Meta-analysis of TEAEs associated with PD-1 and PD-L1 inhibitors

On 25 April, Yucai Wang from Mayo Clinic, Rochester, MN, USA, and colleagues, published in the Journal of the American Medical Association (JAMA) results from a systematic review and meta-analysis1 of adverse events (AEs) associated with the clinical use of programmed cell death ligand 1 (PD-L1) and PD-1 inhibitors.

PD-1 and PD-L1 inhibitors has been widely used to treat various types of cancers, with nivolumab and pembrolizumab (anti-PD-1), as well as atezolizumab, avelumab, and durvalumab (anti-PD-L1) having been approved by the Food and Drug Administration (FDA) for different indications2. Given the widespread use of such inhibitors against cancer, the authors sought to evaluate their safety profile among different pathologies from published clinical trials.

Study design
  • Literature search was conducted from 01 October 2017 to 15 December 2018
  • Search engines used:
    • PubMed
    • Web of Science
    • Scopus
    • Embase
  • Search engine terms:
    • Nivolumab
    • Pembrolizumab
    • Atezolizumab
    • Avelumab
    • Durvalumab
    • PD-1 inhibitor
    • PD-L1 inhibitor
  • Bayesian multilevel regression models were used for data analysis
  • The incidence probability of AEs was adjusted by study characteristics like:
    • Dosing schedule
    • Therapeutic regimen
    • Cancer type
    • AE type
  • The meta-analysis focused on AEs that were either reported in at least 10% of the studies or were possibly immune-related AEs (irAEs)
Key findings
  • Literature search identified 5179 relevant publications:
    • After screening: 125 studies were finally included in the meta-analysis involving N = 20,128 patients in total
  • PD-1 and PD-L1 inhibitors used in these studies included:
    • Nivolumab, n = 46 publications
    • Pembrolizumab, n = 49 publications
    • Atezolizumab, n = 15 publications
    • Avelumab, n = 9 publications
    • Durvalumab, n = 6 publications
  • Patients who developed at least one AE of any grade: 66% (n = 12,277/18,610) among 106 studies
  • Patients who developed at least one Grade ≥ 3 AE: 14% (n = 2627/18,715) among 110 studies
  • The meta-analysis identified 75 AEs that were most commonly observed
  • Overall mean incidence of any grade AEs: 1.66% (95% CI, 1.47−86)
  • Mean incidence of Grade ≥ 3 AEs: 0.11% (95% CI, 0.08−14)
  • Most common AEs across studies:

Any grade AE

Incidence

95% CI

Fatigue

18.26%

16.49−20.11

Pruritus

10.61%

9.46−11.83

Diarrhea

9.47%

8.43−10.58

 

 

 

Grade ≥ 3 AE

Incidence

95% CI

Fatigue

0.89%

0.69−1.14

Anemia

0.78%

0.59−1.02

Aspartate aminotransferase (AST) increase

0.75%

0.56−0.99

  • Most common endocrine irAEs across studies:

Any grade endocrine irAEs

Incidence

95% CI

Hypothyroidism

6.07%

5.35−6.85

Hyperthyroidism

2.82%

2.40−3.29

Hyperglycemia  

1.20%

0.91−1.55

Thyroiditis

0.75%

0.52−1.04

Adrenal insufficiency

0.69%

0.50−0.93

 

 

 

Grade ≥ 3 endocrine irAEs

Incidence

95% CI

Hyperglycemia

0.24%

0.13−0.38

Adrenal insufficiency

0.18%

0.10−0.30

Type I diabetes              

0.18%

0.10−0.30

Hypohysitis

0.16%

0.09−0.27

Hypothyroidism

0.08%

0.04−0.13

  • Most common other irAEs across studies:

Any grade other irAEs

Incidence

95% CI

Diarrhea

9.47%

8.43−10.58

AST increase

3.39%

2.94−3.89

Vitiligo

3.26%

2.80−3.79

Alanine aminotransferase (ALT) increase

3.14%

2.71−3.62

Pneumonitis

2.79%

2.39−3.23

Colitis

1.24%

0.99−1.54

 

 

 

Grade ≥ 3 other irAEs

Incidence

95% CI

AST increase

0.75%

0.56−0.99

ALT increase

0.70%

0.52−0.93

Pneumonitis

0.67%

0.50−0.89

Diarrhea

0.59%

0.45−0.77

Colitis

0.47%

0.34−0.65

  • AEs that were more likely to be severe (high risk ratio [RR]: incidence of AE with Grade ≥ 3 divided by any grade AE incidence) included:
    • Hepatitis: RR = 50.59%
    • Lipase increase: RR = 42.01%
    • Gamma-glutamyltransferase increase: RR = 41.96%
    • Type I diabetes: RR = 41.86%
    • Colitis: RR = 37.90%
  • Treatment-related deaths were reported in 89.6% of the evaluated studies (112/125)
  • Overall incidence of treatment-related deaths: 0.45%
  • Most common causes of treatment-related deaths (n = 82) were:
    • Pneumonitis: 28.0%
    • Pneumonia: 6.1%
    • Sepsis: 8.5%
    • Respiratory failure: 6.1%
    • Cardiovascular failure: 3.7%
  • In total, respiratory causes accounted for the most treatment-related deaths (48%)
  • When PD-1 and PD-L1 inhibitors were compared:
    • Nivolumab (3 mg/kg every two weeks) led to higher mean incidence of any grade (OR = 1.28; 95% CI, 0.97−79) and Grade ≥ 3 (OR = 1.30; 95% CI, 0.89−2.00) AEs compared to pembrolizumab (10 mg/kg every two weeks) and when compared to PD-L1 inhibitors (OR = 1.81; 95% CI, 1.04−3.01)
    • PD-1 inhibitors led to a higher overall mean incidence of Grade ≥ 3 AEs when compared to PD-L1 inhibitors (OR = 1.58; 95% CI, 1.00−2.54)
Conclusions

This meta-analysis has identified the most common AEs occurring with PD-1 and PD-L1 inhibitors when used for the treatment of various types of cancers in clinical trials. This systematic analysis will aid in the future management of such treatments and provides a useful tool for clinicians.

References
  1. Wang Y. 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 Apr 25. DOI: 10.1001/jamaoncol.2019.0393 [Epub ahead of print]
  2. Gong, J. et al. 2018. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J. Immunother. Cancer 6, 8.  DOI: 10.1186/s40425-018-0316-z
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