The efficacy and safety of combination of PD-1 and CTLA-4 inhibitors: a meta-analysis
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Background: Recently, a series of clinical trials showed that combination of anti-programmed cell death-1 (α-PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (α-CTLA-4) could effectively eliminate tumor. However, in comparison with widely adopted mono-immune checkpoint inhibitors, chemotherapy, and targeted therapy, the advantage of combination therapy of α-PD-1 and α-CTLA-4 in response rate and prognosis is controversial especially considering probably increased treatment related adverse event. Thus, we conducted this meta-analysis to explore the efficacy and safety of combination treatment of α-PD-1 and α-CTLA-4. Methods: This meta-analysis involved 8 clinical trials. In most trials, the primary endpoint was objective response rate (ORR). Thus we calculated risk ratio (RR) and 95% confidence interval (CI) to compare ORR of patients undergoing different treatment strategies. Moreover, the co-primary endpoints in few trials included progression-free survival and overall survival. Hazard ratio (HR) with 95% CI were employed to weigh the influence of different treatments on prognosis of patients. Subgroup analysis was conducted in patients with high and low expression of PD-L1. Lastly, the safety of combination therapy was evaluated by comparing treatment related adverse events among various treatment groups. Results: Our results showed that ORR was significantly higher in patients receiving α-PD-1 plus α-CTLA-4 compared with α-PD-1 (RR 1.31, 95% CI 1.16–1.48) or α-CTLA-4 monotherapy (RR 2.11, 95% CI 1.84–2.43), chemotherapy and targeted therapy (RR 1.41, 95% CI 1.26–1.58). α-PD-1 plus α-CTLA-4 treated patients had a great advantage on monotherapy, chemotherapy and targeted therapy treated patients in PFS. Notably, no significant alteration in total adverse event rate was observed in α-PD-1 plus α-CTLA-4 treated patients. Results of subgroup analysis showed that combination therapy could enhance anti-tumor response in comparison with other treatments, especially for low PD-L1 expression patients undergoing nivolumab treatment (ORR: RR 1.35, 95% CI 1.11–1.65). Conclusion: Combination treatment of α-PD-1 and α-CTLA-4 is a feasible strategy with enhanced efficacy and acceptable adverse event. Moreover, for some low PD-L1 expression patients, α-CTLA-4 might decrease the risk of resistance to α-PD-1 and demonstrate the synergistic anti-tumor effect.
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Accumulating evidence has indicated that dual PD-1/PD-L1 and CTLA-4 blockade has superior antitumor activity in some types of cancers.
“Accumulating evidence has indicated that dual PD-1/PD-L1 and CTLA-4 blockade has superior antitumor activity in some types of cancers [131].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [131]
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- Authors
- Wu, K., Yi, M., Qin, S., Chu, Q., Zheng, X., & Wu, K.
- Affiliations
- Pingdingshan University (CN)
- Tongji Hospital (CN)
- Corresponding author
- Zheng, Xinhua
- Wu, Kongming
- Venue
- Experimental Hematology & Oncology
- Published
- 2019-10-25
- Volume
- 8
- Issue
- 1
- Pages
- 26-26
- ISSN
- 2162-3619 (ISSN-L)
- PMC
- PMC6815037
- OpenAlex
- W2981646551
- Cited by
- 96
- References
- 38
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 18 · 2023: 12 · 2022: 15 · 2021: 27 · 2020: 10
- FWCI
- 1.29
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Experimental Hematology and Oncology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Natural Science Foundation of China (81874120, 81572608, 81672984)
- Wuhan Municipal Science and Technology Bureau (2017060201010170)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- PD-1 inhibitors, CTLA-4 inhibitors, combination immunotherapy, immune checkpoint inhibitors, objective response rate, progression-free survival, overall survival, PD-L1 expression, nivolumab, treatment-related adverse events, cancer immunotherapy, treatment efficacy and safety, hazard ratio, relative risk, prognostic outcome
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