Pneumonitis as a complication of immune system targeting drugs?-a meta-analysis of anti-PD/PD-L1 immunotherapy randomized clinical trials.
Immunotherapy
pembrolizumab
pneumonitis
response
survival
Journal
Journal of thoracic disease
ISSN: 2072-1439
Titre abrégé: J Thorac Dis
Pays: China
ID NLM: 101533916
Informations de publication
Date de publication:
Feb 2019
Feb 2019
Historique:
entrez:
10
4
2019
pubmed:
10
4
2019
medline:
10
4
2019
Statut:
ppublish
Résumé
Anti-PD/PD-L1-targeted immunotherapy is associated with remarkably high rates of durable clinical responses in patients across a range of tumor types, although their high incidence of skin, gastrointestinal, and endocrine side effects with their use. The risk of pneumonitis associated with checkpoint inhibition therapy is not well described. A systematic review of the literature was conducted on randomized clinical trials (RCTs) comparing anti-PD/PD-L1 mono-immunotherapy (IMM) to chemotherapy (CTH) protocols in cancer patients. The primary endpoint was the pneumonitis rate in IMM compared to CTH. Secondary endpoints were (I) high-grade pneumonitis rate in IMM compared to CTH and (II) tumor response rate, progression-free survival (PFS), and overall survival (OS) between IMM and CTH. Random model and leave-one-out-analysis were performed. Thirteen RCTs studying 7,246 patients were included; 3,704 (51.12%) patients in the IMM arm and 3,542 (48.88%) patients in the chemotherapy arm. Seven non-small cell lung cancer (NSCLC) RCTs were included with 4,164 patients; 2,101 in the IMM arm and 2,063 patients in the CTH arm. Three RCTs were on melanoma patients (n=1,390). Nine RCTs compared mono-immunotherapy to CTH [docetaxel in 5 studies (38.5%), platinum-based in 2 studies (15.4%), dacarbazine in 1 study (7.7%) and everolimus in 1 study]. Both high-grade and all-grade pneumonitis were higher among patients in the IMM arm when compared to the CTH arm (OR =4.39, 95% CI: 1.65-11.69, P=0.003 and OR =2.46, 95% CI: 1.29-4.6, P=0.007). Tumor response rate was significantly better in the immunotherapy arm (OR =2.31, 95% CI: 1.62-3.29, P<0.001). PFS and OS were longer in patients who received IMM compared to patients in the CTH arm (HR =0.75, 95% CI: 0.65-0.85, P<0.001, and HR =0.71, 95% CI: 0.66-0.77, P<0.001). The incidence of high-grade and all-grade pneumonitis is higher in anti-PD-1 therapy but not in anti-PD-L1 therapy when compared to traditional CTH regimens for NSCLC and melanoma. High-grade adverse events were otherwise more common in the CTH arm. Tumor response rate, PFS, and OS are all substantially improved with IMM over CTH. These results can be used to guide therapy selection and set expectations for treatment effect in these patients.
Sections du résumé
BACKGROUND
BACKGROUND
Anti-PD/PD-L1-targeted immunotherapy is associated with remarkably high rates of durable clinical responses in patients across a range of tumor types, although their high incidence of skin, gastrointestinal, and endocrine side effects with their use. The risk of pneumonitis associated with checkpoint inhibition therapy is not well described.
METHODS
METHODS
A systematic review of the literature was conducted on randomized clinical trials (RCTs) comparing anti-PD/PD-L1 mono-immunotherapy (IMM) to chemotherapy (CTH) protocols in cancer patients. The primary endpoint was the pneumonitis rate in IMM compared to CTH. Secondary endpoints were (I) high-grade pneumonitis rate in IMM compared to CTH and (II) tumor response rate, progression-free survival (PFS), and overall survival (OS) between IMM and CTH. Random model and leave-one-out-analysis were performed.
RESULTS
RESULTS
Thirteen RCTs studying 7,246 patients were included; 3,704 (51.12%) patients in the IMM arm and 3,542 (48.88%) patients in the chemotherapy arm. Seven non-small cell lung cancer (NSCLC) RCTs were included with 4,164 patients; 2,101 in the IMM arm and 2,063 patients in the CTH arm. Three RCTs were on melanoma patients (n=1,390). Nine RCTs compared mono-immunotherapy to CTH [docetaxel in 5 studies (38.5%), platinum-based in 2 studies (15.4%), dacarbazine in 1 study (7.7%) and everolimus in 1 study]. Both high-grade and all-grade pneumonitis were higher among patients in the IMM arm when compared to the CTH arm (OR =4.39, 95% CI: 1.65-11.69, P=0.003 and OR =2.46, 95% CI: 1.29-4.6, P=0.007). Tumor response rate was significantly better in the immunotherapy arm (OR =2.31, 95% CI: 1.62-3.29, P<0.001). PFS and OS were longer in patients who received IMM compared to patients in the CTH arm (HR =0.75, 95% CI: 0.65-0.85, P<0.001, and HR =0.71, 95% CI: 0.66-0.77, P<0.001).
CONCLUSIONS
CONCLUSIONS
The incidence of high-grade and all-grade pneumonitis is higher in anti-PD-1 therapy but not in anti-PD-L1 therapy when compared to traditional CTH regimens for NSCLC and melanoma. High-grade adverse events were otherwise more common in the CTH arm. Tumor response rate, PFS, and OS are all substantially improved with IMM over CTH. These results can be used to guide therapy selection and set expectations for treatment effect in these patients.
Identifiants
pubmed: 30962996
doi: 10.21037/jtd.2019.01.19
pii: jtd-11-02-521
pmc: PMC6409275
doi:
Types de publication
Journal Article
Langues
eng
Pagination
521-534Déclaration de conflit d'intérêts
Conflicts of Interest: The authors have no conflicts of interest to declare.
Références
BMJ. 2003 Sep 6;327(7414):557-60
pubmed: 12958120
Annu Rev Immunol. 2008;26:677-704
pubmed: 18173375
South Med J. 2008 Jul;101(7):730-4
pubmed: 18580722
PLoS Med. 2009 Jul 21;6(7):e1000100
pubmed: 19621070
BMJ. 2011 Oct 18;343:d5928
pubmed: 22008217
N Engl J Med. 2015 Jan 22;372(4):320-30
pubmed: 25399552
Lancet Oncol. 2015 Apr;16(4):375-84
pubmed: 25795410
J Clin Oncol. 2015 Jun 20;33(18):2004-12
pubmed: 25897158
Ann Pharmacother. 2015 Aug;49(8):907-37
pubmed: 25991832
N Engl J Med. 2015 Jul 9;373(2):123-35
pubmed: 26028407
Ann Oncol. 2015 Dec;26(12):2375-91
pubmed: 26371282
N Engl J Med. 2015 Nov 5;373(19):1803-13
pubmed: 26406148
N Engl J Med. 2015 Oct 22;373(17):1627-39
pubmed: 26412456
Lancet. 2016 Apr 9;387(10027):1540-50
pubmed: 26712084
Ther Adv Respir Dis. 2016 Jun;10(3):183-93
pubmed: 26944362
Lancet. 2016 Apr 30;387(10030):1837-46
pubmed: 26970723
JAMA Oncol. 2016 Dec 1;2(12):1607-1616
pubmed: 27540850
N Engl J Med. 2016 Nov 10;375(19):1856-1867
pubmed: 27718784
N Engl J Med. 2016 Nov 10;375(19):1823-1833
pubmed: 27718847
Oncotarget. 2017 Jan 31;8(5):8910-8920
pubmed: 27852042
Lancet. 2017 Jan 21;389(10066):255-265
pubmed: 27979383
N Engl J Med. 2017 Mar 16;376(11):1015-1026
pubmed: 28212060
World J Clin Oncol. 2017 Feb 10;8(1):37-53
pubmed: 28246584
Sci Rep. 2017 Mar 08;7:44173
pubmed: 28272463
Chest. 2017 Aug;152(2):271-281
pubmed: 28499515
N Engl J Med. 2017 Jun 22;376(25):2415-2426
pubmed: 28636851
Eur J Cancer. 2017 Nov;86:37-45
pubmed: 28961465
Control Clin Trials. 1986 Sep;7(3):177-88
pubmed: 3802833
Stat Med. 1998 Dec 30;17(24):2815-34
pubmed: 9921604