Cancer Res Treat.  2021 Apr;53(2):339-354. 10.4143/crt.2020.790.

The Pattern of Time to Onset and Resolution of Immune-Related Adverse Events Caused by Immune Checkpoint Inhibitors in Cancer: A Pooled Analysis of 23 Clinical Trials and 8,436 Patients

• Tang SQ
• Tang LL
• Mao YP
• Li WF
• Chen L
• Zhang Y
• Guo Y
• Liu Q
• Sun Y
• Xu C
• Ma J

• KMID: 2514917
• DOI: http://doi.org/10.4143/crt.2020.790

Abstract

Purpose
The occurrence pattern of immune-related adverse events (irAEs) induced by immune checkpoint inhibitor (ICI) in cancer treatment remains unclear.
Materials and Methods
Phase II-III clinical trials that evaluated ICI-based treatments in cancer and were published between January 2007 and December 2019 were retrieved from public electronic databases. The pooled median time to onset (PMT-O), resolution (PMT-R), and immune-modulation resolution (PMT-IMR) of irAEs were generated using the metamedian package of R software.
Results
Twenty-two eligible studies involving 23 clinical trials and 8,436 patients were included. The PMT-O of all-grade irAEs ranged from 2.2 to 14.8 weeks, with the longest in renal events. The PMT-O of grade ≥ 3 irAEs was significantly longer than that of all-grade irAEs induced by programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1) inhibitors (27.5 weeks vs. 8.4 weeks, p < 0.001) and treatment of nivolumab (NIV) plus ipilimumab (IPI) (7.9 weeks vs. 6.0 weeks, p < 0.001). The PMT-R of all-grade irAEs ranged from 0.1 to 54.3 weeks, with the shortest and longest in hypersensitivity/infusion reaction and endocrine events, respectively. The PMT-IMR of grade ≥ 3 irAEs was significantly shorter than that of all-grade irAEs caused by PD-1/PD-L1 blockade (6.9 weeks vs. 40.6 weeks, p=0.002) and NIV+IPI treatment (3.1 weeks vs. 5.9 weeks, p=0.031).
Conclusion
This study revealed the general and specific occurrence pattern of ICI-induced irAEs in pan-cancers, which was deemed to aid the comprehensive understanding, timely detection, and effective management of ICI-induced irAEs.

Keyword

Immune checkpoint inhibitors; Immune-related adverse event; Occurrence pattern; Neoplasms

Figure

• 

  Fig. 1 The pattern of time to onset of all-grade (A, C, E) and grade ≥ 3 (B, D, F) irAEs. Circles and bars represent median values and 95% confidence intervals, respectively. Number and percent of an event indicate the incidence of the irAE. CTLA-4, cytotoxic T-lymphocyte antigen 4; IPI, ipilimumab; irAEs, immune-related adverse events; NIV, nivolumab; PD-1/PD-L1, programmed cell death protein 1 or its ligand 1. a)p < 0.05 between the comparison of time to onset of all-grade irAEs and grade ≥ 3 irAEs. A total of 3,977 and 1,261 patients were included in the analysis of all-grade and grade ≥ 3 irAEs, respectively, for PD-1/PD-L1 inhibitors; 2,958 and 1,294 patients for CTLA-4 inhibitors; 828 and 867 patients for NIV+IPI.

• 

  Fig. 2 The pattern of resolution (A, B, E, F, I, J) and immune-modulation resolution (C, D, G, H, K, L) of all-grade (A, E, I, C, G, K) and grade ≥ 3 (B, F, J, D, H, L) irAEs. Circles and bars represent median values and 95% confidence intervals, respectively. Number and percent of an event indicate the patients whose irAE resolved (A, B, E, F, I, J) and patients whose irAE resolved with usage of immune-modulation agents (C, D, G, H, K, L). CTLA-4, cytotoxic T-lymphocyte antigen 4; IM, immune-modulation; IPI, ipilimumab; irAEs, immune-related adverse events; NIV, nivolumab; PD-1/PD-L1, programmed cell death protein 1 or its ligand 1. a)p < 0.05 between the comparison of time to resolution of all-grade and grade ≥ 3 irAEs, b)p < 0.05 between the comparison of time to immune-modulation resolution of all-grade and grade ≥ 3 irAEs, c)p < 0.05 between the comparison of time to resolution and immune-modulation resolution of all-grade, d)p < 0.05 between the comparison of time to resolution and immune-modulation resolution of grade ≥ 3 irAEs. A total of 1,196 and 192 patients were included in the analysis of time to resolution and immune-modulation resolution of all-grade irAEs, respectively, for PD-1/PD-L1 inhibitors; 2,611 and 402 patients for CTLA-4 inhibitors; 1,572 and 247 patients for NIV+IPI. A total of 71 and 37 patients were included in the analysis of time to resolution and immune-modulation resolution of grade ≥ 3 irAEs, respectively, for PD-1/PD-L1 inhibitors; 348 and 194 patients for CTLA-4 inhibitors; 254 and 117 patients for NIV+IPI.

• 

  Fig. 3 Kinetics (A–C) and ranking (D) of the onset and resolution of all-grade irAEs caused by nivolumab (A), IPI (B), and nivolumab plus IPI (C). The beginning and end of each curve in Fig. 3A–C represent the median time to the onset of an irAE and the median time to resolution, respectively; the peak and tail of each curve show the proportion of patients who developed an irAE and the proportion of patients whose irAE had not been resolved, respectively. The number in parentheses of Fig. 3D represents the pooled median time (weeks). The ranking is arranged from the shortest to the longest pooled median time. Items with underlining share the same ranking. IPI, ipilimumab; irAEs, immune-related adverse events; NA, not applicable; NIV, nivolumab. a)p < 0.05 between the comparison of NIV and NIV+IPI, b)p < 0.05 between the comparison of NIV and IPI, c)p < 0.05 between the comparison of IPI and NIV+IPI. A total of 1,815 and 1,196 patients were included in the analysis of time to onset and resolution, respectively, for NIV; 2,092 and 2,123 patients for IPI; 828 and 1,572 patients for NIV+IPI.

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