Real-World Primary Resistance to First-Line Immune-Based Combinations in Patients with Advanced Renal Cell Carcinoma (ARON-1)
Clinical features and response to immune combinations in patients with renal cell carcinoma and sarcomatoid de-differentiation (ARON-1 study).
Sex and survival outcomes in patients with renal cell carcinoma receiving first-line immune-based combinations
Real-World Impact of Upfront Cytoreductive Nephrectomy in Metastatic Non-Clear Cell Renal Cell Carcinoma Treated with First-Line Immunotherapy Combinations or Tyrosine Kinase Inhibitors (A Sub-Analysis from the ARON-1 Retrospective Study)
Abstract
Background: About 20% of patients with renal cell carcinoma present with non-clear cell histology (nccRCC), encompassing various histological types. While surgery remains pivotal for localized-stage nccRCC, the role of cytoreductive nephrectomy (CN) in metastatic nccRCC is contentious. Limited data exist on the role of CN in metastatic nccRCC under current standard of care.
Objective: This retrospective study focused on the impact of upfront CN on metastatic nccRCC outcomes with first-line immune checkpoint inhibitor (IO) combinations or tyrosine kinase inhibitor (TKI) monotherapy.
Methods: The study included 221 patients with nccRCC and synchronous metastatic disease, treated with IO combinations or TKI monotherapy in the first line. Baseline clinical characteristics, systemic therapy, and treatment outcomes were analyzed. The primary objective was to assess clinical outcomes, including progression-free survival (PFS) and overall survival (OS). Statistical analysis involved the Fisher exact test, Pearson’s correlation coefficient, analysis of variance, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models.
Results: Median OS for patients undergoing upfront CN was 36.8 (95% confidence interval [CI] 24.9-71.3) versus 20.8 (95% CI 12.6-24.8) months for those without CN (p = 0.005). Upfront CN was significantly associated with OS in the multivariate Cox regression analysis (hazard ratio 0.47 [95% CI 0.31-0.72], p < 0.001). In patients without CN, the median OS and PFS was 24.5 (95% CI 18.1-40.5) and 13.0 months (95% CI 6.6-23.5) for patients treated with IO+TKI versus 7.5 (95% CI 4.3-22.4) and 4.9 months (95% CI 3.0-8.1) for those receiving the IO+IO combination (p = 0.059 and p = 0.032, respectively). Conclusions: Our study demonstrates the survival benefits of upfront CN compared with systemic therapy without CN. The study suggests that the use of IO+TKI combination or, eventually, TKI monotherapy might be a better choice than IO+IO combination for patients who are not candidates for CN regardless of IO eligibility. Prospective trials are needed to validate these findings and refine the role of CN in current mRCC management.
Papillary Renal Cell Carcinoma: Outcomes for Patients Receiving First-line Immune-based Combinations or Tyrosine Kinase Inhibitors from the ARON-1 Study
Background and objective: Papillary renal cell carcinoma (pRCC) is the most frequent histological subtype of non-clear cell RCC (nccRCC). Owing to the heterogeneity of nccRCC, patients are often excluded from large phase 3 trials focused on clear cell RCC, so treatment options for nccRCC remain limited. Our aim was to investigate the efficacy of first-line treatment with tyrosine kinase inhibitors (TKIs) or immuno-oncology (IO)-based combinations in patients with pRCC.
Methods: We performed a multicenter retrospective analysis of real-world data collected for patients with advanced pRCC treated in 40 centers in 12 countries as part of the ARON-1 project (NCT05287464). The primary endpoints were overall survival (OS), progression-free survival (PFS), the overall response rate (ORR), and time to second progression (PFS2). OS, PFS, and PFS2 were estimated using the Kaplan-Meier method and results were compared between the treatment groups using a log-rank test. Univariate and multivariable analyses were carried out using Cox proportional-hazard models.
Key findings and limitations: We included 200 patients with metastatic pRCC, of whom 73 were treated with IO-based combinations and 127 with TKIs. Median OS was 22.5 mo in the TKI group 28.8 mo in the IO group (p = 0.081). Median PFS was 6.4 mo in the TKI group and 17.4 mo in the IO group (p < 0.001). The ORR was higher in the IO group than in the TKI group (41% vs 27%; p = 0.037). Conclusions and clinical implications: Our results show that IO-based combinations have superior efficacy outcomes to TKIs for first-line treatment of metastatic pRCC. Patient summary: The ARON-1 project collects clinical data for patients with kidney cancer treated in multiple centers worldwide to assess outcomes in the real-world setting. We analyzed data for patients with metastatic kidney cancer of a specific subtype to evaluate the efficacy of different first-line treatments. Patients treated with immune-based combinations had better outcomes than patients treated with tyrosine kinase inhibitors. Keywords: ARON-1; Immuno-oncology combinations; Immunotherapy; Papillary renal cell carcinoma; Survival; Tyrosine kinase inhibitors.
Systemic Immune-Inflammation Index in Patients Treated With First-Line Immune Combinations for Metastatic Renal Cell Carcinoma: Insights From the ARON-1 Study
**Abstract**
**Background:** Systemic treatment with immune combinations is the gold standard for metastatic renal cell carcinoma (mRCC). The systemic immune-inflammation index (SII), a prognostic marker for various malignancies, has limited and conflicting data regarding its value in mRCC patients treated with immunotherapy.
**Methods:** We retrospectively analyzed data from 1034 mRCC patients across 56 centers in 18 countries. SII (Platelet × Neutrophil/Lymphocyte count) was calculated prior to first-line treatment, with a cut-off value of 1265 determined by receiver operating characteristic (ROC) analysis. The primary objective was to assess the outcomes of patients treated with immunotherapy.
**Results:** After a median follow-up of 26.7 months, the overall survival (OS) and progression-free survival (PFS) were 39.8 and 15.7 months, respectively. Patients with low SII had significantly longer OS (55.7 vs. 22.2 months, P < .001), improved PFS (20.8 vs. 8.5 months, P < .001), and a higher overall response rate (52% vs. 37%, P = .033) compared to those with high SII. **Conclusion:** High SII is associated with poorer outcomes in mRCC patients treated with immunotherapy. SII may serve as a simple, accessible prognostic tool in clinical practice. **Keywords:** Immune checkpoint inhibitors; Prognostic biomarker; Systemic immune-inflammation index; Metastatic renal cell carcinoma.
Geographical differences in the management of metastatic de novo renal cell carcinoma in the era of immune-combinations
Abstract
Background: The upfront treatment of metastatic renal cell carcinoma (mRCC) has been revolutionized by the introduction of immune-based combinations. The role of cytoreductive nephrectomy (CN) in these patients is still debated. The ARON-1 study (NCT05287464) was designed to globally analyze real-world data of mRCC patients receiving first-line immuno-oncology combinations. This sub-analysis is focused on the role of upfront or delayed partial or radical CN in three geographical areas (Western Europe, Eastern Europe, America/Asia).
Methods: We conducted a multicenter retrospective observational study in mRCC patients treated with first-line immune combinations from 55 centers in 19 countries. From 1152 patients in the ARON-1 dataset, we selected 651 patients with de novo mRCC. 255 patients (39%) had undergone CN, partial in 14% and radical in 86% of cases; 396 patients (61%) received first-line immune-combinations without previous nephrectomy.
Results: Median overall survival (OS) from the diagnosis of de novo mRCC was 41.6 months and not reached (NR) in the CN subgroup and 24.0 months in the no CN subgroup, respectively (P<0.001). Median OS from the start of first-line therapy was NR in patients who underwent CN and 22.4 months in the no CN subgroup (P<0.001). Patients who underwent CN reported longer OS compared to no CN in all the three geographical areas. Conclusions: No significant differences in terms of patients' outcome seem to clearly emerge, even if the rate CN and the choice of the type of first-line immune-based combination varies across the different Cancer Centers participating in the ARON-1 project.
Systemic Immune-Inflammation Index in Patients Treated With First-Line Immune Combinations for Metastatic Renal Cell Carcinoma: Insights From the ARON-1 Study
**Abstract**
**Background:** Renal cell carcinoma (RCC) is one of the most common urological cancers globally, with increasing incidence. Immunotherapy, either alone or in combination with tyrosine kinase inhibitors (TKIs), has become a key treatment option for advanced RCC, though head-to-head comparisons are lacking. Real-world evidence is essential to guide treatment decisions.
**Objective:** This study aimed to assess outcomes in advanced RCC patients treated with first-line immune-oncology (IO) combinations or IO-TKI combinations.
**Design, Setting, and Participants:** Data were retrospectively collected from 930 advanced RCC patients (654 intermediate-risk, 276 poor-risk) from 58 centers in 20 countries. Variables such as sarcomatoid differentiation, prior nephrectomy, metastatic sites, and biochemical markers were included.
**Outcome Measurements and Statistical Analysis:** Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. The median follow-up was 18.7 months.
**Results:** In intermediate-risk patients, IO + TKI therapy was associated with significantly longer OS (55.7 vs 40.2 months; p = 0.047) and PFS (30.7 vs 13.2 months; p < 0.001) compared to IO + IO therapy. In the poor-risk subgroup, no significant differences in OS or PFS were observed between the two treatment approaches. The retrospective nature of the study represents a limitation. **Conclusions:** In real-world data, intermediate-risk RCC patients benefit more from IO + TKI combinations compared to IO + IO combinations, with longer OS and PFS. No significant differences were found in poor-risk patients. These findings may influence treatment decision-making in clinical practice. **Patient Summary:** This study analyzed data from 930 renal cancer patients across 20 countries to compare treatment strategies. Intermediate-risk patients benefited more from the combination of immunotherapy with antiangiogenic therapy (IO + TKI) than from dual immunotherapy (IO + IO). No such differences were observed in poor-risk patients, informing treatment choices for these populations.
Geographical differences in the management of metastatic de novo renal cell carcinoma in the era of immune-combinations
**Abstract**
**Background:** The introduction of immune-based combinations has transformed the upfront treatment of metastatic renal cell carcinoma (mRCC), though the role of cytoreductive nephrectomy (CN) remains debated. This sub-analysis of the ARON-1 study (NCT05287464) evaluates the impact of upfront or delayed partial or radical CN in mRCC patients across three geographical regions (Western Europe, Eastern Europe, and America/Asia).
**Methods:** A multicenter, retrospective observational study was conducted involving mRCC patients treated with first-line immune-combination therapies across 55 centers in 19 countries. From the ARON-1 dataset of 1152 patients, 651 de novo mRCC patients were selected. Among them, 255 (39%) underwent CN (14% partial, 86% radical), while 396 (61%) received first-line immune therapies without prior nephrectomy.
**Results:** Median overall survival (OS) from the diagnosis of de novo mRCC was 41.6 months in the CN group and 24.0 months in the no CN group (P<0.001). From the start of first-line therapy, OS was not reached (NR) in the CN group and was 22.4 months in the no CN group (P<0.001). CN was associated with improved OS across all geographical regions analyzed. **Conclusions:** While CN rates and the choice of immune-based first-line combinations varied across centers, patients who underwent CN experienced better survival outcomes. These findings suggest a potential benefit of CN in mRCC patients receiving immune-combination therapies.
Real-world Outcome of Patients with Advanced Renal Cell Carcinoma and Intermediate- or Poor-risk International Metastatic Renal Cell Carcinoma Database Consortium Criteria Treated by Immune-oncology Combinations: Differential Effectiveness by Risk Group?
**Abstract**
**Background:** Immuno-oncology (IO) combination therapies have demonstrated survival benefits in patients with metastatic renal cell carcinoma (mRCC).
**Objective:** The ARON-1 study (NCT05287464) aimed to collect real-world data on the effectiveness of first-line IO combination therapies in mRCC patients globally.
**Patients and Methods:** This retrospective analysis included 729 patients aged ≥18 years with cytologically or histologically confirmed mRCC, treated with IO combinations across 47 international institutions in 16 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall clinical benefit (OCB).
**Results:** Of the 729 patients, 86% had clear-cell RCC. IO + IO therapy was administered to 313 patients, while 416 received IO + tyrosine kinase inhibitor (IO + TKI) therapy. The median OS and PFS in the overall population were 36.5 and 15.0 months, respectively. Among 616 patients with intermediate/poor International mRCC Database Consortium (IMDC) risk, IO + TKI therapy was associated with a significantly longer median OS compared to IO + IO (55.7 vs 29.7 months; p = 0.045). OCB was 84% with IO + TKI and 72% with IO + IO (p < 0.001). **Conclusions:** The ARON-1 study suggests that IO combinations are effective as first-line therapy for mRCC in a real-world setting, with notable differences in outcomes between IO + IO and IO + TKI therapies in specific patient subgroups.
