Validation of the Lung Immune Prognostic Index (LIPI) as a prognostic biomarker in metastatic renal cell carcinoma.

BACKGROUND: The Lung Immune Prognostic Index (LIPI) is associated with immune checkpoint inhibitors (ICI) outcomes across different solid tumors, particularly in non-small cell lung cancer. Data regarding the prognostic and/or predictive role of LIPI in metastatic renal cell carcinoma (mRCC) are still scarce. The aim of this study was to evaluate whether LIPI could be predictive of survival in mRCC patients. METHODS: We used patient level data from three different prospective studies (NIVOREN trial: nivolumab; TORAVA trial: VEGF/VEGFR-targeted therapy (TT); CheckMate 214: nivolumab-ipilimumab vs sunitinib). LIPI was calculated based on a derived neutrophils/(leukocyte-neutrophil) ratio > 3 and lactate-dehydrogenase >upper limit of normal, classifying patients into three groups (LIPI good, 0 factors;LIPI intermediate (int), 1 factor;LIPI poor, 2 factors) and/or into two groups (LIPI good, 0 factors;LIPI int/poor, 1-2 factors) according to trial sample size. Primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: In the Nivolumab dataset (n = 619), LIPI was significantly associated with OS (LIPI-good 30.1 vs 13.8 months in the LIPI int/poor; HR= 0.47) and PFS (HR=0.74). In the VEGF/VEGFR-TT dataset (n = 159), only a correlation with PFS was observed. In the CheckMate214 dataset (n = 1084), LIPI was significantly associated with OS (nivolumab-ipilimumab OS LIPI good vs int/poor: HR=0.55, p < 0.0001; sunitinib: OS LIPI good vs int/poor: 0.38, p < 0.0001) in both treatment groups in univariate and multivariate analysis. CONCLUSIONS: Pretreatment-LIPI correlated with worse survival outcomes in mRCC treated with either ICI or antiangiogenic therapy, confirming LIPI's prognostic role in mRCC irrespective of systemic treatment used.

PEC-PRO: A new prognostic score from a series of 87 patients with localized perivascular epithelioid cell neoplasms (PEComas) treated with curative intent.

BACKGROUND: Perivascular epithelioid cell neoplasms (PEComas) encompass a heterogeneous family of mesenchymal tumors. Previously described clinicopathologic features aimed at distinguishing benign from malignant variants but lacked prognostic value. METHODS: This retrospective analysis examined clinicopathologic data from patients who had localized PEComa across French Sarcoma Network centers. The authors analyzed 12 clinicopathologic features in a Cox proportional hazard framework to derive a multivariate prognostic risk model for event-free survival (EFS). They built the PEComa prognostic score (PEC-PRO), in which scores ranged from 0 to 5, based on the coefficients of the multivariate model. Three groups were identified: low risk (score = 0), intermediate risk (score = 1), and high risk (score ≥ 2). RESULTS: Analyzing 87 patients who had a median 46-month follow-up (interquartile range, 20-74 months), the median EFS was 96.5 months (95% confidence interval [CI], 47.1 months to not applicable), with 2-year and 5-year EFS rates of 64.7% and 58%, respectively. The median overall survival was unreached, with 2-year and 5-year overall survival rates of 82.3% and 69.3%, respectively. The simplified Folpe classification did not correlate with EFS. Multivariate analysis identified three factors affecting EFS: positive surgical margins (hazard ratio [HR], 5.17; 95% CI, 1.65-16.24; p = .008), necrosis (HR, 3.94; 95% CI, 1.16-13.43; p = .030), and male sex (HR, 3.13; 95% CI, 1.19-8.27; p = 0.023). Four variables were retained in the prognostic model. Patients with low-risk PEC-PRO scores had a 2-year EFS rate of 93.7% (95% CI, 83.8%-100.0%), those with intermediate-risk PEC-PRO scores had a 2-year EFS rate of 67.4% (95% CI, 53.9%-80.9%), and those with high-risk PEC-PRO scores had a 2-year EFS rate of 2.3% (95% CI, 0.0%-18.3%). CONCLUSIONS: The PEC-PRO score reliably predicts the risk of postoperative recurrence in patients with localized PEComa. It has the potential to improve follow-up strategies but requires validation in a prospective trial.

Safety and efficacy of nivolumab in elderly patients with metastatic clear cell renal cell carcinoma: Analysis of the NIVOREN GETUG-AFU 26 study.

INTRODUCTION: Immune checkpoint inhibitors are standard of care in metastatic renal cell carcinoma but their activity and safety in elderly patients is insufficiently explored. We evaluated outcomes of elderly patients with mRCC treated with nivolumab in the GETUG-AFU 26 NIVOREN phase 2 trial (NCT03013335) and conducted exploratory circulating biomarker analyses. METHODS: Patients with mRCC were treated with nivolumab after at least one antiangiogenic therapy. The main endpoint of this analysis was safety in patients ≥ 70 years old (y.o), as per the rate of treatment-related grade 3-5 events (TRAE). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival. Exploration of candidate biomarkers associated with aging included baseline circulating cytokines involved in inflammation, adhesion, immune checkpoints, angiogenesis (IL6, IL7, IL8, BAFF, CXCL13, VCAM-1, 4-1BB, VEGF). RESULTS: Of 720 patients, 515 were < 70 y.o and 205 ≥ 70 y.o. Patients ≥ 70 y.o exhibited numerically less IMDC poor risk disease (21.0% vs 26.9%), sarcomatoid component (4.9% vs 9.8%) or brain metastases (5.9% vs. 14.7%), but more previous treatment lines (≥ 2 in 54.1% vs 48.5%). TRAE were higher in patients ≥ 70 y.o (24.9% vs. 17.9%, p = 0.033). Respective ORR (19.2% vs. 22.1%) and median PFS (4.5 versus 3.0 months, HR 0.97 [95%CI 0.81-1.15]) were similar. Overall survival was shorter in patients ≥ 70 y.o (19.3 versus 26.9 months, HR 1.26 [95%CI 1.04-1.51]), but not significantly in a competitive risk model. Only V-CAM1 and 4-1BB were found to be increased in patients ≥ 70 y.o. CONCLUSIONS: Nivolumab displayed higher grade 3/4 TRAE but manageable toxicity in elderly patients, with sustained activity. Elderly patients did not display specific inflammatory or angiogenic circulating profiles.

Assessing Long-term Treatment Benefits Using Complementary Statistical Approaches: An In Silico Analysis of the Phase III Keynote-045 and Checkmate-214 Immune Checkpoint Inhibitor Trials.

BACKGROUND: The Keynote-045 trial illustrates that the long-term benefit (LTB) of treatment does not always translate to improved progression-free survival (PFS). Milestone survival and flexible parametric survival model with cure (FPCM) have been proposed as complementary statistical approaches to more comprehensively evaluate LTBs of treatments. OBJECTIVE: The current study compares milestone survival and FPCM analyses to evaluate treatment effects of immune checkpoint inhibitor (ICI) phase III trials. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data, from initial and follow-up analyses of Keynote-045 (urothelial cancer) and Checkmate-214 (advanced renal cell carcinoma), were reconstructed for PFS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Each trial was reanalyzed using the Cox proportional hazard regression and two complementary methods (milestone survival and FPCM) to estimate treatment impact on the LTB. RESULTS AND LIMITATIONS: For each trial, there was evidence of nonproportional hazards. For the long-term analysis of the Keynote-045 trial, FPCM identified a time-dependent effect on PFS, but the Cox model found no statistical difference in PFS (hazard ratio, 0.90; 95% confidence interval, 0.75-1.08). Milestone survival and FPCM identified improvements in the LTB fractions. This was consistent with the results from the reanalysis of Keynote-045, based on the shorter follow-up, although the LTB fraction was not retained. The increase in PFS in Checkmate-214 was identified by both Cox model and FPCM. Experimental treatment-dependent improvement in the LTB fraction was demonstrated using milestone survival and FPCM. The LTB fraction estimated with FPCM was consistent with the results from the reanalysis of the shorter follow-up period. CONCLUSIONS: Although ICIs show substantial shifts toward LTBs in terms of PFS, based on a conventional Kaplan-Meier or Cox model analysis, our approach provides an alternative assessment of benefit-risk ratios for new therapeutics and facilitates communicating risk to patients. Kidney patients treated with ICIs can be counseled that they are potentially cured, but future work will need to definitively validate this conclusion. PATIENT SUMMARY: Although immune checkpoint inhibitor treatments show substantial shifts toward long-term benefits in terms of progression-free survival, a more rigorous attempt to quantify this shift, rather than simply using a Kaplan-Meier estimate or comparing progression-free survival curves using the classic Cox model, is warranted. Our results suggest that advanced renal cell carcinoma patients who had not received a previous treatment are functionally cured by nivolumab and ipilimumab, which is not the case for second-line urothelial carcinoma.

Perioperative dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin in muscle-invasive bladder cancer (VESPER): survival endpoints at 5 years in an open-label, randomised, phase 3 study.

BACKGROUND: The optimal perioperative chemotherapy for patients with muscle-invasive bladder cancer is not defined. The VESPER (French Genito-Urinary Tumor Group and French Association of Urology V05) trial reported improved 3-year progression-free survival with dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (dd-MVAC) versus gemcitabine and cisplatin (GC) in patients who received neoadjuvant therapy, but not in the overall perioperative setting. In this Article, we report on the secondary endpoints of overall survival and time to death due to bladder cancer at 5-year follow-up. METHODS: VESPER was an open-label, randomised, phase 3 trial done at 28 university hospitals or comprehensive cancer centres in France, in which adults (age ≤18 years and ≤80 years) with primary bladder cancer and histologically confirmed muscle-invasive urothelial carcinoma were randomly allocated (1:1; block size four) to treatment with dd-MVAC (every 2 weeks for a total of six cycles) or GC (every 3 weeks for a total of four cycles). Overall survival and time to death due to bladder cancer (presented as 5-year cumulative incidence of death due to bladder cancer) was analysed by intention to treat (ITT) in all randomly assigned patients. Overall survival was assessed by the Kaplan-Meier method with the treatment groups compared with log-rank test stratified for mode of administration of chemotherapy (neoadjuvant or adjuvant) and lymph node involvement. Time to death due to bladder cancer was analysed with an Aalen model for competing risks and a Fine and Gray regression model stratified for the same two covariates. Results were presented for the total perioperative population and for the neoadjuvant and adjuvant subgroups. The trial is registered with ClinicalTrials.gov, NCT01812369, and is complete. FINDINGS: From Feb 25, 2013, to March 1, 2018, 500 patients were randomly assigned, of whom 493 were included in the final ITT population (245 [50%] in the GC group and 248 [50%] in the dd-MVAC group; 408 [83%] male and 85 [17%] female). 437 (89%) patients received neoadjuvant chemotherapy. Median follow-up was 5·3 years (IQR 5·1-5·4); 190 deaths at the 5-year cutoff were reported. In the perioperative setting (total ITT population), we found no evidence of association of overall survival at 5 years with dd-MVAC treatment versus GC treatment (64% [95% CI 58-70] vs 56% [50-63], stratified hazard ratio [HRstrat] 0·79 [95% CI 0·59-1·05]). Time to death due to bladder cancer was increased in the dd-MVAC group compared with in the GC group (5-year cumulative incidence of death: 27% [95% CI 21-32] vs 40% [34-46], HRstrat 0·61 [95% CI 0·45-0·84]). In the neoadjuvant subgroup, overall survival at 5 years was improved in the dd-MVAC group versus the GC group (66% [95% CI 60-73] vs 57% [50-64], HR 0·71 [95% CI 0·52-0·97]), as was time to death due to bladder cancer (5-year cumulative incidence: 24% [18-30] vs 38% [32-45], HR 0·55 [0·39-0·78]). In the adjuvant subgroup, the results were not conclusive due to the small sample size. Bladder cancer progression was the cause of death for 157 (83%) of the 190 deaths; other causes of death included cardiovascular events (eight [4%] deaths), deaths related to chemotherapy toxicity (four [2%]), and secondary cancers (four [2%]). INTERPRETATION: Our results on overall survival at 5 years were in accordance with the primary endpoint analysis (3-year progression-free survival). We found no evidence of improved overall survival with dd-MVAC over GC in the perioperative setting, but the data support the use of six cycles of dd-MVAC over four cycles of GC in the neoadjuvant setting. These results should impact practice and future trials of immunotherapy in bladder cancer. FUNDING: French National Cancer Institute.

Management of tumor volume changes during preoperative radiotherapy for extremity soft tissue sarcoma: a new strategy of adaptive radiotherapy.

BACKGROUND: Using adaptive radiotherapy (ART), to determine objective clinical criteria that identify extremity soft tissue sarcoma (ESTS) patients requiring adaptation of their preoperative radiotherapy (RT) plan. PATIENTS AND METHODS: We included 17 patients with a lower extremity ESTS treated between 2019 and 2021 with preoperative RT, using helicoidal intensity-modulated RT (IMRT) tomotherapy, before surgical resection. We collected clinical, tumor parameters and treatment data. Repositioning was ascertained by daily Megavoltage computed tomography (MVCT) imaging. Using the PreciseART technology we retrospectively manually delineated at least one MVCT for each patient per week and recorded volume and dosimetric parameters. A greater than 5% change between target volume and planned target volume (PTV) dosimetric coverage from the initial planning CT scan to at least one MVCT was defined as clinically significant. RESULTS: All 17 patients experienced significant tumor volume changes during treatment; 7 tumors grew (41%) and 10 shrank (59%). Three patients (18%), all undifferentiated pleomorphic sarcomas (UPS) with increased volume changes, experienced significant reductions in tumor dose coverage. Seven patients required a plan adaptation, as determined by practical criteria applied in our departmental practice. Among these patients, only one ultimately experienced a significant change in PTV coverage. Three patients had a PTV decrease of coverage. Among them, 2 did not receive plan adaptation according our criteria. None of the patients with decreased tumor volumes had reduced target volume coverage. Monitoring volume variations by estimating gross tumor volume (GTV) on MVCT, in addition to axial and sagittal linear tumor dimensions, appeared to be most effective for detecting reductions in PTV coverage throughout treatment. CONCLUSIONS: Variations in ESTS volume are evident during preoperative RT, but significant dosimetric variations are rare. Specific attention should be paid to grade 2-3 UPSs during the first 2 weeks of treatment. In the absence of dedicated software in routine clinical practice, monitoring of tumor volume changes by estimating GTV may represent a useful strategy for identifying patients whose treatment needs to be replanned.

Regorafenib in patients with advanced Ewing sarcoma: results of a non-comparative, randomised, double-blind, placebo-controlled, multicentre Phase II study.

BACKGROUND: The REGOBONE multi-cohort study explored the efficacy and safety of regorafenib for patients with advanced bone sarcomas; this report details the Ewing sarcoma (ES) cohort. METHODS: Patients with relapsed ES progressing despite prior standard therapy, were randomised (2:1) to receive regorafenib or placebo. Patients on placebo could crossover to receive regorafenib after centrally confirmed progression. The primary endpoint was the progression-free rate at 8 weeks. With one-sided α of 0.05, and 80% power, at least 14/24 progression-free patients at 8 weeks were needed for success. RESULTS: From September 2014 to November 2019, 41 patients were accrued. 36 patients were evaluable for efficacy: 23 on regorafenib and 13 on placebo. Thirteen patients (56%; one-sided 95% CI [37.5%-[)) were progression-free at 8 weeks on regorafenib vs. 1 (7.7%; 95% CI [0.4%-[) on placebo. Median PFS was 11.4 weeks on regorafenib, and 3.9 weeks on placebo. Ten placebo patients crossed over to receive regorafenib after progression. The most common grade ≥3 regorafenib-related adverse events were pain (22%), asthenia (17%), thrombocytopenia (13%) and diarrhoea (13%). CONCLUSION: Although the primary endpoint was not met statistically in this randomised cohort, there is evidence to suggest that regorafenib might modestly delay tumour progression in relapsed ES after failure of prior chemotherapy.

Comprehensive analyses of immune tumor microenvironment in papillary renal cell carcinoma.

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.

Adrenal Metastases Are Associated with Poor Outcomes in Patients with Metastatic Clear Cell Renal Cell Carcinoma Treated with Nivolumab in the GETUG-AFU-26 NIVOREN Phase 2 Trial.

BACKGROUND: Glandular metastases (GMs; adrenal gland, pancreas, thyroid, ovary, breast, or prostate) are rare in metastatic clear cell renal cell carcinoma (mccRCC). Previous studies have indicated that GM patients treated with antiangiogenic therapy experience significantly longer overall survival (OS). OBJECTIVES: To assess outcomes for mccRCC with or without GMs treated with nivolumab. DESIGN, SETTING, AND PARTICIPANTS: The GETUG-AFU-26 NIVOREN phase 2 trial evaluated the activity and safety of nivolumab in patients with mccRCC who experienced failure of antiangiogenic therapies (NCT03013335). In this ancillary study, patients were divided into two groups according to the presence or absence of at least one GM. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was OS; secondary outcomes were progression-free survival (PFS) and the objective response rate (ORR). Survival was estimated using the Kaplan-Meier method. Univariate and multivariable Cox regression models are used to estimate the hazard ratio (HR) with 95% confidence interval (CI) for survival outcomes. Subgroup analyses were performed for patients with pancreatic metastases and patients with adrenal metastases. RESULTS AND LIMITATIONS: Among 720 patients treated with nivolumab between February 2016 and July 2017, 217 had GMs, of whom 151/217 had adrenal metastases and 86/217 had pancreatic metastasis. Patients with adrenal metastases had worse 12-mo OS (64% vs 71.1%) and 6-mo PFS (27.2% vs 36.6%) and a lower objective response rate (12.5%, 95% CI 7.6%-19.0%, vs 23.2%, 95% CI 19.8-27.0%; p = 0.005) than patients without adrenal metastases. Conversely, univariate analysis showed that patients with pancreatic metastases had significantly better 12-mo OS (82.3% vs 67.9%; HR 0.59, 95% CI 0.40-0.85) in comparison to patients with nonpancreatic GMs. On multivariable analysis, only adrenal metastasis remained associated with adverse prognosis. CONCLUSIONS: Adrenal metastasis is an independent prognostic factor for poor response and survival in the GETUG-AFU-26 NIVOREN trial. Limited activity with nivolumab was observed for patients with mccRCC with adrenal metastases. These results warrant an evaluation of the prognostic value of adrenal metastases in patients treated with immunotherapy combinations with ipilimumab or tyrosine kinase inhibitors. PATIENT SUMMARY: Our study showed that metastasis in the adrenal glands could be an independent factor associated with poor response to immunotherapy and survival for patients with metastatic kidney cancer. It would be useful to evaluate the prognostic value of adrenal gland metastasis in patients treated with immunotherapy combinations or immunotherapy agents combined with drugs called tyrosine kinase inhibitors.

Initial Active Surveillance Strategy for Patients with Peripheral Sporadic Primary Desmoid-Type Fibromatosis: A Multicentric Phase II Observational Trial.

BACKGROUND: Stabilization or spontaneous regressions are demonstrated in more than half of patients affected by primary desmoid-type fibromatosis (DF) in retrospective studies. The objective of this phase II study was to prospectively assess the behavior of primary sporadic DT managed by active surveillance (AS). METHODS: This prospective, multicenter, observational study (NCT01801176) included patients ≥18 years of age with primary sporadic DF located in an extremity or the abdominal/thoracic wall. At inclusion, all patients were initially placed on AS. Follow-up was based on clinical and radiological evaluation by magnetic resonance imaging (MRI) performed at 1, 3, 6, 9, and 12 months, and then every 6 months for 3 years. The primary endpoint was progression-free survival (PFS) at 3 years according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as evaluated by a Central Review Board. RESULTS: Between 2012 and 2015, 100 patients were enrolled. The female/male ratio was 8 and the median age was 34 years (interquartile range [IQR] 30.8-43.9). Median follow-up was 46.6 months (IQR 36.8-61.1) and the 3-year PFS was 53.4% (95% confidence interval 43.5-63.1%). At progression (48 patients), 23 patients received active treatment. Fifty-eight patients (58%) presented with spontaneous tumor regression (decrease > 0% compared with the initial size) during the first 3 months (n = 35, 35%) or after an initial progression (n = 23, 23%), of whom 26 (26%) had partial responses (PRs). The median time to PR was 31.7 months (25.3-not available). CONCLUSIONS: These data support the use of AS as the primary approach to select patients with peripheral DF who require aggressive treatment.

Impact of First Line Antiangiogenic Therapy Duration on Nivolumab Outcome in Metastatic Renal Cell Carcinoma Patients Treated in the GETUG-AFU 26 NIVOREN.

BACKGROUND: In metastatic renal clear cell carcinoma (ccRCC), vascular endothelial growth factor receptor (VEGFR) and immune checkpoint are 2 main therapeutic targets. We investigated the impact of duration exposure to antiangiogenic on immunotherapy clinical outcomes in metastatic ccRCC. METHODS: Patients from NIVOREN trial who received nivolumab after only 1 prior antiangiogenic therapy were included. Response rate, clinical benefit, progression free survival (PFS) and overall survival (OS) were prospectively analyzed depending on the duration of the first line (< 6 months, ≥6 months) and exploratory in patients with long first line exposure (≥18 months). The circulating levels of 8 plasma proteins and cytokines at baseline were collected and compared according to first line antiangiogenic duration. RESULTS: Among 354 patients, 127 (36%) and 227 (64%) patients had received first line antiangiogenic for < 6months and ≥ 6months respectively. Respective duration of first line therapy was not associated with objective response to nivolumab (20.5% vs. 23.9%, P = .50), or PFS (HR 0.92; P = .421). Median OS was respectively 16.6 and 31.3 months in the <6 and ≥6 months subgroups respectively. Adjusted on international metastatic renal cell carcinoma database consortium risk, age and metastatic site, OS was longer in patients with longer treatment duration in the first line setting (HR 0.73; P = .017). Duration of first line VEGFR TKI was independent from circulating levels of 8 proteins and cytokines at nivolumab baseline. CONCLUSION: Nivolumab activity in second line is independent from first-line duration of VEGFR TKI. However, first line VEGFR TKI duration ≥ 6 months is associated with longer OS.

Special features of sarcomas developed in patients with Lynch syndrome: A systematic review.

Lynch syndrome (LS) is a genetic predisposition leading to colorectal and non-colorectal tumors such as endometrial, upper urinary tract, small intestine, ovarian, gastric, biliary duct cancers and glioblastoma. Though not classically associated with LS, growing literature suggests that sarcomas might develop in patients with LS. This systematic review of literature identified 44 studies (N = 95) of LS patients who developed sarcomas. It seems that most sarcomas developed in patients with a germline mutation of MSH2 (57 %) exhibit a dMMR (81 %) or MSI (77 %) phenotype, as in other LS-tumors. Although undifferentiated pleomorphic sarcoma (UPS), leiomyosarcoma, and liposarcoma remain the most represented histologic subtype, a higher proportion of rhabdomyosarcoma (10 %, especially pleomorphic rhabdomyosarcoma) is reported. Further studies are required to better characterize this sub-population.

Mesenchymal-like Tumor Cells and Myofibroblastic Cancer-Associated Fibroblasts Are Associated with Progression and Immunotherapy Response of Clear Cell Renal Cell Carcinoma.

Immune checkpoint inhibitors (ICI) represent the cornerstone for the treatment of patients with metastatic clear cell renal cell carcinoma (ccRCC). Despite a favorable response for a subset of patients, others experience primary progressive disease, highlighting the need to precisely understand the plasticity of cancer cells and their cross-talk with the microenvironment to better predict therapeutic response and personalize treatment. Single-cell RNA sequencing of ccRCC at different disease stages and normal adjacent tissue (NAT) from patients identified 46 cell populations, including 5 tumor subpopulations, characterized by distinct transcriptional signatures representing an epithelial-to-mesenchymal transition gradient and a novel inflamed state. Deconvolution of the tumor and microenvironment signatures in public data sets and data from the BIONIKK clinical trial (NCT02960906) revealed a strong correlation between mesenchymal-like ccRCC cells and myofibroblastic cancer-associated fibroblasts (myCAF), which are both enriched in metastases and correlate with poor patient survival. Spatial transcriptomics and multiplex immune staining uncovered the spatial proximity of mesenchymal-like ccRCC cells and myCAFs at the tumor-NAT interface. Moreover, enrichment in myCAFs was associated with primary resistance to ICI therapy in the BIONIKK clinical trial. These data highlight the epithelial-mesenchymal plasticity of ccRCC cancer cells and their relationship with myCAFs, a critical component of the microenvironment associated with poor outcome and ICI resistance. SIGNIFICANCE: Single-cell and spatial transcriptomics reveal the proximity of mesenchymal tumor cells to myofibroblastic cancer-associated fibroblasts and their association with disease outcome and immune checkpoint inhibitor response in clear cell renal cell carcinoma.

Gemcitabine plus platinum-based chemotherapy in combination with bevacizumab for kidney metastatic collecting duct and medullary carcinomas: Results of a prospective phase II trial (BEVABEL-GETUG/AFU24).

BACKGROUND: Renal medullary carcinoma (RMC) and collecting duct carcinoma (CDC) are rare entities with a poor outcome. First-line metastatic treatment is based on gemcitabine + platinum chemotherapy (GC) regimen but retrospective data suggest enhanced anti-tumour activity with the addition of bevacizumab. Therefore, we performed a prospective assessment of the safety and efficacy of GC + bevacizumab in metastatic RMC/CDC. METHODS: We conducted a phase 2 open-label trial in 18 centres in France in patients with metastatic RMC/CDC and no prior systemic treatment. Patients received bevacizumab plus GC up to 6 cycles followed, for non-progressive disease, by maintenance therapy with bevacizumab until progression or unacceptable toxicity. The co-primary end-points were objective response rates (ORRs) and progression-free survival (PFS) at 6 months (ORR-6; PFS-6). PFS, overall survival (OS) and safety were secondary end-points. At interim analysis, the trial was closed due to toxicity and lack of efficacy. RESULTS: From 2015 to 2019, 34 of the 41 planned patients have been enroled. After a median follow-up of 25 months, ORR-6 and PFS-6 were 29.4% and 47.1%, respectively. Median OS was 11.1 months (95% confidence interval [CI]: 7.6-24.2). Seven patients (20.6%) discontinued bevacizumab because of toxicities (hypertension, proteinuria, colonic perforation). Grade 3-4 toxicities were reported in 82% patients, the most common being haematologic toxicities and hypertension. Two patients experienced grade 5 toxicity (subdural haematoma related to bevacizumab and encephalopathy of unknown origin). CONCLUSION: Our study showed no benefit for bevacizumab added to chemotherapy in metastatic RMC and CDC with higher than expected toxicity. Consequently, GC regimen remains a therapeutic option for RMC/CDC patients.

Population pharmacokinetic analysis reveals no impact of aprepitant on the pharmacokinetics of ifosfamide, 2-dechloroifosfamide, and 3-dechloroifosfamide.

PURPOSE: Several case reports and retrospective series have clearly pointed to the role of aprepitant, an antiemetic drug, in the development of encephalopathy when used with ifosfamide. Described as an inhibitor of several CYP metabolic pathways, aprepitant is suspected of drug-drug-interaction on ifosfamide pharmacokinetics. The pharmacokinetics of ifosfamide and two of its metabolites (2-dechloroifosfamide and 3-dechloroifosfamide) was studied in patients with soft tissue sarcomas to evaluate the impact of aprepitant administration. METHODS: A population pharmacokinetic approach was applied to analyze data obtained in 42 patients at cycle 1 (without aprepitant) and cycle 2 (with aprepitant for 34 of them). RESULTS: A previously published pharmacokinetic model including a time-dependency process well fit the data. Aprepitant had no impact on ifosfamide or its two metabolite pharmacokinetic parameters. CONCLUSION: This study suggests that aprepitant does not lead to a significant modification of ifosfamide metabolization, even though other metabolites such as 4 hydroxyifosfamide and chloroacetaldehyde were not monitored in this study.

[Endometrial stromal sarcoma: French Guidelines from the French Sarcoma Group and the Rare Malignant Gynecologic Tumors Group]. / Sarcomes du stroma endométrial de bas grade : référentiels de prise en charge du GSF-GETO/NETSARC+ et du groupe TMRG.

Low-grade endometrial stromal sarcoma (LG-ESS) accounts for approximately 15% of all uterine sarcomas. Median age of patients is around 50 years and half of the patients are premenopausal. In all, 60% of cases present with FIGO stage I disease. Preoperatively radiologic findings of ESS are not specific. Pathological diagnosis remains essential. This review aimed to present the French guidelines for low grade ESS treatment within the Groupe sarcome français - Groupe d'étude des tumeurs osseuse (GSF-GETO)/NETSARC+ and tumeur maligne rare gynécologique (TMRG) networks. Treatments should be validated in multidisciplinary team involved in sarcomas or rare gynecologic tumors. Hysterectomy is the cornerstone of treatment for localized ESS, and morcellation should be avoided. Systematic lymphadenectomy in ESS does not improve the outcome and is not recommended. Leaving the ovaries in situ in stage I tumors could be discussed for young women. Adjuvant hormonal treatment could be considered, for two years for stage I with morcellation or stage II and livelong for stages III or IV. Nevertheless, several questions remain, such as optimal doses, regimens (progestins or aromatase inhibitors) and duration of therapy. Tamoxifen is contraindicated. Secondary cytoreductive surgery if feasible for recurrent disease, appears to be an acceptable approach. Systemic treatment for recurrent or metastatic disease is mainly hormonal, with or without surgery.

Refining the Characterization and Outcome of Pathological Complete Responders after Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: Lessons from the Randomized Phase III VESPER (GETUG-AFU V05) Trial.

Neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy and pelvic lymph node dissection is the optimal treatment for patients with muscle-invasive bladder cancer. In recent years, the VESPER trial showed a statistically significant higher progression-free survival with dd-MVAC (dose dense methotrexate, vinblastine, doxorubicin, and cisplatin) compared to GC (gemcitabine and cisplatin). In the present report, we refine the characterization and outcome of patients whose cystectomy specimens were pathologically free of cancer (pathological complete response, pCR). We confirm that these patients portend a better outcome as compared to patients with invasive disease (≥pT1N0) at cystectomy. Nested variant and lymphovascular invasion were identified as adverse predictive factors of pCR. Progression-free survival probability three years after pCR on cystectomy was about 85%, regardless of the NAC regimen. A lower creatinine clearance and the delivery of less than four cycles were associated with a higher risk of relapse. Predicting the efficacy of NAC remains a major challenge. The planned analysis of molecular subtypes in the VESPER trial could help predict which patients may achieve complete response and better outcome.

Efficacy and safety of nivolumab in bone metastases from renal cell carcinoma: Results of the GETUG-AFU26-NIVOREN multicentre phase II study.

INTRODUCTION: Bone metastases (BM) in renal cell carcinoma (RCC) are associated with a poor prognosis based on retrospective studies evaluating antiangiogenic agents. Few data are available regarding immune checkpoint inhibitors (ICI) in patients with bone metastatic RCC. NIVOREN is a multicentre prospective study in which patients were treated with nivolumab after the failure of antiangiogenic agents. We aim to assess the impact of BM on prognosis, and the efficacy and safety of nivolumab in patients enrolled in the NIVOREN trial. MATERIALS AND METHODS: All patients with BM at inclusion were included in our study. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), safety, and skeletal-related events (SRE). RESULTS: Among 720 patients treated with nivolumab, 194 presented BM at inclusion. The median follow-up was 23.9 months. Median OS was 17.9 months in patients with BM versus 26.1 months in patients without BM (p = 0.0023). The difference was not statistically significant after adjustment (p = 0.0707). The median PFS was shorter in patients with BM even after adjustment (2.8 versus 4.6 months, p = 0.0045), as well as the ORR (14.8% versus 23.3%). SRE occurred for 36% of patients with BM. A post-hoc analysis evaluating the impact of bone-targeting agents (BTA) on SRE incidence showed a significant benefit of BTA on the incidence of SRE (OR = 0.367, CI95% [0.151-0.895]). CONCLUSION: Nivolumab is associated with shorter PFS, and lower ORR in RCC patients with BM. Our study suggests that BTA in association with immunotherapy decreases the incidence of SRE.

Consolidative Radiotherapy for Metastatic Urothelial Bladder Cancer Patients with No Progression and with No More than Five Residual Metastatic Lesions Following First-Line Systemic Therapy: A Retrospective Analysis.

Local consolidative radiotherapy in the treatment of metastatic malignancies has shown promising results in several types of tumors. The objective of this study was to assess consolidative radiotherapy to the bladder and to residual metastases in metastatic urothelial bladder cancer with no progression following first-line systemic therapy. MATERIALS/METHODS: Patients who received first-line therapy for the treatment of metastatic urothelial bladder cancer (mUBC) and who were progression-free following treatment with no more than five residual metastases were retrospectively identified through the database of four Comprehensive Cancer Centers, between January 2005 and December 2018. Among them, patients who received subsequent definitive radiotherapy (of EQD2Gy > 45Gy) to the bladder and residual metastases were included in the consolidative group (irradiated (IR) group), and the other patients were included in the observation group (NIR group). Progression-free survival (PFS) and overall survival (OS) were determined from the start of the first-line chemotherapy using the Kaplan-Meier method. To prevent immortal time bias, a Cox model with time-dependent covariates and 6-month landmark analyses were performed to examine OS and PFS. RESULTS: A total of 91 patients with at least stable disease following first-line therapy and with no more than five residual metastases were analyzed: 51 in the IR group and 40 in the NIR group. Metachronous metastatic disease was more frequent in the NIR group (19% vs. 5%, p = 0.02); the median number of metastases in the IR group vs. in the NIR group was 2 (1-9) vs. 3 (1-5) (p = 0.04) at metastatic presentation, and 1 (0-5) vs. 2 (0-5) (p = 0.18) after completion of chemotherapy (residual lesions), respectively. Two grade 3 toxicities (3.9%) and no grade 4 toxicity were reported in the IR group related to radiotherapy. With a median follow up of 85.9 months (95% IC (36.7; 101.6)), median OS and PFS were 21.7 months (95% IC (17.1; 29.7)) and 11.1 months (95% IC (9.9; 14.1)) for the whole cohort, respectively. In multivariable analysis, consolidative radiotherapy conferred a benefit in both PFS (HR = 0.49, p = 0.007) and OS (HR = 0.47, p = 0.015) in the whole population; in the landmark analysis at 6 months, radiotherapy was associated with improved OS (HR = 0.48, p = 0.026), with a trend for PFS (HR = 0.57, p = 0.082). CONCLUSION: Consolidative radiotherapy for mUBC patients who have not progressed after first-line therapy and with limited residual disease seems to confer both OS and PFS benefits. The role of consolidative radiotherapy in the context of avelumab maintenance should be addressed prospectively.