International Metastatic Renal Cell Carcinoma Research Articles

Perirenal Fat Thickness Significantly Associated with Prognosis of Metastatic Renal Cell Cancer Patients Receiving Anti-VEGF Therapy.

Although high body mass index (BMI) was reported to associate with a better prognosis for metastatic renal cell cancer (mRCC) patients receiving anti-vascular endothelial growth factor (anti-VEGF) therapy, it is an imperfect proxy for the body composition, especially in Asian patients with a lower BMI. The role of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and perirenal fat thickness (PRFT) in mRCC patients was still unknown. Therefore, a multicenter retrospective study of 358 Chinese mRCC patients receiving anti-VEGF therapy was conducted and their body composition was measured via computed tomography. We parameterized VAT, SAT and PRFT according to their median value and BMI according to Chinese criteria (overweight: BMI ≥ 24). We found VAT, SAT, and PRFT (all p < 0.05) but not BMI, significantly associated with overall survival (OS) and progression-free survival (PFS). Multivariate Cox analysis identified PRFT was the independent predictor of OS and PFS, and IMDC expanded with PRFT showed the highest C-index in predicting OS (OS:0.71) compared with VAT, SAT, and BMI. PRFT could increase the area under the curve of the traditional International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model in OS (70.54% increase to 74.71%) and PFS (72.22% increase to 75.03%). PRFT was introduced to improve the IMDC model and PRFT-modified IMDC demonstrated higher AIC in predicting OS and PFS compared with the traditional IMDC model. Gene sequencing analysis (n = 6) revealed that patients with high PRFT had increased angiogenesis gene signatures (NES = 1.46, p = 0.04) which might explain why better drug response to anti-VEGF therapy in mRCC patients with high PRFT. The main limitation is retrospective design. This study suggests body composition, especially PRFT, is significantly associated with prognosis in Chinese mRCC patients receiving anti-VEGF therapy. PRFT-modified IMDC model proposed in this study has better clinical predictive value.

Significance of timing of therapeutic line on effectiveness of nivolumab for metastatic renal cell carcinoma.

This study aimed to clarify the significance of therapeutic timing on the effectiveness of nivolumab for treating metastatic renal cell carcinoma. Fifty-eight patients with metastatic renal cell carcinoma treated with nivolumab monotherapy were retrospectively studied. Patients who were treated with nivolumab as second-line therapy were included in the second-line group, while the others were included in the later-line group. The clinicopathological characteristics, effects of nivolumab, and prognoses of these groups were compared. Twenty and thirty-eight patients were included in the second-line and later-line groups, respectively. There were no significant differences in the distribution of International Metastatic Renal Cell Carcinoma Database Consotium risk and other clinicopathological characteristics between the 2 groups. The proportion of patients whose objective best response was progressive disease in the second-line group was significantly lower than that in the later-line group (15% vs. 50%, p = 0.0090). The 50% progression-free survival with nivolumab in the second-line group was significantly better than that in the later-line group (not reached and 5 months, p = 0.0018). Multivariate analysis showed that the second-line setting was an independent predictive factor for better progression-free survival (p = 0.0028, hazard ratio = 0.108). The 50% overall survival after starting nivolumab in the second-line and later-line groups was not reached and 27.8 months, respectively (p = 0.2652). The therapeutic efficacy of nivolumab as second-line therapy is expected to be better than that of later therapy.

A CASE OF RENAL CELL CARCINOMA WITH SMALL INTESTINE METASTASIS DURING NIVOLUMAB PLUS IPILIMUMAB

A 71-year-old man with a history of hoarseness and right upper extremity numbness was referred to our department for evaluation of an intrathoracic mass that was detected on chest radiography and a right kidney tumor observed on computed tomography (CT). Histopathological examination of percutaneous kidney biopsy and bronchoscopic lung biopsy specimens revealed renal clear cell carcinoma with multiple lung metastases. The patient showed a poor risk based on the International Metastatic renal cell carcinoma Database Consortium score, and nivolumab plus ipilimumab were initiated as first-line therapy. His symptoms gradually improved, following four courses of nivolumab plus ipilimumab treatment, and CT revealed shrinkage of all lesions. However, he developed diarrhea, rash, anemia, and elevated serum C-reactive protein levels (CRP) following this therapy. Diarrhea and rash were considered immune-related adverse events, and he was treated with oral prednisolone and topical corticosteroid. Nivolumab administration was discontinued because anemia worsened together with elevated serum CRP levels despite improvement in diarrhea. He subsequently developed constipation and abdominal bloating, following further treatment for 4 months. CT revealed intestinal tumor-induced intussusception, necessitating partial resection of the small intestinal tumor, which was histopathologically diagnosed as metastases. Both anemia and elevated CRP improved postoperatively. Currently, all metastatic lesions other than the resected intestine have continued to respond to treatment over 12 months after initiation of nivolumab plus ipilimumab therapy.

Imaging Response to Contemporary Immuno-oncology Combination Therapies in Patients With Metastatic Renal Cell Carcinoma

The association between treatment with first-line immuno-oncology (IO) combination therapies and physician-assessed objective imaging response among patients with metastatic renal cell carcinoma (mRCC) remains uncharacterized. To compare the likelihood of objective imaging response (ie, complete or partial response) to first-line IO combination ipilimumab-nivolumab (IOIO) therapy vs approved IO with vascular endothelial growth factor inhibitor (IOVE) combination therapies among patients with mRCC. This multicenter international cohort study was nested in routine clinical practice. A data set from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) was used to identify consecutive patients with mRCC who received treatment with IO combination therapies between May 30, 2013, and September 9, 2021. A total of 899 patients with a histologically confirmed diagnosis of mRCC who received treatment with a first-line IOVE or IOIO regimen and had evaluable responses were included. Best overall response to first-line IO combination therapy based on Response Evaluation Criteria in Solid Tumors, version 1.1. The primary outcome was the difference in treating physician-assessed objective imaging response based on the type of first-line IO combination therapy received. Secondary outcomes included the identification of baseline characteristics positively associated with objective imaging response and the association of objective imaging response with overall survival. Among 1085 patients with mRCC who received first-line IO combination therapies, 899 patients (median age, 62.8 years [IQR, 55.9-69.2 years]; 666 male [74.2%]) had evaluable responses. A total of 794 patients had information available on IMDC risk classification; of those, 127 patients (16.0%) had favorable risk, 442 (55.7%) had intermediate risk, and 225 (28.3%) had poor risk. With regard to best overall response among all participants, 37 patients (4.1%) had complete response, 344 (38.3%) had partial response, 315 (35.0%) had stable disease, and 203 (22.6%) had progressive disease. Corresponding median overall survival was not estimable (95% CI, 53.3 months to not estimable) among patients with complete response, 55.9 months (95% CI, 44.1 months to not estimable) among patients with partial response, 48.1 months (95% CI, 33.4 months to not estimable) among patients with stable disease, and 13.0 months (95% CI, 8.4-18.1 months) among patients with progressive disease (log rank P < .001). Treatment with IOVE therapy was found to be independently associated with an increased likelihood of obtaining response (OR, 1.89; 95% CI, 1.26-2.81; P = .002) compared with IOIO therapy. The presence of lung metastases (odds ratio [OR], 1.49; 95% CI, 1.01-2.20), receipt of cytoreductive nephrectomy (OR, 1.59; 95% CI, 1.04-2.43), and favorable IMDC risk (OR, 1.93; 95% CI, 1.10-3.39) were independently associated with an increased likelihood of response. In this study, treatment with IOVE therapy was associated with significantly increased odds of objective imaging response compared with IOIO therapy. The presence of lung metastases, receipt of cytoreductive nephrectomy, and favorable IMDC risk were associated with increased odds of experiencing objective imaging response. These findings may help inform treatment selection, especially in clinical contexts associated with high-volume multisite metastatic disease, in which obtaining objective imaging response is important.

Comparison of outcomes for Hispanic and non-Hispanic patients with advanced renal cell carcinoma in the International Metastatic Renal Cell Carcinoma Database.

6590 Background: Epidemiologic studies suggest that Hispanic patients with renal cell carcinoma (RCC) have worse outcomes than non-Hispanic White patients (NHW). It is unclear if this disparity is related to inherent biological differences or patients’ social determinants of health (SDOH). Utilizing the International Metastatic Renal Cell Carcinoma Database (IMDC) of patients with RCC primarily receiving care at academic medical centers, we investigated outcomes of Hispanic and NHW patients with advanced RCC. Methods: Eligible patients included patients who self-reported being non-Black Hispanic or NHW with locally advanced or metastatic RCC initiating systemic therapy. The primary endpoint was overall survival (OS) and secondary endpoint was time to treatment failure (TTF) for the first-line therapy. Kaplan Meier curves were constructed for OS and TTF. Cox regression was used to estimate hazard ratios (HR) adjusted for confounding variables. Results: The cohort included 1,563 patients, of which 181 (11.6%) were Hispanic. Most patients were male (74%) with clear cell histology (82%). IMDC risk groups were 18%, 58%, 24% for favorable, intermediate, and poor risk, respectively, and were similar by ethnic groups. Compared to NHW, Hispanic patients were younger at diagnosis (median 57 vs 59 years, p = 0.036), less likely to have &gt; 1 metastatic site (61% vs 77%, p &lt; 0.001) and bone metastases (24% vs 33%, p = 0.009). 1,178 patients (124 Hispanic vs. 1,054 NWH) received treatment before 2018, 385 patients (57 Hispanic vs. 328 NWH) received treatment during or after 2018. With regards to first line therapy, the majority received tyrosine kinase inhibitor (TKI) monotherapy (70%), 10% received immunotherapy (IO) + IO, 9% received TKI + IO, 4% received IO monotherapy, and 8% received other treatments. Median TTF was 7.8 months (95% Confidence Interval (CI): 6.2-9.0) in Hispanic patients and 7.5 months (95% CI: 6.9-8.1) in NHW patients. On multivariable analysis, there was no significant difference in TTF between Hispanic and NHW patients (HR 1.05, 95% CI: 0.89-1.25, p = 0.558). Significant predictors of TTF were presence of unfavorable site of metastases, histology, IMDC risk group, and therapy type. Median OS was 38.0 months (95% CI: 28.1-59.2) in Hispanic patients and 35.7 months (95% CI: 31.9-39.2) in NHW patients. On multivariable analysis, there was no significant difference in OS between Hispanic and NHW patients (HR 1.07, 95% CI: 0.87-1.32, p = 0.544). Significant predictors of OS were number of metastatic sites, presence of unfavorable metastasis, histology, IMDC risk group, and therapy type. Conclusions: In this analysis, we did not detect a difference in OS or TTF for Hispanic patients with RCC. Our data suggest that access to care (as available in a tertiary cancer hospital) can mitigate the historic difference in outcomes in Hispanic versus NWH patients.

Racial differences in treatment patterns and outcomes of first-line (1L) therapies for advanced renal cell carcinoma (aRCC) in the real-world (RW) setting.

4548 Background: In 1L therapy for aRCC, nivolumab plus ipilimumab (NIVO+IPI) and pembrolizumab plus axitinib (PEM+AXI) have demonstrated significantly improved clinical outcomes versus sunitinib in phase III trials. African American/Black (AA) patients are grossly underrepresented in all aRCC trials. Little is known about the impact of racial differences on the use of 1L therapies and clinical outcomes in the RW setting. Methods: This retrospective chart review included AA and White American (WA) patients diagnosed with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC)/Memorial Sloan Kettering Cancer Center (MSKCC) intermediate/poor (I/P)-risk aRCC who initiated on 1L NIVO+IPI, PEM+AXI, or tyrosine kinase inhibitor (TKI) monotherapy with sunitinib, pazopanib, or cabozantinib. Patients’ demographic/clinical characteristics and outcomes were abstracted from medical charts by treating oncologists. Use of 1L therapy, treatment discontinuation, and clinical outcomes including disease response, landmark progression-free survival (PFS), landmark overall survival (OS), and treatment-related adverse event (TRAE) rates were assessed descriptively by race. Results: Of 473 patients, 95 (20.1%) were AA, and 378 (79.9%) were WA patients. Median follow-up was 10.9 months. A higher proportion of AA vs. WA patients had received 1L TKI monotherapy (21.1% vs. 16.1%). Treatment discontinuation rate was higher in AA vs. WA patients (49.5% vs. 43.4%). Treatment response was lower in AA than WA patients (overall response rate [ORR]: 58.8% vs. 74.8%; complete response [CR]: 8.2% vs. 11.4%). The TRAE rate was slightly lower in AA vs. WA patients (25.3% vs. 32.5%). Stratified clinical outcomes including landmark PFS and OS rates at 6 and 9 months are shown in the Table. Conclusions: In this RW I/P-risk aRCC cohort, fewer AA patients were treated with standard of care immune-oncology (IO)-based therapy vs. WA patients, which may contribute to differences in therapy discontinuation and survival outcomes. Also, even with short follow-up, clinically meaningful ORR differences are noted in AA and WA patients. [Table: see text]

Prognostic factors for patients with advanced renal cell carcinoma (aRCC) in the era of first-line (1L) treatment with immune checkpoint inhibitors (ICIs).

4544 Background: The most commonly used prognostic models in aRCC, the Memorial Sloan-Kettering Cancer Center (MSKCC) and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores, were developed when cytokines and VEGF targeted monotherapies were standard of care, respectively. aRCC 1L treatment now includes combination therapy with 2 ICIs or ICI+VEGF receptor inhibitor. Re-evaluation of the MSKCC and IMDC prognostic models in the era of ICI therapy and identification of additional prognostic factors are overdue. Methods: Data from 1052 patients with aRCC treated on the CheckMate-214 (CM214) clinical trial with 1L nivolumab/ipilimumab (NIVO/IPI) or sunitinib (SUN) were analyzed retrospectively at median follow-up 5 yrs. For each treatment group, multivariable Cox model hazard ratios (HR) were compared to the published MSKCC and IMDC model HRs. Discrimination (c index) was assessed based upon the continuous scores obtained as the weighted combination of regression parameters from the published MSKCC &amp; IMDC models. Results: KPS &lt; 80% remained highly prognostic in both treatment groups (HRs &gt; 2.5). With the exception of high calcium, the other factors of time from dx to treatment &lt; 1 yr, hemoglobin &lt; lower limit of normal (LLN), neutrophils &gt; upper limit of normal (ULN), platelets &gt; ULN and LDH &gt; 1.5xULN consistently retained prognostic value for SUN (HRs ≥ published model HRs) but had diminished prognostic value for NIVO/IPI (each HR &lt; published model HR). High calcium had diminished prognostic value for SUN and retained prognostic value for NIVO/IPI. The c-indices for discrimination were 0.61 and 0.64 for the MSKCC model in the NIVO/IPI and SUN treatment groups, respectively, and were 0.63 and 0.67 for the IMDC model in the NIVO/IPI and SUN treatment groups compared to reported IMDC c-index of 0.73 (Heng 2009). (Table) Conclusions: The prognostic ability of the MSKCC and IMDC risk models is reduced with combination ICI treatment. Evaluation of additional prognostic factors and development of new risk scores are needed and this work is ongoing. [Table: see text]

Real-world data on the efficacy and safety of pazopanib in IMDC favorable- and intermediate-risk metastatic renal cell carcinoma: a multicenter retrospective cohort study of Chinese patients.

BackgroundPazopanib was recommended as first-line treatment option for Metastatic renal cell carcinoma (mRCC), while evidence from strictly selected patients has poor external validity and clinical characteristics are complex in real-world clinical practice. This study aimed to illustrate the survival benefits and safety of pazopanib monotherapy using real-world data of mRCC patients.MethodsThis was a retrospective, multicenter, cohort study. We recruited adult patients with International Metastatic renal cell carcinoma Database Consortium (IMDC) favorable- and intermediate-risk mRCC receiving first-line pazopanib from May 2017 to February 2020. Patients were treated with pazopanib 800 mg or 600 mg orally once daily. Treatment efficacy, and drug safety were analyzed. Response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Drug safety was assessed according to the grade of treatment-related adverse reactions.ResultsBased on IMDC risk stratification, there were 46 (32.2%) patients in the favorable-risk group and 97 (67.8%) patients in the intermediate-risk group. The median progression-free survival (PFS) of the entire cohort, favorable- and intermediate risk groups was 21.2, 27.1 and 17.2 months, respectively. In the intermediate-risk group, PFS was much longer in patients with 1 risk factor than in patients with 2 risk factors, with a median of 25.9 months versus 11.2 months (P<0.0001). Patients with lung metastasis only had longer PFS than those with bone metastasis only, with a median PFS of 25.9 vs. 21.2 months, respectively. Furthermore, local therapy for the metastatic site appeared to benefit patients in the IMDC favorable-risk group but not those in the IMDC intermediate-risk group. The best response was 40/140 (29%) partial response (PR), 86/140 (61%) stable disease (SD), and 14/140 (10%) progressive disease (PD). The most common adverse drug reactions (ADRs) were change in hair color (47.7%), hypertension (40.0%), diarrhea (40.0%), proteinuria (38.5%), elevation of transaminase (35.4%), and hand–foot skin reaction (32.3%).ConclusionsThis real-world data analysis recommended that patients in intermediate-risk group need to be further stratified according to the number of risk factors. Pazopanib was most suitable for patients with lung metastasis only. Local treatment for metastatic lesions should only be recommended in IMDC favorable patients.

Metastatic Renal Cell Carcinoma With Sarcomatoid Features.

A previously healthy woman, aged 38 years, presented with a 3-month history of fatigue, dyspnea on exertion, significant weight loss, and severe left flank pain; her symptoms restricted any work activities. Laboratory test results were notable for hypercalcemia (corrected serum calcium, 12.8 mg/dL), anemia (9.3 g/dL), and lactate dehydrogenase elevation (>1.5 times the upper limit of normal). A CT scan revealed a 14-cm left renal mass and multiple lung and mediastinal lymph node metastases. A surgical open biopsy was performed; histopathological analysis concluded clear cell renal carcinoma (RCC) with 30% sarcomatoid features. The patient was diagnosed with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) poor-risk metastatic RCC with sarcomatoid features. She started first-line systemic treatment.

Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma.

BackgroundConditional survival estimates provide critical prognostic information for patients with advanced renal cell carcinoma (aRCC). Efficacy, safety, and conditional survival outcomes were assessed in CheckMate 214 (ClinicalTrials.gov identifier NCT02231749) with a minimum follow‐up of 5 years.MethodsPatients with untreated aRCC were randomized to receive nivolumab (NIVO) (3 mg/kg) plus ipilimumab (IPI) (1 mg/kg) every 3 weeks for 4 cycles, then either NIVO monotherapy or sunitinib (SUN) (50 mg) daily (four 6‐week cycles). Efficacy was assessed in intent‐to‐treat, International Metastatic Renal Cell Carcinoma Database Consortium intermediate‐risk/poor‐risk, and favorable‐risk populations. Conditional survival outcomes (the probability of remaining alive, progression free, or in response 2 years beyond a specified landmark) were analyzed.ResultsThe median follow‐up was 67.7 months; overall survival (median, 55.7 vs 38.4 months; hazard ratio, 0.72), progression‐free survival (median, 12.3 vs 12.3 months; hazard ratio, 0.86), and objective response (39.3% vs 32.4%) benefits were maintained with NIVO+IPI versus SUN, respectively, in intent‐to‐treat patients (N = 550 vs 546). Point estimates for 2‐year conditional overall survival beyond the 3‐year landmark were higher with NIVO+IPI versus SUN (intent‐to‐treat patients, 81% vs 72%; intermediate‐risk/poor‐risk patients, 79% vs 72%; favorable‐risk patients, 85% vs 72%). Conditional progression‐free survival and response point estimates were also higher beyond 3 years with NIVO+IPI. Point estimates for conditional overall survival were higher or remained steady at each subsequent year of survival with NIVO+IPI in patients stratified by tumor programmed death ligand 1 expression, grade ≥3 immune‐mediated adverse event experience, body mass index, and age.ConclusionsDurable clinical benefits were observed with NIVO+IPI versus SUN at 5 years, the longest phase 3 follow‐up for a first‐line checkpoint inhibitor‐based combination in patients with aRCC. Conditional estimates indicate that most patients who remained alive or in response with NIVO+IPI at 3 years remained so at 5 years.

Impact of the Discordance Between Scales of Memorial Sloan-Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium in Patients’ Prognosis With Metastatic Renal Cancer

BackgroundIn Mexico, about 30% of renal cancer patients are diagnosed in a metastatic state. Despite the recent advances in the treatment of cancer, metastatic renal cancer is still an incurable illness. Thus, identifying prognostic factors helps improve prognosis accuracy and survival prediction for patients.MethodsIn this study, we retrospectively analyzed 26 patients with histological diagnosis of renal cell carcinoma, including clear cell and other subtypes in stage IV (metastatic), recurrent or unresectable disease. We performed a multivariate analysis of overall survival regarding the congruity between prognostic scales.ResultsOur results showed a significant difference in favor of patients with congruity between scales for progression-free survival (18.9 vs. 3.1 months; P = 0.048) and a tendency towards better overall survival in patients with the congruity of both scales compared to the discordant patients (112 vs. 32 months; P = 0.99).ConclusionThis study highlights the discordance between Memorial Sloan-Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium scales, which was associated with worse prognosis with a significant difference in progression-free survival but not in overall survival.

CABOSEQ: The efficacy of cabozantinib post up-front immuno-oncology combinations in patients with advanced renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

318 Background: There are limited data to understand 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 (VEGF) inhibitor combinations (IOVE). The activity of subsequent 3L approved therapies post CABO has not been established. Methods: Using the IMDC dataset, we examined all patients who received 2L CABO. We sought to identify the overall response rate (ORR), time to treatment failure (TTF) and overall survival (OS) of 2L CABO after IPI-NIVO, approved IOVE combinations and other 1L approaches. Additionally, we examined these outcomes for patients that received an approved 3L treatment post 2L CABO. Hazard ratios were adjusted for IMDC risk groups. Results: 346 patients were identified who had all received 2L CABO (78 post 1L IPI NIVO, 46 post 1L IOVE, 222 post 1L other). Of the entire cohort, 12.6%, 62.6% and 24.8% were IMDC favourable, intermediate and poor risk, respectively. 84% had clear cell histology, 18.5% had a sarcomatoid component and 38.3% had bone metastases at diagnosis. Outcomes for patients that received 2L CABO, stratified by 1L therapy are outlined in the table, followed by outcomes for patients that received subsequent 3L therapy post 2L CABO. After adjustment for IMDC criteria, the HR for 2L CABO OS and TTF for IOVE vs IPI-NIVO were 1.73 (95% CI 0.83-3.62 p = 0.14) and 1.62 (0.89-2.95 p = 0.11), respectively. Conclusions: There is clinically meaningful activity of CABO post IPI-NIVO, IOVE and other standard 1L approved therapies. Broadly, time to event endpoints and response rates are similar irrespective of 1L therapy. Approved systemic therapies post CABO, mainly single agent VEGF inhibitors also have activity, though as expected this is diminished compared to earlier lines of therapy. These are real world benchmarks with which to counsel our patients when using single agent CABO.[Table: see text]

First-line therapy for metastatic renal cell carcinoma with pancreatic metastases: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

317 Background: Metastatic renal cell carcinoma (mRCC) with pancreatic metastases (PM) is characterised by heightened angiogenesis, which is associated with improved outcomes with vascular endothelial growth factor (VEGF) inhibitors. We aimed to compare the efficacy of first-line (1L) ipilimumab/nivolumab (IOIO) vs. anti-PD(L)1/anti-VEGF (IOVE) vs. VEGF monotherapy (VE) in mRCC patients with and without PM. Methods: We performed a retrospective analysis of patients with and without PM, using the IMDC. Sites of metastases were captured at initiation of 1L. Patients with PM could also have metastases at other sites. We studied overall survival (OS) from start of 1L therapy using Cox regression, adjusted for IMDC risk groups. Kaplan Meier survival curves were generated. Results: 543/7,634 (7%) patients had PM. Patients with PM in the overall population had improved OS compared to those without, 56 vs 25.6 months respectively (HR 0.63, 95% CI 0.55-0.73, p&lt;0.0001). When examining the effect of PM within 1L options, those treated with IOVE exhibited a longer OS if PM were present vs absent, median not reached vs 45 months respectively (HR 0.41, 95% CI 0.18-0.93 p=0.03). This association was also seen in patients with treated with 1L VE, in those with PM vs absent, median 53.1 vs 25.1 months respectively (HR 0.65, 95% CI 0.55-0.76, p &lt;0.0001). Contrastingly there was no difference in median OS of patients with or without PM in patients receiving IOIO, 41.4 vs 44.4 months respectively (HR 0.86, 95% CI 0.48-1.56, p=0.62). Comparing the outcomes between 1L therapies in patients with PM the median OS of IOVE vs VE was not reached vs 53.1 months respectively (HR 0.37, 95% CI 0.16-0.83 p=0.02). Conversely, upfront VE and IOIO had a similar median OS of 53.1 vs 41.4 months respectively (HR 0.81, 95% CI 0.45-1.47 p=0.49). We were unable to find any difference in OS between those treated with IOVE vs IOIO, median not reached vs 41.4 months respectively (HR 0.52 95%, CI 0.19-1.45, p=0.21), but the low event rate limited this interpretation. Conclusions: We found that the presence of PM leads to an indolent biological behavior and was associated with improved outcomes when 1L therapy included a VE component. PM patients had comparable OS outcomes on 1L VE and 1L IOIO therapy, but improved OS when treated with 1L IOVE. Anti-angiogenic therapy may be necessary to optimize outcomes in PM and this warrants prospective evaluation. [Table: see text]

Predictors of Survival in Favorable Risk Patients with Metastatic Renal Cell Carcinoma Treated with a Single-Agent First-Line Therapy

Introduction: The aim of this retrospective study was to elucidate predictors of survival in metastatic renal cell carcinoma (mRCC) patients in an International Metastatic Renal Cell Carcinoma Database Consortium favorable risk group treated with frontline therapy without immune checkpoint inhibitors. Methods: A total of 238 patients with mRCC were reviewed. Among them, 55 patients in favorable risk group treated with single-agent systemic therapy were retrospectively analyzed. Clinical and pathological data were retrieved and analyzed retrospectively. The prognostic effect of each marker on overall survival (OS) was investigated with univariate and multivariate Cox’s proportional hazards regression models. Results: After a median follow-up of 46.2 months after first-line treatment initiation, the median progression-free survival (PFS) was 29.3 months, and the median OS has not been reached. The estimated percentage of patients who were alive at 12 and 24 months were 96.1 and 94.1%, respectively. Multivariate analysis revealed that the long-term duration of first-line treatment (hazard ratio [HR]: 0.972, 95% confidence interval [CI]: 0.944–0.997, p = 0.0299) and the metastases limited to lung (HR: 3.852, 95% CI: 1.080–24.502, p = 0.0361) were independent predictors for longer OS in favorable risk mRCC patients. Conclusion: First-line systemic therapy for favorable risk mRCC patients with a single agent resulted in relatively longer PFS and OS. A longer duration of first-line treatment and lung only metastases are correlated with longer OS.

Safety and efficacy of nivolumab plus ipilimumab in patients with advanced non-clear cell renal cell carcinoma: results from the phase 3b/4 CheckMate 920 trial

BackgroundCheckMate 920 (NCT02982954) is a multicohort, phase 3b/4 clinical trial of nivolumab plus ipilimumab treatment in predominantly US community-based patients with previously untreated advanced renal cell carcinoma (RCC) and clinical...

Outcomes of sorafenib treatment of advanced renal cell carcinoma according to IMDC risk criteria: analysis of Japanese real-world data from postmarketing all-patient surveillance of sorafenib.

Aim: To assess sorafenib survival outcomes in renal cell carcinoma patients using standard International Metastatic Renal Cell Carcinoma Data Consortium (IMDC) risk criteria. Patients & methods: The authors restratified a real-world cohort of 3255 advanced renal cell carcinoma patients, obtained from Japanese sorafenib postmarketing surveillance, to assess survival outcomes using IMDC criteria; intermediate risk was subdivided into intermediate 1 (Int-1) and imterdemiate 2 (Int-2; one and two risk factors, respectively). Results: Overall, 2225 (68%) IMDC-evaluable patients were reclassified as favorable (17%), intermediate (62%) and poor (21%) risk, with median progression-free survival of 10.4, 8.1 and 3.4months, respectively. Int-1 (36%) and Int-2 (26%) subgroups had median progression-free survival of 10.1 and 6.0months, respectively. Sorafenib had acceptable safety/tolerability. Conclusion: Sorafenib effectiveness was promising for IMDC intermediate risk, particularly Int-1, warranting further investigation.

Exposure-Response Analysis to Support Nivolumab Once Every 4 Weeks Dosing in Combination with Cabozantinib in Renal Cell Carcinoma.

A benefit:risk assessment for a less-frequent nivolumab 480 mg every 4 weeks + cabozantinib 40 mg every day dosing regimen was predicted using modeling and simulation of clinical trial data from nivolumab monotherapy studies and from the nivolumab 240 mg every 2 weeks + cabozantinib 40 mg every day dosing regimen, which demonstrated clinical benefit versus sunitinib in previously untreated advanced renal cell carcinoma (aRCC) in the phase III CheckMate 9ER trial (NCT03141177). Multivariable Cox proportional hazards analyses were conducted using nivolumab monotherapy data in previously treated aRCC and data from CheckMate 9ER to evaluate progression-free survival (PFS), overall survival (OS), and grade ≥2 immune-mediated adverse events (IMAE). Nivolumab 240 mg every 2 weeks + cabozantinib versus nivolumab monotherapy showed improvement in PFS (HR, 0.38; 95% CI, 0.31-0.47), OS (HR, 0.63; 95% CI, 0.46-0.85), and increased risk of grade ≥2 IMAEs (HR, 2.19; 95% CI, 1.79-2.67). Nivolumab exposure was not a predictor of PFS/OS or grade ≥2 IMAEs. Lower nivolumab clearance, male sex, higher baseline bodyweight, and Karnofsky performance (100) were each associated with PFS/OS improvements. Region and International Metastatic Renal Cell Carcinoma Database Consortium poor score were negative OS predictors. Age, baseline albumin, and programmed death ligand 1 status were not significant PFS/OS predictors. Cabozantinib was a significant grade ≥2 IMAE predictor, driven by diarrhea and hepatic events. Model-predicted PFS/OS and grade ≥2 IMAE rates were similar (<2.5% difference) for nivolumab 240 mg every 2 weeks + cabozantinib and 480 mg every 4 weeks + cabozantinib. Comparable benefit:risk was predicted for nivolumab 480 mg every 4 weeks + cabozantinib and nivolumab 240 mg every 2 weeks + cabozantinib.

Efficacy of nivolumab plus ipilimumab as first-line therapy for primary tumors in patients with renal cell carcinoma.

With the emergence of several effective combination therapies, information on their effects at the primary site will be crucial for planning future cytoreductive nephrectomy (CN). The present study focused exclusively on changes in primary tumor sizes following treatment with nivolumab plus ipilimumab and investigated the clinical factors associated with a good response in primary tumors. We retrospectively assessed 27 patients diagnosed with advanced renal cell carcinoma (RCC) who started treatment with nivolumab plus ipilimumab. Changes in tumor sizes at the primary site were described using waterfall and spider plots, respectively. We analyzed the correlation of tumor shrinkage between primary and metastatic site. The parameters analyzed between responders and non-responders according to primary tumor sizes were International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores, peripheral blood markers, and CRP. The median age and follow-up period were 66 years and 9.3 months, respectively. The median IMDC risk score was 3 (range: 1-6). Nineteen patients were diagnosed with clear-cell RCC (ccRCC) and 8 patients with non-ccRCC. Among ccRCC patients, 9 (47.4%) achieved a significant response with a maximum reduction of 30% or more in the size of the primary tumor from baseline within 4 months, while 3 (37.5%) out of 8 patients with non-ccRCC achieved a significant response. Shrinkage of the primary tumor correlated with the metastatic tumors in both ccRCC and non-ccRCC cases. Of note, 6 patients underwent CN and no viable tumor cells were detected in the surgical specimens of 3 patients whose primary tumors shrank by approximately 50%-60% with a reduction to 4 cm or less. Among ccRCC patients, the neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio were slightly lower in responders than in non-responders (P = 0.0944 and P = 0.0691). The platelet-to-lymphocyte ratio was significantly lower in responders than in non-responder (P = 0.0391). Significant responses in primary tumors to nivolumab plus ipilimumab were observed in 50% of ccRCC patients, while responses varied among non-ccRCC patients. Inflammation markers may be predictive factors of treatment responses in primary tumors. Although further studies are needed, the present results suggest the importance of considering CN from radiological and pathological viewpoints.

Evolving landscape of first-line combination therapy in advanced renal cancer: a systematic review.

Background:Renal cell carcinoma (RCC) is a common malignancy with approximately 30% of cases diagnosed at the advanced or metastatic stage. While single-agent vascular endothelial growth factor-targeted therapy has been a mainstay of treatment, data from multiple phase III trials assessing first-line immune checkpoint inhibitor (ICI) combinations have demonstrated a significant survival benefit.Methods:A systematic search of the published and presented literature was performed to identify phase III trials assessing ICI combination regimens in RCC using search terms ‘immune checkpoint inhibitors’ AND ‘renal cell carcinoma,’ AND ‘advanced’.Results:Six phase III trials showed significant benefits for ICI combinations compared with sunitinib. Nivolumab plus ipilimumab significantly improved overall survival [OS; median, 47.0 versus 26.6 months, hazard ratio (HR) = 0.68, 95% confidence interval (CI) = 0.58–0.81, p < 0.0001) and progression-free survival (PFS; median 11.6 versus 8.3 months, HR = 0.73, 95% CI = 0.61–0.87, p = 0.0004) in International Metastatic renal cell carcinoma Database Consortium intermediate and poor-risk patients. OS was also significantly improved for ICI plus tyrosine kinase inhibitor combinations regardless of risk, including pembrolizumab plus either axitinib (HR = 0.73, 95% CI = 0.60–0.88, p < 0.001) or lenvatinib (HR = 0.66, 95% CI = 0.49–0.88, p = 0.005) and nivolumab plus cabozantinib (HR = 0.66, 95% CI = 0.50–0.87, p = 0.003). No new safety signals were identified.Conclusions:Phase III first-line trials of ICI combinations showed survival benefits compared with a control arm of sunitinib. Global access to these combinations should be made available to patients with advanced RCC.

Prognostic and Clinicopathological Significance of the Systemic Immune-Inflammation Index in Patients With Renal Cell Carcinoma: A Meta-Analysis

BackgroundThe systemic immune-inflammation index (SII) is a hematological parameter based on neutrophil, platelet, and lymphocyte counts. Studies that have investigated the prognostic value of SII in patients with renal cell carcinoma (RCC) have reported controversial results. In this study, we systematically investigated the prognostic value of SII in patients with RCC.MethodsWe systematically searched English articles in the PubMed, Embase, Web of Science, and Cochrane Library databases up to October 2021. Hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were used to obtain pooled results.ResultsThe meta-analysis included 10 studies that enrolled 3,180 patients. A high SII was associated with poor overall survival (HR 1.75, 95% CI 1.33–2.30, p<0.001) in patients with RCC. However, a high SII was not shown to be a significant prognostic factor for progression-free survival/disease-free survival (HR 1.22, 95% CI 0.84–1.76, p=0.293) or poor cancer-specific survival (HR 1.46, 95% CI 0.68–3.12, p=0.332) in patients with RCC. A high SII was correlated with male sex (OR 1.51, 95% CI 1.11–2.04, p=0.008), Fuhrman grade G3–G4 (OR 1.80, 95% CI 1.08–3.00, p=0.024), and poor risk based on the International Metastatic Renal Cell Carcinoma Database Consortium criteria (OR 19.12, 95% CI 9.13–40.06, p<0.001).ConclusionA high SII was independently associated with poor survival outcomes in patients with RCC. Additionally, an elevated SII indicated more aggressive disease. The SII may serve as a useful cost-effective prognostic indicator in patients with RCC.