PURPOSE:Mismatch repair deficiency (dMMR) or microsatellite instability (MSI) represents a distinct phenotype among solid tumors resulting in the generation of highly immunogenic neoantigens. Pembrolizumab has been approved in first-line unresectable or metastatic dMMR/MSI colorectal cancers (CRC). We aimed to assess efficacy and tolerance of perioperative pembrolizumab in dMMR/MSI CRC. PATIENTS AND METHODS:The prospective multicenter phase II trial IMHOTEP enrolled patients with localized resectable dMMR/MSI CRC to receive one or two cycles of IV pembrolizumab 400 mg once every 6 weeks before surgery and 1-year total duration thereafter. The primary end point was pathologic complete response (pCR) rate (ypT0N0). Secondary objectives included safety, event-free survival, and overall survival. RESULTS:IMHOTEP enrolled 81 patients with dMMR/MSI CRC who received at least one cycle of pembrolizumab from November 26, 2021, to February 22, 2023: median age was 66 (21-89) years, 46 (52%) were women, and 63 (71%) had clinical stage III disease at baseline. Out of the 72 patients included in the efficacy population, 38 patients (52.7% [95% CI, 41.4 to 63.9]) achieved a pCR. The exploratory post hoc analysis showed a pCR rate increased from 46% (23/50) after one cycle to 68.2% (15/22) after two cycles of neoadjuvant pembrolizumab (P = .0125). With a median follow-up of 24.5 (95% CI, 23.3 to 25.6) months, three disease recurrences occurred. Grade ≥3 immune-related toxicities were reported in 14 (15.7%) patients including one grade 5 (myasthenia). CONCLUSION:The IMHOTEP trial showed promising results, with pCR achieved after one or two cycles of neoadjuvant pembrolizumab in 53% of patients with dMMR/MSI CRC. To our knowledge, this prospective study is the first to demonstrate the feasibility and the safety of perioperative pembrolizumab.

BACKGROUND:The phase II trial CABRAMET evaluates the efficacy of the VEGFR tyrosine kinase inhibitor (TKI) cabozantinib in patients with non-locally pretreated brain metastases (BM) from renal cell carcinoma (RCC). Faced with historical challenges in treating BM in RCC, this study aimed to provide prospective data on systemic treatment outcomes. PATIENTS AND METHODS:This multicenter open-label trial included RCC patients with BM with less than three prior systemic treatments excluding cabozantinib. Eligible patients received 60mg/day oral cabozantinib with dose adjustments for toxicity. The primary endpoint was the 6-month progression-free rate in brain metastases (6m-BM-PFR). The main secondary endpoints included BM objective response rate (ORR) and response duration in BM, extra-cranial ORR, BM and overall progression-free survival (PFS), overall survival (OS), and safety. RESULTS:The study enrolled 26 patients, with a median follow-up of 38.8 months (range 28.3-52.7 months). The 6m-BM-PFR was 56% (unilateral 95%CI 37.9-) by central review. BM partial responses were achieved in 16/26 patients (BM ORR of 61.5%) by investigator assessment. The median BM response duration was not reached and 58.3% (95%CI 29.3-78.9%) of the patients were event-free at 24 months. The median BM-PFS was 10.7 (95%CI 5.4-NR) months, and the median overall PFS was 8.1 (95%CI 4-11.9) months. The median OS was 15.0 (95%CI 9.3-35.0) months. Cabozantinib exhibited significant efficacy as first-line treatment with BM ORR of 86%, 67% in patients with prior immunotherapy, 40% in patients previously treated with TKI. CONCLUSION:The CABRAMET trial is the first to prospectively assess cabozantinib in the challenging population of non-locally pretreated brain metastases from RCC, highlighting its prolonged efficacy and tolerability in selected patients with BM. CLINICAL TRIAL REGISTRATION:NCT03967522.

BACKGROUND:Paclitaxel-induced peripheral neuropathy (PIPN) is a severe side effect frequently associated with premature treatment discontinuation. Frozen gloves (FG) therapy reported moderate efficiency, but FG are often poorly tolerated. Surgical gloves (SG) showed encouraging results. We investigated the efficacy of SG vs FG to prevent PIPN. METHODS:This prospective monocentric self-controlled case series study included breast cancer patients receiving 12 cycles weekly paclitaxel treatment. During each cycle, patients wore two superimposed SG on their dominant hand and FG on their other hand. The primary objective was patient satisfaction at the end of paclitaxel treatment using 10-point numeric scale (10p-NS). Secondary objectives included the rate of patients with PN, patient comfort and pain using 10p-NS and nurses' preference. A total of 84 patients was required to identify a 2-point difference in satisfaction with 2-sided paired Student t-test (α: 5 %; β:5 %). RESULTS:Between September 2019 and December 2020, 94 patients were included. The median dose of paclitaxel received per cycle was 132 mg (107-164) for a median of 12 (4-12) cycles. 21 (22 %) patients required ≥ 1 paclitaxel dose reduction related to PN occurrence. Median overall satisfaction was significantly improved (SG: 9/10; FG: 6/10; p < 0.001) with increased comfort (8/10; 5/10; p < 0.001) and less pain (1/10; 4/10; p < 0.001). Less patients reported at least one grade ≥ 2 PN (18 %; 28 %; p = 0.0117). CONCLUSION:Compression therapy with SG reported high patient satisfaction and is effective to reduce PIPN. Such PN prevention is easy to implement and improves patient quality of life. ELEGANT trial has been registered on www. CLINICALTRIALS:gov; NCT03872908 (first post: March 8th, 2019).

241 Background: Neoadjuvant treatment with immune check point inhibitors has shown promising results in localized deficient mismatch repair/microsatellite instability (dMMR/MSI) colorectal cancer (CRC), notably in terms of pathologic response. However, pathologic response has rarely been precisely assessed on both primary tumor and its corresponding lymph nodes (LN) as an end-point. We performed this analysis on the CRC samples selected from the IMHOTEP trial, a multicenter, single-arm study evaluating peri-operative Pembrolizumab in 4 different cohorts of patients with localized resectable dMMR/MSI tumors. Methods: We analyzed pathologic response on the 56 surgical specimens available from the CRC cohort. Pathologic response was assessed on primary tumor according to the percentage of Residual Viable Tumor (RVT) score, encompassing 4 groups : 0% = pathologic Complete Response (pCR) ; ≤10% = Major Pathologic Response (MPR) ; >10% < 50% = partial Pathologic Response (pPR) ; > 50% = lack of response (noPR). Pathologic response was assessed on lymph node (LN) according to 4 groups : negative LN without sign of sterilization (yN0 reg-), negative LN with sterilization (yN0 reg+) ; metastatic LN without tumor regression (yN+ reg-) ; metastatic LN with tumor regression (yN+ reg+).The type of regression, including colloid, fibrotic and necrotic features was reported, as well as the presence of tertiary lymphoid structures (TLS). pCR and MPR corresponded to pathologic responder patients and pPR and noPR to pathologic non responder patients. Results: In thisCRC cohort pCR, MPR, pPR and noPR were observed in n= 33 (58.9%), 7 (12.5%), 5 (8.9%) and 11 (19.6 %) cases and yN0 reg-, yN0 reg+, yN+ reg-, yN+ reg+ in 41 (73.2%) , 7 (12.5%), 7 (12.5%), and 1 (1.8 % ) cases. There was a significant association between pathologic responders (pCR + MPR) and negative LN status encompassing sterilized LN (p=0.04). Pathologic responders were more frequently associated with classical (Lieberkuhnian) adenocarcinoma than with other CRC special subtypes (mucinous, signet ring-cell, poorly cohesive subtypes)(p<0.01). Colloid response was the most frequent pattern of regression, observed in 42 (75%) cases, and predominant (>80% of pathologic response areas) in 14 (25%) cases. TLS were seen in 46 (82%) cases, without any significant association with the RVT score. However TLS were observed in all CRC cases with MPR. Conclusions: These preliminary results show pembrolizumab efficacy as a neoadjuvant monotherapy in terms of pathologic response on both primary CRC and corresponding LN, highlighting the need for a new and more accurate pathologic score. It also illustrates the potential impact of the histological subtypes. Complementary data will be available after updated pathologic reviewing of additional specimens from CRC patients and will also be correlated with outcome. Clinical trial information: NCT04795661 .

533 Background: Despite dramatic progress in metastatic RCC treatments, pts with BM remain with poor outcome and were mostly excluded from clinical trials. Local treatments on BM are standard today. Methods: Adult pts with histologically proven RCC and BM ≥ 5 mm (or > 8 mm if solitary) including at least one non-locally pretreated, < 3 prior systemic treatments excluding cabozantinib, ECOG PS 0 or 1 and steroids < 40 mg/day were included. Primary endpoint was BM progression free survival rate at 6 months (6m-BM-PFS) according to modified RANO-BM criteria by central review. Secondary endpoints were BM response and response duration, extracranial response, PFS, overall survival and safety. 25 evaluable pts were required to evaluate the main endpoint. Results: 26 pts were included, 25 were evaluable for the primary endpoint and median follow up time was 39.8 months [5.9-49.7]. The 6m-BM-PFS was 56.0% [unilateral 95%CI 37.9-] (14/25 pts). BM response was partial response (PR) for 61.5% (16/26) pts and median duration of response was not reached, 66.7% pts being event-free 24 months after BM response. Extracranial response was PR for 38.5% (10/26). Median PFS was 8.1 months [95%CI 4-11.9], and median BM PFS 8.4 months [95%CI 5.4-NR]. Median overall survival was 15.8 months [95%CI 9.7-35.0]. No new safety signals were observed. Conclusions: This is the first prospective trial assessing cabozantinib in RCC pts with non-locally pretreated BM. These results confirm the efficacy of cabozantinib on BM previously reported in retrospective series. Clinical trial information: NCT03967522 . Pts characteristics. Pts number N = 26 Median age (years) [range] 67 [44-86] Gender: F / M, n 5 / 21 ECOG PS: 0 / 1,n 10 / 16 RCC: non-clear cell / clear cell, n 2 / 24 Prior nephrectomy : n 16 Number of BM: 1 / 2 / >3, n 9 / 7 / 10 Prior BM treatments: Overall/ Surgery/ Radiation, n 10 / 3 / 10 Prior systemic treatment: 0 / 1 / >2, n 7 / 15 / 4 IMDC: Favorable / Intermediate / Poor, n 7 / 10 / 9

Background Ifosfamide is a major anti-cancer drug in children with well-known renal toxicity. Understanding the mechanisms underlying this toxicity could help identify children at increased risk of toxicity. Methods The IFOS01 study included children undergoing ifosfamide-based chemotherapy for Ewing sarcoma or rhabdomyosarcoma. A fully evaluation of renal function was performed during and after chemotherapy. Proton nuclear magnetic resonance (NMR) and conventional biochemistry were used to detect early signs of ifosfamide-induced tubulopathy. The enzymatic activity of aldehyde dehydrogenase (ALDH) was measured in the peripheral blood lymphocytes as a marker of ifosfamide-derived chloroacetaldehyde detoxification capacity. Plasma and urine concentrations of ifosfamide and dechloroethylated metabolites were quantified. Results The 15 participants received a median total ifosfamide dose of 59 g/m 2 (range: 24–102), given over a median of 7 cycles (range: 4–14). All children had acute proximal tubular toxicity during chemotherapy that was reversible post-cycle, seen with both conventional assays and NMR. After a median follow-up of 31 months, 8/13 children presented overall chronic toxicity among which 7 had decreased glomerular filtration rate. ALDH enzymatic activity showed high inter- and intra-individual variations across cycles, though overall activity looked lower in children who subsequently developed chronic nephrotoxicity. Concentrations of ifosfamide and metabolites were similar in all children. Conclusions Acute renal toxicity was frequent during chemotherapy and did not allow identification of children at risk for long-term toxicity. A role of ALDH in late renal dysfunction is possible so further exploration of its enzymatic activity and polymorphism should be encouraged to improve the understanding of ifosfamide-induced nephrotoxicity.

BackgroundChemotherapy for non-seminomatous germ cell tumours (NSGCT) exposes to dose-dependent toxicities. The TGM13-NS protocol (EudraCT 2013-004039-60) aimed to decrease the chemotherapy burden compared to the previous TGM95 protocol while maintaining the 5-year event-free survival (EFS) at 80% or more. ProcedurePatients less than 19 years of age with disseminated NSGCT were enrolled (May 2014 to May 2019) and stratified into four groups: two intermediate-risk (IR: localised tumour with low tumour markers [TM]) groups treated with VBP (vinblastine-bleomycin-cisplatin): three courses for IR1 (ovarian tumour any age/testis tumour less than or equal to 10 years) and four courses for IR2 (extragonadal tumour 10 years or less) groups, and two high-risk (HR: metastatic and/or high TM) groups treated with etoposide-cisplatin and either ifosfamide (VIP) or bleomycin (BEP): three courses for HR1 (ovarian tumour any age/testis tumour less than or equal to 10 years and low TM/testis tumour more than 10 years and very low TM) groups and four courses for HR2 (remainder) groups. ResultsOne hundred fifteen patients were included: median age of 12.8 years (0.4-18.9); tumour sites: 44 ovaries, 37 testes and 34 extragonadal. The 5-year EFS and overall survival (OS) were 87% (95% CI: 80-92) and 95% (89-98), respectively (median follow-up: 3.5 years, range: 0.2-5.9), similar to those of the TGM95 protocol (5-year EFS 89% (84-93), 5-year OS 93% (89-95), p = .561). The 5-year EFS were 93% (95% CI: 80-98), 88% (71-95) and 79% (62-90) for ovarian, testicular and extragonadal tumours, respectively. The 5-year EFS varied (p = .02) according to the risk groups: 90% (66-97), 64% (30-85), 95% (72-99) and 87% (74-94) for IR1, IR2, HR1 and HR2, respectively. TM decline adjusted to tumour site, and alpha-fetoprotein (AFP) level revealed a prognostic impact of time to normalisation on EFS: HR = 1.03 (1.003-1.007). ConclusionRisk-adapted and globally decreased chemotherapy burden maintains excellent outcomes, exclusive of the IR2 group, which warrants more intensive chemotherapy.

2591 Background: Immune checkpoint inhibitors (ICI) have demonstrated their efficacy in advanced dMMR/MSI (deficient mismatch repair/microsatellite instability) tumors and increasing data are also accumulating in localized resectable stages with about 60% of pathological complete response rate. The goal of the IMHOTEP trial is to assess the safety and efficacy of peri-operative pembrolizumab in localized dMMR/MSI tumors independently of their anatomical origin. Methods: IMHOTEP is a prospective, multicenter, phase II study aimed to include 120 patients (pts) with localized resectable dMMR/MSI tumors, eligible for curative surgery. Pembrolizumab 400 mg flat dose is administered as a perioperative treatment with 1 or 2 doses every 6 weeks before surgery and thereafter every 6 weeks for one year. Primary objective is to evaluate the pathological complete response (pCR) rate defined as ypT0N0 stage. Secondary objectives are to assess major pathological response, centralized pathological review, safety, clinical response rate, recurrence-free survival and overall survival. Here, we present the interim analysis of safety and pathologic response data for the first 70 treated pts. Results: Median age was 67.5 years (26-89), 54.3% were males, and 42.0% were ECOG-PS 0. Surgery was performed in 54/70 pts including 27/35 colorectal (CRC), 16/21 oesogastric (OGC), 4/5 endometrial (EC) and 7/9 other (6 small intestine, 1 bile duct) (OC) cancers. 16 pts (22.9%) were not operated, mainly due to patient’s decision following complete clinical response (n=7). Only one patient was not submitted to surgery because of disease progression. Focusing on the 54 operated pts, 31 and 23 pts received 1 and 2 neoadjuvant pembrolizumab doses respectively. The pCR rate was 38.9% (40.7%, 25.0%, 0.0% and 85.7% in CRC, OGC, EC and OC respectively). Grade 3-4 immune-related adverse events were observed in 4 (5.7%) patients including transaminases increase (n=1), arthritis (n=1), acute kidney injury (n=1) and pneumonitis (n=1). Conclusions: In this IMHOTEP interim analysis, we observed a limited complete pathologic response rate to short-course neoadjuvant pembrolizumab. If we add patients in clinical complete response who chose not to be operated to those with pCR, our results compare with those previously reported. But we can also hypothesize that preoperative treatment duration should be prolonged to obtain more pCR. Overall, tolerance of pembrolizumab was acceptable without new safety signal. Centralized pathological review, major pathological response evaluation and clinical response rate analysis are ongoing. IMHOTEP trial has been registered (first post: March 12 th , 2021). Clinical trial information: NCT04795661 .

Background Papillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC, and associated with poor outcomes in the metastatic setting. In this study, we aimed to comprehensively evaluate the immune tumor microenvironment (TME), largely unknown, of patients with metastatic pRCC and identify potential therapeutic targets.Methods We performed quantitative gene expression analysis of TME using Microenvironment Cell Populations-counter (MCP-counter) methodology, on two independent cohorts of localized pRCC (n=271 and n=98). We then characterized the TME, using immunohistochemistry (n=38) and RNA-sequencing (RNA-seq) (n=30) on metastatic pRCC from the prospective AXIPAP trial cohort.Results Unsupervised clustering identified two “TME subtypes”, in each of the cohorts: the “immune-enriched” and the “immune-low”. Within AXIPAP trial cohort, the “immune-enriched” cluster was significantly associated with a worse prognosis according to the median overall survival to 8 months (95% CI, 6 to 29) versus 37 months (95% CI, 20 to NA, p=0.001). The two immune signatures, Teff and JAVELIN Renal 101 Immuno signature, predictive of response to immune checkpoint inhibitors (CPI) in clear cell RCC, were significantly higher in the “immune-enriched” group (adjusted p<0.05). Finally, five differentially overexpressed genes were identified, corresponding mainly to B lymphocyte populations.Conclusion For the first time, using RNA-seq and immunohistochemistry, we have highlighted a specific immune TME subtype of metastatic pRCC, significantly more infiltrated with T and B immune population. This “immune-enriched” group appears to have a worse prognosis and could have a potential predictive value for response to immunotherapy, justifying the confirmation of these results in a cohort of metastatic pRCC treated with CPI and in combination with targeted therapies.Trial registration number NCT02489695.

TPS434 Background: At diagnosis, 10 to 15% of testicular pure seminomas have a stage II defined by the presence of retroperitoneal lymph node metastases. The optimal choice of treatment modalities are associated with excellent efficacy but also acute and late toxicities. De-escalating treatment for seminoma patients with stage IIb, IIc and III and good prognosis according to IGCCCG (International Germ Cell Cancer Collaborative Group) based on negative FDG-PET (Fluorodeoxyglucose Positron Emission Tomography) after 2 cycles of EP (etoposide, cisplatine) chemotherapy seems feasible and safe according to SEMITEP cohort 2 results (Loriot Y, and al GETUG SEMITEP Trial: Eur Urol. 2022 Aug;82(2):172-179). Serum levels of microRNA (miR)-371a-3p (miRNA-M371) have been significantly associated with clinical stage and response to treatment in testicular germ cell tumors, with sensitivity and specificity higher than those of classic markers. The aim of the study NCT05529251 is to propose a new therapeutic approach for the stages IIa/IIb. Methods: This phase II, multicenter, prospective, randomized, non-comparative, de-escalation study will include patient with primary testicular seminomatous germ cell tumor with stage IIa/IIb < 3 cm in largest diameter seminoma, histologically proved after orchiectomy and good prognosis according to IGCCCG and LDH (Lactate DesHydogenase) < 2.5 x Upper Limit of Normal (ULN). They must have progressive disease and no prior treatment with radiotherapy or chemotherapy. In case of negative week-3 (after 1 EP cycle) PET-scan, patients will be randomized according to 2 arms ARM A: Boost of radiotherapy 20 to 30 Gray (Gy); ARM B Carboplatin AUC7 chemotherapy. In case of positive week-3 PET-scan: 3 courses of EP chemotherapy (ARM C). Primary outcome will include progression-free rate at 36 months. Secondary Outcome Measures will be serum level of miRNA M371, correlation with response to treatments and PET scan results, overall survival (OS), quality of life and tolerance to treatment. Blood samples (miRNA-M371) will be collected at screening, at the time of randomization before second cycle of chemotherapy or radiotherapy, at the end of treatment and at relapse. Enrollment has started in October 2022. A total of 90 patients will be included in the interventional study, leading to approximately 60 patients with negative FDG-PET randomized. Clinical trial information: NCT05529251 .

Introduction: Local control in sarcoma is rarely achieved with exclusive radiotherapy (RT). We aim to assess the feasibility and safety of sunitinib continuously administrated with concomitant RT in inoperable non-GIST sarcomas patients. Methods: This multicentric French 3 + 3 dose escalation study included patients with inoperable locally advanced or recurrent sarcoma, ECOG-PS <2, <= 2 metastatic sites and no brain metastases, adequate organ functions and absence of uncontrolled hypertension, who had never received sunitinib or radiotherapy. The escalation phase planned to use sunitinib dose levels (DL1: 25; DL2: 37.5; DL3: 50 mg/day) with standard RT (60 Gy, 30 fractions, 5 fractions/week/6 weeks). The primary endpoint was to determine the incidence of dose-limiting toxicities (DLT) in the first 14 weeks and the maximal tolerated dose (MTD). Secondary endpoints included safety (acute and late toxicities), local control at 6 months including local progression free rate (L-PFR) progression free survival (PFS), overall survival (OS), proportion of patients eligible for surgery after treatment. Results: From May 2011 to April 2016, the dose-escalation phase enrolled 10 patients (DL1 N = 4; DL2 N = 6). No DLT was observed in at DLL One DLT (grade 4 thrombopenia) occurred at DL2. The 19 patients treated at DL2 (including the 13 patients from the expansion phase) received sunitinib for a median duration of 42.7 (2.8-79.1) days, and radiotherapy for 6.4 (1-8) weeks; all but 3 patients received 60 Gy (40 Gy, early progression (N = 1); 8 Gy, early death (N = 1), prescribed dose, 50 Gy (N = 1)). With a median follow-up of 19.5 (14-36.5) months, the median PFS was 6.5 (1.9-31.1) months. Median OS was not reached. At 6 months, L-PFR was 73.3% (95%CI 44.9%-92.2%). One patient was amendable to surgery after treatment. Sunitinib-related grade >= 3 adverse events occurred in 58% of the patients treated at DL2 (Escalation N = 4; Expansion N = 7). Seven (36.8%) deaths related to disease progression were reported. Conclusion: This is the first trial assessing the combination of continuous administration of sunitinib 37.5 mg with exclusive RT in non-GIST sarcoma. Whereas this combination was found feasible, efficient, further investigations of combinations of more recent multikinase inhibitors with RT need to be explored. (C) 2022 Elsevier B.V. All rights reserved.

With an overall survival rate of 2–9% at 5 years, pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related deaths in the industrialized world and is predicted to become the second by 2030. Owing to often late diagnosis and rare actionable molecular alterations, PDAC has not yet benefited from the recent therapeutic advances that immune checkpoint inhibitors (ICI) have provided in other cancer types, except in specific subgroups of patients presenting with tumors with high mutational burden (TMB) or microsatellite instability (MSI). The tumor microenvironment (TME) plays a substantial role in therapeutic resistance by facilitating immune evasion. An extracellular stromal protein, βig-h3/TGFβi, is involved in the pathogenesis of PDAC by hampering T cell activation and promoting stiffness of the TME. The study BIGHPANC included 41 patients with metastatic PDAC, and analyzed βig-h3 levels in serum and tumor samples to assess the βig-h3 prognostic value. βig-h3 serum levels are significantly associated with overall survival (HR 2.05, 95%CI 1.07–3.93; p = 0.0301). Our results suggest that βig-h3 serum levels may be considered a prognostic biomarker in patients with metastatic PDAC.

Papillary Renal Cell Carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC). In silico, we identified 4 subgroups according to the proportion of immune and stromal cell populations in a preliminary study in 271 localized pRCC tumors using RNA-seq data from The Cancer Genome Atlas (TCGA), validated in independent cohort. Thus, the microenvironment of pRCC is yet to be described in a cohort of metastatic pRCC treated with systemic therapy and its association with response and outcomes to be assessed. We performed a post-hoc analysis of the AXIPAP trial which explored axitinib in first line metastatic pRCC specifically (Negrier et al, EJC, 2020, by the GETUG collaborative group). In immunohistochemistry (IHC), the immune infiltration was analyzed by the CD8/CD3/PD-L1/CD68 staining, intra-tumoral and invasion front, and tumor-infiltrating lymphocytes scoring. The angiogenesis was analyzed by CD31 and VEGF staining. Among 38 pRCC included in our analysis, we applied unsupervised clustering from IHC staining, identifying 3 different groups of pRCC: “immunolow/Angiolow”, “Immunolow/Angiohigh” and “Immunohigh/Angiolow” groups. Only “Immunolow/Angiohigh” group (n=13) was associated to high vascular density, with more aggressive prognostic factors such as high grade (85%), Fuhrman grade 3-4 (85%), type 2 (77%), with rabdoid or sarcomatoid component (38%). The endpoints are presented in the table. As in silico analysis with localized pRCC from TCGA, the "Immunolow/Angiohigh” cluster, in this metastatic cohort, appeared to have a worse prognosis.Table: 1472PEndpointsimmunolow/AngiolowN = 14 (37%)Immunolow/AngiohighN = 13 (34%)Immunohigh/AngiolowN = 11 (29%)Overall cohortN = 38ORR14%31%18%22%6-month PFS57.1%61.5%45.7%55.7%6-month OS92.8%61.5%90.9%81.6% Open table in a new tab For the first time, we characterized the tumor microenvironment of metastatic pRCC treated by VEGF-TKI in prospective trial. We identified 3 different groups by using IHC clustering on immune and vascular infiltration, with different response and outcomes. These rare tumors require specific biomarkers of response. Further transcriptomics analyses and response of treatment will be presented to ESMO meeting.