Journal Home > Volume 1 , Issue 4
Cancer Innovation 2022, 1(4): 293-304 https://doi.org/10.1002/cai2.34
Meta-analysis | Open Access | Issue | Published: 14 November 2022

Deaths and adverse events from adjuvant therapy with immune checkpoint inhibitors in solid malignant tumors: A systematic review and network meta‐analysis

Show Author's Information Ruiyang Xie1,  Jie Wu1,  Bingqing Shang1,  Xingang Bi1,  Chuanzhen Cao1,  Youyan Guan1( ),  Hongzhe Shi1( ),  Jianzhong Shou1 ( )
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
Keywords:
cancer, adjuvant therapy, immune checkpoint inhibitor, adverse event, death
Cite this article:
Xie R, Wu J, Shang B, et al. Deaths and adverse events from adjuvant therapy with immune checkpoint inhibitors in solid malignant tumors: A systematic review and network meta‐analysis. Cancer Innovation, 2022, 1(4): 293-304. https://doi.org/10.1002/cai2.34
Download citation
EndNote(RIS)
BibTeX

718

Views

26

Downloads

Citations

0

Crossref

N/A

WoS

0

Scopus

N/A

CSCD

Abstract Full text About this article
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.


menu
Abstract
Full text
Outline
About this article

Deaths and adverse events from adjuvant therapy with immune checkpoint inhibitors in solid malignant tumors: A systematic review and network meta‐analysis

Show Author's information Ruiyang Xie1, Jie Wu1, Bingqing Shang1, Xingang Bi1, Chuanzhen Cao1, Youyan Guan1( ), Hongzhe Shi1( ), Jianzhong Shou1 ( )
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

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.

Keywords: cancer, adjuvant therapy, immune checkpoint inhibitor, adverse event, death

References(38)

Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359(6382):1350–5.
DOI Google Scholar
Sharma 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.
DOI Google Scholar
Luke 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.
DOI Google Scholar
Choueiri 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.
DOI Google Scholar
Johnson DB, Nebhan CA, Moslehi JJ, Balko JM. Immune‐checkpoint inhibitors: long‐term implications of toxicity. Nat Rev Clin Oncol. 2022;19(4):254–67.
DOI Google Scholar
Zhou 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.
DOI Google Scholar
Wang 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.
DOI Google Scholar
Kelly 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.
DOI Google Scholar
Felip 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.
DOI Google Scholar
Eggermont 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.
DOI Google Scholar
Moher 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.
DOI Google Scholar
Coomarasamy 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.
DOI Google Scholar
Darnell 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.
DOI Google Scholar
Freites‐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.
DOI Google Scholar
Higgins 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.
DOI Google Scholar
Mills EJ, Thorlund K, Ioannidis JPA. Demystifying trial networks and network meta‐analysis. BMJ. 2013;346:f2914.
DOI Google Scholar
Salanti 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.
DOI Google Scholar
Lu G, Ades AE. Assessing evidence inconsistency in mixed treatment comparisons. J Am Stat Assoc. 2006;101(474):447–59.
DOI Google Scholar
Higgins JPT. Measuring inconsistency in meta‐analyses. BMJ. 2003;327(7414):557–60.
DOI Google Scholar
Thorlund K, Mills EJ. Sample size and power considerations in network meta‐analysis. Syst Rev. 2012;1:41.
DOI Google Scholar
Neupane 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.
DOI Google Scholar
Schmid 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.
DOI Google Scholar
Bajorin 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.
DOI Google Scholar
Bellmunt 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.
DOI Google Scholar
Weber 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.
DOI Google Scholar
Eggermont 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.
DOI Google Scholar
Puzanov 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.
DOI Google Scholar
Soularue 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.
DOI Google Scholar
Collins 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.
DOI Google Scholar
Seth 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.
DOI Google Scholar
Koyama 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.
DOI Google Scholar
Naidoo 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.
DOI Google Scholar
Zhang 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.
DOI Google Scholar
Gao 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.
DOI Google Scholar
Shimabukuro‐Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, et al. Cytokine release syndrome. J Immunother Cancer. 2018;6(1):56.
DOI Google Scholar
Lee 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.
DOI Google Scholar
Neelapu 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.
DOI Google Scholar
Braun 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.
DOI Google Scholar
Publication history
Copyright
Acknowledgements
Rights and permissions

Publication history

Received: 10 August 2022
Accepted: 28 September 2022
Published: 14 November 2022
Issue date: December 2022

Copyright

© 2022 The Authors.

Acknowledgements

The authors thank Jingyi Hou for her kind help in language editing. There are no other relationships or activities that could appear to have influenced the submitted work.

Rights and permissions

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

Return