Deaths and adverse events from adjuvant therapy with immune checkpoint inhibitors in solid malignant tumors: A systematic review and network meta-analysis
Ruiyang Xie
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Contribution: Data curation (equal), Formal analysis (equal)
Search for more papers by this authorJie Wu
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Contribution: Data curation (equal), Formal analysis (equal)
Search for more papers by this authorBingqing Shang
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Contribution: Investigation (equal), Methodology (equal)
Search for more papers by this authorXingang Bi
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Contribution: Funding acquisition (equal), Investigation (equal)
Search for more papers by this authorChuanzhen Cao
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Contribution: Conceptualization (equal), Methodology (equal)
Search for more papers by this authorCorresponding Author
Youyan Guan
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Correspondence Youyan Guan, Hongzhe Shi, and Jianzhong Shou, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Panjiayuan Nanli #17, Chaoyang District, Beijing 100021, China.
Email: [email protected], [email protected] and [email protected]
Contribution: Investigation (equal), Project administration (equal)
Search for more papers by this authorCorresponding Author
Hongzhe Shi
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Correspondence Youyan Guan, Hongzhe Shi, and Jianzhong Shou, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Panjiayuan Nanli #17, Chaoyang District, Beijing 100021, China.
Email: [email protected], [email protected] and [email protected]
Contribution: Funding acquisition (equal), Investigation (equal)
Search for more papers by this authorCorresponding Author
Jianzhong Shou
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Correspondence Youyan Guan, Hongzhe Shi, and Jianzhong Shou, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Panjiayuan Nanli #17, Chaoyang District, Beijing 100021, China.
Email: [email protected], [email protected] and [email protected]
Contribution: Project administration (lead)
Search for more papers by this authorRuiyang Xie
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Contribution: Data curation (equal), Formal analysis (equal)
Search for more papers by this authorJie Wu
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Contribution: Data curation (equal), Formal analysis (equal)
Search for more papers by this authorBingqing Shang
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Contribution: Investigation (equal), Methodology (equal)
Search for more papers by this authorXingang Bi
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Contribution: Funding acquisition (equal), Investigation (equal)
Search for more papers by this authorChuanzhen Cao
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Contribution: Conceptualization (equal), Methodology (equal)
Search for more papers by this authorCorresponding Author
Youyan Guan
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Correspondence Youyan Guan, Hongzhe Shi, and Jianzhong Shou, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Panjiayuan Nanli #17, Chaoyang District, Beijing 100021, China.
Email: [email protected], [email protected] and [email protected]
Contribution: Investigation (equal), Project administration (equal)
Search for more papers by this authorCorresponding Author
Hongzhe Shi
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Correspondence Youyan Guan, Hongzhe Shi, and Jianzhong Shou, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Panjiayuan Nanli #17, Chaoyang District, Beijing 100021, China.
Email: [email protected], [email protected] and [email protected]
Contribution: Funding acquisition (equal), Investigation (equal)
Search for more papers by this authorCorresponding Author
Jianzhong Shou
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Correspondence Youyan Guan, Hongzhe Shi, and Jianzhong Shou, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Panjiayuan Nanli #17, Chaoyang District, Beijing 100021, China.
Email: [email protected], [email protected] and [email protected]
Contribution: Project administration (lead)
Search for more papers by this authorRuiyang Xie and Jie Wu contributed equally to this study.
Abstract
Background
By prolonging overall survival and reducing disease recurrence rates, immune checkpoint inhibitors (ICIs) are an emerging adjuvant therapy option for patients with resectable malignant tumors. However, the safety profile (deaths and adverse events [AEs]) of adjuvant ICIs has not been fully described.
Methods
We searched the literature for phase III randomized clinical trials that compared PD-1, PD-L1, and CTLA-4 inhibitors in solid malignant tumors. Incidences of death, discontinuation, AEs of any cause, treatment-related adverse events (TRAEs), and immune-related adverse events (IRAEs) were extracted for the network meta-analysis. Network meta-analyses with low incidence and poor convergence are reported as incidences with 95% confidence intervals (95% CIs).
Results
Ten randomized clinical trials that included 9243 patients who received ICI adjuvant therapy were eligible. In total, 21 deaths due to TRAEs were recorded, with an overall incidence of 0.40% (95% CI: 0.26–0.61). The treatment-related mortality rates for ipilimumab (0.76%, 95% CI: 0.31–1.55) and atezolizumab (0.56%, 95% CI: 0.18–1.31) were higher than for pembrolizumab (0.24%, 95% CI: 0.10–0.56) and nivolumab (0.30%, 95% CI: 0.08–0.77). The most frequent causes of death were associated with the gastrointestinal (0.10%, 95% CI: 0.04–0.24) and pulmonary (0.08%, 95% CI: 0.03–0.21) systems. Compared with the control arm, we found that nivolumab (odds ratio [OR]: 2.73, 95% CI: 0.49–15.85) and atezolizumab (OR: 12.43, 95% CI: 2.42–78.48) caused the fewest grade ≥3 TRAEs and IRAEs. Commonly reported IRAEs of special interest were analyzed, and two agents were found to have IRAEs with incidences >10%, i.e., hepatitis for atezolizumab (14.80%, 95% CI: 12.53–17.32) and hypophysitis for ipilimumab (13.53%, 95% CI: 11.38–15.90).
Conclusions
Ipilimumab and atezolizumab were correlated with higher treatment-related death rates than pembrolizumab and nivolumab, in which the gastrointestinal and pulmonary systems were mostly involved. Regarding severe TRAEs and IRAEs, nivolumab and atezolizumab are likely to be the safest agent, respectively. This study will guide clinical practice for ICI adjuvant therapies.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The datasets supporting the conclusions of this article are included within the article and its additional file.
Supporting Information
| Filename | Description |
|---|---|
| cai234-sup-0001-Supplementary_data.docx3.1 MB | Supplementary information. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018; 359(6382): 1350–5. https://doi.org/10.1126/science.aar4060
- 2Sharma P, Siddiqui BA, Anandhan S, Yadav SS, Subudhi SK, Gao J, et al. The next decade of immune checkpoint therapy. Cancer Discov. 2021; 11(4): 838–57. https://doi.org/10.1158/2159-8290.CD-20-1680
- 3Luke JJ, Rutkowski P, Queirolo P, Del Vecchio M, Mackiewicz J, Chiarion-Sileni V, et al. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet. 2022; 399(10336): 1718–29. https://doi.org/10.1016/S0140-6736(22)00562-1
- 4Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang YH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021; 385(8): 683–94. https://doi.org/10.1056/NEJMoa2106391
- 5Johnson DB, Nebhan CA, Moslehi JJ, Balko JM. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol. 2022; 19(4): 254–67. https://doi.org/10.1038/s41571-022-00600-w
- 6Zhou X, Yao Z, Bai H, Duan J, Wang Z, Wang X, et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitor-based combination therapies in clinical trials: a systematic review and meta-analysis. Lancet Oncol. 2021; 22(9): 1265–74. https://doi.org/10.1016/S1470-2045(21)00333-8
- 7Wang Y, Zhou S, Yang F, Qi X, Wang X, Guan X, et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis. JAMA Oncol. 2019; 5(7): 1008–19. https://doi.org/10.1001/jamaoncol.2019.0393
- 8Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med. 2021; 384(13): 1191–203. https://doi.org/10.1056/NEJMoa2032125
- 9Felip E, Altorki N, Zhou C, Csőszi T, Vynnychenko I, Goloborodko O, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021; 398(10308): 1344–57. https://doi.org/10.1016/S0140-6736(21)02098-5
- 10Eggermont AMM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016; 375(19): 1845–55. https://doi.org/10.1056/NEJMoa1611299
- 11Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009; 62(10): 1006–12. https://doi.org/10.1016/j.jclinepi.2009.06.005
- 12Coomarasamy A, Williams H, Truchanowicz E, Seed PT, Small R, Quenby S, et al. PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages – a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation. Health Technol Assess. 2016; 20(41): 1–92. https://doi.org/10.3310/hta20410
- 13Darnell EP, Mooradian MJ, Baruch EN, Yilmaz M, Reynolds KL. Immune-related adverse events (irAEs): diagnosis, management, and clinical pearls. Curr Oncol Rep. 2020; 22(4):39. https://doi.org/10.1007/s11912-020-0897-9
- 14Freites-Martinez A, Santana N, Arias-Santiago S, Viera A. CTCAE versión 5.0. Evaluación de la gravedad de los eventos adversos dermatológicos de las terapias antineoplásicas. Actas Dermosifiliogr. 2021; 112(1): 90–2. https://doi.org/10.1016/j.ad.2019.05.009
- 15Higgins JPT, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The cochrane collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011; 343:d5928. https://doi.org/10.1136/bmj.d5928
- 16Mills EJ, Thorlund K, Ioannidis JPA. Demystifying trial networks and network meta-analysis. BMJ. 2013; 346:f2914. https://doi.org/10.1136/bmj.f2914
- 17Salanti G, Ades AE, Ioannidis JPA. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol. 2011; 64(2): 163–71. https://doi.org/10.1016/j.jclinepi.2010.03.016
- 18Lu G, Ades AE. Assessing evidence inconsistency in mixed treatment comparisons. J Am Stat Assoc. 2006; 101(474): 447–59. https://doi.org/10.1198/016214505000001302
- 19Higgins JPT. Measuring inconsistency in meta-analyses. BMJ. 2003; 327(7414): 557–60. https://doi.org/10.1136/bmj.327.7414.557
- 20Thorlund K, Mills EJ. Sample size and power considerations in network meta-analysis. Syst Rev. 2012; 1:41. https://doi.org/10.1186/2046-4053-1-41
- 21Neupane B, Richer D, Bonner AJ, Kibret T, Beyene J. Network meta-analysis using R: a review of currently available automated packages. PLoS One. 2014; 9(12):e115065. https://doi.org/10.1371/journal.pone.0115065
- 22Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020; 382(9): 810–21. https://doi.org/10.1056/NEJMoa1910549
- 23Bajorin DF, Witjes JA, Gschwend JE, Schenker M, Valderrama BP, Tomita Y, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021; 384(22): 2102–14. https://doi.org/10.1056/NEJMoa2034442
- 24Bellmunt J, Hussain M, Gschwend JE, Albers P, Oudard S, Castellano D, et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2021; 22(4): 525–37. https://doi.org/10.1016/S1470-2045(21)00004-8
- 25Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017; 377(19): 1824–35. https://doi.org/10.1056/NEJMoa1709030
- 26Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018; 378(19): 1789–801. https://doi.org/10.1056/NEJMoa1802357
- 27Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, Dadu R, Hamad L, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017; 5(1):95. https://doi.org/10.1186/s40425-017-0300-z
- 28Soularue E, Lepage P, Colombel JF, Coutzac C, Faleck D, Marthey L, et al. Enterocolitis due to immune checkpoint inhibitors: a systematic review. Gut. 2018; 67(11): 2056–67. https://doi.org/10.1136/gutjnl-2018-316948
- 29Collins M, Michot JM, Danlos FX, Mussini C, Soularue E, Mateus C, et al. Inflammatory gastrointestinal diseases associated with PD-1 blockade antibodies. Ann Oncol. 2017; 28(11): 2860–5. https://doi.org/10.1093/annonc/mdx403
- 30Seth R, Messersmith H, Kaur V, Kirkwood JM, Kudchadkar R, McQuade JL, et al. Systemic therapy for melanoma: ASCO guideline. J Clin Oncol. 2020; 38(33): 3947–70. https://doi.org/10.1200/JCO.20.00198
- 31Koyama N, Iwase O, Nakashima E, Kishida K, Kondo T, Watanabe Y, et al. High incidence and early onset of nivolumab-induced pneumonitis: four case reports and literature review. BMC Pulm Med. 2018; 18(1):23. https://doi.org/10.1186/s12890-018-0592-x
- 32Naidoo J, Wang X, Woo KM, Iyriboz T, Halpenny D, Cunningham J, et al. Pneumonitis in patients treated with anti-programmed Death-1/programmed death ligand 1 therapy. J Clin Oncol. 2017; 35(7): 709–17. https://doi.org/10.1200/JCO.2016.68.2005
- 33Zhang M, Cheng Y, Hu Y, Nie L. Cytokine release syndrome and successful response to pembrolizumab therapy in a patient with EGFR-mutated non-small-cell lung cancer: a case report. Thorac Cancer. 2022; 13(9): 1419–22. https://doi.org/10.1111/1759-7714.14390
- 34Gao C, Xu J, Han C, Wang L, Zhou W, Yu Q. An esophageal cancer case of cytokine release syndrome with multiple-organ injury induced by an anti-PD-1 drug: a case report. Ann Palliat Med. 2020; 9(4): 2393–9. https://doi.org/10.21037/apm-20-1310
- 35Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, et al. Cytokine release syndrome. J Immunother Cancer. 2018; 6(1):56. https://doi.org/10.1186/s40425-018-0343-9
- 36Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014; 124(2): 188–95. https://doi.org/10.1182/blood-2014-05-552729
- 37Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy – assessment and management of toxicities. Nat Rev Clin Oncol. 2018; 15(1): 47–62. https://doi.org/10.1038/nrclinonc.2017.148
- 38Braun DA, Street K, Burke KP, Cookmeyer DL, Denize T, Pedersen CB, et al. Progressive immune dysfunction with advancing disease stage in renal cell carcinoma. Cancer Cell. 2021; 39(5): 632–648.e8. https://doi.org/10.1016/j.ccell.2021.02.013
