Adverse Event Reporting with Immune Checkpoint Inhibitors in Older Patients: Age Subgroup Disproportionality Analysis in VigiBase
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. VigiBase
2.2. Study Design
2.3. Disproportionality Analysis
2.4. Safety Assessment of Signals of Disproportionate Reporting in Specific Age Subgroups
3. Results
3.1. Descriptive Analysis of ICI-Related Safety Reports by Age Subgroups
3.2. Disproportionality Analysis
3.3. Signal of Disproportionate Reporting for ICI-Related Eye Disorders in the Age Subgroup 18–64 Years
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Characteristics | <18 Years (N = 173) | 18–64 Years (N = 25,252) | 65–74 Years (N = 19,214) | 75–84 Years (N = 9808) | ≥85 Years (N = 1344) |
---|---|---|---|---|---|
Median age (IQR), years | 12 (5–15) | 56 (49–61) | 69 (67–72) | 78 (76–80) | 87 (85–88) |
Patient sex | |||||
Male | 94 (54.3) | 14,530 (57.5) | 12,850 (66.9) | 6627 (67.6) | 828 (61.6) |
Female | 74 (42.8) | 10,236 (40.5) | 6038 (31.4) | 3009 (30.7) | 486 (36.2) |
Not reported | 5 (2.9) | 486 (1.9) | 326 (1.7) | 172 (1.8) | 30 (2.2) |
Reporting country | |||||
North America | 84 (48.6) | 9830 (38.9) | 6005 (31.3) | 2991 (30.5) | 586 (43.6) |
South America | 16 (9.2) | 379 (1.5) | 215 (1.1) | 97 (1.0) | 17 (1.3) |
Europe | 50 (28.9) | 9042 (35.8) | 6416 (33.4) | 3238 (33.0) | 413 (30.7) |
Asia | 18 (10.4) | 5107 (20.2) | 5963 (31.0) | 3186 (32.5) | 278 (20.7) |
Oceania | 3 (1.7) | 734 (2.9) | 564 (2.9) | 282 (2.9) | 49 (3.6) |
Africa | 2 (1.2) | 160 (0.6) | 51 (0.3) | 14 (0.1) | 1 (0.1) |
Reporting year | |||||
2008 | - | 8 (0) | - | - | - |
2009 | - | 26 (0.1) | 1 (0) | 3 (0) | - |
2010 | - | 32 (0.1) | 5 (0) | 3 (0) | - |
2011 | - | 114 (0.5) | 46 (0.2) | 18 (0.2) | 1 (0.1) |
2012 | 5 (2.9) | 397 (1.6) | 185 (1.0) | 92 (0.9) | 14 (1.0) |
2013 | 1 (0.6) | 311 (1.2) | 163 (0.8) | 59 (0.6) | 8 (0.6) |
2014 | 8 (4.6) | 696 (2.8) | 299 (1.6) | 177 (1.8) | 29 (2.2) |
2015 | 9 (5.2) | 1597 (6.3) | 910 (4.7) | 397 (4.0) | 60 (4.5) |
2016 | 14 (8.1) | 2415 (9.6) | 1623 (8.4) | 766 (7.8) | 100 (7.4) |
2017 | 32 (18.5) | 4090 (16.2) | 3245 (16.9) | 1627 (16.6) | 220 (16.4) |
2018 | 42 (24.3) | 5790 (22.9) | 4792 (24.9) | 2435 (24.8) | 334 (24.9) |
2019 | 34 (19.7) | 6613 (26.2) | 5739 (29.9) | 3092 (31.5) | 402 (29.9) |
2020 (up to 30 August) | 28 (16.2) | 3163 (12.5) | 2206 (11.5) | 1139 (11.6) | 176 (13.1) |
Reporter qualification | |||||
Physician | 71 (41.0) | 13,175 (52.2) | 11,624 (60.5) | 6066 (61.8) | 732 (54.5) |
Other Health Professional | 59 (34.1) | 6227 (24.7) | 3705 (19.3) | 1766 (18.0) | 231 (17.2) |
Consumer/Non Health Professional | 27 (15.6) | 3457 (13.7) | 1985 (10.3) | 958 (9.8) | 225 (16.7) |
Pharmacist | 11 (6.4) | 1668 (6.6) | 1380 (7.2) | 755 (7.7) | 112 (8.3) |
Lawyer | - | 10 (0) | 6 (0) | 2 (0) | - |
Not reported | 5 (2.9) | 715 (2.8) | 514 (2.7) | 261 (2.7) | 44 (3.3) |
Seriousness | |||||
Yes | 135 (78.0) | 20,291 (80.4) | 15,630 (81.3) | 7985 (81.4) | 1046 (77.8) |
Caused/prolonged hospitalization | 42 (24.3) | 8541 (33.8) | 6958 (36.2) | 3491 (35.6) | 406 (30.2) |
Death | 29 (16.8) | 4214 (16.7) | 3226 (16.8) | 1838 (18.7) | 290 (21.6) |
Disabling/incapacitating | 2 (1.2) | 185 (0.7) | 178 (0.9) | 84 (0.9) | 12 (0.9) |
Life threatening | 11 (6.4) | 1054 (4.2) | 873 (4.5) | 438 (4.5) | 47 (3.5) |
Congenital anomaly/birth defect | - | 8 (0) | - | 1 (0) | - |
Other medically important condition | 51 (29.5) | 6264 (24.8) | 4386 (22.8) | 2132 (21.7) | 290 (21.6) |
Unknown | - | 25 (0.1) | 9 (0) | 1 (0) | 1 (0.1) |
No | 34 (19.7) | 4445 (17.6) | 3203 (16.7) | 1642 (16.7) | 265 (19.7) |
Not reported | 4 (2.3) | 516 (2.0) | 381 (2.0) | 181 (1.8) | 33 (2.5) |
Suspected ICI(s) | |||||
Anti-CTLA-4 monotherapy | |||||
ipilimumab | 20 (11.6) | 3382 (13.4) | 1698 (8.8) | 839 (8.6) | 119 (8.9) |
Anti-PD-1 monotherapy | |||||
nivolumab | 71 (41.0) | 8960 (35.5) | 7247 (37.7) | 3548 (36.2) | 442 (32.9) |
pembrolizumab | 49 (28.3) | 6591 (26.1) | 5748 (29.9) | 3379 (34.5) | 540 (40.2) |
cemiplimab | - | 33 (0.1) | 47 (0.2) | 75 (0.8) | 48 (3.6) |
Anti-PD-L1 monotherapy | |||||
atezolizumab | 8 (4.6) | 1993 (7.9) | 1674 (8.7) | 777 (7.9) | 88 (6.5) |
avelumab | 1 (0.6) | 215 (0.9) | 214 (1.1) | 142 (1.4) | 22 (1.6) |
durvalumab | 2 (1.2) | 912 (3.6) | 894 (4.7) | 380 (3.9) | 18 (1.3) |
Combination of anti-PD-1 and anti-CTLA-4 | 13 (7.5) | 1826 (7.2) | 1039 (5.4) | 397 (4.0) | 35 (2.6) |
≥2 suspected ICIs but regimen not definable # | 9 (5.2) | 1340 (5.3) | 653 (3.4) | 271 (2.8) | 32 (2.4) |
Cancer type | |||||
Lung cancer | 11 (6.4) | 7740 (30.7) | 8127 (42.3) | 3933 (40.1) | 375 (27.9) |
Malignant melanoma | 31 (17.9) | 6526 (25.8) | 3502 (18.2) | 2137 (21.8) | 418 (31.1) |
Renal cell carcinoma | 11 (6.4) | 1585 (6.3) | 1299 (6.8) | 570 (5.8) | 62 (4.6) |
Urothelial carcinoma | 2 (1.2) | 708 (2.8) | 961 (5.0) | 685 (7.0) | 85 (6.3) |
Squamous cell carcinoma of head and neck | - | 557 (2.2) | 370 (1.9) | 154 (1.6) | 11 (0.8) |
Breast cancer | 1 (0.6) | 530 (2.1) | 108 (0.6) | 37 (0.4) | 6 (0.4) |
Cancer of the female reproductive system | 1 (0.6) | 454 (1.8) | 261 (1.4) | 98 (1.0) | 6 (0.4) |
Haematological malignancy | 31 (17.9) | 722 (2.9) | 335 (1.7) | 172 (1.8) | 26 (1.9) |
Gastrointestinal tract cancer | 7 (4.0) | 1080 (4.3) | 833 (4.3) | 356 (3.6) | 47 (3.5) |
Skin cancer | - | 70 (0.3) | 50 (0.3) | 98 (1.0) | 73 (5.4) |
Cancer of the male reproductive system | - | 104 (0.4) | 142 (0.7) | 86 (0.9) | 15 (1.1) |
Brain cancer | 18 (10.4) | 225 (0.9) | 84 (0.4) | 18 (0.2) | 3 (0.2) |
Colon cancer | - | 143 (0.6) | 49 (0.3) | 38 (0.4) | - |
Sarcoma | 12 (6.9) | 132 (0.5) | 36 (0.2) | 17 (0.2) | 1 (0.1) |
Thyroid cancer/parathyroid gland cancer | - | 74 (0.3) | 32 (0.2) | 17 (0.2) | 5 (0.4) |
Mesothelioma | - | 64 (0.3) | 86 (0.4) | 43 (0.4) | 6 (0.4) |
Neuroendocrine carcinoma | 1 (0.6) | 47 (0.2) | 79 (0.4) | 4 (0) | 8 (0.6) |
Other ῀ | 1 (0.6) | 305 (1.2) | 231 (1.2) | 139 (1.4) | 13 (1.0) |
Not reported | 46 (26.6) | 4186 (16.6) | 2629 (13.7) | 1206 (12.3) | 184 (13.7) |
ICI-Related Safety Reports of Eye Disorders | Anti-CTLA-4 Monotherapy (N = 121) | Anti-PD-1/PD-L1 Monotherapy (N = 411) | Combination of Anti-PD-1 and Anti-CTLA-4 (N = 65) | ≥2 Suspected ICIs but Regimen Not Definable * (N = 37) |
---|---|---|---|---|
Median age (IQR), years | 52 (46–58) | 55 (48–60) | 54 (47–59) | 56 (52–60) |
Patient sex | ||||
Male | 65 (53.7) | 210 (51.1) | 35 (53.8) | 21 (56.8) |
Female | 55 (45.5) | 196 (47.7) | 30 (46.2) | 16 (43.2) |
Unknown | 1 (0.8) | 5 (1.2) | - | - |
Cancer type | ||||
Lung cancer | - | 127 (30.9) | 2 (3.1) | 1 (2.7) |
Malignant melanoma | 94 (77.7) | 120 (29.2) | 42 (64.6) | 27 (73.0) |
Renal cell carcinoma | - | 33 (8.0) | 7 (10.8) | 1 (2.7) |
Urothelial carcinoma | - | 9 (2.2) | - | - |
Squamous cell carcinoma of head and neck | - | 9 (2.2) | - | - |
Breast cancer | - | 9 (2.2) | - | - |
Cancer of the female reproductive system | - | 11 (2.7) | 3 (4.6) | 1 (2.7) |
Haematological malignancy | 3 (2.5) | 8 (1.9) | 1 (1.5) | - |
Gastrointestinal tract cancer | - | 6 (1.5) | 2 (3.1) | - |
Cancer of the male reproductive system | - | 2 (0.5) | - | - |
Brain cancer | 1 (0.8) | 6 (1.5) | 1 (1.5) | - |
Colon cancer | - | 4 (1.0) | - | - |
Sarcoma | - | 2 (0.5) | - | 1 (2.7) |
Thyroid cancer/parathyroid gland cancer | - | 1 (0.2) | - | - |
Mesothelioma | - | 1 (0.2) | - | - |
Neuroendocrine carcinoma | - | 2 (0.5) | - | - |
Nasopharyngeal cancer | - | 5 (1.2) | - | - |
Salivary gland cancer | - | 2 (0.5) | - | - |
Thymoma | - | 1 (0.2) | - | - |
Not reported | 23 (19.0) | 53 (13.0) | 7 (10.8) | 6 (16.2) |
Safety reports with co-reported ICI-related toxicities | 98 (81.0) | 293 (71.3) | 52 (81.3) | 28 (75.7) |
Safety reports with co-suspected drugs | 15 (12.4) | 62 (15.1) | 10 (15.4) | 1 (2.7) |
of which antineoplastic drugs (ATC L01) | 4 (3.3) | 44 (10.7) | 6 (9.2) | 1 (2.7) |
Eye Disorders # | with Anti-CTLA-4 Monotherapy (N = 185) | with Anti-PD-1/PD-L1 Monotherapy (N = 549) | with Combination of Anti-PD-1 and Anti-CTLA-4 (N = 82) | with ≥2 Suspected ICIs but Regimen Not Definable * (N = 50) |
---|---|---|---|---|
Spectrum + | ||||
Uveitis/autoimmune uveitis | 19 | 78 | 9 | 5 |
Visual impairment | 16 | 48 | 8 | 1 |
Vision blurred | 14 | 45 | 10 | 2 |
Dry eye | 1 | 25 | 6 | 2 |
Diplopia | 12 | 16 | 4 | 1 |
Iridocyclitis | 6 | 14 | 2 | 8 |
Ocular hyperaemia | 11 | 12 | 3 | - |
Blindness | 5 | 16 | 2 | 1 |
Visual acuity reduced | 7 | 16 | 1 | - |
Eyelid ptosis | 2 | 19 | 2 | - |
Eye pain | 4 | 9 | 9 | - |
Vogt-Koyanagi-Harada disease | 3 | 15 | 1 | 2 |
Papilloedema | 3 | 7 | 1 | 5 |
Lacrimation increased | 4 | 10 | 1 | - |
Photophobia | 5 | 7 | 1 | 1 |
Retinal detachment | 2 | 7 | - | 2 |
Eye irritation | 2 | 6 | 1 | 1 |
Eye swelling | 2 | 6 | 1 | 1 |
Cataract | 2 | 5 | 2 | - |
Time to onset | 29 (15.7) | 104 (18.9) | 12 (14.6) | |
Median (IQR), weeks | 7.6 (2.6–12.9) | 5.8 (2.1–14.0) | 5.3 (3.1–8.4) | - |
Outcome | ||||
Recovered/recovering | 77 (41.6) | 202 (36.8) | 30 (36.6) | 18 (36.0) |
Recovered with sequelae | 3 (1.6) | 11 (2.0) | 1 (1.2) | 1 (2.0) |
Not recovered | 13 (7.0) | 98 (17.9) | 11 (13.4) | 5 (10.0) |
Fatal | - | 3 (0.5) | - | - |
Not reported | 92 (49.7) | 235 (42.8) | 40 (48.8) | 26 (52.0) |
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Noseda, R.; Bonaldo, G.; Motola, D.; Stathis, A.; Ceschi, A. Adverse Event Reporting with Immune Checkpoint Inhibitors in Older Patients: Age Subgroup Disproportionality Analysis in VigiBase. Cancers 2021, 13, 1131. https://doi.org/10.3390/cancers13051131
Noseda R, Bonaldo G, Motola D, Stathis A, Ceschi A. Adverse Event Reporting with Immune Checkpoint Inhibitors in Older Patients: Age Subgroup Disproportionality Analysis in VigiBase. Cancers. 2021; 13(5):1131. https://doi.org/10.3390/cancers13051131
Chicago/Turabian StyleNoseda, Roberta, Giulia Bonaldo, Domenico Motola, Anastasios Stathis, and Alessandro Ceschi. 2021. "Adverse Event Reporting with Immune Checkpoint Inhibitors in Older Patients: Age Subgroup Disproportionality Analysis in VigiBase" Cancers 13, no. 5: 1131. https://doi.org/10.3390/cancers13051131