Outcomes for International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Groups in Contemporary First-line Combination Therapies for Metastatic Renal Cell Carcinoma.

The combination of immuno-oncology (IO) agents ipilimumab and nivolumab (IPI-NIVO) and vascular endothelial growth factor targeted therapies (VEGF-TT) combined with IO (IO-VEGF) are current standard of care first-line treatments for metastatic renal cell carcinoma (mRCC). To establish real-world clinical benchmarks for IO combination therapies based on the International mRCC Database Consortium (IMDC) criteria. Patients with mRCC who received first-line IPI-NIVO, IO-VEGF, or VEGF-TT from 2002 to 2021 were identified using the IMDC database and stratified according to IMDC risk groups. Overall survival (OS), time to next treatment (TTNT), and treatment duration (TD) were calculated using the Kaplan-Meier method and compared between IMDC risk groups within each treatment cohort by the log-rank test. The overall response rate (ORR) was calculated by physician assessment of the best overall response. The primary outcome was OS at 18 mo. In total, 728 patients received IPI-NIVO, 282 IO-VEGF, and 7163 VEGF-TT. The median follow-up times for patients remaining alive were 14.3 mo for IPI-NIVO, 14.9 mo IO-VEGF, and 34.4 mo for VEGF-TT. OS at 18 mo for favorable, intermediate, and poor risk was, respectively, 90%, 78%, and 50% for those receiving IPI-NIVO; 93%, 83%, and 74% for IO-VEGF; and 84%, 64%, and 28% for VEGF-TT. ORRs in favorable-, intermediate-, and poor-risk groups were 41.3%, 40.6%, and 33.0% for those receiving IPI-NIVO; 60.3%, 56.8%, and 40.9% for IO-VEGF; and 39.3%, 33.5%, and 20.9% for VEGF-TT, respectively. The IMDC model stratified patients into statistically distinct risk groups for the three endpoints of OS, TTNT, and TD within each treatment cohort. Limitations of this study were the retrospective design and short follow-up. This study demonstrated that the IMDC model continues to risk stratify patients with mRCC treated with contemporary first-line IO combination therapies and provided real-world survival benchmarks. The International Metastatic Renal Cell Carcinoma Database Consortium model continues to stratify patients with metastatic renal cell carcinoma receiving modern combination treatments in the real-world setting.

Ernst MS ，Navani V ，Wells JC ，Donskov F ，Basappa N ，Labaki C ，Pal SK ，Meza L ，Wood LA ，Ernst DS ，Szabados B ，McKay RR ，Parnis F ，Suarez C ，Yuasa T ，Lalani AK ，Alva A ，Bjarnason GA ，Choueiri TK ，Heng DYC ... -  《-》

First-line Immuno-Oncology Combination Therapies in Metastatic Renal-cell Carcinoma: Results from the International Metastatic Renal-cell Carcinoma Database Consortium.

In metastatic renal-cell carcinoma (mRCC), recent data have shown efficacy of first-line ipilimumab and nivolumab (ipi-nivo) as well as immuno-oncology (IO)/vascular endothelial growth factor (VEGF) inhibitor combinations. Comparative data between these strategies are limited. To compare the efficacy of ipi-nivo versus IO-VEGF (IOVE) combinations in mRCC, and describe practice patterns and effectiveness of second-line therapies. Using the International Metastatic Renal-cell Carcinoma Database Consortium (IMDC) dataset, patients treated with any first-line IOVE combination were compared with those treated with ipi-nivo. All patients received first-line IO combination therapies. First- and second-line response rates, time to treatment failure (TTF), time to next treatment (TNT), and overall survival (OS) were analysed. Hazard ratios were adjusted for IMDC risk factors. In total, 113 patients received IOVE combinations and 75 received ipi-nivo. For IOVE combinations versus ipi-nivo, first-line response rates were 33% versus 40% (between-group difference 7%, 95% confidence interval [CI] -8% to 22%, p =  0.4), TTF was 14.3 versus 10.2 mo (p =  0.2), TNT was 19.7 versus 17.9 mo (p =  0.4), and median OS was immature but not statistically different (p = 0.17). Adjusted hazard ratios for TTF, TNT, and OS were 0.71 (95% CI 0.46-1.12, p =  0.14), 0.65 (95% CI 0.38-1.11, p =  0.11), and 1.74 (95% CI 0.82-3.68, p =  0.14), respectively. Sixty-four (34%) patients received second-line treatment. In patients receiving subsequent VEGF-based therapy, second-line response rates were lower in the IOVE cohort than in the ipi-nivo cohort (15% vs 45%; between-group difference 30%, 95% CI 3-57%, p =  0.04; n = 40), though second-line TTF was not significantly different (3.7 vs 5.4 mo; p =  0.4; n = 55). Limitations include the study's retrospective design and sample size. There were no significant differences in first-line outcomes between IOVE combinations and ipi-nivo. Most patients received VEGF-based therapy in the second line. In this group, second-line response rate was greater in patients who received ipi-nivo initially. There were no significant differences in key first-line outcomes for patients with metastatic renal-cell carcinoma receiving immuno-oncology/vascular endothelial growth factor inhibitor combinations versus ipilimumab and nivolumab.

Dudani S ，Graham J ，Wells JC ，Bakouny Z ，Pal SK ，Dizman N ，Donskov F ，Porta C ，de Velasco G ，Hansen A ，Iafolla M ，Beuselinck B ，Vaishampayan UN ，Wood LA ，Liow E ，Yan F ，Yuasa T ，Bjarnason GA ，Choueiri TK ，Heng DYC ... -  《-》

Checkpoint inhibitors in patients with metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

To the authors' knowledge, outcomes and prognostic tools have yet to be clearly defined in patients with metastatic renal cell carcinoma (mRCC) who are treated with immuno-oncology (IO) checkpoint inhibitors (programmed death-ligand 1 [PD-L1] inhibitors). In the current study, the authors aimed to establish IO efficacy benchmarks in patients with mRCC and update patient outcomes in each International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic class. A retrospective analysis was performed using the IMDC database with data from 38 centers. It included patients with mRCC who were treated with ≥1 line of IO. Overall response rates (ORRs), duration of treatment (DOT), and overall survival (OS) were calculated. Patients were stratified using IMDC prognostic factors. A total of 687 patients (90% with clear cell and 10% with non-clear cell) were included. The ORR was 27% in evaluable patients (461 patients). In patients treated with first-line nivolumab and ipilimumab (49 patients), the combination of PD-L1 inhibitor and vascular endothelial growth factor inhibitor (72 patients), and PD-L1 inhibitor (51 patients), the ORR was 31%, 39%, and 40%, respectively, and the median DOT was 8.3 months, 14.7 months, and 8.3 months, respectively. The ORR for second-line, third-line, and fourth-line nivolumab was 22%, 24%, and 26%, respectively. The median DOT was 5.7 months, 6.2 months, and 8.3 months, respectively, in the second-line, third-line, and fourth-line settings. When segregated into IMDC favorable-risk, intermediate-risk, and poor-risk groups, the median OS rates for the first-line, second-line, third-line, and fourth-line treatment settings were not reached (NR), NR, and NR, respectively (P = .163); NR, 26.7 months, and 7.4 months, respectively (P < 0. 0001); 36.1 months, 28.2 months, and 11.1 months, respectively (P = .016); and NR, NR, and 6.7 months, respectively (P = .047). The ORR was not found to deteriorate from the first-line to the fourth-line of IO therapy. In the second line through fourth line, the IMDC criteria appropriately stratified patients into favorable-risk, intermediate-risk, and poor-risk groups for OS.

Yip SM ，Wells C ，Moreira R ，Wong A ，Srinivas S ，Beuselinck B ，Porta C ，Sim HW ，Ernst DS ，Rini BI ，Yuasa T ，Basappa NS ，Kanesvaran R ，Wood LA ，Canil C ，Kapoor A ，Fu SYF ，Choueiri TK ，Heng DYC ... -  《-》

Real-world Assessment of Clinical Outcomes in Patients with Metastatic Renal Cell Carcinoma with or Without Sarcomatoid Features Treated with First-line Systemic Therapies.

Sawaya GB ，Dragomir A ，Wood LA ，Kollmannsberger C ，Basappa NS ，Kapoor A ，Soulières D ，Finelli A ，Heng DYC ，Castonguay V ，Canil C ，Winquist E ，Graham J ，Bjarnason GA ，Bhindi B ，Lalani AK ，Pouliot F ，Breau RH ，Saleh R ，Tanguay S ... -  《European Urology Oncology》

Real-world Outcome of Patients with Advanced Renal Cell Carcinoma and Intermediate- or Poor-risk International Metastatic Renal Cell Carcinoma Database Consortium Criteria Treated by Immune-oncology Combinations: Differential Effectiveness by Risk Group?

Renal c carcinoma (RCC) is one of the most common urinary cancers worldwide, with a predicted increase in incidence in the coming years. Immunotherapy, as a single agent, in doublets, or in combination with anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs), has rapidly become a cornerstone of the RCC therapeutic scenario, but no head-to-head comparisons have been made. In this setting, real-world evidence emerges as a cornerstone to guide clinical decisions. The objective of this retrospective study was to assess the outcome of patients treated with first-line immune combinations or immune oncology (IO)-TKIs for advanced RCC. Data from 930 patients, 654 intermediate risk and 276 poor risk, were collected retrospectively from 58 centers in 20 countries. Special data such as sarcomatoid differentiation, body mass index, prior nephrectomy, and metastatic localization, in addition to biochemical data such as hemoglobin, platelets, calcium, lactate dehydrogenase, neutrophils, and radiological response by investigator's criteria, were collected. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. The median follow-up was calculated by the inverse Kaplan-Meier method. The median follow-up time was 18.7 mo. In the 654 intermediate-risk patients, the median OS and PFS were significantly longer in patients with the intermediate than in those with the poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria (38.9 vs 17.3 mo, 95% confidence interval [CI] p < 0.001, and 17.3 vs 11.6 mo, 95% CI p < 0.001, respectively). In the intermediate-risk subgroup, the OS was 55.7 mo (95% CI 31.4-55.7) and 40.2 mo (95% CI 29.6-51.6) in patients treated with IO + TKI and IO + IO combinations, respectively (p = 0.047). PFS was 30.7 mo (95% CI 16.5-55.7) and 13.2 mo (95% CI 29.6-51.6) in intermediate-risk patients treated with IO + TKI and IO + IO combinations, respectively (p < 0.001). In the poor-risk subgroup, the median OS and PFS did not show a statistically significant difference between IO + IO and IO + TKI. Our study presents several limitations, mainly due to its retrospective nature. Our results showed differences between the IO + TKI and IO + IO combinations in intermediate-risk patients. A clear association with longer PFS and OS in favor of patients who received the IO + TKI combinations compared with the IO-IO combination was observed. Instead, in the poor-risk group, we observed no significant difference in PFS or OS between patients who received different combinations. Renal cancer is one of the most frequent genitourinary tumors. Treatment is currently based on immunotherapy combinations or immunotherapy with tyrosine kinase inhibitors, but there are no comparisons between these.In this study, we have analyzed the clinical course of 930 patients from 58 centers in 20 countries around the world. We aimed to analyze the differences between the two main treatment strategies, combination of two immunotherapies versus immunotherapy + antiangiogenic therapy, and found in real-life data that intermediate-risk patients (approximately 60% of patients with metastatic renal cancer) seem to benefit more from the combination of immunotherapy + antiangiogenic therapy than from double immunotherapy. No such differences were found in poor-risk patients. This may have important implications in daily practice decision-making for these patients.

Santoni M ，Buti S ，Myint ZW ，Maruzzo M ，Iacovelli R ，Pichler M ，Kopecky J ，Kucharz J ，Rizzo M ，Galli L ，Büttner T ，De Giorgi U ，Kanesvaran R ，Fiala O ，Grande E ，Zucali PA ，Kopp RM ，Fornarini G ，Bourlon MT ，Scagliarini S ，Molina-Cerrillo J ，Aurilio G ，Matrana MR ，Pichler R ，Cattrini C ，Büchler T ，Massari F ，Seront E ，Calabrò F ，Pinto A ，Berardi R ，Zgura A ，Mammone G ，Ansari J ，Atzori F ，Chiari R ，Bamias A ，Caffo O ，Procopio G ，Sunela K ，Bassanelli M ，Ortega C ，Grillone F ，Landmesser J ，Milella M ，Messina C ，Küronya Z ，Mosca A ，Bhuva D ，Santini D ，Vau N ，Morelli F ，Incorvaia L ，Rebuzzi SE ，Roviello G ，Soares A ，Bisonni R ，Bimbatti D ，Zabalza IO ，Rizzo A ，Mollica V ，Sorgentoni G ，Monteiro FSM ，Battelli N ，Bracarda S ，Porta C ... -  《European Urology Oncology》