Adverse events of different PD-1 inhibitors in lung cancer patients: a real-world study

Introduction

With an estimated 2,206,771 new cases and an estimated 1,796,144 deaths in 2020, lung cancer is the leading cause of cancer-related death worldwide (1). Programmed death-1 (PD-1) inhibitors, which are recommended for first-line therapy for non-small cell lung cancer (NSCLC) and second-line therapy for small cell lung cancer (SCLC) in the National Comprehensive Cancer Network (NCCN) guidelines, have revolutionized lung cancer therapy. The overall response rate (ORR) and overall survival (OS) were significantly improved compared to standard chemotherapy in both pretreated and treatment-naïve lung cancer patients (2).

However, the treatment-related adverse events (tr-AEs) caused by PD-1 inhibitors, which potentially affect any organ with a very wide occurrence time (from days after first dose to one year after discontinuation) seriously affect drug tolerance and safety (3-5). A meta-analysis revealed that 66% of patients treated with PD-1/programmed death-ligand 1 (PD-L1) inhibitors experienced all-grade tr-AEs, 14.0% experienced grade 3 or higher tr-AEs and 0.45% died from tr-AEs (6). The most commonly tr-AEs mainly involve skin, endocrine glands, gastrointestinal tract, lung, kidney and liver (3-6). In immune checkpoint inhibitor (ICI)-related pneumonitis patients, the mortality rate has been reported to be as high as 18.2% (7). Further, it has been reported that 5–14% of patients discontinue treatment due to tr-AEs (8-10).

Currently, more than 8 PD-1 inhibitors have been approved worldwide and are commonly used to treat lung cancer. Different PD-1 inhibitors were different in immunoglobulin G (IgG) subclasses, fragment antigen-binding (Fab) extracellular domains, Fc receptors and the degree of humanization which result in difference in affinity and specificity to PD-1, antibody dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), IgG-Fc receptors (FcγR) mediate phagocytosis and immunogenicity (11-15). The above biological characteristics may lead to different antitumor activity and tr-AEs of various PD-1 blockers. Capillary hemangioma, a benign proliferation of the capillary endothelial cells, has only been observed in patients treated with camrelizumab (16,17). Besides, incidences of AEs also vary between different PD-1 inhibitors, for example, nivolumab is associated with higher incidences of all-grade AEs [odds ratio (OR) =1.28; 95% confidence interval (CI): 0.97–1.79] and grade 3 or higher AEs (OR =1.30; 95% CI: 0.89–2.00) than pembrolizumab (6).

Therefore, it is important to formulate special monitoring plans according to the spectrum of AEs of different PD-1 inhibitors to ensure treatment safety. Although there have been numerous studies on tr-AEs of PD-1 inhibitors, most of them focus on the comparison between a specific PD-1 inhibitor and chemotherapy, or the relationship between tr-AEs and efficacy either in lung cancer or other cancers. There is a lack of literature to study the tr-AEs of multiple PD-1 inhibitors in the same population. Thus, we conducted a real-world study to evaluate the incidence and spectrum of tr-AEs with all available PD-1 inhibitors in a tertiary cancer hospital in lung cancer patients.

We present the following article in accordance with the STROBE reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-21-6899/rc).

Methods

Patients

This retrospective study was conducted at a tertiary cancer hospital in China. Patients with histologically confirmed lung cancer who had been treated with at least 1 dose of PD-1 inhibitors between January 2017 and December 2019 were included in the study (see Figure 1). Patients with incomplete information were excluded from the study. Clinical data and tr-AEs were collected independently by 2 pharmacists from the patients’ electronic medical records. The sample size was determined by the eligible cases during the study period. The tr-AE grades were evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 5.0 (CTCAE 5.0). This study was approved by the Ethics Committee of the Zhejiang Cancer Hospital (No. IRB-2020-57), and complied with the principles of the Declaration of Helsinki (as revised in 2013). All patients signed the informed consent form.

Figure 1 Research flow chart. Lung cancer patients were screened, and 227 eligible patients were included. Treatment-related adverse events (tr-AEs) were collected for each PD-1 inhibitor group.

Statistical analysis

The data statistician was blinded to the group information. Baseline characteristics and tr-AEs are presented as frequencies and proportions, and were analyzed using χ² tests if all the theoretical frequencies were ≥5 and the total sample size was ≥40, otherwise, Fisher’s exact test was used. Differences were evaluated with 2-sided tests, with an α level of 0.05. A multivariate logistic regression analysis was conducted to identify potential risk factors for tr-AEs. All analyses were performed using SPSS statistical package version 22.0 (IBM, Chicago, IL, USA).

Results

Baseline characteristics

A total of 227 lung cancer patients treated with PD-1 inhibitors were included. The median follow-up period was 2.9 (range, 0.27–24.9) months. Among the 227 patients, 36.56% were treated with nivolumab (n=83), 28.63% with pembrolizumab (n=65), 11.89% with camrelizumab (n=27), 13.66% with sintilimab (n=31), and 9.25% with toripalimab (n=21). Patients had a median age of 63 (range, 34–82) years, and 83.70% (n=190) were male and 16.30% (n=37) were female. In total, 45.81% (n=104) of the patients were treated with PD-1 inhibitors as a monotherapy, and 15.86% (n=36) received more than 10 cycles (see Table 1).

Tr-AE incidence rates of different PD-1 inhibitors

In relation to nivolumab, pembrolizumab, camrelizumab, sintilimab, and toripalimab, the total incidence rates of all-grade tr-AEs were 37.34% (31/83), 24.62% (16/65), 62.96% (17/27), 29.03% (9/31), and 9.52% (2/21), respectively (P=0.01), and the total incidence rates of grade 3–4 tr-AEs were 2.41% (2/83), 3.08% (2/65), 22.22% (6/27), 3.23% (1/31), and 0%, respectively (P=0.05). Further, comparisons between each 2 groups after Bonferroni adjustment showed that camrelizumab had a higher incidence of all-grade tr-AEs than pembrolizumab and toripalimab, and a higher incidence of grade 3–4 tr-AEs than nivolumab and pembrolizumab. Tr-AEs led to permanent discontinuation (6.02% for nivolumab, 1.54% for pembrolizumab, 3.70% for camrelizumab, 3.23% for sintilimab and 0% for toripalimab), and dose interruptions (7.23% for nivolumab, 3.08% for pembrolizumab, 7.41% for camrelizumab, 12.90% for sintilimab and 4.76% for toripalimab) did not differ significantly between the different PD-1 inhibitors (see Table 2).

Pneumonitis was the most common all-grade tr-AE for nivolumab and pembrolizumab (12.05% and 6.15%, respectively). Conversely, capillary hemangioma (22.22%) and abnormal liver function (22.22%) were the most common tr-AEs for camrelizumab, while nausea/vomiting (12.9%) was the most common tr-AE for sintilimab. In the toripalimab group, the most common tr-AEs were pneumonitis (4.76%), rash/pruritus (4.76%), and shingles (4.76%) (see Table 2). Fisher’s exact tests showed that there were significant differences between PD-1 inhibitors in relation to capillary hemangioma (P=0.000). Further, a comparison between each 2 groups after Bonferroni adjustment showed that the incidence of capillary hemangioma was higher in the camrelizumab group than the nivolumab and pembrolizumab groups. Pneumonitis was the most common grade 3–4 tr-AE in the nivolumab (2.41%) and pembrolizumab groups (3.08%), while abnormal liver function was the most common grade 3–4 tr-AE in the camrelizumab (11.11%) and sintilimab groups (3.22%). There was no grade 3–4 tr-AEs in patients treated with toripalimab.

Risk factors for tr-AEs

The univariate analysis revealed that sex (P=0.000), age (P=0.008), PD-1 inhibitors (P=0.000), clinical stage (P=0.000), histology (P=0.000), treatment line (P=0.008), combined treatment (P=0.001), PD-1 inhibitor cycles (P=0.004), smoking (P=0.043), drinking alcohol (P=0.017), and thoracic radiotherapy history (P=0.000) were significantly associated with tr-AEs (see Table 3). The multivariate analysis revealed that male (OR =2.993; 95% CI: 1.296–6.912; P=0.001), an age >60 years (OR =1.688; 95% CI: 1.090–2.613; P=0.019), SCLC (OR =5.674; 95% CI: 2.690–11.551; P=0.000), and ≥10 PD-1 cycles (OR =2.607; 95% CI: 1.450–4.687; P=0.001) were independent risk factors for tr-AEs (see Table 3). PD-1 inhibitors (P=0.000) were also significantly associated with tr-AEs.

Discussion

Pd-1 inhibitors are widely used in lung cancer patients, but there is still a lack of head-to-head research on the differences between efficacy and adverse events. Clinical studies on individual drugs have shown that the incidence and spectrum of tr-AEs are seems to be different in different PD-1 inhibitor. The incidence rates of all-grade tr-AEs with nivolumab, pembrolizumab, camrelizumab, sintilimab and toripalimab were (48–92.3%) (18-23), 51–93% (24-27), 89–100% (28-30), 43.2–93% (31,32) and 77.6–93.8% (33-35), respectively. Conversely, our study reported much lower incidence rates of 37.34%, 24.62%, 62.96%, 29.03% and 9.52%, respectively. This may be because this was a retrospective study, and tr-AEs that were not recorded in the electronic medical system were not able to be included. In addition, traditional Chinese medicine (TCM) was commonly used to treat our patients, which may reduce the occurrence of tr-AEs. Studies have shown that TCM can reduce chemotherapy-related toxicities, such as thrombocytopenia, vomiting, diarrhea, fatigue, and loss of appetite (36-39). Additionally, TCM can affect gut microbiome and T lymphocytes subsets in cancer patients (40). In relation to toripalimab, there was another possible reason for the lower incidence: previous studies have mainly been conducted in patients who had been heavily pretreated, but in our study, 42.86% (9/21) of the patients were treatment naïve. Thus, the physiological and psychological conditions related to AEs should have been better in our study, which may be associated with tr-AEs.

Reports on the most common tr-AEs of PD-1 inhibitors differ among previous studies (30-35). This may be related to whether chemotherapy or other targeted drugs are combined, disease status, patients’ conditions, and concomitant medication. In our study, a higher incidence of pneumonitis was observed in the nivolumab group (12.05%) compared to that previously reported (3–6%) (19,41,42). This may be because 51.80% (43/83) of patients in the nivolumab group had a previous history of radiotherapy in our study. Additionally, the incidence of capillary hemangioma was lower in our study (22.22%) than that reported previously (80–97.3%) (30-32,43). This may be because 37.04% (10/27) of patients received combined therapy, 25.93% (7/27) received apatinib, 7.41% (2/27) received bevacizumab, and 3.70% (1/27) received pemetrexed plus cisplatin. Studies have shown that the incidence of capillary hemangioma decreased sharply to 8.9% and 22% when the therapy was combined with apatinib (44) or gemcitabine plus cisplatin (32).

Mechanisms of tr-AEs caused by PD-1 inhibitors have not been fully elucidated, but it is known that tr-AEs may result from some combination of autoreactive T cells, autoantibodies, and proinflammatory cytokines (45,46). The underlying mechanisms of why different PD-1 inhibitors have different tr-AEs are still unclear. The difference of biological characteristics maybe is associated with that. Camrelizumab, a potent agonist of human VEGFR-2, can drive hemangioma development by activating vascular endothelial cell proliferation and lead to high incidence of capillary hemangioma (47).

The risk factors for tr-AEs remain unclear and reports are very inconsistent in different articles. One study reported that concomitant chemotherapy, a higher body mass index, and the presence of epidermal growth factor receptor mutation were predictors for irAEs (48). Another study found that serum albumin ≥3.6 g/dL [hazards ratio (HR) =1.62; 95% CI: 1.10–2.39; P=0.015] and a history of type I hypersensitivity reactions (HR =1.48; 95% CI: 1.02–2.14; P=0.037) were risk factors for irAEs (49). Our research found that sex, age, PD-1 inhibitors, histology type, and PD-1 inhibitor cycles were significantly associated with tr-AEs.

Our results should be interpreted with caution in light of the limitations of the study. First, this was a retrospective study; thus, information bias cannot be excluded, and unrecorded adverse events could not be counted, which may have led to the underestimation of tr-AEs. Second, the incidence rates of tr-AEs with PD-1 inhibitor monotherapy and in combination were not statistically significant separately due to the small sample size. Thus, further studies need to be conducted to clarify the characteristics of the immune-related AEs associated with different PD-1 inhibitors.

In this study, only cases with incomplete data were excluded, and there were no restrictions in relation to age, previous treatment, or the combined use of drugs in the included population; thus, it has good external applicability. Based on results of our research, it is suggested that: (I) differentiated monitoring plan should be made according to different PD-1 inhibitors, for example, capillary hemangioma and liver function should been closely monitored when camrelizumab adopted; (II) special attention should be paid to patients with male sex, age >60 years, SCLC and use PD-1 inhibitor 10 or more cycles.

Conclusions

There was significant differences in the incidence and spectrum of tr-AEs with different PD-1 inhibitors.

Acknowledgements

We would like to thank all the patients who participated in this study.

Funding: This study was supported by the National Natural Science Foundation of China (82003189 and 82173855), the Natural Science Foundation of Zhejiang Province (LQ17H310002 and LY20H310001), the Key Laboratory of Endocrine Gland Diseases of Zhejiang Province (2021E10020), the Medical and Health Research Program of Zhejiang (WKJ-ZJ-2115), the Zhejiang Provincial Program for the Cultivation of New Heath Talents (to Y Zhang), the Zhejiang Provincial Program for the Cultivation of 151 Talents (to P Huang), the Zhejiang Provincial Program for the Cultivation of High-Level Innovative Heath Talents (to P Huang), and the “10000 Talents Plan” of Zhejiang Province (to P Huang).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-21-6899/rc

Data Sharing Statement: Available at https://atm.amegroups.com/article/view/10.21037/atm-21-6899/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-21-6899/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the Ethics Committee of the Zhejiang Cancer Hospital (No. IRB-2020-57). All patients signed the informed consent form. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
2. Somasundaram A, Burns TF. The next generation of immunotherapy: keeping lung cancer in check. J Hematol Oncol 2017;10:87. [Crossref] [PubMed]
3. Inno A, Metro G, Bironzo P, et al. Pathogenesis, clinical manifestations and management of immune checkpoint inhibitors toxicity. Tumori 2017;103:405-21. [Crossref] [PubMed]
4. Ramos-Casals M, Brahmer JR, Callahan MK, et al. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Prim 2020;6:38. [Crossref] [PubMed]
5. Parakh S, Cebon J, Klein O. Delayed autoimmune toxicity occurring several months after cessation of anti-PD-1 therapy. Oncologist 2018;23:849-51. [Crossref] [PubMed]
6. Wang Y, Zhou S, Yang F, 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;5:1008-19. [Crossref] [PubMed]
7. Cho JY, Kim J, Lee JS, et al. Characteristics, incidence, and risk factors of immune checkpoint inhibitor-related pneumonitis in patients with non-small cell lung cancer. Lung Cancer 2018;125:150-6. [Crossref] [PubMed]
8. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:1627-39. [Crossref] [PubMed]
9. Gettinger S, Rizvi NA, Chow LQ, et al. Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 2016;34:2980-7. [Crossref] [PubMed]
10. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 2018;379:2040-51. [Crossref] [PubMed]
11. Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol 2014;5:520. [Crossref] [PubMed]
12. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy-inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res 2012;18:6580-7. [Crossref] [PubMed]
13. Chames P, Van Regenmortel M, Weiss E, Baty D. Therapeutic antibodies: successes, limitations and hopes for the future. Br J Pharmacol 2009;157:220-33. [Crossref] [PubMed]
14. Harding FA, Stickler MM, Razo J, DuBridge RB. The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions. MAbs 2010;2:256-65. [Crossref] [PubMed]
15. Almagro JC, Daniels-Wells TR, Perez-Tapia SM, et al. Progress and challenges in the design and clinical development of antibodies for cancer therapy. Front Immunol 2018;8:1751. [Crossref] [PubMed]
16. Teng Y, Guo R, Sun J, et al. Reactive capillary hemangiomas induced by camrelizumab (SHR-1210), an anti-PD-1 agent. Acta Oncol 2019;58:388-9. [Crossref] [PubMed]
17. Yu Q, Wang WX. Camrelizumab (SHR-1210) leading to reactive capillary hemangioma in the gingiva: A case report. World J Clin Cases 2020;8:624-9. [Crossref] [PubMed]
18. Spigel DR, McCleod M, Jotte RM, et al. Safety, efficacy, and patient-reported health-related quality of lLife and symptom burden with nivolumab in patients with advanced non-small cell lung cancer, including patients aged 70 years or older or with poor performance ptatus (CheckMate 153). J Thorac Oncol 2019;14:1628-39. [Crossref] [PubMed]
19. Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 2016;17:883-95. [Crossref] [PubMed]
20. Carbone DP, Reck M, Paz-Ares L, et al. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. N Engl J Med 2017;376:2415-26. [Crossref] [PubMed]
21. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med 2019;381:2020-31. [Crossref] [PubMed]
22. Xu C, Chen YP, Du XJ, et al. Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis. BMJ 2018;363:k4226. [Crossref] [PubMed]
23. Spigel DR, Reynolds C, Waterhouse D, et al. Phase 1/2 Study of the safety and tolerability of nivolumab plus crizotinib for the first-line treatment of anaplastic lymphoma kinase translocation - positive advanced non-small cell lung cancer (CheckMate 370). J Thorac Oncol 2018;13:682-8. [Crossref] [PubMed]
24. Chatterjee M, Turner DC, Felip E, et al. Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer. Ann Oncol 2016;27:1291-8. [Crossref] [PubMed]
25. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 2016;17:1497-508. [Crossref] [PubMed]
26. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33. [Crossref] [PubMed]
27. Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019;393:1819-30. [Crossref] [PubMed]
28. Huang J, Xu J, Chen Y, et al. Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a multicentre, randomised, open-label, phase 3 study. Lancet Oncol 2020;21:832-42. [Crossref] [PubMed]
29. Li N, Liu L, Xiang P, et al. Addition of low-dose decitabine to bortezomib and dexamethasone as second-line therapy in multiple myeloma. Br J Haematol 2020;189:e258-62. [Crossref] [PubMed]
30. Fang W, Yang Y, Ma Y, et al. Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials. Lancet Oncol 2018;19:1338-50. [Crossref] [PubMed]
31. Yang Y, Wang Z, Fang J, et al. Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol 2020;15:1636-46. [Crossref] [PubMed]
32. Shi Y, Su H, Song Y, et al. Safety and activity of sintilimab in patients with relapsed or refractory classical Hodgkin lymphoma (ORIENT-1): a multicentre, single-arm, phase 2 trial. Lancet Haematol 2019;6:e12-9. [Crossref] [PubMed]
33. Keam SJ. Toripalimab: First Global Approval. Drugs 2019;79:573-8. [Crossref] [PubMed]
34. Tang B, Chi Z, Chen Y, et al. Safety, Efficacy, and Biomarker Analysis of Toripalimab in Previously Treated Advanced Melanoma: Results of the POLARIS-01 Multicenter Phase II Trial. Clin Cancer Res 2020;26:4250-9. [Crossref] [PubMed]
35. Wang F, Wei XL, Wang FH, et al. Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in phase Ib/II clinical trial NCT02915432. Ann Oncol 2019;30:1479-86. [Crossref] [PubMed]
36. Qi S, Li X, Dong Q, et al. Chinese herbal medicine (Xiaoaiping) injections for chemotherapy-induced thrombocytopenia: a randomized, controlled, multicenter clinical trial. J Altern Complement Med 2019;25:648-55. [Crossref] [PubMed]
37. Jiao L, Dong C, Liu J, et al. Effects of chinese medicine as adjunct medication for adjuvant chemotherapy treatments of non-small cell lung cancer patients. Sci Rep 2017;7:46524. [Crossref] [PubMed]
38. Xiao Z, Chen Z, Han R, et al. Comprehensive TCM treatments combined with chemotherapy for advanced non-small cell lung cancer: A randomized, controlled trial. Medicine (Baltimore) 2021;100:e25690. [Crossref] [PubMed]
39. Xu M, Wang Y, Wang HC. Adjuvant concomitant treatment with traditional Chinese medicines in patients receiving chemotherapy for HER2-Positive breast cancer: A pilot randomized controlled trial. Complement Ther Clin Pract 2021;43:101373. [Crossref] [PubMed]
40. Sun L, Yan Y, Chen D, et al. Quxie capsule modulating gut microbiome and its association with T cell regulation in patients with metastatic colorectal cancer: result from a randomized controlled clinical trial. Integr Cancer Ther 2020;19:1534735420969820. [Crossref] [PubMed]
41. Haratani K, Hayashi H, Chiba Y, et al. Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol 2018;4:374-8. [Crossref] [PubMed]
42. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-35. [Crossref] [PubMed]
43. Song Y, Wu J, Chen X, et al. A Single-arm, multicenter, phase II study of camrelizumab in relapsed or refractory classical hodgkin lymphoma. Clin Cancer Res 2019;25:7363-9. [Crossref] [PubMed]
44. Lan C, Shen J, Wang Y, et al. Camrelizumab llus apatinib in patients with advanced cervical cancer (CLAP): a multicenter, open-label, single-arm, phase II trial. J Clin Oncol 2020;38:4095-106. [Crossref] [PubMed]
45. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018;378:158-68. [Crossref] [PubMed]
46. Esfahani k, Miller WH Jr. Reversal of autoimmune toxicity and loss of tumor response by interleukin-17 blockade. N Engl J Med 2017;376:1989-91. [Crossref] [PubMed]
47. Finlay WJJ, Coleman JE, Edwards JS, et al. Anti-PD1 'SHR-1210' aberrantly targets proangiogenic receptors and this polyspecificity can be ablated by paratope refinement. MAbs 2019;11:26-44. [Crossref] [PubMed]
48. Huang Y, Soon YY, Aminkeng F, et al. Risk factors for immune-related adverse events from anti-PD-1 or anti-PD-L1 treatment in an Asian cohort of nonsmall cell lung cancer patients. Int J Cancer 2022;150:636-44. [Crossref] [PubMed]
49. Shimozaki K, Sukawa Y, Sato Y, et al. Analysis of risk factors for immune-related adverse events in various solid tumors using real-world data. Future Oncol 2021;17:2593-603. [Crossref] [PubMed]

(English Language Editor: L. Huleatt)