Abstract
Purpose
To compare the risk of immune-associated pneumonitis between PD-1 and PD-L1 inhibitors, the meta-analysis was designed.
Method
The difference in risk of immune-associated pneumonitis between PD-1 and PD-L1 inhibitors was assessed by two different meta-analysis methods, the Mirror-pairing and the PRISMA guidelines.
Results
A total of eighty-eight reports were used for meta-analysis, while thirty-two studies were used for the Mirror-pairing. Both PD-1 and PD-L1 inhibitors (used alone or combined with chemotherapy) increased the risk of develo** immune-related pneumonitis (P < 0.00001; P < 0.00001). Based on indirect analyses results (subgroup analyses), the risk of PD-L1-induced pneumonitis was weaker than that of PD-1 inhibitors when the control group was chemotherapy (OR = 3.33 vs. 5.43) or placebo (OR = 2.53 vs. 3.19), while no obvious significant differences were found (P = 0.17; P = 0.53). For the Mirror-pairing-based meta-analysis, the risk of PD-1-induced pneumonitis was significantly higher than that of PD-L1 inhibitors (OR = 1.46, 95%CI [1.08, 1.98], I2 = 0%, Z = 2.47 (P = 0.01)). However, this difference was not significant, when they were combined with chemotherapy (OR = 1.05, 95%CI [0.68, 1.60], I2 = 38%, Z = 0.21 (P = 0.84)).
Conclusion
Both PD-1 and PD-L1 inhibitors increased the risk of immune-related pneumonitis, while the risk of PD-1-induced pneumonitis was significantly higher than that of PD-L1 inhibitors.
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Introduction
Many clinical trials have confirmed that programmed death-1 (PD-1) or Programmed cell death ligand 1 (PD-L1) inhibitors have excellent clinical efficacy for malignant tumors [1,2,3,4,5,6,7,8,1,2,3,4,5,6,7,8,2A), while there was no statistical significance (P = 0.17). No heterogeneity was found in the above results (I2 = 0%). No significant publication bias was found through the corresponding funnel plots (SFigure 2A). Further subgroup analysis based on different tumor types revealed a higher risk of pneumonitis in the PD-1 subgroup of different tumor types (SFigure 4), especially for the Gastric or Gastro-oesophageal Junction Cancer (GC/GEJC) and UC subgroups.
Forest blots of the analysis results for different groups. A The OR of pneumonitis for all-grade checked using the random effect (RE) model in Group A (PD-1/PD-L1 VS. Chemotherapy): Subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). B The OR of pneumonitis for all-grade checked using the random effect (RE) model in Group B (PD-1/PD-L1 + Chemotherapy VS. Chemotherapy): Subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). C The OR of pneumonitis for all-grade checked using the random effect (RE) model in Group C (PD-1/PD-L1 VS. Placebo): Subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). D The OR of pneumonitis for all-grade checked using the random effect (RE) model in Group D (PD-1/PD-L1 VS. PD-1/PD-L1 + CTLA-4): Subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). E The OR of pneumonitis for all-grade checked using the random effect (RE) model in Group E (PD-1/PD-L1 VS. PD-1/PD-L1 + Chemotherapy): Subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1)
When PD-1 or PD-L1 inhibitors combined with chemotherapy were compared with chemotherapy alone (PD-1/PD-L1 + Chemotherapy VS. Chemotherapy), the risk of immune-related pneumonitis was also significantly increased (OR = 2.47, 95%CI [1.84, 3.32], I2 = 34%, Z = 6.02 (P < 0.00001); Fig. 2B) [20, 21, 23, 35, 36, 38,39,2B). For moderate heterogeneity (I2 = 34%), further subgroup analysis indicated that it might be caused by 3 Triple-negative Breast Cancer (TNBC) clinical trials (IMpassion130, IMpassion031, IMpassion131; SFigure 5) [51, 53, 56]. No significant publication bias was found through the corresponding funnel plots (SFigure 2B).
When the control group was placebo but chemotherapy (PD-1/PD-L1 VS. Placebo), the incidence risk of pneumonitis was also increased by PD-1/PD-L1 inhibitors (OR = 2.53, 95%CI [1.59, 4.02], I2 = 40%, Z = 3.94(P < 0.0001); Fig. 2C) [69,70,71,72,73, 75,76,77,78,79,80]. Similar to the above, subgroup analysis indicated that the PD-1 subgroup presented a higher risk of develo** pneumonitis (3.19 VS. 2.34; Fig. 2C). For moderate heterogeneity (I2 = 40%), further subgroup analysis indicated that it might be caused by three NSCLC clinical trials (PACIFIC, GEMSTONE-301, IMpower010; SFigure 6) [69,70,71]. No significant publication bias was found through the corresponding funnel plots (SFigure 2C).
Compared with the combination of PD-1/PD-L1 and CTLA-4 (PD-1/PD-L1 VS. PD-1/PD-L1 + CTLA-4), the impact of PD-1/PD-L1 on the risk of pneumonitis was weaker than that of the control group (OR = 0.43, 95%CI [0.25, 0.74], I2 = 25%, Z = 3.09 (P = 0.002); Fig. 2D) [23, 74, 81, 82, 86]. For moderate heterogeneity (I2 = 25%), subgroup analysis suggested that heterogeneity might originate from the data themselves (SFigure 7) [23, 74, 81, 82, 86]. No significant publication bias was found through the corresponding funnel plots (SFigure 2D).
Compared with PD-1/PD-L1 in combination with chemotherapy (PD-1/PD-L1 VS. PD-1/PD-L1 + Chemotherapy), the risk of pneumonitis was not significantly increased (OR = 1.11, 95%CI [0.78, 1.59], I2 = 0%, Z = 0.59 (P = 0.56); Fig. 2E) [88, 89]. We carefully reviewed the data of all enrolled clinical trials and conducted a comprehensive systematic evaluation of random sequence generation (selection bias), allocation consideration (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and others. After the comprehensive evaluation, data with any kind of high risk biases would be excluded, and only the high-quality and complete clinical trial data were retained, ensuring the reliability and authenticity of our analyses results (SFigure 1; STable 1). The previous Mirror-pairing principles had been improved[88.89], which would make the pairing much more accurate. After a detailed analysis of clinical trials using the Mirror-pairing principle, 16 Mirror pairings were obtained, which was the largest number of PD-1/PD-L1 related Mirror pairings first reported so far (Table 1; SFigure 3) [1, 2, 4, 6,7,8, 10, 12, 14, 15, 17, 2A and C) [1,2,3, 5,6,7,8,9,10,11, 13, 15,16,17,18,19,20,21,22,23,24,25,26,27, 29,30,31,32,33,34, 69,70,71,72,73, 75,76,77,78,79,80]. Although subgroup analyses could not draw statistically significant conclusions, PD-1 might cause a higher risk trend for pneumonitis (Fig. 2A and C) [1,2,3, 5,6,7,8,9,10,11, 13, 15,16,17,18,19,20,21,22,23,24,25,26,27, 29,30,31,32,33,34, 69,70,71,72,73, 75,76,77,78,79,80], which laid the foundation for the following Mirror-pairing meta-analysis.
Compared with chemotherapy, the PD-1/PD-L1 inhibitors played a much more important role in increasing the risk of immune-related pneumonitis (Fig. 2B and E) [19,20,21,22,23,24, 34,35,36, 38,39,40,41,42,43, 45,46,47,48,49,50,51, 53,54,55,56, 58,59,60, 62,63,64,65,66,67, 82]. When PD-1/PD-L1 inhibitors were combined with CTLA-4, this effect was obviously evident (Fig. 2D) [23, 74, 81, 82, 86]. Based on the above analyses, we concluded that PD-1/PD-L1 inhibitors increased the risk of pneumonitis; Furthermore, it seemed that PD-1 inhibitors had a higher risk of causing pneumonitis (Fig. 2) [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87], which further enhanced the necessity of conducting Mirror-pairing analysis.
When using the Mirror-pairing for comparing PD-1 with PD-L1, the risk of pneumonitis caused by PD-1 was significantly higher than that of the PD-L1 group (OR = 1.46, 95%CI [1.08, 1.98], I2 = 0%, Z = 2.47 (P = 0.01); Fig. S3A) [1, 2, 4, 6,7,8, 10, 12, 14, 15, 17, 19, 21, 23, 71, 78, 79], which the difference was statistically significant. When chemotherapy was incorporated into the Mirror-pairing, this difference became no longer statistically significant (OR = 1.05, 95%CI [0.68, 1.60], I2 = 38%, Z = 0.21 (P = 0.84); Fig. S3B) [22, 24, 36,37,38, 42, 43, 45, 48, 49, 51, 53, 57, 63]. In the previous subgroup analyses (Fig. 2A and B), similar results could also be found after the addition of chemotherapy. Therefore, we concluded that chemotherapy might induce excessive heterogeneity and inconsistency and desalinate the true differences between PD-1 and PD-L1 (Figs. 2A, B, and S3A). When there were fewer interfering factors, whether it was indirect subgroup analysis (Fig. 2A) or the Mirror-pairing analysis (Fig. S3A), the conclusions drawn were consistent, which further confirmed the practicality and feasibility of this improved Mirror-pairing analysis method [88, 89]. The difference in the risk of pneumonitis between PD-1 and PD-L1 was evaluated using the Mirror-pairing meta-analysis, accompanied by improvements in the Mirror-pairing method, which indicated a better innovation. This comparative method solves the dilemma of lacking head-to-head clinical trials of PD-1 versus PD-L1.
Due to the inevitable existence of intergroup heterogeneity in the real world, RE models were used for OR and 95% CI calculations [96]. Although no highly heterogeneous results were found, we conducted sufficient subgroup analyses and speculated on the source of the corresponding heterogeneity (SFigure 4, SFigure 5, SFigure 6, and SFigure 7) [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87]. There were no data found that affected the analysis results. Furthermore, no significant bias was found through the corresponding funnel plot (SFigure 2 and SFigure 3), which confirmed the authenticity and reliability of the above analysis results.
Based on the subgroup analysis results (Fig. S3A, SFigure 4, SFigure 5, and SFigure 6), we found that the risk of pneumonitis in UC patients receiving PD-1 inhibitors was the highest among all tumor types. This meant that special attention should be paid to the risk of immune-related pneumonitis for PD-1 inhibitor use in UC patients.
By comparing the subgroup analysis results of the PRISMA meta-analysis with the results of the Mirror-pairing analysis, we found that the risk trend of the analysis results was basically consistent, while the analysis results of the Mirror-pairing seemed to be much more sensitive (Figs. 2A,2C; S3A). It indicated that when mild differences in subgroup analysis was found, the Mirror-pairing analysis could be conducted to clarify the significance of these differences. Furthermore, this would be beneficial for clinicians to determine the choice of drugs (PD-1 or PD-L1) based on the degree of toxicities, as well as whether PD-1 was needed to be replaced by PD-L1.
Conclusions
Both PD-1 and PD-L1 inhibitors increased the risk of immune-related pneumonitis, while the risk of PD-1-induced pneumonitis was significantly higher than that of PD-L1 inhibitors.
The limitations of the study
The Mirror-pairing analysis is an indirect paired comparison of existing clinical trials while minimizing heterogeneity. Its reliability still needs to be validated with more head-to-head clinical trial data in the real world.
Abbreviations
- CI:
-
Confidence interval
- CnP:
-
Carboplatin + Nab-paclitaxel
- CP:
-
Carboplatin + Paclitaxel
- CRC:
-
Colorectal cancer
- CTLA-4:
-
Cytotoxic T lymphocyte associate protein-4
- EC:
-
Etoposide + Carboplatin
- EP:
-
Etoposide + Platinum
- ESCC:
-
Oesophageal squamous cell carcinoma
- GC/GEJC:
-
Gastric or gastro-oesophageal junction cancer
- GC/GP:
-
Carboplatin/Cisplatin + Gemcitabine
- HCC:
-
Hepatocellular carcinoma
- HNSCC:
-
Head and neck squamous cell carcinoma
- HR:
-
Hazard ratios
- NOS:
-
Newcastle–Ottawa scale
- NSCLC:
-
Non-small cell lung cancer
- OR:
-
Odds ratio
- PD-1:
-
Programmed cell death-1
- PD-L1:
-
Programmed cell death ligand 1
- PF:
-
Cisplatin + Fluorouracil
- PICOS:
-
Participants, interventions, comparisons, outcomes, and study design
- PRISMA:
-
Preferred reporting items for systematic reviews and meta-analyses
- RCC:
-
Renal cell carcinoma
- RE:
-
Random effect
- SCLC:
-
Small cell lung cancer
- TNBC:
-
Triple-negative breast cancer
- UC:
-
Urothelial cancer
- UC:
-
Urothelial cancer
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Acknowledgements
This study was funded by the Clinical Research Special Support Fund of Wu Jie** Medical Foundation (320.6570.2023-16-12; Yuan Tian), Shandong Medical Association Clinical Special Fund—Qilu Special Fund (YXH2022ZX02016; Yuan Tian), and Shandong Second People's Hospital Research Fund (2023MS01; Yuan Tian).
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Qi Dang designed the meta-analysis. Yuan Tian, Zongxiu Yin, Chi Zhang, Zhuoqi Li, Yuanyuan Wang, Kai Zhang, and Feng Chen had the full data of the manuscript. Yuan Tian, Zongxu Yin, Chi Zhang, and Zhuoqi Li conducted literature search and quality evaluation. Yuan Tian drafted the manuscript.
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262_2024_3736_MOESM2_ESM.tif
S Figure 1: Risk of bias summary: review authors' judgements about each risk of bias item for each included study. (TIF 1698 KB)
262_2024_3736_MOESM3_ESM.tif
S Figure 2: Funnel plots of the analysis results for different groups. A: The OR of pneumonitis for all-grade checked using the fixed effect (FE) model in Group A (PD-1/PD-L1 VS. Chemotherapy): Subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). B: The OR of pneumonitis for all-grade checked using the fixed effect (FE) model in Group B (PD-1/PD-L1+Chemotherapy VS. Chemotherapy): Subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). C: The OR of pneumonitis for all-grade checked using the fixed effect (FE) model in Group C (PD-1/PD-L1 VS. Placebo): Subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). D: The OR of pneumonitis for all-grade checked using the fixed effect (FE) model in Group D (PD-1/PD-L1 VS. PD-1/PD-L1+CTLA-4): Subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). E: The OR of pneumonitis for all-grade checked using the fixed effect (FE) model in Group E (PD-1/PD-L1 VS. PD-1/PD-L1+Chemotherapy): Subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). (TIF 2042 KB)
262_2024_3736_MOESM4_ESM.tif
S Figure 3: Funnel plots of comparison in Mirror-pairing clinical trials. A: The OR of pneumonitis for all grades was checked using the fixed effect (FE) model (PD-1 VS. PD-L1). Subgroup analyses were carried out according to the tumor types. B: The OR of pneumonitis for all grades was checked using the fixed effect (FE) model (PD-1+Chemotherapy VS. PD-L1+Chemotherapy). Subgroup analyses were carried out according to the tumor types. (TIF 2023 KB)
262_2024_3736_MOESM5_ESM.tif
S Figure 4: Forest blots of the subgroup analysis in Group A (PD-1/PD-L1 VS. Chemotherapy): The OR of pneumonitis for all-grade checked using the random effect (RE) model: Subgroup analyses were carried out according to the tumor types and PD-1/PD-L1. (TIF 2856 KB)
262_2024_3736_MOESM6_ESM.tif
S Figure 5: Forest blots of the subgroup analysis in Group B (PD-1/PD-L1+Chemotherapy VS. Chemotherapy): The OR of pneumonitis for all-grade checked using the random effect (RE) model: Subgroup analyses were carried out according to the tumor types and PD-1/PD-L1. (TIF 2913 KB)
262_2024_3736_MOESM7_ESM.tif
S Figure 6: Forest blots of the subgroup analysis in Group C (PD-1/PD-L1 VS. Placebo): The OR of pneumonitis for all-grade checked using the random effect (RE) model: Subgroup analyses were carried out according to the tumor types and PD-1/PD-L1. (TIF 2504 KB)
262_2024_3736_MOESM8_ESM.tif
S Figure 7: Forest blots of the subgroup analysis in Group D (PD-1/PD-L1 VS. PD-1/PD-L1+CTLA-4): The OR of pneumonitis for all-grade checked using the random effect (RE) model: Subgroup analyses were carried out according to the tumor types and PD-1/PD-L1. (TIF 1597 KB)
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Tian, Y., Yin, Z., Zhang, C. et al. Differences in the risk of immune-related pneumonitis between PD-1 and PD-L1 inhibitors: a meta-analysis according to the new mirror-principle and PRISMA guidelines. Cancer Immunol Immunother 73, 162 (2024). https://doi.org/10.1007/s00262-024-03736-z
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DOI: https://doi.org/10.1007/s00262-024-03736-z