded Prognostic Assessment
KW - PATIENTS PTS
KW - OPEN-LABEL
KW - NIVOLUMAB
KW - PEMBROLIZUMAB
KW - DOCETAXEL
KW - SYSTEM
KW - EFFICACY
KW - LIFE
U2 - 10.1016/j.jtho.2019.02.009
DO - 10.1016/j.jtho.2019.02.009
M3 - Article
C2 - 30780002
SN - 1556-0864
VL - 14
SP - 1244
EP - 1254
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 7
ER -