International Metastatic Database Consortium Risk Research Articles

Immune checkpoint inhibitors combined with tyrosine kinase inhibitors or immunotherapy for treatment-naïve metastatic clear-cell renal cell carcinoma-A network meta-analysis. Focus on cabozantinib combined with nivolumab.

Introduction: The combination of immunotherapy and targeted therapy is currently marking a new era in the treatment of renal cancer. The latest clinical guidelines recommend the use of drug combinations for the first-line treatment of advanced renal cancer. The aim of this review is to compare the efficacy of combined cabozantinib + nivolumab therapy with other immune checkpoint inhibitors combined with tyrosine kinase inhibitors or monoclonal antibodies blocking the CTLA-4 (cytotoxic T cell antigen 4) in the first-line treatment of metastatic clear-cell renal cell carcinoma (RCC). Methodology: A systematic literature search was carried out in the PubMed and EMBASE databases. Randomized controlled trials (RCTs) on therapies recommended by the latest EAU and ESMO guidelines for treatment-naïve metastatic RCC (i.e., lenvatinib + pembrolizumab, axitinib + pembrolizumab and nivolumab + ipilimumab) were searched. A network meta-analysis (NMA) was performed for data synthesis. The methodology of included RCTs was assessed using the Cochrane RoB two tool. The data were analyzed in the overall population as well as in risk subgroups defined according to the International Metastatic Database Consortium (IMDC) i.e., patients with a favorable and intermediate or poor prognoses. The most recent cut-off dates from included studies were analyzed. Results: Four RCTs (CheckMate 9 ER, KEYNOTE-426, CLEAR and CheckMate 214) were included in the review. No studies directly comparing cabozantinib + nivolumab with any of the drug combinations included in this review were available. NMA showed that cabozantinib + nivolumab was superior compared to axitinib + pembrolizumab and nivolumab + ipilimumab in all analyzed comparisons (overall population and IMDC risk subgroups), both in terms of overall survival and progression-free survival (PFS). The advantage of cabozantinib + nivolumab was statistically significant only for PFS when compared to nivolumab + ipilimumab in the overall population. The results for the comparison of cabozantinib + nivolumab with lenvatinib + pembrolizumab showed numerical superiority of lenvatinib + pembrolizumab combination in terms of overall survival, but none of the results were statistically significant. The advantage of lenvatinib + pembrolizumab over cabozantinib + nivolumab in terms of PFS was statistically significant in the overall and favorable prognosis population. Conclusion: Inclusion of the most recent cut-off data from CheckMate 9 ER did not affect the role of the cabozantinib + nivolumab combination for treatment-naïve metastatic RCC. Cabozantinib + nivolumab is an effective therapeutic option for the first-line treatment of advanced renal cancer that is recommended both in the latest European and American guidelines for all IMDC risk groups.

Tumor diameter response in patients with metastatic clear cell renal cell carcinoma is associated with overall survival.

Tumor shrinkage of at least 10% after presurgical targeted molecular therapy (TMT) in renal cell carcinoma (RCC) patients has been associated with better overall survival (OS) outcomes. We characterized primary and metastatic tumor diameter response and OS in patients with metastatic clear cell RCC (ccRCC) who received preoperative TMT, immunotherapy, or both followed by deferred cytoreductive nephrectomy (dCN). Patients with metastatic ccRCC (n = 198) who underwent preoperative therapy and dCN from 2005 to 2019 were identified retrospectively. Longest primary and metastatic tumor diameters were calculated using cross-sectional images obtained before systemic therapy and dCN using the Response Evaluation Criteria in Solid Tumors. Patients were stratified by tumor shrinkage of at least 10% in the primary and/or metastatic tumors after systemic therapy. The Kaplan-Meier method was used to estimate OS, and Cox proportional hazards models were used to assess the association of patient characteristics with OS. In total, 31.31% of patients had only metastatic tumor shrinkage (MTS) ≥ 10%, 8.08% had only primary tumor shrinkage (PTS) ≥ 10%, 32.32% had PTS and MTS ≥ 10%, and 28.28% had PTS/MTS < 10%. The median OS, number of patients with tumor shrinkage ≥ 10%, and International Metastatic Database Consortium (IMDC) scores were similar among the 3 systemic therapy groups (all P ≥ 0.80). Patients with MTS ≥ 10%, PTS ≥ 10%, and PTS/MTS ≥ 10% had significantly longer median OS compared to patients with PTS/MTS < 10% (P < 0.01). Patients with intermediate-risk IMDC scores had significantly longer median OS compared to patients in the poor-risk group. After adjusting for preoperative therapy and IMDC risk group, MTS ≥ 10%, PTS ≥ 10%, and PTS/MTS ≥ 10% were associated with better OS outcomes (HR 0.48 95% CI 0.32-0.73, P < 0.001; HR 0.48, 95% CI 0.23-0.98, P = 0.04; HR 0.44, 95% CI 0.29-0.67, P < 0.001, respectively). Intermediate risk score and shrinkage of at least 10% in the primary tumor, metastases, or both were associated with better OS outcomes in patients with metastatic ccRCC who underwent dCN independent of the type of preoperative systemic therapy.

Prognostic biomarkers of systemic inflammation in patients on active surveillance for metastatic renal cell carcinoma (mRCC): A biobank analysis.

348 Background: A subset of patients with metastatic renal cell carcinoma (mRCC) follow an indolent disease course. Given the toxicity and non-curative nature associated with systemic anti-cancer therapy (SACT), some patients may benefit from initial active surveillance (AS). However, selecting patients suitable for this approach is challenging. Biomarkers of systemic inflammation predict survival in mRCC, both independently and as part of the International Metastatic Database Consortium (IMDC) risk score. We sought to use these biomarkers to characterise the time to initiation of SACT (tSACT) in mRCC patients on AS. Methods: 126 mRCC patients clinically assessed and commenced on AS prior to any systemic therapy were retrospectively identified from a regional mRCC clinical database. Patients who underwent metastasectomy for oligometastatic disease at any time were excluded. The primary endpoint, tSACT, was defined as the time from radiological diagnosis of mRCC until SACT initiation, or death, or censorship if continuing AS at follow-up date. Inflammatory biomarkers from routine blood tests (haemoglobin, white cell count, neutrophil count, platelets, C-reactive protein (CRP), albumin) and the IMDC score, measured at the time of diagnosis of mRCC, were recorded. The relationship between these and tSACT was examined using Kaplan-Meier and Cox-regression methods. Results: 66 (52%) patients had commenced SACT. 17 (13.5%) had died without commencing SACT (median survival of the 17 was 40.4 months, range 9.1-130.2 months, and comorbidities may have affected fitness for starting therapy or led to all-cause mortality). 43 patients remained on AS, with minimum and median follow-up of 12.6 months and 39.6 months respectively. The median tSACT was 17.2 months (IQR 8.8-34.8 months). On univariate analysis, CRP and albumin were predictive of time on AS ( p= 0.01 and p= 0.049 respectively). On multivariate analysis, only CRP was independently associated with tSACT ( p= 0.035), stratifying tSACT from 9.1 months (CRP &gt; 10) to 20.9 months (CRP≤10) ( p= 0.009). 111 (88.1%) patients were IMDC 0-1, while 12 (9.5%) and 3 (2.4%) were IMDC 2 or 3 and may have had comorbidities that influenced the initial AS decision. In our cohort the IMDC risk score did not predict time on AS. Conclusions: These results highlight that some patients with mRCC may undergo active surveillance for a marked time period before SACT initiation. We identify routine biomarkers of the systemic inflammatory response that predict time to systemic therapy. In particular CRP, a simple measure of inflammation, stratifies the time to initiation of SACT across a clinically significant time period. This simple, widely available test may help to objectively inform clinical decisions about AS in patients in mRCC. Additional experience is necessary to further define the risks and benefits of this approach.

Prognostic Value of Plasma hPG80 (Circulating Progastrin) in Metastatic Renal Cell Carcinoma.

Simple SummaryMetastatic renal cell carcinoma (mRCC) accounts for one-third of all newly diagnosed renal cell cancers. A better understanding of the biology and molecular basis of disease progression has resulted in several drug targets being identified and led to approval of several new drugs for treating mRCC in the past decade. A growing need has emerged for identifying novel molecular tumor biology based and stage-specific prognostic and predictive biomarkers in mRCC reflective of biology beyond the currently available prognostic models which are solely based on clinical characteristics. We investigated hPG80 (circulating progastrin), which is associated with kidney cancer biology and found that hPG80 levels is both an independent prognostic marker in mRCC and also improves current clinical prognostic models. This will help stratify mRCC patients more accurately in future and improve the management of mRCC patients.Precise management of kidney cancer requires the identification of prognostic factors. hPG80 (circulating progastrin) is a tumor promoting peptide present in the blood of patients with various cancers, including renal cell carcinoma (RCC). In this study, we evaluated the prognostic value of plasma hPG80 in 143 prospectively collected patients with metastatic RCC (mRCC). The prognostic impact of hPG80 levels on overall survival (OS) in mRCC patients after controlling for hPG80 levels in non-cancer age matched controls was determined and compared to the International Metastatic Database Consortium (IMDC) risk model (good, intermediate, poor). ROC curves were used to evaluate the diagnostic accuracy of hPG80 using the area under the curve (AUC). Our results showed that plasma hPG80 was detected in 94% of mRCC patients. hPG80 levels displayed high predictive accuracy with an AUC of 0.93 and 0.84 when compared to 18–25 year old controls and 50–80 year old controls, respectively. mRCC patients with high hPG80 levels (>4.5 pM) had significantly lower OS compared to patients with low hPG80 levels (<4.5 pM) (12 versus 31.2 months, respectively; p = 0.0031). Adding hPG80 levels (score of 1 for patients having hPG80 levels > 4.5 pM) to the six variables of the IMDC risk model showed a greater and significant difference in OS between the newly defined good-, intermediate- and poor-risk groups (p = 0.0003 compared to p = 0.0076). Finally, when patients with IMDC intermediate-risk group were further divided into two groups based on hPG80 levels within these subgroups, increased OS were observed in patients with low hPG80 levels (<4.5 pM). In conclusion, our data suggest that hPG80 could be used for prognosticating survival in mRCC alone or integrated to the IMDC score (by adding a variable to the IMDC score or by substratifying the IMDC risk groups), be a prognostic biomarker in mRCC patients.

Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Nivolumab plus Cabozantinib Joins Immune Checkpoint Inhibition Combination Therapies for Treatment-naïve Metastatic Clear-Cell Renal Cell Carcinoma

Longer follow-up and new trial data from phase 3 randomised controlled trials investigating immune checkpoint blockade (PD-1 or its ligand PD-L1) in advanced clear-cell renal cell carcinoma (RCC) have recently become available. The CheckMate 9ER trial demonstrated an improved progression-free survival (PFS) and overall survival (OS) benefit for the combination of cabozantinib plus nivolumab. A Keynote-426 update demonstrated an ongoing OS benefit for pembrolizumab plus axitinib in the intention-to-treat population, with a PFS benefit seen across all International Metastatic Database Consortium (IMDC) subgroups, while an update of CheckMate 214 confirmed the long-term benefit of ipilimumab plus nivolumab in IMDC intermediate and poor risk patients. The RCC Guidelines Panel continues to recommend these tyrosine kinase inhibitors + immunotherapy (IO) combination across IMDC risk groups in advanced first-line RCC and dual immunotherapy of ipilimumab and nivolumab in IMDC intermediate and poor risk. Patient summaryNew data from trials of immune checkpoint inhibitors for advanced kidney cancer confirm a survival benefit with the combination of cabozantinib plus nivolumab and pembrolizumab plus axitinib and ipilimumab plus nivolumab. These combination therapies are recommended as first-line treatment for advanced kidney cancer.

Prediction of watchful waiting in newly diagnosed metastatic clear cell renal cell carcinoma patients with a good or intermediate prognosis.

5079 Background: In metastatic clear cell renal cell carcinoma (mccRCC), the number of International Metastatic Database Consortium (IMDC) risk factors plus metastatic sites may identify patients with rapid or slow disease progression in a period of watchful waiting (WW) (median WW of 8.4 vs 22.2 months; Rini et al. Lancet Oncol. 2016). We aimed to validate this and prospectively assess the added value of baseline PET with [18F]FDG and [89Zr]Zr-DFO-girentuximab to predict the WW-period in the multicenter IMaging PAtients for Cancer drug selecTion (IMPACT)-RCC cohort study. (NCT02228954). Methods: Between February 2015 and March 2018, 40 treatment-naïve mccRCC patients with a good (n=13) or intermediate prognosis (n=25) according to IMDC, were enrolled. Following baseline CT, [18F]FDG and [89Zr]Zr-DFO-girentuximab-PET, CT scans (RECIST1.1) were acquired at 2, 4, 6, 9, 12 months and thereafter every 4 months. Primary endpoint was time to radiological and/or clinical disease progression, requiring systemic treatment. Patients were assigned to a favorable (&lt;2 IMDC risk factors and &lt;3 metastatic sites) or unfavorable for WW-group (all others; Rini et al). Maximum standardized uptake values (SUVmax) were measured in PET-positive lesions measuring ≥10mm, or 15mm in lymph nodes. High and low-uptake groups were defined based on median geometric mean (gm) SUVmax across patients. A one-sided test was used to validate observations by Rini et al; other tests were two-sided. Results: The median WW-period was 9.3 months in the unfavorable WW-group (n=19) vs 20.4 months in the favorable WW-group (n=21) (HR 1.89 95%CI 0.94-3.89; p=0.037), confirming observations of Rini et al. Patients with high [18F]FDG uptake had a median WW-period of 8.5 months compared to 25.2 months in the low-uptake group (HR 4.08 95%CI 1.89-9.28; p=0.0002). Patients with high [89Zr]Zr-DFO-girentuximab uptake had a median WW-period of 10.7 versus 16.4 months in the low-uptake group (HR 1.37; 95%CI 0.69-2.76; p=0.37). [18F]FDG uptake groups improved a Cox-model for WW based on the prognostic groups of Rini et al (p=0.0015); [89Zr]Zr-DFO-girentuximab did not (p=0.98). Conclusions: The IMPACT-RCC study validated the observations by Rini et al. and shows that adding baseline [18F]FDG PET further improves the prediction of the duration of the WW-period in mccRCC patients. Clinical trial information: NCT02228954 .

Axitinib plus pembrolizumab in patients with advanced renal cell carcinoma: Long-term efficacy and safety from a phase Ib study.

5080 Background: Axitinib (AXI) plus pembrolizumab (pembro) showed superior overall survival (OS), progression-free survival (PFS) and response rate compared with sunitinib in a randomized Phase 3 trial in advanced renal cell carcinoma (RCC). Here, we report long-term efficacy and safety data of the combination AXI/pembro from the Phase 1 trial, with almost 5 years of follow-up. Methods: 52 treatment-naïve patients with advanced RCC were enrolled between 23 September 2014 and 13 October 2015, and were treated with oral AXI 5 mg twice daily and intravenous pembro 2 mg/kg every 3 weeks. Planned treatment duration was 2 years for pembro and not limited for AXI. Based on International Metastatic Database Consortium (IMDC) criteria, 46.2%, 44.2% and 5.8% of patients were reported as having favourable, intermediate and poor risk. Results: At data cut-off date (July 3, 2019), median OS was not reached; 38 (73.1%) patients were alive. 14 (26.9%) patients had died, none were related to treatment. The probability of being alive was 96.1% (95% CI 85.2–99.0) at 1 year, 88.2% (95% CI 75.7– 94.5) at 2 years, 82.2 % (95% CI 68.5– 90.3) at 3 years, and 66.8 % (95% CI 49.1–79.5) at 4 years. Median PFS was 23.5 (95% CI 15.4–30.4) months. Median duration of response was 22.1 (95% CI 15.1–not evaluable) months. Median time on treatment with the combination AXI/pembro was 14.5 months (n=52), median time on pembro after AXI discontinuation was 9.0 months (n=10), and median time on AXI after pembro discontinuation was 7.5 months (n=11). After stopping study treatment, 22 patients received subsequent systemic therapy, including nivolumab and cabozantinib (n=6 each). Grade 3/4 AEs were reported in 38 (73.1%) patients. 20 (38.5%) patients discontinued either drug due to AEs: 17 (32.7%) patients discontinued AXI, and 13 (25.0%) patients discontinued pembro with 10 (19.2%) discontinuing both drugs. Dose reduction of AXI due to AEs was reported in 16 (30.8%) patients. The most common AEs reported were diarrhea (84.6%), fatigue (80.8%), hypertension (53.8%), cough (48.1%), and dysphonia (48.1%). Increased alanine aminotransferase and aspartate aminotransferase occurred in 44.2% and 36.5% of patients, respectively. With this longer follow-up, there were no cumulative AEs or new AEs. OS by IMDC risk group will be presented. Conclusions: In patients with advanced RCC with almost 5 years of follow-up, the combination of AXI/pembro continues to demonstrate clinical benefit with no new safety signals. Clinical trial information: NCT02133742 .

Identification and validation of dichotomous immune subtypes based on intratumoral immune cells infiltration in clear cell renal cell carcinoma patients

BackgroundIncreasing evidence has elucidated the clinical significance of tumor infiltrating immune cells in predicting outcomes and therapeutic efficacy. In this study, we comprehensively analyze the tumor microenvironment (TME) immune cell...

Clinical Activity of Ipilimumab Plus Nivolumab in Patients With Metastatic Non-Clear Cell Renal Cell Carcinoma.

Ipilimumab plus nivolumab has been approved for intermediate- and poor-risk metastatic renal cell carcinoma (RCC). However, the activity in non-clear cell RCC (nccRCC) is unknown. Patients from Cleveland Clinic and the University of Texas Southwestern who had received ipilimumab plus nivolumab for metastatic nccRCC from October 2017 to May 2019 were retrospectively identified. Ipilimumab plus nivolumab was administered in accordance with the CHECKMATE 214 trial. Imaging was obtained at baseline and every 12 weeks. The baseline patient characteristics, objective response per Response Evaluation Criteria in Solid Tumors, version 1.1, and treatment-related adverse events (TRAEs) per Common Terminology Criteria for Adverse Events, version 5.0, were analyzed. Eighteen patients were identified. The median age was 59 years (range, 32-81 years), 77.8% were men, and the Eastern Cooperative Oncology Group performance status was 0 (38%) or 1 (50%). The median treatment duration was 2.4 months (range, 0.7-12.3 months). The non-clear cell histologic types included 6 papillary, 5 chromophobe, 3 unclassified, 2 adenocarcinoma of renal origin, 1 translocation, and 1 medullary. Most had an intermediate (66%) or poor (22%) International Metastatic Database Consortium risk. The best objective response included 6 partial responses (PRs; 33.3%) and 3 with stable disease (16.7%). Of the patients with a PR, the median time to the best response was 3.0 months, and median duration of the PR was 4.3 months. The median progression-free survival was 7.1 months. All-grade TRAEs were noted in 11 patients (61.1%) and included colitis (22%), hepatotoxicity (16%), rash (11%), and fatigue (11%). Eleven patients (61%) had TRAEs requiring high-dose glucocorticoids (> 40 mg of prednisone equivalent daily). Ipilimumab plus nivolumab demonstrated objective responses and notable toxicity in patients with nccRCC.

Consistent efficacy of nivolumab plus ipilimumab across number of International Metastatic Database Consortium (IMDC) risk factors in CheckMate 214.

4575 Background: The IMDC prognostic model was created based on anti-VEGF treatments for advanced renal cell carcinoma (aRCC), and may not be relevant for immunotherapy. Methods: In a post hoc analysis of CheckMate 214, we compared efficacy with nivolumab + ipilimumab (N+I) vs sunitinib (S) by number of IMDC risk factors present. Results: Among 1096 intent-to-treat (ITT) patients (pts) in both arms, 21%, 61%, and 18% had favorable, intermediate (int), or poor-risk, respectively. Of int-risk pts, 58% had 1 factor (most commonly &lt;1 y from diagnosis [Dx], 52%; Hb &lt; LLN, 27%; or KPS ≤70%, 10%); and 42% had 2 factors (of these pts, the most common combination of 2 factors was &lt;1 y from Dx and Hb &lt; LLN, 59%). Of poor-risk pts, 58% had 3 factors, 29% had 4 factors, and few had 5 (10%) or 6 (3%) factors. Due to small numbers, pts with 4–6 factors were pooled. At 30-mo minimum follow-up, RECIST v1.1-confirmed objective response rate (ORR) and complete response (CR) rate per investigator remained consistently higher with N+I vs S across pts with 1–4 factors, although with S, ORR decreased with increasing number of factors (Table). Improved progression-free survival (PFS) and overall survival (OS) were seen with N+I over S irrespective of the number of factors present, including in pts with only 1 risk factor (Table). Conclusions: N+I showed consistent efficacy across number of IMDC risk factors, while S decreased in efficacy with increasing number of factors. Efficacy of N+I was superior to S in all int- and poor risk pts. These CheckMate 214 results along with prior CheckMate 025 data showing consistent OS benefit with N monotherapy across IMDC risk categories show a need for improved prognostic models for immunotherapies in aRCC. Clinical trial information: NCT02231749. [Table: see text]

Rates of occult brain metastases in patients (pts) with advanced renal cell carcinoma (RCC): A cohort study from patients treated across 22 clinical trials.

673 Background: National guidelines for RCC management only recommend brain imaging ‘if clinically indicated’; the rate of occult brain metastases is not defined. Early detection of CNS disease has major implications as it typically triggers early intervention with the aim to limit morbidity, including major complications of local progression. In an effort to define the utility of brain screening, we investigated the rate of occult brain metastasis in a large cohort of metastatic RCC pts. Methods: We performed a retrospective review of completed and actively accruing metastatic RCC clinical trials conducted at Memorial Sloan Kettering Cancer Center. Individual charts of pts screening for those studies with mandatory brain imaging at baseline were reviewed to identify subjects harboring occult brain metastases. We collected patient demographics, International Metastatic Database Consortium (IMDC) risk status, sites of metastatic disease, and tumor histology. Patients with neurologic symptoms were excluded. Descriptive statistics were applied to analyze findings across the cohort. Results: A total of 22 clinical trials for metastatic RCC conducted from 2004-2017 required brain imaging at baseline, and a total of 535 pts were screened in this context. A total of 25/535 pts were found to have occult brain metastasis (4.67%), which was multi-focal in 10/25 (40%) and sub-cm in 15/25 (60%). For these 25 pts, the mean age at diagnosis was 56 years (38-77), and IMDC risk score at enrollment was: 1/24 favorable (4%), 21/24 intermediate (88%), and 2/24 poor-risk (8%) patients. 18/25 patients presented with de novo metastatic disease; 13/25 had received prior therapies; and 24/25 patients (96%) had &gt; 2 additional non-CNS sites of metastatic disease at time of screening. 21/23 pts and 2/23 pts were then treated with radiation and surgical resection, respectively. Conclusions: This retrospective cohort study shows a 5% rate of occult CNS disease in asymptomatic patients with advanced RCC. These findings can inform current screening guidelines for full disease assessment in metastatic RCC patients.

895P - SPAZO2 (SOGUG): Validation of the international metastatic database consortium (IMDC) prognostic classification for targeted therapies as 2nd-line after 1st-line pazopanib (1stPz) in metastatic renal cell carcinoma (mRC)

Background: Only 2% of pt included in the IMDC prognostic model for 2nd-line targeted agents in mRC had received 1stPz (Ko, Lancet Oncol 2015). We aimed to validate the IMDC model for this population of patients receiving 1stPz. Methods: SPAZO2 (NCT03091465) was a retrospective real-world study to analyze the effectiveness of 1stPz and subsequent therapies in mRC in several settings in every day practice. Data from 530 pt treated with frontline pazopanib outside CT in 50 centers in Spain were collected by investigators, but monitored and entered in a database by an external CRO. Results: A total of 285 pt received antiVEGF or mTOR inhibitor as 2nd line (37.6% everolimus, 2.5% temsirolimus, 36% axitinib, 9.9% sunitinib, 8.3% sorafenib, 2.9% cabozantinib, 2.1% pazopanib, 0.4% beva-Inf, 0.4% savolitinib), 242 after true progression and 43 due to other causes after 1stPz. Unlike in IMDC, no pt had received 1st-line immunotherapy. Mean age was 66 y, 67.7% were male, 74.4% nephrectomized, and 12.3% pure nonclear-cell. Metastatic sites were: lung 74%, lymph nodes 55%, bone 36%, soft tissue/skin 27%, liver 24.8%, CNS 7%, adrenal gland 5%, pleura/peritoneum 6%, pancreas 5%, kidney 3% and other organs 2%. Classification of pt into the IMDC risk groups were: favorable (FR, 14.4%), intermediate (IR: 64.2%), or poor (PR: 21.4%). Median follow-up since 2nd-line was 29 mo; 67% of pt has progressed, 64% had received or subsequent lines, and 73% had died. Response, PFS and OS (and 95%CI) since 2nd-line are showed in the table. Differences in PFS and OS were statistically significant among groups (FR vs IR and FR vs PR). The C-Index was 0.635 (95%CI: 0.627 – 0.642). We also provide an estimation of outcomes according to if pt received 2ndline after “true progression” or due to any cause.Table895PSPAZO2IMDCOverallFRIRPROverallFRIRPRORR14.6%22.5%15.8%5.5%Not repostedMedian PFS (1)*Months; 1: 2nd-line due to any cause (N = 285); 2: 2nd-line due to progression to Pz (N = 242).5.1 (4-6)11.5 (5-18)5 (4-6)3 (2-4)3.9Not reportedMedian PFS (2)*Months; 1: 2nd-line due to any cause (N = 285); 2: 2nd-line due to progression to Pz (N = 242).4.7 (4-5)9.7 (4-15)4.8 (4-6)3 (2-4)Median OS (1)*Months; 1: 2nd-line due to any cause (N = 285); 2: 2nd-line due to progression to Pz (N = 242).11.3 (9-13)24.4 (18-30)12.7 (10-15)6.5 (5-8)12.5 (11-14)35.3 (28-48)16.6 (15-18)5.4 (5-7)Median OS (2)*Months; 1: 2nd-line due to any cause (N = 285); 2: 2nd-line due to progression to Pz (N = 242).11.1 (9-13)19.8 (12-27* Months; 1: 2nd-line due to any cause (N = 285); 2: 2nd-line due to progression to Pz (N = 242). Open table in a new tab Conclusions: Our results validate the use of the IMDC prognostic classification as a discrimination tool, for predicting prognosis in pt receiving 2nd-line targeted therapies after pazopanib in mRC. Pt who received 2nd-line after true progression had a poorer prognostic than the predicted by the IMDC. Clinical trial identification: NCT03091465 Legal entity responsible for the study: SOGUG Funding: Novartis Disclosure: B. Pérez-Valderrama: Consulting/Advisory role for Astellas Pharma, Novartis, Pfizer, Pierre Fabre, Bayer, Sanofi, Bristol-Myers Squib and Roche. J. Arranz Arija: AdBo from Novartis and Pfizer. G. de Velasco: Consulting and Advisory board for Pfizer, Novartis, Bayer, Roche. M.A. Gonzalez Del Alba Baamonde: Advisory boards for Novartis, Pfizer, Bristol-Myers Squib, Ipsen. All other authors have declared no conflicts of interest.