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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.

Background Drug-drug interactions are a major concern in oncology and may potentially affect the outcome of patients with cancer. Objective In this study, we aimed to determine whether the concomitant use of statins, metformin, or proton pump inhibitors affects survival in patients with metastatic renal cell carcinoma treated with first-line combination therapies. Methods Medical records of patients with documented metastatic renal cell carcinoma between January 2016 and November 2021 were reviewed at 17 participating centers. This research was conducted in ten institutions, including both referral centers and local hospitals. Patients were assessed for overall survival, progression-free survival, and overall clinical benefit. Univariate and multivariate analyses were conducted to explore the association of variables of interest with overall survival and progression-free survival. Results A total of 304 patients receiving dual immunotherapy (51%) or immunotherapy/vascular endothelial growth factor-tyrosine kinase inhibitor (49%) combinations were eligible for inclusion in this retrospective study. Statin use was a significant prognostic factor for longer overall survival in a univariate analysis (hazard ratio 0.48, 95% confidence interval 0.26-0.87; p = 0.016) and a multivariate analysis (hazard ratio 0.48, 95% confidence interval 0.31-0.74; p < 0.001) and was significantly associated with an overall clinical benefit (83% in statin users vs 71% in non-users; p = 0.045). Otherwise, the use of metformin or proton pump inhibitors did not affect the outcome of these patients. Conclusions Our study suggests a prognostic impact of statin use in patients receiving first-line immuno-oncology combinations. The mechanism of this interaction warrants further elucidation.

Background: Tyrosine-kinase inhibitors (TKIs) still represent a first-line option for selected patients with metastatic Renal Cell Carcinoma (mRCC). We aimed to compare the real-world efficacy of nivolumab or cabozantinib as second-line therapy in specific mRCC subpopulations. Patients and Methods: We retrospectively collected data from 11 centers from Italy, Spain and US. Overall Survival (OS) and Progression-Free Survival (PFS) were analyzed using Kaplan-Meier curves. Cox proportional models were used at univariate and multivariate analyses. Results: We collected data from 343 patients with mRCC, 123 (36%) treated with cabozantinib and 220 (64%) with nivolumab. The median OS resulted longer, but not statistically significant, with nivolumab in patients aged >70 years (21.4 vs. 15.4 months, P = .746), treated with first-line pazopanib (26.8 vs. 11.6 months, P = .450), or with good (47.0 vs. 15.5 months, P = .285) or intermediate-risk criteria (14.4 vs. 11.0 months, P = .357), while it was longer, but even not statistically significant, for cabozantinib in patients who received previous sunitinib (25.7 vs. 21.7 months, P = .638) or with bone metastases (28.4 vs. 24.4 months, P = .871). The median PFS was significantly longer with cabozantinib in patients with clear cell histology (7.8 vs. 5.4 months, P = .026) and in patients with good risk features (12.3 vs. 5.7 months, P = .022). Conclusions: Nivolumab and cabozantinib resulted active in mRCC patients, showing distinct results when stratified into clinico-pathological features.

Statins are commonly prescribed to reduce plasma cholesterol levels and risk of cardiovascular events and mortality. Statin exposure may have cancer-preventive properties in some solid tumors, including Renal Cell Carcinoma (RCC). Emerging evidences show that statins can inhibit RCC cell growth by inducing cell cycle arrest and apoptosis in a dose- and time-dependent manner. In addition, statins inhibit the phosphorylation of AKT, mammalian target of rapamycin (mTOR), and ERK leading to reduced motility of RCC cells. Interestingly, the potential impact of concomitant statin intake has been recently evaluated in RCC patients treated by targeted therapy or immunotherapy. In this review, we illustrate the most recent data on the preclinical activity of statins in Renal Cell Carcinoma models and discuss the impact of their use on the prevention and survival of patients affected by this tumor.

Renal cell carcinoma (RCC) is the seventh most frequently diagnosed tumor in adults in Europe and represents approximately 2.5 % of cancer deaths. In metastatic setting, clinical strategies including angiogenesis inhibition with tyrosine kinase inhibitors, as well as immunotherapy against immune checkpoint proteins, such as PD-1/PDL-1 and CTLA-4, have revolutionized the treatment landscape. Unfortunately, most patients progress to anti angiogenic and immunotherapy treatment. Epigenetic aberrations are commonly found in RCC, showing that changes in epigenetic modifications, like promoter methylation or abnormal microRNA expression, are key in the development of RCC due to gene expression alterations without changes in the genome sequence. Nowadays, new drugs in the field of epigenetics are able to modify gene expression to induce antitumoral effect in the tumor cell. In kidney cancer, drugs targeting epigenetics are in early development, but could be promising in the near future. In this review, we summarize the main epigenetic alterations found in RCC and their involvement in pathological signaling pathways, being a new potential target that could potentially be added to the treatment flow of patients with advanced RCC.

e16541 Background: Immune-checkpoint inhibitors (ICIs) are key in the current management of mUC pts. Recent data in melanoma revealed a link in between the circadian rhythm of the immune-system and expected activity with ICIs (Quian et al, Lancet Oncol 2021). In preclinical models naïve CD4 and CD8 T cells in blood have shown to approach nadir levels around 4 P.M., and therefore, to lower adaptative immune responses after that time. We aimed to correlate the activity of single agent ICIs for the systemic treatment of mUC pts depending on the time of administration. Methods: This is a multicenter and retrospective study performed in 3 academic institutions in Spain and 1 in Italy of patients with mUC who initiated treatment with anti-PD1 or anti-PDL1 as 1st or subsequent line. ICIs were administered and managed according to product labelling. Time cut-off as adaptive immune-modulation for ICIs administration was considered after 4:30 PM. We divided pts into those who received at least 20% of their infusions after 4:30 PM and those who received fewer than 20% after that time. Other data such as patient characteristics and adverse-events related to the treatment were also collected. We carried out a survival analysis by a Cox regression model. Results: From 2016, 92 pts were treated with single agent ICIs for mUC. Most of the pts (n = 62; 67.4%) received less than 20% of the doses after 4:30 PM, while a lower proportion (n = 26; 28.3%) received at least 20% of the doses after that time. Median follow-up time of immunotherapy was 8.6 months. 35 (38.0%) and 57 (62.0%) pts received ICIs as 1st and subsequent lines of treatment respectively. There were no differences in the proportion of pts in 1st vs subsequent lines and time of administration, nor other well prognostic baseline factors like PD-L1 expression, or Bajorin or Bellmunt’s scoring. A significant benefit in both PFS (11.38 vs 3.58 months; HR 2.66: 95%CI 1.53-4.63; p = 0.001) and in OS (14.04 vs 6.80 months; HR 2.62: 95%CI 1.48-4.63: p = 0.001) benefited to pts who received less than 20% of the doses after 4:30 PM. Response rate also favored (59.3% vs 16.0%) the earlier administration of the treatments. Neither corticosteroids concomitant use nor immune-related toxicity appeared to impact on these outcomes. Conclusions: Time of the day administration of ICIs may influence the efficacy of ICIs in mUC pts. Although the small size of the sample and the short median follow-up is something to be considered, this data are promising and consistent with the previous studies. Prospective confirmation is needed.

e16512 Background: Recent data in metastatic melanoma patients shows that time-of-day infusion of ICIs may directly impact on the efficacy based on the dependence of the adaptive immune system on circadian rhythm. ICIs either as single agents or in combinations, are now considered the backbone systemic treatment of mRCC pts. There is a strong biological rational showing that “Clock genes”, particularly PER2, TIMELESS and TIPIN have an altered expression in RCC compared with normal tissue. We conducted a retrospective analysis in pts with mRCC receiving ICIs-based therapies in order to determinate whether timing of ICIs administration has an impact on survival outcomes. Methods: This is a multicenter and retrospective study performed in 3 academic institutions in Spain and 3 in Italy to describe the outcome of all pts who received ICIs-ICIs or ICIs-TKI treatment for the first line setting of mRCC in daily standarc practice related to the timing of administration. We selected 16.30h as the time-limit and identified the pts receiving more than 20% of the treatment infusion after that time. Pts were treated and evaluated according to institutional local guidelines. Pts characteristics, efficacy and treatment-related toxicities were gathered. A Cox regression analysis was conducted to explore the association of baseline variables. Results: From 2019, 61 pts received either Nivolumab/Ipilimumab (N = 46, 75.4%) or pembrolizumab/axitinib (N = 15, 24,6%) for the upfront mRCC treatment. 52 (85.2%) pts (17 ICI+TKI and 25 ICI+ICI) received less than 20% of the ICIs combination treatment infusion after 16.30h compared with 9 (14.8%) pts (3 ICI+TKI and 6 ICI+ICI) who received more than 20% of the treatment infusion after 16.30h. Median follow up was 14.6 months (m). Pts who received most treatment before 16.30h had a significantly longer median PFS compared with those pts with the latest administration (12.3 vs 5.6m; HR 2.28: 95%CI 1.1-5.15; p = 0.048). Overall Survival (OS) data were immature but showed a tend to a better survival for those patients with earlier infusion administration (HR 2.33 p = 0.16). Corticosteroids concomitant administration or immune-related adverse events did not seem to have an impact on these results. Conclusions: Consistently to the melanoma findings, we also identified a potential survival impact from timing of IO administration in mRCC pts receiving ICIs-based combinations in first line treatment. Despite these promising results, there are study limitations such as number of patients and heterogeneous treatment groups. Larger prospective and randomized data are needed to assess the robustness of this hypothesis in the clinic.

585 Background: Breast cancer (BC) in early stages exhibit a naïve and competent immune system that translates into a more prominent TIL infiltration and higher PD-L1 expression as compared to the advanced BC scenario were immunoescape and exhaustion are more prevalent. Expression of PD-L1 has been related to a better pCR when immune checkpoint inhibitors (IPI) have been added to neaodjuvant chemotherapy (NACT) in triple negative BC (TNBC). Our prior results shown dendritic cells vaccines (DCV) increased pCR in both TNBC and luminal B subtypes, with an absolute gain of 20% (p = 0.03) and a safe tolerance. Methods: Eighty-three HER2 negative BC patients with untreated stage II-III were included: 39 patients from the NCT01431196 trial that combine NACT with autologous DCV and 44 patients from a historic control group treated with the same NACT alone. NACT consists of dose dense Epirubicin plus Cyclophosphamide for 4 cycles sequenced to Docetaxel for 4 cycles. PD-L1 expression was measured in the membrane of tumoral cells with monoclonal rabbit anti PD-L1 28.8 pharmaDX (DAKO, Agilent Technologies) in FFPE samples at diagnosis. Primary endpoint was pathologic complete response (pCR) stratified by PD-L1 expression (positive or negative), while secondary endpoints were event-free survival (EFS) and overall survival (OS), also stratified by PD-L1 expression. Results: Both cohorts were well balanced in most of the features. Thirty-three percent of the tumors in the experimental group were PD-L1 positive, whereas 50% of them in the CG expressed PD-L1 (p = 0.06). Pathological CR was observed in 50% of the PD-L1 positive population, in contrast to a 2.8% in the PD-L1 negative in the NACT cohort (p < 0.01) as compared to the patients assigned to the DCV group (33.4% in PD-L1 positive vs 23.1% in PD-L1 negative population; p = 0.16). Among PD-L1 positive population, more pCR were seen in the CG than in the DCV group (50% vs 33.4%; p = 0.06). Within the PD-L1 negative population, more pCR were observed in the DCV group than in the CG (23.1% vs 2.8%; p < 0.05). With a median follow-up of 7 years, no significant differences were observed between the different subgroups neither in EFS (HR = 1.7; 0.42-6.8; p = 0.19) nor in OS (HR = 2.5; 0.56-11, p = 0.43). At 7 years, 20% and 14.4% of the patients relapsed according to the PD-L1 positive versus negative status respectively, and 10.78% versus 13.33% were dead. Conclusions: The benefit of DCV seems to be outstanding in the PD-L1 negative tumors that have a basal immune appropriate milieu. PD-L1 expression implies a more suppressed niche in which DCV are not able to stimulate antigen presentation and cell cytotoxic activity. PD-L1 positive population reach higher responses with both NACT±DCV than PD-L1 negative group, although the benefit seem to be higher in the NACT alone cohort. Further studies combining DVC+IPI together with NACT are needed. Clinical trial information: NCT01431196.

ResumenObjetivoComparar los resultados de la cirugía artroscópica con los de la cirugía abierta en el tratamiento de la epicondilitis lateral.MétodosEstudio de cohortes prospectivo de 30 pacientes atendidos por epicondilitis lateral que habiendo seguido tratamiento rehabilitador durante un mínimo de 3 meses, presentaron persistencia de los síntomas, divididos en 2 grupos: cirugía abierta y cirugía artroscópica.ResultadosSe analizaron 30 pacientes con edad media de 47,63±1,19 años, 17 mujeres y 13 varones, con un seguimiento medio de 69,07±4,01 días. El dolor preoperatorio (escala visual analógica (EVA) 9,27±0,12) disminuyó (p