ABSTRACT
Aims
To investigate the effect of uric acid level on prognosis in patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab.
Materials and methods
This retrospective study utilized data from the Turkish Oncology Group Kidney Cancer Consortium (TKCC), which is a multicenter registry encompassing 13 cancer centers across Türkiye.
Results and conclusions
A total of 189 patients were included in the study. The median age was 61 years in all cohort. Univariable analyses revealed longer TTF (17.87 vs. 6.57 months, p = 0.014) and OS (52.01 vs. 25.36, p = 0.032) in the uric acid-high (UAH) group than in the uric acid-low (UAL) group. In multivariable analyses, low uric acid level emerged as an independent risk factor for OS (hazard ratio (HR): 1.82, 95% confidence interval (CI): 1.09–3.05; p = 0.022), whereas no significant association was observed with TTF (HR: 1.24, 95% CI: 0.72–2.13; p = 0.431). While uric acid levels were a significant independent prognostic factor for OS, no association was found with TTF. Our findings underscore the prognostic importance of uric acid in mRCC, suggesting its potential role as a biomarker for risk stratification
KEYWORDS: Immunotherapy, kidney cancer, prognosis, biomarker, renal cell carcinoma, survival, nivolumab
1. Introduction
The management of metastatic renal cell carcinoma (mRCC) has been changed drastically over the last decade. It consists of various options such as immune checkpoint inhibitors (ICI), tyrosine kinase inhibitors (TKIs), mammalian target of rapamycin (mTOR) pathway inhibitors, hypoxia inducible factor-2α (HIF-2α) inhibitors, and combinations, such as ICI plus ICI or ICI plus TKI [1,2]. Although combination therapies are the preferred first-line treatment for patients with mRCC, some patients might still be candidates for single-agent TKIs due to contraindications or limited access to ICIs [3,4]. Therefore, nivolumab might still be a good candidate for following lines after failure with TKIs in the first line.
The most important factors affecting the prognosis in RCC are the stage of the disease, histopathological subtype, International mRCC Database Consortium (IMDC) risk group, performance status of the patient, obesity, and age [5–9]. Serum laboratory values and inflammatory markers have also been shown to affect prognosis in mRCC [10,11].
In the Checkmate 025 study, nivolumab treatment provided both better survival results and better quality of life compared to everolimus treatment in patients with advanced RCC who had previously received antiangiogenic therapy and progressed [12]. Various factors related to inflammation and immune system have been shown to affect prognosis in mRCC patients receiving nivolumab treatment. Patients with high CRP variability were found to have better survival results with nivolumab treatment. Patients with higher CRP levels and neutrophil–lymphocyte ratio had a worse prognosis. Increased PD-L1 expression and CD8+ cell ratio in tumor pathology were associated with better responses to ICIs. Pan-immune-inflammation value was evaluated to affect prognosis in mRCC patients receiving nivolumab [13–16].
There is conflicting information in the literature about the effect of uric acid on cancer prognosis. It has been shown that mortality increases in various cancer types as uric acid level increases. On the other hand, there are studies showing that uric acid is secreted into the tissue by inflammatory cells and thus the immune system, especially CD8+ T cells, is activated [17,18]. Conversely, in patients diagnosed with primary liver cancer and receiving ICIs, it has been observed that the prognosis worsens with increasing uric acid levels [19]. This study aimed to evaluate the prognostic impact of serum uric acid levels in patients with mRCC treated with nivolumab.
2. Methods
This retrospective study utilized data from the Turkish Oncology Group Kidney Cancer Consortium (TKCC), a multicenter registry comprising 13 cancer centers in Türkiye. We extracted patients with mRCC receiving second-line or later nivolumab from the database. Patients who were over 18 years of age, histopathologically diagnosed with RCC, metastatic, receiving nivolumab treatment, and whose uric acid level was measured before the study were included in the study. Patients under 18 years of age, without a diagnosis of RCC, non-metastatic, not receiving nivolumab treatment, and without pre-treatment uric acid level measurements were excluded from the study. Extracted data included demographics (e.g., age and gender), nephrectomy status, metastatic sites, treatment line, pathological characteristics (e.g., histological type, grade, sarcomatoid features), and treatment initiation and discontinuation dates. The uric acid level of the patients one day before starting nivolumab treatment was recorded. Patients were divided into two groups based on the cutoff value, which was determined by using maximally selected rank analysis: uric acid-low (UAL) (≤6.7 mg/dl) and uric acid-high (UAH) ( >6.7 mg/dl). Harrel’s C-index analysis was performed for the area under curve (AUC) value of the cutoff value of uric acid level. AUC value is determined as 0.56. Primary endpoints were time to treatment failure (TTF), defined as the interval from nivolumab initiation to discontinuation for any reason, and overall survival (OS), defined as the time from nivolumab initiation to death from any cause.
Continuous variables were described as medians (interquartile range (IQR)) and categorical variables as percentages. The chi-square test was used to compare categorical variables, while the Mann–Whitney U test or Student’s t-test was used to compare continuous variables. Survival curves and rates were estimated using the Kaplan–Meier method. A log-rank test was performed to compare survival curves. Multivariable analyses were performed using variables with a p value of ≤0.10 in the univariable analyses. Cox’s proportional hazard regression models were used to calculate hazard ratio (HR) and its 95% confidence interval (CI). All reported p values were two-sided, and p values <0.05 were regarded as statistically significant. All statistical analyses were performed using the SPSS 26.0 for Mac (IBM Corp., Armonk, NY) and RStudio (version 2023.12.1 + 402).
3. Results
A total of 189 patients were included in this study. The median age of the patients was 61 years (IQR: 14). The most of patients were male (75.7%), had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 (72.5%), underwent nephrectomy (75.7%), and had clear cell histology (82%). According to IMDC scores, 16 (8.5%), 116 (61.4%), and 38 (20.1%) patients were grouped in the favorable, intermediate, and poor risk groups, respectively. The most common metastatic sites were liver (53.4%), lung (32.3%), and brain (29.1%). Most patients (84.1%) received nivolumab in the second line.
Based on the uric acid levels, 136 (72.0%) and 53 (28.0%) patients were included in the UAL and UAH groups, respectively. Baseline characteristics were similar in the UAL and UAH groups. Only patients who underwent nephrectomy had a higher percentage of elevated uric acid level than patients who did not undergo nephrectomy. All baseline characteristics of patients are shown in Table 1.
Table 1.
Baseline characteristics of patients receiving nivolumab in mRCC.
| Variables | All patients N = 189 (%) |
Uric acid-low N = 136 (%) |
Uric acid-high N = 53 (%) |
p | |
|---|---|---|---|---|---|
| Gender, male | 143 (75.7) | 102 (75) | 41 (77.4) | 0,851 | |
| Age, years (median, IQR) | 61 (14) | 60 (14) | 62 (17) | 0.317 | |
| Age | < 65 years | 121 (64) | 89 (65.4) | 32 (60.4) | 0.475 |
| ≥65 years | 67 (35.5) | 46 (33.8) | 21 (39.6) | ||
| Unknown | 1 (0.5) | 1 (0.7) | 0 | ||
| Hypertension | Yes | 68 (35.9) | 45 (33.1) | 23 (43.4) | 0.176 |
| No | 118 (62.4) | 89 (65.4) | 29 (54.7) | ||
| Unknown | 3 (1.6) | 2 (1,5) | 1 (1.9) | ||
| Diabetes mellitus | Yes | 34 (18) | 27 (19.8) | 7 (13.2) | 0.323 |
| No | 152 (80.4) | 108 (79.4) | 44 (83) | ||
| Unknown | 3 (1.6) | 1 (0.7) | 2 (3.8) | ||
| ECOG performance status | 0–1 | 137 (72.5) | 99 (72.8) | 38 (71.7) | 0.881 |
| 2–4 | 45 (23.8) | 32 (23.5) | 13 (24.5) | ||
| Unknown | 7 (3.7) | 5 (3.7) | 2 (3.8) | ||
| Smoking | Never | 71 (37.6) | 49 (36) | 22 (41.5) | 0.864 |
| Ex-smoker | 53 (28) | 40 (29.4) | 13 (24.5) | ||
| Current smoker | 20 (10.6) | 15 (11) | 5 (9.4) | ||
| Unknown | 45 (23.8) | 32 (23.5) | 13 (24.5) | ||
| Nephrectomy | Yes | 143 (75.7) | 97 (71.3) | 46 (86.8) | 0.031 |
| No | 45 (23.8) | 38 (27.9) | 7 (13.2) | ||
| Unknown | 1 (0.5) | 1 (0.7) | 0 | ||
| Histologic subtype | Clear cell | 155 (82) | 111 (81.6) | 44 (83) | 0.819 |
| Non-clear cell | 23 (12.2) | 17 (12.5) | 6 (11.3) | ||
| Unknown | 11 (5.8) | 8 (5.9) | 3 (5.7) | ||
| Presence of sarcomatoid features | Yes | 21 (11.1) | 14 (10.3) | 7 (13.2) | 0.486 |
| No | 138 (73) | 102 (75) | 36 (67.9) | ||
| Unknown | 30 (15.9) | 20 (14.7) | 10 (18.9) | ||
| IMDC risk group | Favorable | 16 (8.5) | 11 (8.1) | 5 (9.4) | 0.931 |
| Intermediate | 116 (61.4) | 83 (61) | 33 (62.3) | ||
| Poor | 38 (20.1) | 28 (20.5) | 10 (18.9) | ||
| Unknown | 19 (10) | 14 (10.3) | 5 (9.4) | ||
| CNS metastasis | Yes | 55 (29.1) | 45 (33.1) | 10 (18.9) | 0.359 |
| No | 89 (47.1) | 67 (49.3) | 22 (41.5) | ||
| Unknown | 45 (23.8) | 24 (17.6) | 21 (39.6) | ||
| Lung metastasis | Yes | 61 (32.3) | 44 (32.3) | 17 (32.1) | 0.968 |
| No | 116 (61.4) | 84 (61.8) | 32 (60.4) | ||
| Unknown | 12 (6.3) | 8 (5.9) | 4 (7.5) | ||
| Liver metastasis | Yes | 101 (53.4) | 77 (56.6) | 24 (45.3) | 0.198 |
| No | 77 (40.7) | 52 (38.2) | 25 (47.2) | ||
| Unknown | 11 (5.8) | 7 (5.1) | 4 (7.5) | ||
| Bone metastasis | Yes | 52 (27.5) | 39 (28.7) | 13 (24.5) | 0.607 |
| No | 125 (66.1) | 89 (65.4) | 36 (67.9) | ||
| Unknown | 12 (6.3) | 8 (5.9) | 4 (7.5) | ||
| Nivolumab treatment line | 2 | 159 (84.1) | 114 (83.8) | 45 (84.9) | 0.855 |
| ≥3 | 30 (15.9) | 22 (16.2) | 8 (15.1) | ||
Abbreviations: CNS = Central Nervous System, ECOG = Eastern Cooperative Oncology Group, IMDC = International Metastatic Renal Cell Carcinoma Database Consortium, IQR = interquartile range, mRCC = Metastatic Renal Cell Carcinoma.
In univariate analyses, median TTF was longer in patients with ECOG PS of 0 or 1 than in patients with ECOG PS of 2–4 (11.24 [95% CI: 6.30–16.17]) vs. 3.71 [95% CI: 0.26–7.17] months, p = 0.001), as well as in UAH group than in the UAL group (17.87 [95% CI: 8.09–27.65] vs. 6.57 [95% CI: 4.67–8.47] months, p = 0.014) (Figure 1). However, median TTF was shorter in patients with IMDC poor risk group (3.35 [95% CI: 2.81–3.89] months) than those with IMDC favorable (10.48 [95% CI: 0.73–20.23] months) and intermediate risk groups (13.34 [95% CI: 7.49–19.19] months) (p < 0.001) (Table 2).
Figure 1.
Kaplan–Meier curve for time to treatment failure dependent on uric acid levels.
Table 2.
Univariate and multivariate analysis for time to treatment failure of patients receiving nivolumab in mRCC.
| Variable | Median TTF (95%CI) |
p | Multivariate |
p | |
|---|---|---|---|---|---|
| HR (95%CI) | |||||
| Age | < 65 | 7.06 (4.47–9.66) | 0.197 | – | – |
| ≥65 | 11.07 (3.38–18.77) | – | |||
| Sex | Female | 5.75 (3.60–7.90) | 0.185 | ||
| Male | 8.48 (4.08–12.87) | ||||
| ECOG PS | 0–1 | 11.24 (6.30–16.17) | 0.001 | 1 | 0.059 |
| 2–3–4 | 3.71 (0.26–7.17) | 1.82 (0.98–3.37) | |||
| Diabetes mellitus | No | 8.48 (3.44–13.51) | 0.296 | – | – |
| Yes | 5.75 (3.27–8.23) | – | |||
| Hypertension | No | 27.75 (3.07–13.88) | 0.877 | – | – |
| Yes | 6.67 (3.13–10.21) | – | |||
| Histological type | Clear | 7.49 (5.02–9.96) | 0.794 | – | – |
| Non-clear | 8.97 (3.4–14.53) | – | |||
| Sarcomatoid feature | No | 7.85 (4.39–11.31) | 0.369 | – | – |
| Yes | 3.74 (2.66–4.83) | – | |||
| Nephrectomy | No | 6.67(4.10–9.23) | 0.334 | – | – |
| Yes | 8.97 (4.37–3.56) | – | |||
| IMDC risk group | Favorable | 10.48 (0.73–20.23) | < 0.001 | 1 | |
| Intermediate | 13.34 (7.49–19.19) | 0.96 (0.47–1.96) | 0.921 | ||
| Poor | 3.35 (2.81–3.89) | 1.64 (0.69–3.88) | 0.262 | ||
| CNS metastasis | No | 8.97 (4.80–13.13) | 0.079 | 1 | 0.110 |
| Yes | 5.32 (4.15–6.49) | 1.42 (0.92–2.18) | |||
| Nivolumab treatment line | 2 | 7.81 (5.00–10.64) | 0.429 | – | – |
| ≥3 | 9.59 (NE-21.37) | – | |||
| Uric acid | High | 17.87 (8.09–27.65) | 0.014 | 1 | 0.431 |
| Low | 6.57 (4.67–8.47) | 1.24 (0.72–2.13) | |||
Abbreviations: CI = Confidence interval, CNS = central nervous system, ECOG = Eastern Cooperative Oncology Group, HR = Hazard ratio, IMDC = International Metastatic Renal Cell Carcinoma Database Consortium, mRCC = Metastatic Renal Cell Carcinoma, NE = Not estimated PS = Performance status, TTF = Time to treatment failure.
Median OS was longer in male patients than female patients (46.00 [95% CI: 31.96–60.03] vs 15.38 [95% CI: 9.55–21.20] months, p = 0.008), ECOG PS of 0 or 1 than in patients with ECOG PS of 2–4 (50.37 (95% CI: 34.43–66.30) vs. 12.09 (95% CI: 4.22–19.96) months, p < 0.001), as well as in UAH group than in the UAL group (52.01 (95% CI: 38.82–66.84) vs. 25.36 (95% CI: 15.84–34.88) months, p = 0.032) in univariate analyses (Figure 2). However, median OS was shorter in patients with IMDC poor risk group (5.45 [95% CI: 1.35–9.56] months) than those with IMDC favorable NE (95% CI: NE–NE) and intermediate risk groups (48.36 [95% CI: 32.84–63.88] months) (p < 0.001) (Table 3).
Figure 2.
Kaplan–Meier curve for overall survival dependent on uric acid levels.
Table 3.
Univariate and multivariate analysis for overall survival of patients receiving nivolumab in mRCC.
| Variable | Median OS (95%CI) |
p | Multivariate |
p | |
|---|---|---|---|---|---|
| HR (95%CI) | |||||
| Age | < 65 | 35.12 (17.24–53.01) | 0.945 | – | – |
| ≥65 | 28.06 (6.54–49.57) | – | |||
| Sex | Female | 15.38 (9.55–21.20) | 0.008 | 1 | 0.005 |
| Male | 46.00 (31.96–60.03) | 0.51 (0.32–0.81) | |||
| ECOG PS | 0–1 | 50.37 (34.43–66.30) | < 0.001 | 1 | 0.009 |
| 2–3–4 | 12.09 (4.22–19.96) | 1.98 (1.18–3.31) | |||
| Diabetes mellitus | No | 33.02 (14.23–51–81) | 0.339 | – | – |
| Yes | 35.12 (5.99–64.25) | – | |||
| Hypertension | No | 30.32 (17.26–43.39) | 0.915 | – | – |
| Yes | 39.69 (17.17–62.21) | - | |||
| Histological type | Clear | 30.32 (17.34–43.30) | 0.158 | – | – |
| Non-clear | 60.16 (20.01–100.30) | – | |||
| Sarcomatoid feature | No | 36.11 (19.28–52.93) | 0.128 | – | – |
| Yes | 23.82 (NE-55.89) | – | |||
| Nephrectomy | No | 22.64 (NE-51.48) | 0.582 | – | – |
| Yes | 35.12 (221.04–49.20) | – | |||
| IMDC risk group | Favorable | NE (NE-NE) | < 0.001 | 1 | |
| Intermediate | 48.36 (32.84–63.88) | 1.63 (0.58–4.56) | 0.353 | ||
| Poor | 5.45 (1.35–9.56) | 4.77 (1.55–14.74) | 0.007 | ||
| CNS metastasis | No | 32.33 (12.39–52.27) | 0.710 | – | – |
| Yes | 39.68 (NE-NE) | – | |||
| Nivolumab treatment line | 2 | 32.33 (14.27–50.39) | 0.786 | – | – |
| ≥3 | 35.12 (24.58–45–66) | – | |||
| Uric acid | High | 52.01 (38.82–66.84) | 0.032 | 1 | 0.022 |
| Low | 25.36 (15.84–34.88) | 1.82 (1.09–3.05) | |||
Abbreviations: CI = Confidence interval, ECOG = Eastern Cooperative Oncology Group, HR = Hazard ratio, IMDC = International Metastatic Renal Cell Carcinoma Database Consortium, mRCC = Metastatic Renal Cell Carcinoma, NE = Not estimated, OS = Overall survival, PS = Performance status.
In multivariable analyses, low serum uric acid level was associated with poor OS (HR: 1.82, 95% CI: 1.09–3.05; p = 0.022), after adjusting for confounding factors (i.e., sex, ECOG PS, and IMDC risk group). However, serum uric acid level was not found to be associated with TTF (HR: 1.24, 95% CI: 0.72–2.13; p = 0.431), after adjusting for confounding variables (i.e., ECOG PS, IMDC risk group, and central nervous system metastasis).
4. Discussion
Our findings demonstrate that serum uric acid level significantly influence outcomes in patients with mRCC treated with nivolumab. Low serum uric acid was identified as an independent predictor of poor OS, highlighting its potential as a prognostic biomarker in this population. This observation provides valuable insight into the role of metabolic and inflammatory markers in shaping treatment outcomes in immunotherapy for mRCC.
Several factors have been shown to affect prognosis in patients with mRCC receiving nivolumab treatment. According to the study by Fukuda et al., it was shown that better OS results were obtained with nivolumab treatment in patients with high CRP variability [13]. Ishihara et al. showed that high CRP levels, high neutrophil-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio have a poor effect on survival [20]. According to the study by Pignon et al., it has been shown that as PD-L1 expression increases, patients respond better to ICIs and survival results are better [15]. In the same study, it was also shown that OS increased as the CD8+ cell ratio increased in tumor infiltrating cells. Buerk et al. created a risk score using alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transferase (GGT), and lactate dehydrogenase (LDH) enzymes and showed that the prognosis may change in patients with RCC using ICIs according to this score [21]. In our study, female gender, poor ECOG PS, high IMDC risk score, and low uric acid level were found to be associated with poor prognosis in mRCC patients receiving nivolumab.
There were conflicting results about the role of serum uric acid levels in the efficacy of ICIs. Rao et al. observed that the prognosis was worse with increasing uric acid levels in patients with primary liver cancer using ICIs [19]. The findings showing that mortality increases in various types of malignancies as uric acid level increases are inconsistent with our study, but in line with the study by Rao et al. In a study conducted by Deng et al. in China, it was observed that the incidence of cancer increased from 30.3 to 100.8 per 10,000 as the uric acid level increased in female patients with diabetes [17]. Kobylecki et al. showed that cancer incidence and mortality are higher in elevated uric acid levels [22]. Although the results of our study and the study of Rao et al. are in contrast, it should be remembered that these studies were performed with ICIs used in different cancer types. There is a need for more large-scale studies to be performed in order to show the efficacy of ICIs with uric acid level and its relationship with prognosis.
On the other hand, according to the study by Shi et al., apoptotic cells and their antigens secrete uric acid and thus activate dendritic cell maturation, immune system, and especially CD8+ T lymphocytes [18]. CD8+ T cells play a key role in the effectiveness of immunotherapy [23]. In line with this information, it is expected that as the uric acid level increases, the activity of CD 8+ T cells and consequently the effectiveness of immunotherapies will increase. In an animal study by Yang et al., it was shown that when purine metabolism was blocked in mice with non-small cell lung cancer, macrophage immunosuppression decreased and anti-tumor immunity and immunotherapy efficacy could be increased [24]. In experiments with mice, both Kool et al. and Min Lee et al. found that adjuvants in vaccines triggering immunogenicity together with increased uric acid in the environment [25,26]. Riteau et al. have shown that an increase in uric acid in the environment causes inflammasome formation and increases immunity with a pathogenesis similar to that of causing gout [27]. In our study, better OS results were observed in the UAH group among patients with mRCC using nivolumab.
IMDC prognostic risk model, which considers six clinical and laboratory parameters, is currently the clinical standard for risk stratification in mRCC and influences treatment decisions [28]. However, future research is required to refine and develop prognostic models that incorporate additional biomarkers and clinical factors, which could improve prognostic accuracy and guide personalized treatment. This is because some patients may experience clinical progressions that do not correspond to their IMDC score [29].
The main limitations of our study include its retrospective design, which may introduce selection bias and missing data, and the inability to use guideline-recommended first-line therapies due to socioeconomic constraints in our region. Additionally, the single-country data may limit the generalizability of our findings to other populations. Furthermore, the results may be influenced by patient-specific factors such as comorbidities and concurrent medications, which could impact uric acid levels. Finally, there is no established cutoff value for uric acid, which may affect the generalizability of our findings, different methods can be used to determine the cutoff value of uric acid level, and new results may emerge with these values in future studies. However, the study’s strengths lie in its multicenter design, incorporating data from 13 centers, which enhances its representativeness and reliability. Furthermore, this is the first study to establish serum uric acid levels as an independent prognostic marker in mRCC patients treated with nivolumab, providing a novel perspective on the role of metabolic markers in immunotherapy outcomes.
5. Conclusion
This study identifies serum uric acid as an independent prognostic marker in patients with mRCC treated with nivolumab, with lower levels associated with worse survival outcomes. These findings underscore the potential role of metabolic markers in guiding treatment decisions and prognostication in mRCC. Future prospective studies with larger, diverse populations are needed to validate these results and explore the underlying mechanisms linking uric acid levels to immunotherapy response. Additionally, integrating uric acid assessment into clinical practice may offer a novel approach to risk stratification and personalized treatment planning in mRCC.
Acknowledgments
We express our deepest gratitude to every member of the Turkish Oncology Group Kidney Cancer Consortium (TKCC) for their invaluable support.
Funding Statement
This paper was not funded.
Article highlights
Nivolumab is a treatment option for metastatic RCC patients who progress after tyrosine kinase inhibitor.
IMDC prognostic risk model, which considers six clinical and laboratory parameters, is currently the clinical standard for risk stratification in mRCC and influences treatment decisions. However, further research is needed to refine and develop prognostic models that take into account additional biomarkers and clinical factors. This could improve the accuracy of prognoses and guide personalized treatment.
In this study, we aim to investigate the effect of uric acid level on prognosis in patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab.
This study identifies serum uric acid as an independent prognostic marker in patients with mRCC treated with nivolumab, with lower levels associated with worse survival outcomes. These findings underscore the potential role of metabolic markers in guiding treatment decisions and prognostication in mRCC.
Author contributions
SS: contributing to the conception, writing the first draft of the manuscript, revising, giving final approval of the version to be published, and agreeing to be accountable for all aspects of the work.
HB, GU, MANS, EY, YU: contributing to drafting the work, giving final approval of the version to be published, revising, supervision, and agreeing to be accountable for all aspects of the work.
OFK, ESC, SS, HK, MG, AFA, SI, DT, CA, SSG, ONS, NK, CK: contributing to the conception, giving final approval of the version to be published, and agreeing to be accountable for all aspects of the work.
All authors have read and agreed to the published version of the manuscript.
Disclosure statement
Yüksel Ürün declared research funding (institutional and personal) from Turkish Oncology Group. Yüksel Ürün has served on the advisory board for Abdi-İbrahim, Astellas, AstraZeneca, Bristol Myers-Squibb, Eczacıbası, Gilead, Janssen, Merck, Novartis, Pfizer, Roche. Yüksel Ürün received honoraria or has served as a consultant for Abdi-İbrahim, Astellas, Bristol MyersSquibb, Eczacıbasi, Janssen, Merck, Novartis, Pfizer, Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Reviewer disclosure
Peer reviewers on this manuscript have received an honorarium from Immunotherapy for their review work but have no other relevant financial relationships to disclose.
Ethical approval
Ethical approval was obtained for the multicentric study from Ankara University Faculty Ethics Committee (No: I09–701–24). The Clinical Research Ethics Committee waived informed consent due to the retrospective study design.
Data availability statement
The datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.