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).

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.

Low-grade myofibrosarcoma of the maxillary sinus: Two case reports.

BACKGROUND: Low-grade myofibroblastic sarcoma (LGMS) is an extremely rare tumor characterized by the malignant proliferation of myofibroblasts. LGMS most commonly develops in adults, predominantly in males, in the head and neck region, oral cavity, especially on the tongue, mandible, and larynx. This article presents 2 cases of LGMS localized to the maxillary sinus and provides an overview of the available literature. CASE SUMMARY: Two patients with LGMS located in the maxillary sinus underwent surgery at the Department of Head and Neck Surgery. Case 1: A 46-year-old patient was admitted to the clinic with suspected LGMS recurrence in the right maxillary sinus (rT4aN0M0), with symptoms of pain in the suborbital area, watering of the right eye, thick discharge from the right nostril, and augmented facial asymmetry. After open biopsy-confirmed LGMS, the patient underwent expanded maxillectomy of the right side with immediate palate reconstruction using a microvascular skin flap harvested surgically from the middle arm. The patient qualified for adjuvant radiotherapy for the postoperative bed, with an additional margin. Currently, the patient is under 1.5 years of observation with no evidence of disease. Case 2: A 45-year-old man was admitted to our clinic with facial asymmetry, strabismus, exophthalmos, and visual impairment in the right eye. Six months earlier, the patient had undergone partial jaw resection at another hospital for fibromatosis. A contrast-enhanced computed tomography scan revealed a tumor mass in the postoperative log after an earlier procedure. An open biopsy confirmed low-grade fibrosarcoma (rT4aN0M0). The patient qualified for an extended total right maxillectomy with orbital excision and right hemimandibulectomy with immediate microvascular reconstruction using an anterolateral thigh flap. The patient subsequently underwent adjuvant radiotherapy to the postoperative area. After 9 months, recurrence occurred in the right mandibular arch below the irradiated area. The lesion infiltrated the base of the skull, which warranted the withdrawal of radiotherapy and salvage surgery. The patient qualified for palliative chemotherapy with a regimen of doxorubicin + dacarbazine + cyclophosphamide and palliative radiotherapy for bone metastases. The patient died 26 months after surgical treatment. The cases have been assessed and compared with cases in the literature. CONCLUSION: No specific diagnostic criteria or treatment strategies have been developed for LGMS. The treatment used for LGMS is the same as that used for sinonasal cancer radical tumor excision; adjuvant radiotherapy or chemoradiotherapy should also be considered. They have low malignant potential but are highly invasive, tend to recur, and metastasize to distant sites. Patients should undergo regular follow-up examinations to detect recurrence or metastasis at an early stage. Patients should be treated and observed at the highest referral centers.

Global real-world experiences with pembrolizumab in advanced urothelial carcinoma after platinum-based chemotherapy: the ARON-2 study.

BACKGROUND: Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy. PATIENTS AND METHODS: Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors. RESULTS: In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1-2 or 3-4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (p < 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (p < 0.001). CONCLUSIONS: Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy.

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.

Analysis of Factors Contributing to Adverse Events and Evaluation of Their Impact on Prognosis in Metastatic Renal Cell Carcinoma Patients-Real-World Experience in a Single-Center Retrospective Study and Narrative Review.

Background and Objectives: More than 430,000 new cases of renal cell carcinoma (RCC) were reported in 2020. Clear cell RCC, which occurs in 80% of cases, is often associated with mutations in the VHL gene, leading to dysregulation of hypoxia-induced transcription factors pathways and carcinogenesis. The purpose of this study is to examine the adverse events (AEs) of cabozantinib treatment and the relationship between individual patient factors and the frequency of their occurrence in detail. Materials and Methods: Seventy-one patients with metastatic RCC were treated with second or further lines of cabozantinib at the Department of Genitourinary Oncology, Maria Sklodowska-Curie National Research Institute of Oncology. Comprehensive data, including demographics, clinicopathological factors, and AEs, were collected from January 2017 to June 2021. This study evaluated the impact of various patient-related factors on the rate of adverse events and treatment tolerance using a Cox proportional hazards model. Results: Cabozantinib-induced AEs were significantly associated with body mass index (BMI), body surface area (BSA), IMDC prognostic score, and treatment line. Notably, patients receiving cabozantinib post-tyrosine kinase inhibitors reported fewer AEs. Dose reduction was unrelated to adverse event frequency, but patients requiring dose reduction were characterized with lower body mass and BSA but not BMI. Conclusions: The factors described make it possible to predict the incidence of AEs, which allows for faster detection and easier management, especially in the high-risk group. AEs should be reported in detail in real-world studies, as their occurrence has a significant impact on prognosis.

Adverse Events of Cabozantinib as a Potential Prognostic Factor in Metastatic Renal Cell Carcinoma Patients: Real-World Experience in a Single-Center Retrospective Study.

Cabozantinib, an oral inhibitor targeting MET, AXL, and VEGF receptors, has become a key component of a sequential treatment strategy for clear cell renal cell carcinoma (ccRCC). The purpose of this work is to show that effective management of adverse events (AEs) during cabozantinib treatment and achieving a balance between AEs and treatment efficacy is crucial to achieving therapeutic goals. In this retrospective study, involving seventy-one metastatic RCC (mRCC) patients receiving second or subsequent lines of cabozantinib at the Department of Genitourinary Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, we explored the impact of AEs on overall survival (OS) and progression-free survival (PFS). AEs were observed in 92% of patients. Hypothyroidism during treatment was significantly associated with prolonged OS and PFS (HR: 0.31; p < 0.001 and HR: 0.34; p < 0.001, respectively). The occurrence of hand-foot syndrome (HFS) was also linked to improved OS (HR: 0.46; p = 0.021). Patients experiencing multiple AEs demonstrated superior OS and PFS compared to those with one or no AEs (HR: 0.36; p < 0.001 and HR: 0.30; p < 0.001, respectively). Hypothyroidism and HFS serve as valuable predictive factors during cabozantinib treatment in ccRCC patients, indicating a more favorable prognosis.

High FLT3 expression increases immune-cell infiltration in the tumor microenvironment and correlates with prolonged disease-free survival in patients with non-small cell lung cancer.

Most of the currently used cancer immunotherapies inhibit the programmed cell death protein 1 (PD1)-programmed cell death 1 ligand 1 (PDL1) axis of T-cells. However, dendritic cells (DCs) controlled by natural killer (NK) cells via the FMS-related tyrosine kinase 3 (FLT3) axis are necessary for activation of T-cells. The aim of the study was to evaluate FLT3 as a prognostic factor and determine its role in immune infiltration (with emphasis on NK cells and DCs). Using The Cancer Genome Atlas (TCGA) database, we performed bioinformatic analysis of the gene expression datasets of 501 lung squamous cell carcinoma (LUSC) and 515 lung adenocarcinoma (LUAD) patient who had corresponding clinical data [analysis was performed in R (version 4.2.0)]. Disease-free survival (DFS) differed between the FLT3-low and FLT3-high expression groups, respectively, in LUSC (61.0 vs 71.3 months P = 0.075) and LUAD (32.7 vs 47.5 months P = 0.045). A tumor microenvironment (TME) with high immune infiltration and rich in T-cell exhaustion markers was observed in the FLT3-high group. We showed overexpression of NK cell and DC gene signatures in the FLT3-high expression group as well as overexpression of key effector genes of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes protein (STING) pathway, which is crucial in response to radiotherapy. High expression of FLT3 in the TME was associated with immune cell infiltration (especially of NK cells and DCs), increased expression of T-cell exhaustion markers and expression of effector genes of the cGAS-STING pathway, which may consequently increase susceptibility to immunotherapy and radiotherapy. High FLT3 expression correlated with prolonged DFS in the LUSC and LUAD cohorts.

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.

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.

Bone targeting agents, but not radiation therapy, improves survival in patients with bone metastases from advanced urothelial carcinoma receiving pembrolizumab: results from the ARON-2 study.

The ARON-2 study (NCT05290038) aimed to assess the real-world efficacy of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy. This retrospective analysis reports the outcomes of urothelial carcinoma (UC) patients with bone metastases (BM). Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were reviewed from60 institutions in 20 countries. Patients were assessed for Overall Response Rate (ORR), Progression-Free Survival (PFS), and Overall Survival (OS). Univariate and multivariate analyses were used to explore the association of variables of interest with OS and PFS. 881 patients were included; of them, 263 (30%) presented BM. Median follow-up time was 22.7 months. Patients with BM showed both shorter median OS (5.9 months vs 13.1 months, p < 0.001) and PFS (3.5 months, vs 7.3 months, p < 0.001) compared to patients without BM. Patients who received bone targeted agents (BTAs) showed a significantly longer median OS (8.5 months vs 4.6 months, p = 0.003) and PFS (6.1 months vs 3.2 months, p = 0.003), while no survival benefits were observed among patients who received radiation therapy for BM during pembrolizumab treatment compared to those who did not. In multivariate analysis, performance status, concomitant liver metastases, and the lack of use of BTAs were significantly associated with worse OS and PFS. Bone involvement in UC patients treated with pembrolizumab predicts inferior survival. Poor performance status and liver metastases may further worsen outcomes, while the use of BTAs is associated with improved outcomes.

Use of concomitant proton pump inhibitors, statins or metformin in patients treated with pembrolizumab for metastatic urothelial carcinoma: data from the ARON-2 retrospective study.

BACKGROUND: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. METHODS: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. RESULTS: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. CONCLUSIONS: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.

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.

Global Real-World Outcomes of Patients Receiving Immuno-Oncology Combinations for Advanced Renal Cell Carcinoma: The ARON-1 Study.

BACKGROUND: Immuno-oncology combinations have achieved survival benefits in patients with metastatic renal cell carcinoma (mRCC). OBJECTIVE: The ARON-1 study (NCT05287464) was designed to globally collect real-world data on the use of immuno-combinations as first-line therapy for mRCC patients. PATIENTS AND METHODS: Patients aged ≥ 18 years with a cytologically and/or histologically confirmed diagnosis of mRCC treated with first-line immuno-combination therapies were retrospectively included from 47 International Institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall clinical benefit (OCB). RESULTS: A total of 729 patients were included; tumor histology was clear-cell RCC in 86% of cases; 313 patients received dual immuno-oncology (IO + IO) therapy while 416 were treated with IO-tyrosine kinase inhibitor (IO + TKI) combinations. In the overall study population, the median OS and PFS were 36.5 and 15.0 months, respectively. The median OS was longer with IO+TKI compared with IO+IO therapy in the 616 patients with intermediate/poor International mRCC Database Consortium (IMDC) risk criteria (55.7 vs 29.7 months; p = 0.045). OCB was 84% for IO+TKI and 72% for IO + IO combination (p < 0.001). CONCLUSIONS: Our study may suggest that immuno-oncology combinations are effective as first-line therapy in the mRCC real-world context, showing outcome differences between IO + IO and IO + TKI combinations in mRCC subpopulations. CLINICAL TRIAL REGISTRATION: NCT05287464.

Real-world effectiveness of pembrolizumab as first-line therapy for cisplatin-ineligible patients with advanced urothelial carcinoma: the ARON-2 study.

BACKGROUND: The advent of immune-checkpoint inhibitors has challenged previous treatment paradigms for advanced urothelial carcinoma (UC) in the post-platinum setting as well as in the first-line setting for cisplatin-ineligible patients. In this study, we investigated the effectiveness of pembrolizumab as first-line treatment for cisplatin-ineligible UC. METHODS: Data from patients aged ≥ 18 years with cisplatin-ineligible UC and receiving first-line pembrolizumab from January 1st 2017 to September 1st 2022 were collected. Cisplatin ineligibility was defined according to the Galsky criteria. Thirty-three Institutions from 18 countries were involved in the ARON-2 study. RESULTS: Our analysis included 162 patients. The median follow-up time was 18.9 months (95%CI 15.3-76.9). In the overall study population, the median OS was 15.8 months (95%CI 11.3-32.4). The median OS was significantly longer in males versus females while no statistically significant differences were observed between patients aged < 65y versus ≥ 65y and between smokers and non-smokers. According to Recist 1.1 criteria, 26 patients (16%) experienced CR, 32 (20%) PR, 39 (24%) SD and 55 (34%) PD. CONCLUSIONS: Our data confirm the role of pembrolizumab as first-line therapy for cisplatin-unfit patients. Further studies investigating the biological and immunological characteristics of UC patients are warranted in order to optimize the outcome of patients receiving immunotherapy in this setting.

Clinico-Pathological Features Influencing the Prognostic Role of Body Mass Index in Patients With Advanced Renal Cell Carcinoma Treated by Immuno-Oncology Combinations (ARON-1).

BACKGROUND: Obesity has been associated with improved response to immunotherapy in cancer patients. We investigated the role of body mass index (BMI) in patients from the ARON-1 study (NCT05287464) treated by dual immuno-oncology agents (IO+IO) or a combination of immuno-oncology drug and a tyrosine kinase inhibitors (TKI) as first-line therapy for metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Medical records of patients with documented mRCC treated by immuno-oncology combinations were reviewed at 47 institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (OS), and overall clinical benefit (OCB), defined as the sum of the rate of partial/complete responses and stable disease. Univariate and multivariate analyses were used to explore the association of variables of interest with survival. RESULTS: A total of 675 patients were included; BMI was >25 kg/m2 in 345 patients (51%) and was associated with improved OS (55.7 vs. 28.4 months, P < .001). The OCB of patients with BMI >25 kg/m2 versus those with BMI ≤25 kg/m2 was significantly higher only in patients with nonclear cell histology (81% vs. 65%, P = .011), and patients with liver metastases (76% vs. 58%, P = .007), Neutrophil to lymphocyte ratio >4 (77% vs 62%, P = .022) or treated by nivolumab plus ipilimumab (77% vs. 64%, P = .044). In the BMI ≤25 kg/m2 subgroup, significant differences were found between patients with NLR >4 versus ≤4 (62% vs. 82%, P = .002) and patients treated by IO+IO versus IO+TKIs combinations (64% vs. 83%, P = .002). CONCLUSION: Our study suggests that the prognostic significance and the association of BMI with treatment outcome varies across clinico-pathological mRCC subgroups.

Complete remissions following immunotherapy or immuno-oncology combinations in cancer patients: the MOUSEION-03 meta-analysis.

BACKGROUND: Immunotherapy has determined unprecedented long-term responses in several hematological and solid tumors. In the MOUSEION-03 study, we conducted a meta-analysis to determine the possibility of achieving complete remissions (CR) with immunotherapy or immuno-oncology combinations in cancer patients. METHODS: The primary endpoint was to assess the incidence of CR in cancer patients receiving immune checkpoint inhibitors (ICIs) alone or in combination with other agents versus control treatments. The pooled odds ratio (OR) and 95% confidence interval (CI) for CR rate were extracted. RESULTS: A total of 12,130 potentially relevant trials were identified; 5 phase II and 80 phase III randomized studies (37 monotherapies and 48 combinations) and 49,425 cancer patients were included. The most frequent types of malignancies were non-small cell lung cancer (n = 14,249; 29%), urothelial cancer (n = 6536; 13%), renal cell carcinoma (n = 5743; 12%), and melanoma (n = 2904; 6%). In patients treated with immunotherapy (as monotherapy or in combination with other anticancer agents), the pooled OR was 1.67 (1.52-1.84). The highest OR was registered by immune-based combinations with two ICIs (3.56, 95% CI 1.28-9.90). CONCLUSIONS: To the best of the authors' knowledge, no comprehensive meta-analysis on the use of ICIs and ICI-based combinations in solid tumors to systematically investigate the probability to achieve CR has been published so far. Although CR is not a common event in several cancer patients receiving immunotherapy, the MOUSEION-03 suggests that the use of ICIs may significantly increase the chance of achieving CR in comparison with control treatments.

Mixed epithelial and stromal tumor of the kidney: A case report.

Mixed epithelial and stromal tumor (MEST) is a rare neoplasm of the kidney, affecting mostly women at menopausal age. While few cases of malignant transformation have been described in the literature, MEST is usually considered a benign tumor with minimal risk of local recurrence or distance metastases. The current study presents a case of a 18-year old male patient with a cystic tumor of the left kidney incidentally diagnosed on magnetic resonance imaging of the heart performed for other reasons. The patient underwent a partial nephrectomy, with perioperative course being uneventful. The pathology report revealed MEST of the kidney. No local recurrence nor disease progression have been observed in the patient during the one-year follow-up period. The present case report is evidence that may help in developing guidelines on the management of patients with benign renal masses.

Prognostic value of pan-immune-inflammation value and body mass index in geriatric patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors as first line treatment. A single-center retrospective study.

Introduction: Geriatric patients with metastatic renal cell carcinoma (mRCC) are underrepresented in clinical trials. Evaluation of the efficacy of the treatment and assignation of individuals to proper prognostic groups is an absolute necessity to guarantee them the best possible care. Material and methods: A total of 138 geriatric patients with mRCC treated with first-line tyrosine kinase inhibitors (TKIs) at the Maria Sklodowska-Curie National Research Institute of Oncology were retrospectively analyzed to determine whether the body mass index (BMI) and pan-immune-inflammation value (PIV) are prognostic values for overall survival (OS) and progression-free survival (PFS) in this type of cancer. For this purpose, Cox's proportional hazard model was used. Results: The median duration of follow-up for surviving patients was 46.6 (95% CI: 17.4-75.8) months. The median OS and PFS were respectively 33.8 months (95% CI: 23.8-47.8) and 19.1 months (95% CI: 15.0-23.3). BMI (p = 0.034) and PIV (p < 0.001) were statistically significantly associated with OS, and PIV (p = 0.001) was statistically significantly associated with PFS. The risk of death for patients from the high-PIV group (cut-off point: 548) was 3.4 times higher than for those with lower PIV values. The corresponding risk of progression for patients from the high-PIV group was 2.2 times higher. The G8 geriatric screening tool was not identified as a prognostic factor. Conclusions: Lower PIV and obesity are associated with longer OS in geriatric mRCC patients treated with TKIs in the first line. These factors may be considered while making treatment decisions if further studies show the same results.

First experience in treating advanced urothelial cancer with enfortumab vedotin. Single-centre retrospective study of patients qualified for a rescue access procedure.

Introduction: Urothelial carcinoma is the most common type of urinary tract malignancy. Current treatment options, including platinum-based chemotherapy or immunotherapy, present significant challenges, ranging from limited efficacy to severe toxicities. Recent developments in antibody-drug conjugates (ADC), such as enfortumab vedotin (EV), promise to significantly improve overall survival. The study aims to evaluate the efficacy and tolerability of EV. In addition, we highlight the observed benefits of next-line treatment after progression. Material and methods: This retrospective study involved 16 patients with advanced urothelial cancer treated with EV at the Department of Genitourinary Oncology, Maria Sklodowska- Curie National Research Institute of Oncology between November 2022 and November 2023. The study evaluated patients' medical history, response to EV treatment, and side effects. Notably, the study included patients who had already exhausted standard treatment options and who were treated with EV through a rescue access procedure. Results: Partial response was observed in 4 out of 9 (44%) patients with available imaging. Common terminology criteria for adverse events (AE) grade 3 and 4 were observed in 3 out of 16 patients, which subsequently required dose reduction. Conclusions: Enfortumab vedotin demonstrates effectiveness in real-world settings in treating advanced urothelial cancer. Proper management of AE in experienced centres may further prolong survival. Personalized treatment and the development of new ADC represent the future for improved patient outcomes.

Activity of cabozantinib in further line treatment of metastatic clear cell renal cell carcinoma. Real-world experience in a single-center retrospective study.

Introduction: Cabozantinib is an oral inhibitor of MET, AXL, and vascular endothelial growth factor receptors. It has an immunomodulatory effect and may influence the tumor's microenvironment and make mutated cells more sensitive to immune-mediated killing. These properties have made cabozantinib an effective drug for first-line or subsequent-line treatment after progression of metastatic renal cell carcinoma (mRCC), even after immunotherapy. Material and methods: Seventy-one patients with mRCC were treated with second or further lines of cabozantinib at the Department of Genitourinary Oncology, Maria Sklodowska-Curie National Research Institute of Oncology. This study retrospectively evaluated the effectiveness of cabozantinib in subsequent lines of treatment. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints. The best overall response (BOR) to cabozantinib was the secondary endpoint. For this purpose, Cox's proportional hazard model was used. Results: The median PFS was 11 months (5; 23) and the median OS was 16 months (10; 42) and differed significantly in the second and further lines of treatment. Progression in the second and further lines was observed in 28 (93%) and 27 (66%) patients, respectively (p = 0.006). Partial response as the BOR was observed in one patient (3%) in the second line and 13 patients (32%) in the further lines (p = 0.012). Conclusions: Cabozantinib has antitumor effects in the second and further lines of treatment. In this study we observed high efficiency of cabozantinib in further lines of treatment.