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. 2022 Feb 10;17(2):e0263402.
doi: 10.1371/journal.pone.0263402. eCollection 2022.

Retrospective analysis of clinical trial safety data for pembrolizumab reveals the effect of co-occurring infections on immune-related adverse events

Tigran Makunts  1 , Keith Burkhart  2 , Ruben Abagyan  1 , Peter Lee  2
Affiliations

Retrospective analysis of clinical trial safety data for pembrolizumab reveals the effect of co-occurring infections on immune-related adverse events

Tigran Makunts et al. PLoS One. .

Abstract

Biologics targeting PD-1, PD-L1, and CTLA-4 immune checkpoint proteins have been used in a variety of tumor types including small and non-small cell lung cancers, melanoma, and renal cell carcinoma. Their anti-tumor activity is achieved through amplifying components of the patient's own immune system to target immune response evading cancer cells. However, this unique mechanism of action causes a range of immune related adverse events, irAEs, that affect multiple physiological systems in the body. These irAEs, depending on severity, often cause suspension or discontinuation of therapy and, in rare cases, may lead to fatal outcomes. In this study we focused on pembrolizumab, a PD-1 inhibitor currently approved for multiple types of cancer. We analyzed over ten thousand adverse event reports from Keynote clinical trials of pembrolizumab for various cancer indications with or without co-occurring infections, and observed a statistically significant 80% increase in the risk of developing an irAE in subjects with infections.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Data and cohort selection, study analysis plan.
Fig 2
Fig 2. Progression of irAEs throughout the treatment period in subjects with and without infections.
Fig 3
Fig 3
a) Frequencies or irAE in cohorts with and without infections: Infections-pathogen unknown (n = 2,052), protozoal infectious disorders (n = 2), mycobacterial infectious disorders (n = 3), bacterial infectious disorders (n = 216), viral infectious disorders (n = 336), fungal infectious disorders (n = 229), irAEs in subjects with any infection (n = 2,528), subjects with infection preceding irAE (n = 2,431), irAEs in subjects without any infection (control) (n = 3,009), subjects with any infection excluding ones with autoimmune comorbidities (n = 2,524), Subjects without any infection (control) excluding ones with autoimmune comorbidities (n = 2,984). b) Odds ratios of irAEs in subjects with infections compared to subjects without infections. X-axis presented in logarithmic scale.
Fig 4
Fig 4
a) Frequencies or irAE in cohorts with and without infections: irAEs in subjects with any infection (n = 2,528), subjects with infection preceding irAE (n = 2,431), irAEs in subjects without any infection (control) (n = 3,009), subjects with any infection excluding ones with autoimmune comorbidities (n = 2,524), Subjects without any infection (control) excluding ones with autoimmune comorbidities (n = 2,984). b) Odds ratios of irAEs in subjects with infections compared to subjects without infections. X-axis presented in logarithmic scale.
Fig 5
Fig 5. First irAE and first infection time to event and duration analysis.
1st infection (blue) vs 1st irAE (red) start date and AE duration with respect to treatment start date (day 0).
See this image and copyright information in PMC

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