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Monitoring PD-1-Blocking Antibodies Bound to T Cells Derived from a Drop of Peripheral Blood
Published on: February 5, 2020
Safety of immune checkpoint modulators beyond PD-1/PD-L1 and CTLA-4 in solid tumors: a meta-analysis
Yu Fujiwara1,2,3, Yui Okamura4, Mrinalini Ramesh3
1Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.
Background:
Novel agents targeting immune checkpoints are under development to overcome resistance to PD-1/PD-L1 and CTLA-4 blockade. Incidences of immune-related adverse events (irAEs) and toxicity profiles of novel agents remain unelucidated.
Methods:
We searched PubMed/MEDLINE, Embase, and Web of Science for clinical trials evaluating agents targeting co-inhibitory (B7-H3, CD47, TIGIT, LAG-3, and TIM-3) or co-stimulatory checkpoints (OX40, 4-1BB, CD27, ICOS, GITR, CD70, and CD40) in solid tumors. Incidences of any-grade and grade 3-5 (G3-5) treatment-related AEs (trAEs) and irAEs were extracted from phase 2 and 3 trials, and phase 1/2 trials with safety information reported at the recommended phase 2 dose. Odds ratios (ORs) from 2-arm studies evaluating the addition of LAG-3 or TIGIT blockade to control-arm therapy were pooled, and AE incidences across immunotherapy subtypes were reported using a random-effects meta-analysis.
Results:
A systematic review identified 27 clinical trials comprising 3946 patients. The addition of LAG-3 blockade increased G3-5 trAEs (OR = 1.79, 95% confidence interval [CI] = 1.26 to 2.54, P = .001), adrenal insufficiency (G3-5: OR = 8.43, 95% CI = 1.04 to 68.37, P = .046; any-grade: OR = 4.81, 95% CI = 1.81 to 12.78, P = .002) and any-grade arthralgia (OR = 2.07, 95% CI = 1.29 to 3.30, P = .002). Adding TIGIT blockade increased any-grade rash (OR = 2.32, 95% CI = 1.01 to 5.34, P = .048). Meta-analyses revealed varying irAE patterns: G5 trAEs (0.9%-2.9%), G3-5 pneumonitis (0.5%-5.5%, highest in TIM-3), G3-5 colitis (0.2%-5.4%, highest in LAG-3), G3-5 hepatitis (1.5%-5.5%, highest in TIM-3), and G3-5 adrenal insufficiency (1.7%-8.4%, highest in TIGIT).
Conclusions:
This study highlights the distinct toxicity profiles of novel immunotherapy agents, providing essential safety data to support clinicians as these therapies approach approval.
Insights
Novel immunotherapies show distinct toxicity profiles. LAG-3 blockade increased severe adverse events, while TIGIT blockade raised rash incidence, providing crucial safety data for clinicians.
Area of Science:
- Oncology
- Immunology
- Clinical Trials
Background:
- Novel immune checkpoint inhibitors are emerging to address resistance to PD-1/PD-L1 and CTLA-4 therapies.
- The safety and immune-related adverse event (irAE) profiles of these new agents require thorough investigation.
Purpose of the Study:
- To systematically review and meta-analyze the toxicity profiles and incidences of irAEs for novel immune checkpoint inhibitors in solid tumors.
- To compare the safety data of agents targeting co-inhibitory (B7-H3, CD47, TIGIT, LAG-3, TIM-3) and co-stimulatory checkpoints (OX40, 4-1BB, CD27, ICOS, GITR, CD70, CD40).
Main Methods:
- A comprehensive search of PubMed/MEDLINE, EMBASE, and Web of Science was conducted for relevant clinical trials.
- Data on treatment-related adverse events (trAEs) and irAEs (any-grade and grade 3-5) were extracted from phase 2, 3, and selected phase 1/2 trials.
- Random-effects meta-analysis was used to pool odds ratios for specific AEs and compare incidences across immunotherapy subtypes.
Main Results:
- The analysis included 27 trials with 3,946 patients. LAG-3 blockade addition significantly increased severe trAEs (OR 1.79) and adrenal insufficiency (OR 8.43).
- TIGIT blockade addition was associated with a higher incidence of any-grade rash (OR 2.32).
- Meta-analyses showed varying irAE patterns, with notable rates of pneumonitis (TIM-3), colitis (LAG-3), hepatitis (TIM-3), and adrenal insufficiency (TIGIT).
Conclusions:
- Novel immunotherapy agents possess distinct toxicity profiles that differ from established checkpoint inhibitors.
- This study provides essential safety data to guide clinical decision-making as these promising therapies move towards broader approval.
