Enfortumab Vedotin Following Platinum Chemotherapy and Avelumab Maintenance in Patients with Metastatic Urothelial Carcinoma: A Retrospective Data from the ARON-2EV Study.

BACKGROUND: Enfortumab vedotin (EV) has been approved for the treatment of patients with locally advanced/metastatic urothelial carcinoma (la/mUC) who previously received platinum-based chemotherapy followed by immune checkpoint inhibitors. However, the pivotal clinical trials did not include patients previously treated with avelumab maintenance therapy. OBJECTIVE: The aim of the present retrospective analysis was to assess the effectiveness of EV following avelumab in patients with mUC enrolled in the ARON-2EV study. PATIENTS AND METHODS: The study included 182 patients with mUC treated with EV following avelumab maintenance. The primary objective was to assess clinical outcomes, including progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and duration of response (DoR). Statistical analysis involved Fisher exact test, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. RESULTS: Median OS and PFS were 12.7 (95% CI 10.2-14.1) and 7.9 (95% CI 6.4-9.9) months, respectively. Complete response (CR) was achieved in 5% and partial response (PR) in 34% of patients, with an ORR of 39%. The DoR in patients who achieved CR/PR was 10.9 months (95% CI 8.1-11.4). The incidence of grade ≥ 3 peripheral neuropathy and skin rash was 9%, followed by 8% of grade ≥ 3 diarrhea and 4% of grade ≥ 3 hyperglycemia. CONCLUSIONS: The results of our large international retrospective study confirm the effectiveness of EV and endorse its use in the population of patients with mUC treated with EV following the frontline platinum-based chemotherapy and subsequent maintenance treatment with avelumab.

Intersectionality Between Country, Gender and Funding in Authorship for Phase III Trials Presented at the ASCO Annual Meeting 2022.

PURPOSE: Multiple disparities have been recognized in the area of location, gender, and funding for leadership in oncology clinical trials. Understanding their intersectionality is crucial to be able to formulate policies and actions, to ensure research is representative of the global oncology community. Here, data from phase III trials presented at the ASCO Annual Meeting of 2022 (ASCO22) were analyzed. METHODS: The location of institution, gender of lead and senior authors, and funding source for solid tumor phase III trial abstracts presented at the ASCO22 were analyzed. World Bank analytical grouping version 2021-2022 was used to describe regions and countries as high (HIC), upper-middle (UMIC), lower-middle (LoMIC), and low-income (LIC). RESULTS: Across 239 phase III abstracts, lead and senior authors respectively represented HIC institutions in 83% and 85%, UMIC in 13% and 12%, and LoMIC in 4% and 3%. No authors worked in LICs or sub-Saharan Africa. Women accounted for 29% of lead and 23% of senior authors. This distribution persisted across regions, with women as lead authors ranging from 19% (UMIC) to 31% (HIC), and as senior authors from 7% (UMIC) to 25% (HIC). Industry funded 62% of trials, academia 17%, and others 15%; 6% lacked funding. Industry funding was highest in HIC trials (66% for lead and senior authors), followed by UMICs (55% lead, 53% senior) and LoMICs (11% lead, 0% senior). Industry-sponsored trials were proportionally equally represented among female and male senior authors (63% each). CONCLUSION: There is marked intersectionality in leadership of oncology clinical trials presented at the world's largest oncology conference.

Tivozanib plus nivolumab versus tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 Study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors are cornerstones of first-line treatment for advanced renal cell carcinoma; however, optimal treatment sequencing after progression is unknown. This study aimed to assess clinical outcomes of tivozanib-nivolumab versus tivozanib monotherapy in patients with metastatic renal cell carcinoma who have progressed following one or two lines of therapy in the post-ICI setting. METHODS: TiNivo-2 is a multicentre, randomised, open-label, phase 3 trial at 190 sites across 16 countries, in Australia, Europe, North America, and South America. Patients with advanced renal cell carcinoma and progression during or after one to two previous lines of therapy (including one ICI) were randomised 1:1 to tivozanib (0·89 mg per day, orally) plus nivolumab (480 mg every 4 weeks, intravenously) or tivozanib (1·34 mg per day, orally). Randomisation was stratified by immediate previous therapy (ICI or non-ICI) and International Metastatic Renal Cell Carcinoma Database Consortium risk category. The primary endpoint was progression-free survival (PFS), defined as the time from randomisation to first documentation of objective progressive disease according to RECIST 1·1 or death from any cause, whichever came first, by independent radiology review. Efficacy was evaluated in the intention-to-treat population, and safety was assessed in patients who received one or more doses of the study drug. This trial was registered on ClinicalTrials.gov (NCT04987203) and is active and not recruiting. FINDINGS: From Nov 4, 2021, to June 16, 2023, 343 patients were randomly assigned to tivozanib-nivolumab (n=171) or tivozanib monotherapy (n=172). Median follow-up was 12·0 months. Median PFS was 5·7 months (95% CI 4·0-7·4) with tivozanib-nivolumab and 7·4 months (5·6-9·2) with tivozanib monotherapy (hazard ratio 1·10, 95% CI 0·84-1·43; p=0·49). Among those with an ICI as their immediate previous therapy (n=244), median PFS was 7·4 months (95% CI 5·6-9·6) with tivozanib-nivolumab and 9·2 months (7·4-10·0) with tivozanib monotherapy. With non-ICIs as the most recent therapy, lower median PFS was observed, with no difference between groups (tivozanib-nivolumab 3·7 months [95% CI 2·7-5·4] and with tivozanib monotherapy 3·7 months [1·9-7·2]). Serious adverse events occurred in 54 (32%) of 168 patients receiving tivozanib-nivolumab and 64 (37%) of 171 patients receiving tivozanib monotherapy. One (<1%) treatment-related death occurred (tivozanib group). INTERPRETATION: These data further support that ICI rechallenge should be discouraged in patients with advanced renal cell carcinoma. Furthermore, these data suggest that tivozanib monotherapy has efficacy in the post-ICI setting. FUNDING: Aveo Pharmaceuticals.

Real-World Primary Resistance to First-Line Immune-Based Combinations in Patients with Advanced Renal Cell Carcinoma (ARON-1).

BACKGROUND: Therapeutic advancements based on immuno-oncology combinations have revolutionized the management of patients with renal cell carcinoma. However, patients who have progressive disease as the best response, "primary refractory" (Pref), face dismal outcomes. OBJECTIVE: Our multicenter retrospective real-world study aims to assess the prevalence and clinicopathological characteristics of Pref patients. METHODS: This study collected data from 72 centers across 22 countries (1709 patients), involving patients aged ≥18 years with metastatic clear cell renal cell carcinoma. All patients were treated with first-line immune-oncology combinations. Data included patient demographics, histology, metastatic sites, and treatment responses. Radiological assessments followed Response Evaluation Criteria in Solid Tumors version 1.1. Statistical analyses employed Kaplan-Meier method, Cox proportional hazard models, logistic regression, and the receiver operating characteristic curve. RESULTS: In our study, the Pref rate was 19%. Nivolumab/ipilimumab showed the highest Pref rate (27%), while pembrolizumab/lenvatinib exhibited the lowest (10%). Primary refactory patients demonstrated significantly lower median overall survival (7.6 months) compared with non-Pref patients (55.7 months), p < 0.001. At the multivariate analysis, nephrectomy, sarcomatoid de-differentiation, intermediate/poor International Metastatic RCC Database Consortium risk, and bone and brain metastases emerged as significant predictors of overall survival for Pref patients with renal cell carcinoma. Logistic regression showed a significant relationship between liver metastases, intermediate/poor International Metastatic RCC Database Consortium risk, and no surgery and an increased risk of Pref. This study presents limitations, mainly because of its retrospective design. CONCLUSIONS: The ARON-1 study provides valuable insights into Pref patients, emphasizing the challenges of this precociously resistant subgroup. Identified predictors could guide risk stratification, aiding clinicians in tailored therapeutic approaches.

Genomic Landscape in Prostate Cancer in a Latin American Population.

PURPOSE: This study aims to describe genomic characteristics of patients with metastatic prostate cancer (mPC). PATIENTS AND METHODS: This study is a retrospective, multicenter cohort study of patients with mPC and reports on genomic testing. Patients were included from 12 academic centers in five countries. RESULTS: A total of 349 patients with PC were included in this study. Most patients (209, 59.9%) were de novo metastatic. Genomic analysis was performed in 233 (66.6%) patients in the metastatic castration-resistant prostate cancer (mCRPC) setting, and only 115 (32.8%) patients had a tumor evaluation in the metastatic hormone sensitive prostate cancer scenario. The evaluation of somatic and/or germline mutations was performed through multigene panel analyses in 290 (83.09%) patients, and next-generation sequencing of BRCA1 and BRCA2 genes was performed in 59 (16.91%) patients. Analyzing the mCRPC subgroup, with a median follow-up of 15.6 months (IQR, 14-19.06), the median progression-free survival (PFS) was not reached (NR) and the PFS at 16 months was 58.7% (95% CI, 50.8 to 67.8). When comparing patients with BRCA mutations with those who are not BRCA-mutated in the mCRPC scenario, the median PFS was NR (95% CI, 14 to NR) and 26.3 months (95% CI, 16.7 to 36.5; P = .2), respectively. Two of six patients with BRCA mutations were treated with targeted therapies (poly-ADP-ribose polymerase inhibitors). CONCLUSION: Our study, to the best of our knowledge, represents one of the larger data sets for somatic testing in patients with PC in Latin America (LATAM). It adds valuable information to the growing body of knowledge about the genomic landscape of advanced PC in real-world daily practice scenarios in LATAM countries, which are not always well-represented in large-scale randomized clinical trials.

Pembrolizumab in Patients with Advanced Urothelial Carcinoma with ECOG Performance Status 2: A Real-World Study from the ARON-2 Project.

BACKGROUND: The benefit of immune checkpoint inhibitors (ICIs) for poor performance status patients with advanced urothelial carcinoma (UC) remains unknown. OBJECTIVE: In the present sub-analysis of the ARON-2 study, we investigated the role of pembrolizumab for advanced UC patients with ECOG (Eastern Cooperative Oncology Group) performance status (ECOG-PS) 2. PATIENTS AND METHODS: Patients aged ≥ 18 years with a cytologically and/or histologically confirmed diagnosis of advanced UC progressing or recurring after platinum-based therapy and treated with pembrolizumab between 1 January 2016 to 1 April 2024 were included. In this sub-analysis we focused on patients with ECOG-PS 2. RESULTS: We included 1,040 patients from the ARON-2 dataset; of these, 167 patients (16%) presented an ECOG-PS 2. The median overall survival (OS) was 14.8 months (95% confidence interval (CI) 12.5-16.1) in the overall study population, 18.2 months (95% CI 15.8-22.2) in patients with ECOG-PS 0-1, and 3.7 months (95% CI 3.2-5.2) in subjects with ECOG-PS 2 (p < 0.001). The median progression-free survival (PFS) in the overall study population was 5.3 months (95% CI 4.3-97.1), 6.2 months (95% CI 5.5-97.1) in patients with ECOG-PS 0-1, and 2.8 months (95% CI 2.1-3.4) in patients with ECOG-PS 2. Among the latter, liver metastases and progressive disease during first-line therapy were significant predictors of OS at both univariate and multivariate analyses. For PFS, univariate and multivariate analyses showed a prognostic role for lung metastases, liver metastases, and progressive disease during first-line therapy. CONCLUSIONS: This large real-world evidence study suggests the effectiveness of second-line pembrolizumab for mUC patients with poor performance status. The presence of liver metastases and progressive disease during first-line therapy is associated with worse clinical outcomes and, thus, should be taken into account when making treatment decisions in clinical practice.

Sex and survival outcomes in patients with renal cell carcinoma receiving first-line immune-based combinations.

BACKGROUND: There is an ongoing debate as to whether sex could be associated with immune checkpoint inhibitor (ICI) benefit. Existing literature data reveal contradictory results, and data on first-line immune combinations are lacking. METHOD: This was a real-world, multicenter, international, observational study to determine the sex effects on the clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with immuno-oncology combinations as first-line therapy. RESULTS: A total of 1827 mRCC patients from 71 cancer centers in 21 countries were included. The median OS was 38.7 months (95% CI 32.7-44.2) in the overall study population: 40.0 months (95% CI 32.7-51.6) in males and 38.7 months (95% CI 26.4-41.0) in females (p = 0.202). The median OS was higher in males vs. females in patients aged 18-49y (36.9 months, 95% CI 29.0-51.6, vs. 24.8 months, 95% CI 16.8-40.4, p = 0.426, with + 19% of 2y-OS rate, 72% vs. 53%, p = 0.006), in the clear cell histology subgroup (44.2 months, 95% CI 35.8-55.7, vs. 38.7 months, 95% CI 26.0-41.0, p = 0.047), and in patients with sarcomatoid differentiation (34.4 months, 95% CI 26.4-59.0, vs. 15.3 months, 95% CI 8.9-41.0, p < 0.001). Sex female was an independent negative prognostic factor in the sarcomatoid population (HR 1.72, 95% CI 1.15 - 2.57, p = 0.008). CONCLUSIONS: Although the female's innate and adaptive immunity has been observed to be more active than the male's, women in the subgroup of clear cell histology, sarcomatoid differentiation, and those under 50 years of age showed shorter OS than males.

Differences in the expression of the phosphatase PTP-1B in patients with localized prostate cancer with and without adverse pathological features.

Introduction: Patients with adverse pathological features (APF) at radical prostatectomy (RP) for prostate cancer (PC) are candidates for adjuvant treatment. Clinicians lack reliable markers to predict these APF preoperatively. Protein tyrosine phosphatase 1B (PTP-1B) is involved in migration and invasion of PC, and its expression could predict presence of APF. Our aim was to compare PTP-1B expression in patients with and without APF, and to explore PTP-1B expression as an independent prognostic factor. Methods: Tissue microarrays (TMAs) were constructed using RP archival specimens for immunohistochemical staining of PTP-1B; expression was reported with a standardized score (0-9). We compared median PTP-1B score between cases with and without APF. We constructed two logistic regression models, one to identify the independence of PTP-1B score from biologically associated variables (metformin use and type 2 diabetes mellitus [T2DM]) and the second to seek independence of known risk factors (Gleason score and prostate specific antigen [PSA]). Results: A total of 73 specimens were suitable for TMA construction. Forty-four (60%) patients had APF. The median PTP-1B score was higher in those with APF: 8 (5-9) vs 5 (3-8) (p=0.026). In the logistic regression model including T2DM and metformin use, the PTP-1B score maintained statistical significance (OR 1.21, 95% CI 1.01-1.45, p=0.037). In the model including PSA and Gleason score; the PTP-1B score showed no independence (OR 1.68, 95% CI 0.97-1.41, p=0.11). The area under the curve to predict APF for the PTP-1B score was 0.65 (95% CI 0.52-0.78, p=0.03), for PSA+Gleason 0.71 (95% CI 0.59-0.82, p=0.03), and for PSA+Gleason+PTP-1B score 0.73 (95% CI 0.61-0.84, p=0.001). Discussion: Patients with APF after RP have a higher expression of PTP-1B than those without APF, even after adjusting for T2DM and metformin exposure. PTP-1B has a good accuracy for predicting APF but does not add to known prognostic factors.

Envisioning Academic Global Oncologists: Proposed Competencies for Global Oncology Training From ASCO.

Recognizing the rising incidence, prevalence, and mortality of cancer in low- and middle-resource settings, as well as the increasingly international profile of its membership, ASCO has committed to expanding its engagement at a global level. In 2017, the ASCO Academic Global Oncology Task Force sought to define the potential role for ASCO in supporting global oncology as an academic field. A set of recommendations to advance the status of global oncology as an academic discipline were created through a consensus-based process involving participation by a diverse group of global oncology and global health practitioners; these recommendations were then published. The recommendations included developing a set of global oncology competencies for trainees and faculty interested in a career in academic global oncology. Here, we describe the global oncology competencies developed by this task force. These competencies consist of knowledge and skills needed in general global health as well as cancer-specific care and research, including understanding global cancer health disparities, defining unique resources and needs in low- and middle-resource settings, and promoting international collaboration. Although the competencies were originally developed for US training programs, they are intended to be widely applicable globally. By formalizing the training of oncologists and supporting career pathways in the field of global oncology, we can make progress in achieving global equity in cancer care and control.

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.

Efficacy of immune checkpoint inhibitors combinations as first-line systemic treatment in patients with advanced urothelial carcinoma: A systematic review and network meta-analysis.

BACKGROUND: Combinations of immune checkpoint inhibitors (ICI) with platinum-based chemotherapy (PlatinumCT) or with another ICI in the first-line setting for patients with metastatic urothelial carcinoma (mUC) have mixed results. METHODS: Records were searched electronically from January 2019 to January 2024. A meta-analysis was performed to evaluate OS, progression-free survival (PFS), and overall response rate (ORR). RESULTS: Immune-based combinations were associated with an OS (HR: 0.75; 95% CI: 0.61-0.92; p < 0.001; I2= 84.1%) and PFS benefit in the intention-to-treat population (HR: 0.67; 95%CI: 0.51-0.89; p < 0.001; I2 = 89.7%). There was no ORR improvement with immune-based combinations (HR: 1.36; 95% CI:0.84-2.20; p < 0.001; I2 = 92.6%). CONCLUSION: This systematic review and study-level meta-analysis demonstrated that the immune-based combinations in first-line treatment for patients with mUC are associated with survival benefit.

Development of PARP inhibitors in advanced prostate cancer.

The relatively high prevalence of alterations in the homologous recombination repair (HRR) pathway described in advanced prostate cancer provides a unique opportunity to develop therapeutic strategies that take advantage of the decreased tumor ability to repair DNA damage. Poly ADP-ribose polymerase (PARP) inhibitors have been demonstrated to improve the outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients with HRR defects, particularly in those with BRCA1/2 alterations. To expand the benefit of PARPi to patients without detectable HRR alterations, multiple studies are addressing potential synergies between PARP inhibition (PARPi) and androgen receptor pathway inhibitors (ARSi), radiation, radioligand therapy, chemotherapy, or immunotherapy, and these strategies are also being evaluated in the hormone-sensitive setting. In this review, we summarize the development of PARPi in prostate cancer, the potential synergies, and combinations being investigated as well as the future directions of PARPi for the management of the disease.

Development of PARP inhibitors in advanced prostate cancer Alterations in the mechanisms responsible for repairing damaged DNA are frequently altered in advanced prostate cancer. This provides a unique opportunity to develop therapies that exploit the decreased ability of these prostate tumours to repair DNA. Poly ADP-ribose polymerase (PARP) inhibitors have been successfully used to treat other tumor types with similar deficiencies and recently, multiple studies have demonstrated its efficacy also in prostate cancer, particularly in tumors with BRCA1/2 alterations. To expand the benefit of PARPi to patients without detectable DNA repair alterations, multiple studies are addressing potential synergies between PARP inhibition (PARPi) and androgen receptor pathway inhibitors (ARSi), radiation, radiopharmaceuticals, chemotherapy and immunotherapy in different disease stages. In this review, we summarize the development of PARPi in prostate cancer, the potential synergies and combinations being evaluated as well as the future directions of PARPi for the management of the disease.

Management of Metastatic Urothelial Carcinoma in Emerging Markets (EM): An Expert Opinion.

Urothelial carcinoma (UC) is the 10th most common cancer globally with an almost 4 times higher prevalence in men. The main risk factors for development of urothelial carcinoma are advanced age, smoking, arsenic contamination, exposure to carcinogens. Metastatic urothelial carcinoma (mUC) has overall poor prognosis with a 5-year overall survival rate of only < 5%. The standard of care comprises of platinum-based chemotherapy, but the responses are often not sustained. A working group was established with an objective to discuss the most recent clinical data on the genitourinary tumors of interest and comprised of experts across Latin America, Emerging Asia (except China, Japan, and South Korea), Africa, and the Middle East (known as Emerging Markets or EM). There is an evident disparity in terms of uneven mortality and incidence rate distribution among various regions. There is a lack and/or insufficient data on epidemiology, treatment, and outcomes in the EM. The lack of registries impacts the healthcare decisions and the lower incidence from the region might not be reflective of the true disease burden. The treatment outcomes of mUC can be improved by understanding the current disease burden and treatment approach of mUC and identifying the gaps and challenges associated with management. Hence, a literature review was developed to summarize the current disease burden and treatment approach of mUC across EM. The review also highlights the unmet needs for mUC management in EM and suggests a way forward to improve the current situation in order to better serve the patients.

Latin American Consensus for the Evaluation and Treatment of Patients With Metastatic/Locally Advanced Urothelial Carcinoma.

PURPOSE: Urothelial cancer accounts for approximately 3% of new cancer cases worldwide, with a high burden of disease in countries with medium and low human development indexes where its incidence and mortality are increasing. The purpose of this consensus is to develop statements on the evaluation and treatment of locally advanced and metastatic urothelial carcinoma that would further guide the clinical practice in Latin America. METHODS: A systematic review of the literature was conducted by an independent team of methodologists. Then, a modified Delphi method was developed with clinical specialists from different Latin American countries. RESULTS: Forty-two consensus statements, based on evidence, were developed to address the staging, the evaluation (suitability for chemotherapy, risk assessment, and biomarkers), and systemic treatment (first-line and subsequent therapies) of locally advanced or metastatic urothelial carcinoma. The statements made in this consensus are suggested practice recommendations in the Latin American context; however, the importance of a complete and individualized patient evaluation as a guide for therapeutic selection is highlighted. The availability and affordability of support tools for the evaluation of the disease, as well as specific therapies, may limit the application of the best practices suggested. RECOMMENDATIONS: Therapeutic decisions need to be tailored to the context-specific clinical setting and availability of resources. Local research is promoted to improve outcomes for patients with this challenging cancer in Latin America.

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?

BACKGROUND: Renal c carcinoma (RCC) is one of the most common urinary cancers worldwide, with a predicted increase in incidence in the coming years. Immunotherapy, as a single agent, in doublets, or in combination with anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs), has rapidly become a cornerstone of the RCC therapeutic scenario, but no head-to-head comparisons have been made. In this setting, real-world evidence emerges as a cornerstone to guide clinical decisions. OBJECTIVE: The objective of this retrospective study was to assess the outcome of patients treated with first-line immune combinations or immune oncology (IO)-TKIs for advanced RCC. DESIGN, SETTING, AND PARTICIPANTS: Data from 930 patients, 654 intermediate risk and 276 poor risk, were collected retrospectively from 58 centers in 20 countries. Special data such as sarcomatoid differentiation, body mass index, prior nephrectomy, and metastatic localization, in addition to biochemical data such as hemoglobin, platelets, calcium, lactate dehydrogenase, neutrophils, and radiological response by investigator's criteria, were collected. 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 calculated by the inverse Kaplan-Meier method. RESULTS AND LIMITATIONS: The median follow-up time was 18.7 mo. In the 654 intermediate-risk patients, the median OS and PFS were significantly longer in patients with the intermediate than in those with the poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria (38.9 vs 17.3 mo, 95% confidence interval [CI] p < 0.001, and 17.3 vs 11.6 mo, 95% CI p < 0.001, respectively). In the intermediate-risk subgroup, the OS was 55.7 mo (95% CI 31.4-55.7) and 40.2 mo (95% CI 29.6-51.6) in patients treated with IO + TKI and IO + IO combinations, respectively (p = 0.047). PFS was 30.7 mo (95% CI 16.5-55.7) and 13.2 mo (95% CI 29.6-51.6) in intermediate-risk patients treated with IO + TKI and IO + IO combinations, respectively (p < 0.001). In the poor-risk subgroup, the median OS and PFS did not show a statistically significant difference between IO + IO and IO + TKI. Our study presents several limitations, mainly due to its retrospective nature. CONCLUSIONS: Our results showed differences between the IO + TKI and IO + IO combinations in intermediate-risk patients. A clear association with longer PFS and OS in favor of patients who received the IO + TKI combinations compared with the IO-IO combination was observed. Instead, in the poor-risk group, we observed no significant difference in PFS or OS between patients who received different combinations. PATIENT SUMMARY: Renal cancer is one of the most frequent genitourinary tumors. Treatment is currently based on immunotherapy combinations or immunotherapy with tyrosine kinase inhibitors, but there are no comparisons between these.In this study, we have analyzed the clinical course of 930 patients from 58 centers in 20 countries around the world. We aimed to analyze the differences between the two main treatment strategies, combination of two immunotherapies versus immunotherapy + antiangiogenic therapy, and found in real-life data that intermediate-risk patients (approximately 60% of patients with metastatic renal cancer) seem to benefit more from the combination of immunotherapy + antiangiogenic therapy than from double immunotherapy. No such differences were found in poor-risk patients. This may have important implications in daily practice decision-making for these patients.

Systemic Immune-Inflammation Index in Patients Treated With First-Line Immune Combinations for Metastatic Renal Cell Carcinoma: Insights From the ARON-1 Study.

BACKGROUND: Systemic treatment with immune combinations is the gold standard for metastatic renal cell carcinoma (mRCC) worldwide. The systemic immune-inflammation index (SII) is a prognostic marker for several types of malignant neoplasms, including mRCC, in the era of tyrosine kinase inhibitor (TKI) treatment. Data regarding the prognostic value of the SII in patients with mRCC treated with immunotherapy are scarce and controversial.  METHODS: We retrospectively collected the data of patients with mRCC from 56 centers in 18 countries. SII (Platelet × Neutrophil/Lymphocyte count) was calculated prior to the first systemic treatment and cut-off was defined by a survival receiver operating characteristic (ROC) analysis. The primary objective of our retrospective study was to assess the outcomes of patients treated with first-line immunotherapy.  RESULTS: Data from 1034 mRCC patients was collected and included in this analysis. The SII cut-off value was 1265. After a follow-up of 26.7 months, and the overall survival (OS) and progression-free survival (PFS) were 39.8 and 15.7 months, respectively. According to SII (low vs. high), patients with low-SII had longer OS (55.7 vs. 22.2 months, P < .001), better PFS (20.8 vs. 8.5 months, P < .001), and higher overall response rate (52 vs. 37%, P = .033). CONCLUSION: A high SII is associated with poor oncological outcomes in patients with mRCC. SII could be an easily accessible prognostic indicator for use in clinical practice.

Impact of healthcare inequities on survival in Mexican patients with metastatic renal cell carcinoma.

Introduction: The survival of patients with metastatic renal cell carcinoma (mRCC) has improved dramatically due to novel systemic treatments. However, mRCC mortality continues to rise in Latin America. Methods: A retrospective, multicenter study of patients diagnosed with mRCC between 2010-2018 in Mexico City was conducted. The aim of the study was to evaluate the impact of healthcare insurance on access to treatment and survival in patients with mRCC. Results: Among 924 patients, 55.4%, 42.6%, and 1.9% had no insurance (NI), social security, (SS) and private insurance (PI), respectively. De novo metastatic disease was more common in NI patients (70.9%) compared to SS (47.2%) and PI (55.6%) patients (p<0.001). According to IMDC Prognostic Index, 20.2% were classified as favorable, 49% as intermediate, and 30.8% as poor-risk disease. Access to systemic treatment differed by healthcare insurance: 36.1%, 99.5%, and 100% for the NI, SS, and PI patients, respectively (p<0.001). NI patients received fewer lines of treatment, with 24.8% receiving only one line of treatment (p<0.001). Median overall survival (OS) was 13.9 months for NI, 98.9 months for SS, and 147.6 months for NI patients (p<0.001). In multivariate analysis, NI status, brain metastases, sarcomatoid features, bone metastases, no treatment were significantly associated with worse OS. Conclusion: OS in mRCC was affected by insurance availability in this resource-limited cohort of Mexican patients. These results underscore the need for effective strategies to achieve equitable healthcare access in an era of effective, yet costly systemic treatments.

Geographical differences in the management of metastatic de novo renal cell carcinoma in the era of immune-combinations.

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.