imDC Group Research Articles

Molecular analysis of the HCRN GU16-260-Cohort A phase II study of first-line (1L) nivolumab (nivo) and salvage nivo + ipilimumab (ipi) in patients (pts) with advanced clear cell renal cell carcinoma (accRCC).

4546 Background: Seven molecular subsets of ccRCC have been proposed: 1: Angiogenic/Stromal; 2: Angiogenic; 3: Complement/Ω-oxidation; 4: T-effector/Proliferative; 5: Proliferative; 6: Stromal/Proliferative; and 7: snoRNA (Motzer et al. Can Cell 2020). In an analysis of IMmotion 151, which compared 1L atezolizumab/bevacizumab to sunitinib, combination immune checkpoint blockade (ICB) and anti-VEGF therapy was associated with improved progression-free survival (PFS) and overall survival (OS) in clusters (CLs) 4 and 5, increased PFS in CL 7, and decreased OS in CL 2 (Motzer Can Cell 2020, Motzer JAMA Onc 2022). CL 4 was also associated with higher PFS and objective response rate (ORR) in >1L nivo compared to everolimus in an analysis of CheckMate-025 (Denize CCR 2022). To date, outcomes have not been compared among accRCC subtypes in pts who received 1L pure ICB. Methods: In HCRN GU16-260-Cohort A, pts with accRCC received 1L nivo monotherapy until progressive disease (PD), unacceptable toxicity, or completion of 96 weeks of therapy. Pre-treatment FFPE tumor samples were obtained. A machine learning model (random forest) was trained on annotated transcriptomic data from bulk RNA-seq and used to classify tumors that passed quality control into one of the 7 molecular subtypes. Results: 70 tumor samples contained adequate RNA quality and were classified as outlined in the table. IMDC rates and ORR (40%) for the RNAseq population closely matched those of the whole study (Atkins JCO 2022). No tumors were classified in CL 7 and only 3 in CL 5. Tumors in each IMDC group contained a mix of subtypes. The highest ORR occurred in CL 4 (6/10, 60.0%); CL 4 median PFS was 15.2 months and 1-year PFS was 60%. ORR was also high in CLs 1 and 3 at 52.4% and 40.0%, respectively and lowest in CL 2 (12.5%). PD as best response (5/10, 50.0%) and short PFS (5.1 months) were seen in CL 6. Conclusions: Consistent with prior analyses with combination ICB + anti-VEGF and >1L ICB, CL 4 was associated with robust 1L ICB monotherapy antitumor efficacy. Surprisingly, ORR was also high in CLs 1 and 3. In this small dataset, transcriptomic signatures enriched for but did not fully predict ORR. Future prospective trials are needed to identify more discriminative biomarkers of efficacy for pure ICB therapy.[Table: see text]

Determinants of resistance to nivolumab (nivo) monotherapy investigated through genomic and transcriptomic analysis of renal cell carcinoma (RCC) tumors from the HCRN GU16-260 study.

4524 Background: Nivo monotherapy demonstrated anti-tumor activity in treatment-naïve RCC in Part A of HCRN GU16-260 across all IMDC groups and in multiple histologies. Patient tumor samples were collected to characterize the tumor-immune microenvironmental determinants of effective anti-tumor immunity with nivo. Methods: Whole exome sequencing (WES) was performed on formalin-fixed, paraffin-embedded tissue collected within one year prior to nivo. For single-cell RNA-sequencing (scRNA-seq), eligible patients (pts) with any RCC histology underwent tumor biopsy prior to and/or at resistance to nivo monotherapy. Gene expression signatures discovered through scRNA-seq were used to interrogate previously published bulk transcriptomic data of nivo in the treatment-refractory setting. Results: WES analysis (n = 96 tumors) identified recurrent focal amplifications within chromosome 11q13 (amp11q13), which was observed in 6 of 18 (33.3%) of tumors from pts with progressive disease (PD) compared to 0 of 20 (0%) of tumors from pts with complete or partial response (CR/PR; p = 0.005). amp11q13 was associated with worse progression free survival (PFS; p = 0.008) and overall survival (OS; p = 0.010). ScRNA-seq was performed on tumors from 17 pts (8 with baseline only, 7 with progression only, and 2 with paired baseline and progression samples) across 7 trial sites. Trajectory inference analysis of tumor-infiltrating T cells revealed a bifurcating structure, starting with naïve T cells and ending either in terminally exhausted CD8+ T cells or SLAMF7+ CD8+ T cells. Surprisingly, the SLAMF7+ T cell population expressed high levels of cytotoxic genes (including GZMA, GZMB, GNLY) and markers of tissue residency ( ZNF683/HOBIT and ITGAE/CD103). Of the 14 pts with at least 100 sequenced tumor-infiltrating T cells, the presence of a higher percentage of SLAMF7+ CD8+ T cells (relative to total T cells) was associated with primary resistance to nivo (mean percentage in PD [n = 4] pts 32.7%; stable disease [n = 4] pts, 9.1%; CR/PR [n = 6] pts, 2.2%; p = 0.019 for CR/PR vs PD). Of 172 pre-treatment tumors from the nivo arms of the CheckMate-009/010/025 trials that we analyzed by bulk RNA-seq, a signature score derived using genes expressed in the SLAMF7+ CD8+ T cell trajectory branch was enriched in pts with PD compared to CR/PR as best response (p = 0.032). Conclusions: Bulk genomic and single-cell transcriptomic analyses uncovered somatic alterations (amp11q13) and infiltrating T cell populations ( SLAMF7+ CD8+) associated with resistance to frontline nivo monotherapy in a phase II study in RCC. Additional independent and functional validation studies are in progress.

Management of Metastatic Renal Cell Carcinoma in a Tertiary Care Hospital.

Background The behavior of metastatic renal cell carcinoma (mRCC) is unpredictable and elusive.International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) scores, histological subtypes, and targeted therapy predict survival and prognosis. However, there is a paucity of literature from the Indian subcontinent on mRCC outcomes. Therefore, this prospective study reports overall survival outcomes and complications due to targeted therapy of mRCC from a single tertiary care center. Methodology Between 2015 and 2020, 110 patients were included in the study. The treatment was based on the IMDC. Cytoreductive nephrectomy was done in 30 patients, and renal mass biopsy was done in 80 patients. Six were lost to follow-up after histopathological diagnosis, and targeted therapy was administered to 104 patients (sunitinib in 41, sorafenib in 33, and pazopanib in 30). During targeted therapy, six died within 30 days of treatment. The overall survival outcomes and complications due to targeted therapy were analyzed. Results The mean overall survival was 21.52 months with a 95% confidence interval of 17.04-25.98 months. Six variables significantly correlated with inferior survival in univariable Cox regression analysis. Weight loss, hemoglobin, platelet count, lung metastasis, and ≥2 visceral metastases were associated with poor outcomes. Performance status >2 and lung metastasis predicted poor outcomes in multivariate analysis. Overall survival was 24.52 months in clear cell carcinoma versus 21.39 months (13.32-29.45 months) in papillary cell carcinoma, which was not significant. Conclusions IMDC groups show significant differences in overall survival.The histological subtypes and types of targeted therapy did not differ in overall survival, and the presence of sarcomatoid differentiation correlated with poor prognosis concerning IMDC.

Examination of resistance to nivolumab monotherapy through single-cell analysis of tumors from patients enrolled in the HCRN GU16-260 study of nivolumab monotherapy.

698 Background: Nivolumab (nivo) monotherapy demonstrated anti-tumor activity in treatment-naïve renal cell carcinoma (RCC) in Part A of HCRN GU16-260 across all IMDC groups and in multiple histologies. Patient tumor samples were collected to characterize the tumor-immune microenvironmental (TME) determinants of effective anti-tumor immunity with nivo. Methods: Eligible patients (with clear cell or non-clear cell histology) underwent tumor biopsy prior to and/or at resistance to nivo monotherapy. Fresh tissue fragments were cryopreserved locally and centrally processed to extract viable single-cells from the RCC TME. Single-cell RNA-sequencing (scRNA-seq) and T cell receptor (TCR)-sequencing (scTCR-seq) was performed on all tumor samples. Gene expression signatures discovered through scRNA-seq were used to interrogate previously published bulk transcriptomic data from the CheckMate-009/010/025 trials of nivo in the treatment-refractory setting. Results: In total, 72,730 viable single-cells (56,900 immune and 15,830 tumor or stromal cells) were sequenced from 17 patients (8 with baseline only, 7 with progression only, and 2 with paired baseline and progression samples) across 7 trial sites. Trajectory inference analysis of tumor-infiltrating T cells revealed a bifurcating trajectory, starting with naïve T cells and ending either in PMCH+ terminally exhausted CD8+ T cells or SLAMF7+ CD8+ T cells. Notably, the SLAMF7+ T cell population expressed high levels of cytotoxic genes (including GZMA, GZMB, GNLY) and markers of tissue residency ( ZNF683/HOBIT and ITGAE/CD103), and had a restricted TCR diversity (normalized Shannon index = 0.57). Among patients with at least 100 sequenced T cells (n = 14), a higher percentage of SLAMF7+ CD8+ T cells (relative to total T cells) was associated with primary resistance (progressive disease [PD] as best response) to nivo (mean percentage in PD [n = 4] patients 32.7%; stable disease [n = 4] patients, 9.1%; complete or partial response [CR/PR; n = 6] patients, 2.2%; p = 0.019 for CR/PR vs PD). A signature derived using genes expressed in the T cell trajectory branch containing the SLAMF7+ CD8+ T cell population was used to interrogate bulk RNA-seq data from 172 pre-treatment tumors from the nivo arms of the CheckMate-009/010/025 trials. The signature score was enriched in patients with PD compared to CR/PR as best response (p = 0.032). Analysis of bulk whole exome sequencing and RNA-seq from patients enrolled in the HCRN GU16-260 is pending. Conclusions: Single-cell transcriptomic analysis uncovered a SLAMF7+ CD8 + T cell population with markers of cytotoxicity and tissue residency that was associated with resistance to nivo monotherapy in RCC. Further, the study highlights that scRNA-seq is a viable scientific strategy for deep correlative analysis in multicenter clinical trials.

Evaluation of PBRM1, PD-L1, CD31, and CD4/CD8 ratio as a predictive signature of response to VEGFR-TKI–based therapy in patients with metastatic renal cell carcinoma (mRCC) with IMDC intermediate prognosis: Results from the APAChE-I Study.

714 Background: Intermediate IMDC group is the largest and most heterogeneous group of mRCC. Current first-line (1L) therapy options for these patients (pts) are based on either an anti-angiogenic agent (VEGFR-TKI) combined with immunotherapy (IO), or a combo of IO (ipilimumab+nivolumab [I/N]). No biomarkers (BM) for selecting the most effective regimen have been identified so far. Methods: Immunohistochemical expression of PBRM1, PD-L1, CD31, and CD4/CD8 ratio was evaluated on histological samples of intermediate-risk mRCC pts treated with VEGFR-TKI monotherapy, and then in pts receiving a VEGFR-TKI-based therapy or the immune doublet I/N. PBRM1 positivity score was based on the percentage of positive cells and on the intensity of nuclear expression; PD-L1 positivity was defined as CPS≥10; CD31 high-density had moderate to strong nuclear staining; and the CD4/CD8 ratio cut-off for positivity was >0.2. Cox model was used to assess the correlation between BM and outcomes; PFS and OS were estimated by Kaplan-Meier method. Results: After screening of tumor tissues from 150 pts, a total of 111 were included in the final analysis (Table). In pts treated with VEGFR-TKI monotherapy, a significant correlation with PFS was observed with loss of PBRM1 expression (HR 0.58, p=0.035), PD-L1 negativity (HR 0.44, p=0.048), and high CD4/CD8 ratio (HR 0.62, p=0.073). CD31 density did not significantly correlate with PFS. A profile potentially predictive of angiogenesis (AP+) was defined based on the PBRM1 loss, PD-L1 negative, and high CD4/CD8. In pts treated with VEGFR-TKI monotherapy, tumors with the AP+ (43% of all cases) had a significantly longer median PFS (mPFS 23.8 vs. 11.8 months, p=0.003) and mOS (41.5 vs. 26.9 months, p=0.024) compared to the others. The AP+ retained its significant correlation with PFS (mPFS 23.8 vs. 11.1 months, p<0.001) and OS (41.5 vs. 24.9, p=0.006) in pts receiving VEGFR-TKI-based therapies. The rate of AP+ tumors was 55.6% and 32.7% in pts with one or two IMDC risk factors, respectively (p=0.022). In the small cohort of pts treated with I/N, no differences were observed in PFS (p=0.64) and OS (p=0.75) between AP+ and AP-negative. Conclusions: The AP+ signature (loss of PBRM1, PD-L1 negative, and CD4/CD8 high ratio) was associated with improved clinical outcomes in mRCC pts at IMDC intermediate prognosis treated with VEGFR-TKI-based therapy; this correlation was significant regardless from the addition of IO to VEGFR-TKI monotherapy. Prospective validation of this signature is required for guiding the selection of the most appropriate 1L therapy. [Table: see text]

CABOSEQ: The Effectiveness of Cabozantinib in Patients With Treatment Refractory Advanced Renal Cell Carcinoma: Results From the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

There are limited data evaluating the activity of cabozantinib (CABO) as second line (2L) therapy post standard of care ipilimumab-nivolumab (IPI-NIVO) or immuno-oncology(IO)/vascular endothelial growth factor inhibitor (VEGFi) combinations (IOVE). Using the IMDC database, we sought to identify the objective response rate, time to treatment failure (TTF) and overall survival (OS) of 2L CABO after IPI-NIVO, IOVE combinations, pazopanib or sunitinib (PAZ/SUN) or other first line (1L) therapies. Multivariable Cox regression, adjusted for underlying differences in IMDC groups, was used to compare differences in OS for 2L CABO based on preceding therapy. Three hundred and forty-six patients received 2L CABO (78 post IPI NIVO, 46 post IOVE, 161 post PAZ/SUN, 61 post Other). Of the entire cohort, 12.6%, 62.6%, and 24.8% were IMDC favourable, intermediate, and poor risk, respectively. Patients that received 1L IPI-NIVO had a median OS of 21.4 (95% CI, 12.1 - NE [Not evaluable]) months compared to 15.7 (95% CI, 9.3 - NE) months in 1L IOVE and 20.7 (95% CI, 15.6 - 35.6) months in 1L PAZ/SUN, P=.28. Median TTF from the initiation of 2L CABO in the overall population was 7.6 (95% CI, 6.6 - 9.0) months. We were unable to detect a significant difference in 2L CABO OS based on type of 1L therapy received: 1L IPI-NIVO (reference group) vs. 1L IOVE HR 1.73 (95% CI, 0.83 - 3.62 P=.14), 1L PAZ/SUN 1.16 (95% CI, 0.67 - 2.00 P=.60), however given the retrospective observational nature of this work a lack of sufficient power may contribute to this. In a large real world dataset, we identified clinically meaningful activity of 2L CABO after all evaluated contemporary 1L therapies, irrespective of whether the 1L regimen included a VEGFi. These are real world benchmarks with which to counsel our patients.

1463P Patterns of care and outcomes of metastatic renal cell carcinoma (mRCC) patients (pts) with bone metastases (BM): A UK multicenter review

BMs are associated with higher morbidity and mortality in mRCC patients. With the evolution of systemic therapies (ST), we conducted a UK multicentre retrospective review of outcomes in mRCC pts with BM. 1246 mRCC pts data from 15 UK centres, who commenced first line ST between 01/01/18 and 30/06/21 were reviewed. Data on BM, IMDC scores, ST, local therapies (LT) were collected. Progression free survival (PFS) & Overall survival (OS) were calculated as time between start of 1st ST and subsequent ST/ date of progression & date of death/last follow-up, respectively. PFS & OS were analysed using Kaplan Meier Analyses (log rank test). 353 (28%) pts had BM (62 bone only; 291 bone & visceral mets) with a median age of 65 (range: 27-90). 102 pts had LT (resection-25, stereotactic radiotherapy (RT)-4, palliative RT-72, vertebroplasty-1). 20 patients presented with cord compression. The IMDC risk groupings were favourable 48, intermediate 195, and poor 109. Pts just receiving 1, 2, 3 or more lines of ST were 171, 125, & 55, respectively. PFS was similar for the different ST (tyrosine kinase inhibitors (TKI), immunotherapy (IO), IO/TKI) either in 1st, 2nd or 3rd line therapies, or between patients with bone only or bone & visceral metastases (all risk groups). In intermediate & poor risk groups there was a trend in favour of PFS advantage with single agent TKI or IO/TKI compared to IO/IO (Table). The median OS of all BM pts was 21. The OS was significantly longer in the favourable IMDC group (favourable-34.4m vs. intermediate-24m vs. poor-8.7m; p<0.0001), pts with prior nephrectomy (32.7 vs. 16.4m; p<0.0001) and pts with bone only metastases (29.9 vs.19.7m; p<0.05).Table: 1463PMedian PFS: Intermediate & poor risk ptsCabozantinibOther TKIIpi/NivoIO/TKINivoBone only metastases (n=51)First-line17.114.64.614.7Second-lineNot reached9.1--2.1Bone + visceral metastases (n=254)First-line8.95.67.18.8Second-line7.16.1--3.6 Open table in a new tab Our analyses indicate that TKIs remain a standard of care in mRCC pts with BM and OS is consistent with published literature. The PFS in intermediate and poor risk mRCC pts with BM favours TKI based ST compared to IO/IO treatment.

Efficacy and safety of nivolumab in renal cell carcinoma patients with BONE metastases: Results of the GETUG: AFU 26 nivoren multicenter phase II study.

342 Background: Bone metastases (BM) in renal cell carcinoma (RCC) are associated with a poor prognosis based on retrospective studies in which patients were treated with antiangiogenic agents. Since the development of immune checkpoint inhibitors, few data are available regarding the prognosis impact of BM or the efficacy and safety of checkpoint inhibitors in patients with bones metastatic RCC. GETUG-AFU26-NIVOREN (NIVOREN) is a French multicenter prospective study in which patients were treated with nivolumab after failure of one or more antiangiogenic tyrosine kinase inhibitors. We therefore aim to evaluate the impact of BM on prognosis, and the efficacy and safety of nivolumab in patients with BM enrolled in NIVOREN trial. Methods: All adult patients with BM at inclusion were included in our study. The primary endpoint of this ancillary study was overall survival (OS). Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), safety, and skeletal-related events (SRE) in patients with BM. Clinical data were collected prospectively, except for SRE data which were collected retrospectively in a complementary consent report form. Results: Among 720 patients treated with nivolumab in the NIVOREN study, 194 had BM at inclusion. After a median follow-up of 23.9 months, the median OS was 17.9 months in patients with BM versus 26.1 months in patients without BM (HR = 1.42 CI95% [1.13-1.79], p = 0.0023). After adjustment on sex, age, IMDC group and line of treatments, the difference was not significant (HR = 1.24, CI95% [0.98-1.56], p = 0.0707). The median PFS was shorter in patients with BM even after adjustment (2.8 versus 4.6 months, HR = 1.30 CI95% [1.08-1.56]), as well as the ORR (14.8% versus 23.3%). The safety profile was similar between patients with or without BM at inclusion. The incidence of SRE in the BM population was 36% during the treatment period with nivolumab. A post-hoc analysis evaluating the impact of bone-targeting agents in association with nivolumab on SRE incidence was performed. There was a statistically significant benefit in patients treated with bone-targeting agents on the incidence of SRE (OR = 0.367, CI95% [0.151-0.895], p = 0.0276). Conclusions: Nivolumab is associated with shorter OS, PFS, and lower ORR in patients with BM. Our study confirms, in the era of immunotherapy that patients with BM are associated with poorer prognosis and suggests that association with bone-targeting agents decreases the incidence of SRE. Clinical trial information: 2015-004117-24.

Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced clear cell renal cell (HCRN GU16-260-Cohort A): Final report.

288 Background: Nivolumab (nivo) is FDA approved for patients (pts) with VEGFR TKI-resistant RCC and the nivo + ipilimumab (nivo/ipi) combination is FDA approved for treatment naïve pts with IMDC intermediate and poor risk renal cell carcinoma (RCC). Little information was available on the efficacy and toxicity of nivo monotherapy in treatment naïve RCC or the efficacy of nivo/ipi salvage in pts with tumors resistant to initial nivo monotherapy. Methods: Eligible pts with treatment naïve RCC received nivo 240mg IV q2 wk x 6 doses followed by 360mg IV q3 wk x 4 doses followed by 480 mg q4 wk until progressive disease (PD), toxicity, or completion of 96 wks of treatment (Part A). Pts with PD prior to, or stable disease (SD) at 48 wks (pSD) were potentially eligible to receive salvage nivo (3mg/kg)/ipi (1 mg/kg) q3 wk x 4 doses followed by q4 wk nivo maintenance for up to 48 wks (Part B). All pts were required to submit tissue from a metastatic lesion obtained within 12 months (mos) prior to study entry and prior to Part B for correlative studies. Results: 123 pts with clear cell(cc) RCC were enrolled between 5/2017 and 12/2019 at 12 participating HCRN sites. Data lock was 04/07/2021. Median Follow-up 26.9 mos. Median age 65 (32-86) years; 72% male. IMDC risk: favorable (Fav) 35 (28%), intermediate (I) 76 (62%) and poor (P) 12 (10%). 22 (18%) had a component of sarcomatoid histology (SARC). RECIST defined ORR was: 34.1% (25.8-43.2%) (CR 6.5%, PR 27.6%), SD 47 (35.8%). ORR by irRECIST was 39%. ORR by IMDC was: Fav 20/35 (57.1%) (39-74%), (I/P) 22/88 (25%) and for SARC 36.4%. ORR by PD-L1 status was 21/78 (27%), 8/16 (50%) and 6/8 (75%) for pts with tumor PD-L1 of 0, 1-20 or &gt; 20%, respectively (trend test p-value 0.002). 5/7 (71.4%) Fav pts with PD-L1 &gt; 1 responded. Median DOR was 27.6 (13.7, NA) mos with 26/42 responders including 17/20 (85%) with Fav Risk remaining progression free. Median PFS was 8.2 (5.5, 10.9) mos; (30.3 for IMDC Fav and 5.4 for I/P). 91 pts remain alive with 24 mos OS rate of 78%. 65 patients (59 PD, 6 pSD) were potentially eligible for salvage nivo/ipi (Part B), but 25 did not enroll due to symptomatic PD (6), grade 3-4 toxicity on nivo (17), or other (2) and 5 were not treated due to inability to confirm residual disease on a biopsy. ORR for Part B by RECIST was 11.4% (4/35) and by irRECIST 17.2%. Grade 3-5 treatment-related AEs (TrAE) (not including asymptomatic amylase/lipase) were seen in 20.3% in Part A and 14.2% in Part B with 1 death in each cohort. Conclusions: Nivo monotherapy is active in treatment naïve ccRCC across all IMDC groups. Although efficacy appears less than combination nivo/ipi in I/P pts, Fav pts had a notably high ORR and DOR. Efficacy appeared to correlate with tumor PD-L1 status, although at least half the responders had a tumor PD-L1 of 0. Salvage treatment with nivo/ipi after nivo was frequently not feasible and of limited benefit. Clinical trial information: NCT03117309.

PD40-08 DOES THE TIME BEFORE STARTING FIRST-LINE TREATMENT INFLUENCES THE SURVIVAL OF PATIENTS WITH METASTATIC RENAL CELL CANCER IN FAVORABLE-RISK GROUPS?

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) II (PD40)1 Sep 2021PD40-08 DOES THE TIME BEFORE STARTING FIRST-LINE TREATMENT INFLUENCES THE SURVIVAL OF PATIENTS WITH METASTATIC RENAL CELL CANCER IN FAVORABLE-RISK GROUPS? Cyrielle Rolley, Marie Cruz, François-Xavier Nouhaud, Arnaud Villers, Karim Bensalah, Franck Bruyere, Solene Ricard, Jean-Christophe Bernhard, and Pierre Bigot Cyrielle RolleyCyrielle Rolley More articles by this author , Marie CruzMarie Cruz More articles by this author , François-Xavier NouhaudFrançois-Xavier Nouhaud More articles by this author , Arnaud VillersArnaud Villers More articles by this author , Karim BensalahKarim Bensalah More articles by this author , Franck BruyereFranck Bruyere More articles by this author , Solene RicardSolene Ricard More articles by this author , Jean-Christophe BernhardJean-Christophe Bernhard More articles by this author , and Pierre BigotPierre Bigot More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002050.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: RCC Data Base Consortium (IMDC). Patients in the favorable IMDC group (F-MRC) have a slow metastatic course and seem to have a poorer response to immunotherapy. Delayed treatment could be a good option in this specific population. A deferred treatment allows: to preserve the quality of life, to avoid side effects, to limit costs, and to delay the occurrence of resistance to treatments. The main objective of this study was to determine if the time before starting first-line treatment influences the survival of patients in the F-MRC group. METHODS: We performed a multicenter national study involving the French Network for Research on Kidney Cancer (UroCCR (NCT03293563)). We included treatment naive F-MRC patients. The initiation of first line treatment was left to the discretion of each physician after a multidisciplinary uro-oncology committee discussion about the treatment strategy. We compared the overall survival between patients with immediate medical treatment (IMT) (started less than 3 months after metastatic diagnosis) and delayed medical treatment (DMT). RESULTS: We included 90 patients treated between 2000 and 2018. The median age was 63 (32-83) years. The median time before occurrence of metastases was 28 (11-137) months. 78 (86.7%) patients had a clear renal cell carcinoma and 29 (32%) patients had a unique site of metastases. IMT was given in 26 (28.8%) patients. Local treatment of metastasis (LTM) was performed in 44 (48%) patients with: 32 (36%) metastasectomy, 8 (8.9%) ablative therapy and 14 (15.9%) radiotherapy. After a median follow-up of 59.5 (11 - 189) months after metastasis diagnosis: 19 (21.1%) patients died. Among patients with DMT, only 26 (40.6%) received a medical treatment with a median time before treatment of 19 (4-77) months. The two groups (IMT vs DMT) were comparable for follow-up, age, sarcomatoid feature, number of metastatic sites and ECOG performans status. Patients with DMT had more LTM (57% vs 27%, p=0.01). Median overall survival was 78 months in the IMT group and 135 months in the DMT group (p=0.067). In multivariable analysis LTM was the only prognostic factor for survival (HR: 0.32; p=0.032). CONCLUSIONS: Patients with F-MRC can safely undergo DMT. LTM positively impacted survival in this population and should be considered whenever possible. Prospective trial with a larger population is needed to confirm these outcomes. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e677-e677 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Cyrielle Rolley More articles by this author Marie Cruz More articles by this author François-Xavier Nouhaud More articles by this author Arnaud Villers More articles by this author Karim Bensalah More articles by this author Franck Bruyere More articles by this author Solene Ricard More articles by this author Jean-Christophe Bernhard More articles by this author Pierre Bigot More articles by this author Expand All Advertisement Loading ...

Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced renal cell carcinoma (RCC) (HCRN GU16-260).

5006 Background: Nivolumab (nivo) is FDA approved for pts with VEGFR TKI-resistant RCC and the nivo + ipilimumab (nivo/ipi) combination is FDA approved for treatment naïve pts with IMDC intermediate and poor risk RCC. Little information is available on the efficacy and toxicity of nivo monotherapy in treatment naïve RCC or the efficacy of nivo/ipi salvage therapy in pts with tumors resistant to initial nivo monotherapy. Methods: Eligible pts with treatment naïve RCC received nivo 240mg IV q2 wk x 6 doses followed by 360mg IV q3 wk x 4 doses followed by 480 mg q4 wk until progressive disease (PD), toxicity, or completion of 96 wks of treatment (Part A). Pts with PD prior to or stable disease (SD) at 48 wks (pSD) were potentially eligible to receive salvage nivo (3mg/kg) /ipi (1 mg/kg) q3 wk x 4 doses followed by q4 wk nivo maintenance for up to 48 wks (Part B). All pts were required to submit tissue from a metastatic lesion obtained within 12 months (mo) prior to study entry and prior to Part B. Pathology specimens will be analyzed by immunohistochemistry, quantitative immunofluorescence, WES and RNAseq with results linked to clinical outcome. Results: 123 pts with clear cell(cc) RCC were enrolled between 5/2017 and 12/2019 at 12 participating HCRN sites. Median age 65 (range 32-86 years); 72% male. IMDC favorable 30 (25%), intermediate 79 (65%) and poor risk 12 (10%). 22 (18%) had a component of sarcomatoid histology (SARC). 117 pts are currently evaluable for response. RECIST defined ORR was: 34 (29.3%)[CR 5 (4.3%), PR 29 (24.8%)], SD 47 (40.2%), PD 36 (30.7%). ORR by irRECIST was 35%. ORR by IMDC was: favorable 12/29 (41.4%), intermediate/poor 22/87 (25.3%) and for SARC 6/22 (27.3%). Median DOR is 13.8 (10.9, NA) mo. Median PFS is 7.4 (5.5, 10.9) mo. 110 pts remain alive. 60 pts (54 PD, 6 pSD) to date were potentially eligible for salvage nivo/ipi (Part B), but 28 did not enroll due to symptomatic PD (17), grade 3-4 toxicity on nivo (8), other (3). 27 of 32 Part B pts are currently evaluable for efficacy and 30 for toxicity. Best response to nivo/ipi was PR (11%), SD (30%), PD (59%). ORR by irRECIST was 19%. Grade 3-5 Treatment-related AEs (TrAE) were seen in 35/123 (28)% on nivo with 1 death due to respiratory failure. Grade 3-4 TrAE were seen in 10/30 (33%) on nivo/ipi with 0 deaths. Correlative studies are pending. Conclusions: Nivo monotherapy is active in treatment naïve ccRCC across all IMDC groups. Toxicity is consistent with prior nivo studies. Salvage treatment with nivo/ipi after nivo monotherapy was feasible in 53% of pts with PD/pSD, with 11% responding. Clinical trial information: NCT03117309 .

Baseline and early change of neutrophil to lymphocyte ratio (bNLR and ΔNLR) as prognostic factors in metastatic renal cell carcinoma (mRCC) treated with Nivolumab: Final results of the Meet-URO 15 (I-BIO-REC) study.

e17081 Background: Biomarkers to select mRCC patients most likely to benefit to immunotherapy are needed. The retrospective multicentre Meet-URO-15 study evaluated the prognostic role of peripheral blood cells in mRCC patients treated with Nivolumab. Methods: Complete blood count was assessed at the first four cycles of Nivolumab. The primary endpoint was median overall survival (mOS) according to bNLR. NLR was defined as neutrophil / lymphocyte (cutoff = 3) and ΔNLR the difference between NLR at 2nd cycle and bNLR (median as cutoff = 1.1). Results: From October 2015 to October 2019, 470 patients started Nivolumab as 2nd (67%), 3rd (22%) and &gt; 3rd (11%) line. Median age was 66 years, 71% were male and 83% had clear cell histology. Baseline IMDC group was favorable in 25%, intermediate in 63% and poor in 12%. Lymph-nodes, visceral and bone metastases were present in 54%, 91% and 36%. mOS and progression-free survival (PFS) were 34.8 and 7.5 months. Overall response rate (ORR) and disease control rate (DCR) were 30% and 61%. bNLR was available in 404 patients: bNLR &lt; 3 (54%) correlated with statistically significant longer PFS [11.4 vs 5.4 months; HR 1.69 (1.33-2.15)] and OS [46.2 vs 17.2 months; HR 2.37 (1.72-3.26)] (both p&lt; 0.001), with similar ORR (35% vs 30%, p= 0.28) but higher DCR (71% vs 52%, p&lt; 0.001). ΔNLR was available in 360 patients: ΔNLR &lt; 1.1 (73%) correlated with a statistically significant improvement of PFS [11.2 vs 4.9 months; HR 1.53 (1.16-2.03), p= 0.03], OS [Not Reached vs 19.7 months; HR 1.83 (1.28-2.61), p= 0.001], ORR (37% vs 23%, p= 0.011) and DCR (68% vs 53%, p= 0.008). Multivariate analyses adjusted for IMDC group, line of therapy and metastatic sites, confirmed the statistically significant correlation of bNLR and ΔNLR with OS, PFS and DCR. Conclusions: Our study showed the statistically significant correlation of lower bNLR and early ΔNLR with longer OS, PFS and higher DCR in mRCC patients treated with Nivolumab.

Baseline and early change of systemic inflammation index (bSII and ΔSII) as prognostic factors in metastatic renal cell carcinoma (mRCC) patients treated with Nivolumab: Final results of the Meet-URO 15 (I-BIO-REC) study.

5072 Background: Biomarkers to select mRCC patients most likely to benefit to immunotherapy are still needed. The retrospective multicentre Meet-URO-15 study evaluated the prognostic role of peripheral blood cells in mRCC patients treated with Nivolumab. Methods: Complete blood count was collected at the first four cycles of Nivolumab. The primary endpoint was median overall survival (mOS) according to baseline neutrophil-to-lymphocyte ratio. Secondary analyses included bSII defined as platelet x NLR (cutoff = 1375) and ΔSII defined as the difference between SII at 2ndcycle and bSII (median used as cutoff = 383). Results: From October 2015 to October 2019, 470 patients started Nivolumab as 2nd(67%), 3rd(22%) and &gt; 3rd(11%) line. Median age was 66 years, 71% were male and 83% had clear cell histology. Baseline IMDC group was favorable in 25%, intermediate in 63% and poor in 12%. Lymph-nodes, visceral and bone metastases were present in 54%, 91% and 36%. mOS and progression-free survival (PFS) were 34.8 and 7.5 months. Overall response rate (ORR) and disease control rate (DCR) were 30% and 61%. SII was available in 404 patients: SII &lt; 1375 (82%) correlated with statistically significant improvement of PFS [10.2 vs 4.1 months, HR 2.06 (1.54-2.76), p&lt; 0.001], OS [46.2 vs 9.5 months, HR 3.16 (2.23-4.49), p&lt; 0.001], ORR (35% vs 21%, p= 0.035) and DCR (67% vs 40%, p&lt; 0.001). ΔSII was available in 360 patients: ΔSII &lt; 383 (75%) correlated with statistically significant improvement of PFS [11.3 vs 4.7 months; HR 1.64 (1.23-2.18), p= 0.001] and OS [NR vs 21.1 months; HR 1.76 (1.21-2.56), p= 0.003], ORR (37% vs 24%, p= 0.023) and DCR (68% vs 53%, p= 0.01). Multivariate analyses adjusted for IMDC group, line of therapy and metastatic sites, confirmed the statistically significant correlation of bSII and ΔSII with OS, PFS and DCR. Conclusions: Our study showed the statistically significant correlation of lower bSII and early ΔSII with longer OS, PFS and higher DCR in mRCC patients treated with Nivolumab.

Outcomes in Black and White Patients With Metastatic Renal Cell Carcinoma Treated With First-Line Tyrosine Kinase Inhibitors: Insights From Two Large Cohorts.

PURPOSETo investigate whether black race is an independent predictor of overall survival (OS) in metastatic renal cell carcinoma (mRCC).METHODSWe performed a retrospective 2-cohort (International Metastatic Renal Cell Carcinoma Database Consortium [IMDC] and trial-database) study of patients with mRCC treated with first-line tyrosine kinase inhibitors (TKIs). Unmatched (UM) and matched (M) analyses accounting for imbalances in region, year of treatment, age, and sex between races were performed. Cox models adjusting for histology, number of metastatic sites, nephrectomy, and IMDC risk compared time to treatment failure (TTF; IMDC cohort), progression-free survival (PFS; trial-database cohort), and OS.RESULTSThe IMDC cohort included 73 black versus 3,381 (UM) and 1,236 (M) white patients. The trial-database cohort included 21 black versus 1,040 (UM) and 431 (M) white patients. Median OS for black versus white patients was 18.5 versus 25.8 months in the IMDC group and 21.0 versus 25.6 months in the trial-database group. Differences in OS were not significant in multivariable analysis in the IMDC group (hazard ratio [HR]M, 1.0; 95% CI, 0.7 to 1.5; HRUM, 1.1; 95% CI, 0.8 to 1.4) and trial-database (HRM, 1.5; 95% CI, 0.8 to 2.7; HRUM, 1.4; 95% CI, 0.8 to 2.6) cohorts. TTF for black patients was shorter in the UM IMDC cohort (HRUM, 1.4; 95% CI, 1.1 to 1.8; P = .003), but not in the M analysis. PFS was shorter for black patients in both analyses in the trial-database cohort (HRM, 2.3; 95% CI, 1.4 to 3.9; P = .002; HRUM, 2.3; 95% CI, 1.4 to 3.9; P = .002).CONCLUSIONBlack patients had more IMDC risk factors and worse outcomes with TKIs versus white patients. Race was not an independent predictor of OS. Strategies to understand biologic determinants of outcomes for minority patients are needed to optimize care.

Baseline and early change of neutrophil to lymphocyte ratio (bNLR and ΔNLR) as prognostic factors in metastatic renal cell carcinoma (mRCC) patients treated with nivolumab: Preliminary results of the Meet-URO 15 (I-BIO-REC) study.

752 Background: Biomarkers to select mRCC patients most likely to benefit to immune-checkpoint inhibitors are still needed. The ongoing retrospective multicentre Meet-URO 15 (I-BIO-REC) study evaluates the prognostic role of peripheral blood cells in mRCC patients treated with nivolumab. Methods:The primary endpoint of the study was median overall survival (mOS) according to bNLR. Complete blood count was collected at the first four cycles of nivolumab. NLR was defined as the ratio of neutrophil to lymphocyte (cutoff = 3) and ΔNLR the difference between NLR at 2nd cycle and bNLR (median used as cutoff = 0.3). Here we reported preliminary analyses on bNLR and DNLR. Results: From May 2016 to January 2019 189 patients started nivolumab as 2nd (62%), 3rd (25%) and &gt; 3rd (13%) line. Median age was 69 years, 67% were male and 87% had clear cell histology. Baseline IMDC group was favorable in 26%, intermediate in 63% and poor in 11%. Lymph-nodes, visceral and bone metastases were present in 55%, 92% and 37%. mOS and progression-free survival (PFS) were 30.5 months and 9.5 months. Overall response rate (ORR) and disease control rate (DCR) were 28% and 57%. bNLR was available in 162 patients: bNLR &lt; 3 (52%) correlated with statistically significant longer PFS [11.5 vs 5.6 months; HR 1.61 (1.09-2.39), p = 0.017] and OS [NR vs 22.4 months; HR 2.61 (1.53-4.46), p &lt; 0.001], with similar ORR (32% vs 32%) but higher DCR (66% vs 55%) compared to NLR ≥ 3. ΔNLR was available in 136 patients: ΔNLR &lt; 0.3 (50%) correlated with statistically significant longer PFS [17.1 vs 8.5 months; HR 1.57 (1.02-2.43) p = 0.04] and OS [medians not reached; HR 1.91 (1.04-3.51) p = 0.038], with similar ORR (39% vs 32%) but higher DCR (73% vs 56%) compared to ΔNLR ≥ 0.3. Univariate and multivariate analyses adjusted for IMDC group, line of therapy and metastatic sites, confirmed the statistically significant correlation between ΔNLR with PFS and OS and NLR with OS but not with PFS. Conclusions: Preliminary analyses of our study showed a prognostic role of bNLR and early ΔNLR in mRCC patients treated with nivolumab.

Baseline lymphocyte to monocyte ratio (LMR) and systemic inflammation index (SII) as prognostic factors in metastatic renal cell carcinoma (mRCC) patients treated with nivolumab: Preliminary results of the Meet-URO 15 (I-BIO-REC) study.

751 Background: Biomarkers to select mRCC patients most likely to benefit to immune-checkpoint inhibitors are still needed. The ongoing retrospective multicentre Meet-URO 15 (I-BIO-REC) study evaluates the prognostic role of peripheral blood cells in mRCC patients treated with nivolumab. Methods:The primary endpoint of the study was median overall survival (mOS) according to baseline neutrophil to lymphocyte ratio (NLR), but here preliminary analyses on baseline LMR and SII (secondary endpoints) are reported. LMR was defined as the ratio of lymphocyte to monocyte (cutoff = 3) and SII as platelet x neutrophil/lymphocyte (cutoff = 1375). Results: From May 2016 to January 2019 189 patients started nivolumab as 2nd (62%), 3rd (25%) and &gt; 3rd (13%) line. Median age was 69 years, 67% were male and 87% had clear cell histology. Baseline IMDC group was favorable in 26%, intermediate in 63% and poor in 11%. Lymph-nodes, visceral and bone metastases were present in 55%, 92% and 37%. mOS and progression-free survival (PFS) were 30.5 months and 9.5 months. Overall response rate (ORR) and disease control rate (DCR) were 28% and 57%. LMR was available in 150 patients: LMR ≥ 3 (44%) correlated with statistically significant longer OS [NR vs 26.8 months, HR 0.50 (0.29-0.88); p = 0.016] but not PFS (10.3 vs 9.9 months, HR 0.87 (0.58-1.31); p = 0.5) with similar ORR (34% vs 33%) and DCR (60% vs 63%) compared to LMR &lt; 3. SII was available in 162 patients. SII &lt; 1375 (82%) correlated with statistically significant longer PFS [11.5 vs 3.4 months; HR 2.16 (1.36-3.43), p = 0.001] and OS [NR vs 9.5 months; HR 3.87 (2.21-6.78), p &lt; 0.001] with higher ORR (35% vs 20%) and DCR (65% vs 40%) compared to SII ≥ 1375. Univariate and multivariate analyses adjusted for IMDC group, line of therapy and metastatic sites, confirmed the statistically significant correlation between SII with PFS and OS, but not for LMR. Conclusions: Preliminary analyses of our study showed a prognostic role of baseline SII, while it is uncertain for LMR in mRCC patients treated with nivolumab.

1255P - Neutrophil to lymphocyte ratio (NLR) kinetics as predictors of outcomes in metastatic renal cell carcinoma (mRCC) and non-small cell lung cancer (NSCLC) patients treated with nivolumab (N)

BackgroundAn elevated pre-treatment Neutrophil to Lymphocytes Ratio (NLR) is associated with poor prognosis in various malignancies. As optimal cut-off is highly variable and few data have been reported in patients treated with anti-PD-1, we investigated the association between NLR kinetics with outcomes in patients receiving anti-PD-1. MethodsWe performed a retrospective study including successive patients with mRCC and NSCLC treated with anti PD-1 N monotherapy in second-line setting or later, between March 2013 and December 2018. NLR were prospectively collected before study entry and before every nivolumab administration. Main clinical and biological characteristics were recorded including IMDC prognostic groups for mRCC cohort. We analysed associations between baseline NLR, NLR kinetics (any increase or decrease) and survival outcomes, including PFS, OS and objective response rate (ORR). Results161 patients (86 mRCC and 75 NSCLC) were included in our study. With a median follow-up of 25 months, median PFS and OS were respectively 4.6 and 24.7 months for mRCC cohort and 4.4 and 16.8 months for NSCLC cohort. Between the first and the fourth N administration, 55 and 45% of the overall cohort had a decreased or an increased NLR. Survival outcomes according to NLR variations between the first and the fourth N administration are summarized in the Table. In multivariate analysis, NLR increase was associated with worse PFS (HR=2.6; p=0.000004) and OS (HR=2.3; p=0.001) for the overall cohort but also for the two cohorts when analysed separately. Association between NLR kinetics and response rate, IMDC groups and adverse events in the mRCC will be presented at the meeting.Table1255P Survival outcomesTableAll patientsNLR increaseNLR decreasepPFS (months, 95% IC)3.7 (2.9-4.4)11 (9-15.3)<0.0001OS (months, 95% CI)18 (10.6-28.2)28.5 (27;4-NR)0.01 ConclusionsWe report the largest multi-cohort analysis of NLR kinetic in N treated patients supporting that early NLR increase is associated with worse survival outcomes in two distinct cohort of mRCC and NSCLC patients. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureD. Borchiellini: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Janssen Cilag; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Astellas. C. Thibault: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: bms; Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer. P. Barthelemy: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Novartis. Y. Vano: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Pfizer; Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Janssen Cilag; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Astellas. All other authors have declared no conflicts of interest.

960P - Nivolumab (N) treatment beyond progression in a real-world cohort of patients (pts) with metastatic renal cell carcinoma (mRCC)

BackgroundN is a standard of care for patients with mccRCC after failure of a TKI. Nevertheless, nearly 45% of pts had a progressive disease (PD) as best response and PFS was disappointing. In this study we sought to describe a “real-world” cohort of pts with mRCC treated with N beyond first progression to identify factors predicting a clinical benefit. MethodsWe included in a retrospective study all consecutive mRCC pts who received at least one N injection at a French single-center between 2013 and 2018. Clinical and biological data were collected prospectively. Radiological evaluations were done by CT-scan using iRECIST. Characteristics of pts who with unconfirmed PD (iuPD) were described and compared according to the continuation of N beyond iuPD or not. Pts with a clinical benefit (CB) (objective response (OR=CR+PR) or stable disease (SD)) from N post-iuPD, were compared with pts with icPD as best response (BOR) post-iuPD. Results109 patients were included, 84% had a clear cell histology; IMDC’s favorable, intermediate and poor prognostic groups at N initiation were 21%, 52% and 27%, respectively. After a median follow-up of 24.4 months [14.9-NA], median PFS and OS were 6.03 months [4.6-10] and 25.8 months [24.2-30.1] respectively. ORR was 18.4% (3.7% CR) and 74 pts experienced a first iuPD, including 5 clinical PD. Among the 69 radiological iUPD, 12 had new lesions (16%), 32 had progression of pre-existing lesions (43%) and 25 had both (33%). 36 pts (49%) received N beyond PD. Responses post-iuPD were 3 (4%) PR, 14 (19%) SD and 17 (23%) icPD.; they were more frequently ECOG-PS 0-1 (86% versus 47%, p=0.0005), had better IMDC group (FAV+INT = 86% vs 53%, p=0.01) and had higher lymphocyte count (p=0.04). 17/18 (48%) pts had a CB with N post-iuPD, with a better OS than those without CB (31.8 months vs 24.9 months, p=0.02). The only factor associated with the absence of CB were LDH>200 (p=0.038). ConclusionsWe report the largest analysis of treatment with N beyond progression in a real world cohort of mRCC supporting that pseudo-progression is a rare event (4%). We show also that treatment beyond progression is very common (49%) and that LDH>200 might be the better ready-to-use predictive factor of a lack of CB. Legal entity responsible for the studyYann-Alexandre Vano. FundingHas not received any funding. DisclosureL. Fournier: Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Sanofi; Research grant / Funding (institution): Invectys; Research grant / Funding (institution): Philips; Research grant / Funding (institution): Evolucare; Research grant / Funding (institution): ArianaPharma; Research grant / Funding (institution): Imagia. C. Thibault: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: BMS; Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer. Y. Vano: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Roche; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Pfizer MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck; Advisory / Consultancy: Janssen-Cilag; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Astellas. All other authors have declared no conflicts of interest.

967P - Skeletal muscle loss as an adverse event during cabozantinib treatment in patients with metastatic renal cell carcinoma

BackgroundCabozantinib (CABO) is currently a standard of care as 2nd or 3rd line in metastatic renal cell carcinoma (mRCC). Previous studies showed that sarcopenia is generally linked with worse survival and/or higher toxicity in oncology. The aim is to evaluate its impact in mRCC patients (pt) treated with CABO. MethodsUnicentric study of consecutive pt treated with CABO for mRCC from January 2014 to December 2018 and with available computed tomography images (CT). CT were centrally reviewed and axial L3 sections were used to measure the total muscle area and calculate skeletal muscle index (SMI, cm²/m²). Sarcopenia was defined as SMI lower than a sex-based threshold. Sarcopenic event-free survival was estimated from CABO start. Treatment-related toxicity (TRT), defined as dose reduction and/or treatment stop, was evaluated. ResultsOverall, 95 pts with median-follow-up of 15.4 months (mo) from CABO start were included. The median age was 61 (range 28-75) years, 71 (74.7%) pts had clear cell histology. IMDC group distribution: 11.7% good, 62.8% intermediate and 25.5% poor. CABO was administered in 1rd (3.2%), 2nd (30.5%), 3rd line (26.3%) and beyond (40.0%). At CABO start, median BMI was 24.7kg/m², median SMI was 46.6 with 61 (64.2%) sarcopenic pt. For non-sarcopenic pt at baseline (n=34), 18 (52.9%) developed sarcopenia during treatment with a median sarcopenic event-free survival of 6.7mo (95%CI 3.5-27.4). Overall, 79 (83.2%) pt experienced muscle mass loss during the treatment: the relative variation of muscle loss between baseline and worst value was ≤5% in 22.1%, ]5-10%] in 26.3%, ]10-20%] in 24.2% and >20% in 10.5%. The best response was CR (1.1%), PR (35.5%), SD (54.8%) and PD (8.6%). Median time-to-TRT was 2.5mo (95%CI 2.1-3.3; 74.7% events) and median overall survival was 20.1mo (95%CI 18.0-NE; 35.8% deaths). Both endpoints were not associated to sarcopenia at CABO start. ConclusionsWe reported the first cohort assessing sarcopenia in pt treated with CABO for mRCC. Baseline sarcopenia is underestimated in this setting. Furthermore, half of non-sarcopenic patients at baseline develop sarcopenia during treatment requiring physician awareness and interventional studies. Legal entity responsible for the studyThe authors. FundingOnco-urology department of Gustave Roussy. DisclosureE. Colomba: Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: PFIZER; Travel / Accommodation / Expenses: SANOFI. B. Escudier: Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Oncorena. L. Albiges: Honoraria (institution), Advisory / Consultancy: Novartis; Honoraria (institution), Advisory / Consultancy: Bristol‐Myers Squibb; Honoraria (institution), Advisory / Consultancy: Merck; Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (institution), Advisory / Consultancy: Amgen; Honoraria (institution), Advisory / Consultancy: Ipsen; Honoraria (institution), Advisory / Consultancy: Astellas Pharma. All other authors have declared no conflicts of interest.

Efficacy of first-line immune checkpoint inhibitors in patients with sarcomatoid and/or rhabdoid (S/R) metastatic renal cell carcinoma (mRCC).

66 Background: Patients with mRCC with S/R components tend to have a poor prognosis with few therapeutic options available. Recent data suggest that immune checkpoint inhibitor (ICI)-based therapies may be especially effective for these patients. Our aim was to evaluate the efficacy of ICI-based therapies in patients with S/R mRCC. Methods: We retrospectively assessed objective response rate (ORR), progression free survival (PFS) &amp; overall survival (OS) of patients with S/R mRCC treated at our institution with first-line ICI-based therapies and compared these to those of patients treated with first-line non-ICI-based therapies. Univariable and multivariable (adjusted for IMDC group) Cox and logistic regressions were performed. Results: 92 patients (70 S, 9 R, and 13 S&amp;R) patients were included, of which 74 with a clear-cell component. For all patients (regardless of therapy), 74 (80.4%) patients experienced a PFS event (progression or death) and 52 (56.5%) died at 25.3 months (m) median follow-up. Overall median PFS was 5.3 m (95% CI= 3.4–7.2) and 24 m OS rate was 39.5% (27.4–51.7). Out of 78 patients in whom response was evaluable, ORR was 30.8% (20.4–41.2). Patients treated with ICI-based therapies had significantly better ORR, PFS, and OS on multivariable analysis (table). Conclusions: mRCC patients with S/R components have significantly better ORR, PFS, and OS with first-line ICI-based compared to non-ICI-based therapies. These data support the use of ICI-based therapies for patients with S/R mRCC. [Table: see text]