To the editor,
In recent years, the combinations of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have become the standard treatments for metastatic renal cell carcinoma (mRCC) irrespective of the International Metastatic RCC Database Consortium (IMDC) prognostic groups [1]. Despite their overall efficacy, not all patients achieve satisfactory response and long-term survival benefits [2]. Hence, the identification of biomarkers and prognostic models to select patients for these combination therapies is a crucial issue in clinical practice.
The Meet-URO score is a novel prognostic model incorporating the presence of bone metastases and baseline peripheral-blood neutrophil-to-lymphocyte ratio (NLR) ≥ 3.2 into the IMDC score, which has been shown to have a better prognostic value than the IMDC score in mRCC patients receiving nivolumab [3]. However, whether the Meet-URO score could accurately predict the prognosis in the TKIs-ICIs combination treatment setting remains unclear. This analysis aims to investigate the prognostic value of the Meet-URO score in mRCC patients receiving 2nd and 3rd-line TKIs-ICIs combination treatment, which has not been reported by previous studies.
Baseline and follow-up data of patients with mRCC were obtained retrospectively from West China Hospital. Overall survival (OS) was defined as the time from the start of 2nd or 3rd -line therapy to death from any cause or to the time of last follow-up for survivors, and progression-free survival (PFS) was calculated from 2nd or 3rd -line therapy start to 2nd or 3rd disease progression or death without disease progression and to death or last follow-up visit. Both OS and PFS were assessed by the Kaplan–Meier method. Harrell’s c-index was estimated to evaluate the accuracy of the prediction ability of the two score models. The Cox proportional hazard-regression model was used for univariable and multivariable analyses. Hazard ratios (HR) with a 95% confidence interval (CI) were calculated. All the statistical analyses were performed by using R software (v 4.1.0). The p-value < 0.05 was considered statistically significant.
A total of 72 patients receiving 2nd and 3rd-line TKIs-ICIs combination (2nd-line: 88.89%, 3rd-line: 11.11%) were included in the final study. The detailed baseline information is provided in Table 1. Patients were divided into three groups according to the Meet-URO score (group 1: score 0–3, group 2: score 4–5, and group 3: score 6–8). Patients in group 1 had the most favorable prognosis with a median OS (mOS) of 56 months. Compared to group 1, group 2 (mOS: 29 vs. 56 months, p = 0.013) and group 3 were associated with significantly poorer survival outcomes (mOS: 14 months vs. 56 months, p < 0.001, Fig. 1). There was no statistically significant difference in PFS between the three groups. Compared to the IMDC score, the Meet-URO score had a higher c-index (0.706 vs. 0.560), which indicated that the Meet-URO score had a higher discriminative ability than the IMDC score in this setting. The univariate analysis revealed that a higher Meet-URO score correlated with shorter OS. However, pre-treatment nephrectomy was a protective factor for prognosis in the univariate analysis. In the multivariate analysis, the Meet-URO score was the only independent prognosticator for OS (Additional file 2).
Table 1.
Baseline characteristics of included patients
| Characteristics | Total | Meet-URO Group 1 (Score: 0–3) | Meet-URO Group 2 (Score: 4–5) | Meet-URO Group 3 (Score: 6–8) | p-value |
|---|---|---|---|---|---|
| Sample size (n) | 72 | 47 | 17 | 8 | |
| ccRCC (%) | 72 (100) | 47 (100) | 17 (100) | 8 (100) | NA |
| Gender (%) | 0.443 | ||||
| Male | 61 (15.28) | 8 (17.02) | 3 (17.65) | 0 (0.00) | |
| Female | 11 (84.72) | 39 (82.98) | 14 (82.35) | 8 (100.00) | |
| Age (median [IQR]) | 56.50 (52.00, 66.00) | 56 (51.50, 66.00) | 56.00 (54.00, 63) | 62.00 (53.75, 67.50) | 0.507 |
| Nephrectomy (%) | 0.004 | ||||
| Yes | 62 (86.11) | 44 (93.62) | 14 (82.35) | 4 (50.00) | |
| No | 10 (13.89) | 3 (6.38) | 3 (17.65) | 4 (50.00) | |
| ISUP (%) | 0.248 | ||||
| ISUP < 3 | 18 (25.00) | 14 (29.79) | 4 (23.53) | 0 (0.00) | |
| ISUP ≥ 3 | 37 (51.39) | 23 (48.94) | 10 (58.82) | 4 (50.00) | |
| NA | 17 (23.61) | 10 (21.28) | 3 (17.65) | 4 (80.00) | |
| T stage ≥ 3 (%) | 0.337 | ||||
| Yes | 24 (33.33) | 17 (36.17) | 4 (23.53) | 3 (37.50) | |
| No | 26 (36.11) | 16 (34.04) | 9 (52.94) | 1 (12.50) | |
| NA | 22 (30.56) | 14 (29.79) | 4 (23.53) | 4 (50.00) | |
| N stage (%) | 0.611 | ||||
| 0 | 48 (66.67) | 33 (70.21) | 11 (64.71) | 4 (50.00) | |
| 1 | 11 (15.28) | 5 (10.64) | 4 (23.53) | 2 (25.00) | |
| Nx | 3 (4.17) | 2 (4.26) | 0 (0.00) | 1 (12.50) | |
| NA | 10 (13.89) | 7 (14.89) | 2 (11.76) | 1 (12.50) | |
| M stage (%) | |||||
| Synchronous | 39 (54.17) | 29 (61.70) | 8 (47.06) | 2 (25.00) | |
| Metachronous | 33 (45.83) | 18 (38.30) | 9 (52.94) | 6 (75.00) | |
| IMDC group (%) | < 0.001 | ||||
| Favorable | 16 (22.22) | 16 (34.04) | 0 (0.00) | 0 (0.00) | |
| Intermediate | 48 (66.67) | 31 (65.96) | 17 (100.00) | 0 (0.00) | |
| Poor | 8 (11.11) | 0 (0.00) | 0 (0.00) | 8 (100.00) | |
| Bone metastasis (%) | 0.435 | ||||
| Yes | 13 (18.06) | 3 (6.38) | 8 (47.06) | 2 (25.00) | |
| No | 59 (81.94) | 44 (93.62) | 9 (52.94) | 6 (75.00) | |
| NLR ≥ 3.2 (%) | 0.579 | ||||
| Yes | 14 (19.44) | 2 (4.26) | 9 (52.94) | 3 (37.50) | |
| No | 58 (80.56) | 45 (95.74) | 8 (47.06) | 5 (62.50) | |
| Prior treatment (%) | 0.776 | ||||
| TKI | 66 (91.67) | 44 (93.62) | 15 (88.24) | 7 (87.50) | |
| TKI + IO | 4 (5.55) | 2 (4.26) | 1 (5.88) | 1 (12.50) | |
| TKI + mTOR | 2 (2.78) | 1 (2.12) | 1 (5.88) | 0 (0.00) | |
| 2nd-line treatment (%) | < 0.001 | ||||
| Yes | 64 (88.89) | 44 (93.62) | 13 (76.47) | 7 (87.50) | |
| No | 8 (11.11) | 3 (6.38) | 4 (23.53) | 1 (12.50) | |
| Based immunotherapy (%) | 0.643 | ||||
| NIV | 2 (2.78) | 2 (4.26) | 0 (0.00) | 0 (0.00) | |
| PEM | 7 (9.72) | 4 (8.51) | 2 (11.76) | 1 (12.50) | |
| SIN | 39 (54.17) | 27 (57.45) | 7 (41.18) | 5 (62.50) | |
| TIS | 3 (4.17) | 3 (6.38) | 0 (0.00) | 0 (0.00) | |
| TOR | 21 (29.17) | 11 (23.40) | 8 (47.06) | 2 (25.00) | |
ccRCC clear cell renal cell carcinoma, IMDC International Metastatic Renal Cell Carcinoma Database Consortium, NLR neutrophil-to-lymphocyte ratio, TKI tyrosine kinase inhibitor, IO immuno-oncology therapy, NIV nivolumab, PEM pembrolizumab, SIN sintilimab, TIS tislelizumab, TOR toripalimab, NA not applicable, IQR interquartile range
Fig. 1.
Kaplan–Meier curves for OS according to the Meet-URO score
The prognostic value of inflammatory index NLR has been investigated in RCC patients, and it is confirmed to be an independent prognostic factor. Inflammatory indices are considered as the most important endpoint in oncological studies, and the combination of NLR and the IMDC score demonstrates great application potential to reflect the heterogeneity of RCC [3]. Different from the IMDC score, which was established in the pre-immunotherapy era, the Meet-URO score is derived from a population treated with an immunotherapeutic strategy and better reflects the current treatment scenario [3, 4]. Compared to historical Meet-URO-related studies (Additional file 1), this small-size analysis explored the prognostic value of the Meet-URO score in similar disease status but with a different treatment type. Moreover, the results about the positive effect of nephrectomy are consistent with a subgroup analysis of the Meet-URO 15 study (HR = 0.48, 95% CI 0.33 to 0.69, p < 0.001) [5]. Although it didn’t reach statistical significance in multivariable analysis, more data based on a larger population is needed.
In conclusion, this study preliminarily illustrates that the Meet-URO score has the potential to present more accurate prognostic stratification than the IMDC score in mRCC patients receiving 2nd or 3rd-line TKIs-ICIs combination treatment. However, considering the limited number of participants and single-center design, more research based on larger cohorts is necessary to validate and strengthen these findings in the future.
Supplementary Information
Additional file 1: Table S1. Summary of application of Meet-URO score in mRCC patients receiving systemic therapies.
Additional file 2: Table S2. Cox regression analysis for survival outcomes according to clinical features and the Meet-URO score.
Acknowledgements
Not applicable.
Abbreviations
- TKI
Tyrosine kinase inhibitor
- ICI
Immune checkpoint inhibitor
- mRCC
Metastatic renal cell carcinoma
- IMDC
International Metastatic RCC Database Consortium
- NLR
Neutrophil-to-lymphocyte ratio
- OS
Overall survival
- CI
Confidence interval
- HR
Hazard ratio
- PFS
Progression-free survival
Author contributions
Conceptualization, JC and HZ; methodology, HL; software, HL; validation, HL; formal analysis, SH; writing—original draft preparation, SH; writing—review and editing, HL and JC; supervision, HZ.
Funding
Not applicable.
Data availability
All data/materials in this present study are available from corresponding authors upon proper request.
Declarations
Ethics approval and consent to participate
All patients were consented to donate clinical samples for this study.
Consent for publication
All authors approved the publication of the manuscript.
Competing interests
All authors declare no competing interests and approve the manuscript for publication.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Sike He and Haoyang Liu contributed equally to this work.
Contributor Information
Junru Chen, Email: jrchen@scu.edu.cn.
Hao Zeng, Email: kucaizeng@163.com.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Additional file 1: Table S1. Summary of application of Meet-URO score in mRCC patients receiving systemic therapies.
Additional file 2: Table S2. Cox regression analysis for survival outcomes according to clinical features and the Meet-URO score.
Data Availability Statement
All data/materials in this present study are available from corresponding authors upon proper request.