Real world treatment sequences and outcomes for metastatic renal cell carcinoma

Objectives The treatment landscape for metastatic renal cell carcinoma changed a lot in the last few years. This study aimed to assess the treatment sequences and outcomes for metastatic renal cell carcinoma in a real-world setting. Materials and methods We enrolled patients with metastatic renal cell carcinomawho received first-line systemic treatment with tyrosin kinase inhibitors monotherapy, ipilimumab plus nivolumab, or pembrolizumab plus axitinibbetween January2009 and May 2023 on the database of TriNetX network. Overall survival, time on treatment and time to next treatment were evaluated using Kaplan-Meiermethod. Results Totally, 4183 received tyrosine kinase inhibitor monotherapy, 1555 received ipilimumab plus nivolumab, and 559 received axitinib plus pembrolizumab. Median time on treatment was 2.5 months for the tyrosine kinase inhibitor monotherapy cohort, 5.4 months for the ipilimumab plus nivolumab cohort, and 8.3 months for the pembrolizumab plus axitinib cohort. Median time to next treatment was 16.6 months for both the tyrosine kinase inhibitor monotherapy and ipilimumab plus nivolumab cohorts, and 22.1 months for the pembrolizumab plus axitinib cohort. Median overall survival was 42.2 months for the tyrosine kinase inhibitor monotherapy cohort, 39.7monthsfor the ipilimumab plus nivolumab cohort, and not reached for the pembrolizumab plus axitinib cohort. In comparison with the tyrosine kinase inhibitor monotherapy cohort, patients in the pembrolizumab plus axitinib cohort showed survival benefit (log-rank p = 0.0168) in overall survival, but not the case in the ipilimumab plus nivolumab cohort. Conclusion There was a trend toward using first-line immuno-oncology based therapy for patients with metastatic renal cell carcinoma in a real-world practice. Axitinib plus pembrolizumuab cohort had survival benefits over tyrosine kinase inhibitor and ipilimumab plus nivolumab cohorts, while patients in the ipilimumab plus nivolumab cohort had more distant metastases and comorbidities.


Data source
We conducted a retrospective analysis of patients with mRCC between January 1, 2009 and May 30, 2023on the database of TriNetX network, a global health research network that provides real-world clinical data of �250 million patients in 120 healthcare organizations.In the present study, we specifically used the US Collaborative Network, which includes 57 healthcare organizations in the US.

Study design and population
We enrolled patients with mRCC aged �18 years old receiving first-line systemic therapies between January 1, 2009 and May 30, 2023.To confirm the diagnosis of distant metastasis, these patients were identified using the International Classification of Diseases, tenth edition, Clinical Modification (ICD-10-CM): ICD-10-CM C64, as well as ICD-10-CM: C78.0, C78.7, C79.3, or C79.5 to confirm the diagnosis of distant metastasis.The index date was set at the date of initiation of first-line systemic treatment for mRCC.Included patients must have �2clinical visits and a follow-up duration of�6 months after the index date.
In the present study, the first-line systemic treatments included TKI monotherapy (sunitinib, pazopanib), ipilimumab plus nivolumab, and axitinib plus pembrolizumab.A combination treatment was defined as any treatments given within one month after the index date.

Outcome measurement
The clinical outcomes we analyzed were the following 3 items: time on treatment (ToT), time to next treatment (TNT), and overall survival (OS).ToT was defined as the duration between the index date and the date when a new treatment was introduced, on the death of the patient, patient's medical record ended, the date of the last administration of first-line treatment if there was a gap of �4 months when a patient did not receive any treatment, or censored at the date of the last administration of first-line therapy, whichever had taken place first.TNT was calculated from the index date to the date of initiation of second-line treatment, or censored at the date of the last administration of first-line therapy, whichever had taken place first.OS was defined as duration between the index date and the date of death from any cause or censored at the date of the study end, whichever had taken place first.

Statistical analyses
Patient baseline characteristics for continuous variables were expressed as mean and standard deviation(SD) and for categorical variables as number and percentage.Inter-group differences were evaluated using Student's t test for continuous variables, and chi-square test for categorical variables.Survival analysis was calculated using Kaplan-Meier method with a log-rank test to assess the inter-group differences on ToT, TNT and OS.Statistical analyses were conducted on the TriNetX platform and statistical significance was set at p<0.05.

Ethics in research
This study was approved by the institutional review board (IRB) of Taichung Veterans General Hospital (IRB number: SE:22220A).The operation was performed in accordance with national regulations and the Helsinki Declaration.
Patient characteristics are showed in Table 1.Compared with TKI monotherapy cohort, patients in the ipilimumab plus nivolumab cohort experienced significantly more instances of distant metastases, including lung (p< 0.0001), liver (p = 0.0002), bone (p< 0.0001), and brain metastasis (p = 0.0064).Additionally, more patients in the ipilimumab plus nivolumab cohort had comorbidity compared with TKI montheray cohort, including diabetes mellitus, hypertension, cerebrovascular disease, ischemic heart disease (all with p< 0.0001).Patients in the axitinib plus pembrolizumab cohort were older (p = 0.01) and had few white people (p = 0.0213) in comparison with the TKI monotherapy cohort.

Trends and sequences
The treatment trends regarding first-line systemic therapy for mRCC are shown in Fig 1.
There has been an increased use of IO combination therapies (ipilimumab plus nivolumab and pembrolizumab plus axitinib) since 2018.

Outcomes
Mean follow-up time (SD) was 35.

Discussion
The treatment landscape for mRCC changed a lot since the introduction of IO-based combination therapy.In the present study, we used TriNetx network database to conduct a cohort Clinical trials are generally associated with highly selected patients in a well controlled circumstance to avoid biases, which may not reflect the real-world clinical practice.In this study, we conducted a retrospective cohort study to show their real-world treatment patterns and outcomes for patients with mRCC.For baseline characteristics, the ipilimumab plus nivolumab cohort was associated with more instances of distant metastases and co-mobidities in comparison with other groups.TKI monotherapy cohort and pembrolizumab plus axitinib cohort showed similar baseline characteristics.A possible explanation of such discrepancy might be that ipilimumab plus nivolumab was used for intermittent-and poor-risk tumors, and patients in this cohort had more risk factors and therefore poor prognosis.
The US Food and Drug Administration approved the use of ipilimumab plusnivolumab in 2018 and pembrolizumab plus axitinib in 2019 for the treatment of advanced RCC.We observed a trend toward an increasing use of ipilimumab plus nivolumab and pembrolizumab plus axitinib after the FDA approval.Literatures reported that second-line therapies are affected by the first-line treatments:patients received TKIs after IO-based therapies; patients received IO-based therapiesafterTKIs treatment [11,13,14].The present study also observed a similar finding: for patients receiving ipilimumab plus nivolumabor pembrolizumab plus axitinib as first-line therapy, the most common second-line treatment was cabozantinib (54.6%).Among patients receiving TKIs as first-line therapy, the frequently used second-line treatments were nivolumab (22.1%), pazopanib (20.5%), sunitinib(16.6%),and axitinib (14.4%).The possible explanation for such discrepancy may be that our study included patients with mRCC between 2008 and 2022, partially reflecting the treatment patterns before the era of IO since nivolumab was first introduced as second-line therapy in 2015 [15].
According to previous studies, TOT and TNT are highly correlated with progression free survival [16,17].We found that the pembrolizumab plus axitinib cohort had the longest TOT and TNT.In additional, the pembrolizumab plus axitinib cohort was associated with a better OS compared with TKI monotherapy and ipilimumab plus nivolumab cohort.Our findings were consistent with the previous literatures regarding pembrolizumab plus axitinib being the most preferable first-line agents [11,18,19].
Contrary to the previous studies [20,21], which reported pembrolizumab plus axitinib and ipilimumab plus nivolumab had similar outcomes, in this study, we found that the ipilimumab  plus nivolumab cohort presented similar OS compared with the TKI montherapy cohort and their OS was worse than the pembrolizumab plus axitinib cohort.This discrepancy might be attributed to the fact that patients in the ipilimumab plus nivolumab cohort carried more instances of distant metastases and co-mobidities than the other two groups.Furthermore, ipilimumab plus nivolumab was not approved for regular use in the favorable risk group, indicating that patients with intermittent-and poor-risk tumors formed the majority of this cohort.
Our study has several limitations.First, its retrospective nature and non-randomization of our study are subject to selection bias.Second, several factors, such as IMDC risk stratification, clinical symptoms, reason of discontinuation and histopathological characteristics, were associated with prognosis and quality of life [12,[22][23][24].The information and a Cox regression model analysis were not available from the database.Lastly, the TKI scohort in our study included patients over the past 10 years.Treatment patterns changed between different time periods, which may lead to bias in outcome comparisons.However, this study summarized the treatment sequences in the past decade for this cohort and showed treatment trends in the era of IO.

Conclusion
We found a temporal trend toward using first-line IO-based therapy for patients with mRCC in a real-world clinical practice.Axitinib plus pembrolizumuab cohort showed survival benefits over TKI and ipilimumab plus nivolumab cohorts, while patients in the ipilimumab plus nivolumab cohort had more risk factors for poorer outcomes.