International Metastatic Renal Cell Carcinoma Database Consortium Research Articles

First-line immunotherapy of metastatic renal cell carcinoma: an updated network meta-analysis including triplet therapy.

To compare the differential efficacy of first-line immune checkpoint inhibitor (ICI)-based combined therapies among patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), as recently, the efficacy of triplet therapy comprising nivolumab plus ipilimumab plus cabozantinib has been published. Three databases were searched in December 2022 for randomised controlled trials (RCTs) analysing oncological outcomes in patients with mRCC treated with first-line ICI-based combined therapies. We performed network meta-analysis (NMA) to compare the outcomes, including progression-free survival (PFS) and objective response rates (ORRs), in patients with intermediate- and poor-risk mRCC; we also assessed treatment-related adverse events. Overall, seven RCTs were included in the meta-analyses and NMAs. Treatment ranking analysis revealed that pembrolizumab + lenvatinib (99%) had the highest likelihood of improved PFS, followed by nivolumab + cabozantinib (79%), and nivolumab + ipilimumab + cabozantinib (77%). Notably, compared to nivolumab + cabozantinib, adding ipilimumab to nivolumab + cabozantinib did not improve PFS (hazard ratio 1.02, 95% confidence interval 0.72-1.43). Regarding ORRs, treatment ranking analysis also revealed that pembrolizumab + lenvatinib had the highest likelihood of providing better ORRs (99.7%). The likelihoods of improved PFS and ORRs of pembrolizumab + lenvatinib were true in both International Metastatic RCC Database Consortium (IMDC) risk groups. Our analyses confirmed the robust efficacy of pembrolizumab + lenvatinib as first-line treatment for patients with intermediate or poor IMDC risk mRCC. Triplet therapy did not result in superior efficacy. Considering both toxicity and the lack of mature overall survival data, triplet therapy should only be considered in selected patients.

Impact of smoking status on clinical outcomes in patients with metastatic renal cell carcinoma treated with first-line immune checkpoint inhibitor-based regimens.

Current tobacco smoking is independently associated with decreased overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) treated with targeted monotherapy (VEGF-TKI). Herein, we assess the influence of smoking status on the outcomes of patients with mRCC treated with the current first-line standard of care of immune checkpoint inhibitor (ICI)-based regimens. Real-world data from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were collected retrospectively. Patients with mRCC who received either dual ICI therapy or ICI with VEGF-TKI in the first-line setting were included and were categorized as current, former, or nonsmokers. The primary outcomes were OS, time to treatment failure (TTF), and objective response rate (ORR). OS and TTF were compared between groups using the log-rank test and multivariable Cox regression models. ORR was assessed between the 3 groups using a multivariable logistic regression model. A total of 989 eligible patients were included in the analysis, with 438 (44.3%) nonsmokers, 415 (42%) former, and 136 (13.7%) current smokers. Former smokers were older and included more males, while other baseline characteristics were comparable between groups. Median follow-up for OS was 21.2 months. In the univariate analysis, a significant difference between groups was observed for OS (P = .027) but not for TTF (P = .9), with current smokers having the worse 2-year OS rate (62.8% vs 70.8% and 73.1% in never and former smokers, respectively). After adjusting for potential confounders, no significant differences in OS or TTF were observed among the 3 groups. However, former smokers demonstrated a higher ORR compared to never smokers (OR 1.45, P = .02). Smoking status does not appear to independently influence the clinical outcomes to first-line ICI-based regimens in patients with mRCC. Nonetheless, patient counseling on tobacco cessation remains a crucial aspect of managing patients with mRCC, as it significantly reduces all-cause mortality.

Treatment-free survival outcomes from the phase II study of nivolumab and salvage nivolumab/ipilimumab in advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A)

BackgroundAs part of a partitioned survival analysis, treatment-free survival (TFS) can characterize the overall survival time patients spend between the cessation of immunotherapy and the start of subsequent therapy; both...

Real World Analysis of Peritoneal Metastasis From Renal Cell Carcinoma. Meet-Uro27

BackgroundPeritoneal metastases (PM) have been reported in approximately 1% of patients with metastatic Renal Cell Carcinoma (mRCC). Outcome data are limited due to the rarity of this metastatic site. Therefore, the aim of our study is to describe renal cell carcinoma (RCC) patients with PM treated as per clinical practice. Materials and MethodsBaseline characteristics and outcome data of patients with PM from RCC were retrospectively collected from 18 Italian oncological referral centers adhering to the Meet-Uro group, from January 2016 to January 2023. ResultsWe collect 81 RCC patients with PM. 78/81 received systemic treatment, 3/81 only best supportive care. First line treatment included tyrosine-kinase inhibitors (TKI) (46/78), ImmuneOncology (IO)-TKI (26/78) and IO-IO (6/78), with different Objective Response Rate (ORR) (43.4% in TKI monotherapy group vs 50% in IO-TKI group, respectively) and Disease Control Rate (DCR) (60.8% in TKI treated patients vs. 76.9% in IO-TKI treated patients). Median PFS was 6.4 months (95%CI 4.18-14.8) in patients treated with TKI monotherapy vs 23.7 months (95%CI 11.1-NR) in patients treated with IO-TKI (p < 0.015). The median OS (mOS) was 22.7 months (95%CI 13.32 – 64.7) in the TKI monotherapy group vs 34.5 mo (95%CI NR-NR) in the IO-TKI group with 53.8% of patients alive at 1 years in the latter group, (p < 0.16). Primary refractory patients were 36.9% for TKI and 15.3% for IO-TKI. According to International Metastatic renal cell carcinoma Database Consortium (IMDC) score, mPFS and mOS were consistent among risk categories. Median PFS was 36.6 months (95%CI 10.9-NR) for good risk patients compared to 10 months (95%CI 7.5-29.8) for intermediate risk and 2.96 months (95%CI 2.43-11.28) for poor risk population (p < 0.0005) whereas mOS was NR (95%CI 28.65-NR) for good risk patients compared to 35.3 months (95%CI 24.6-NA) and 12.4 months (95%CI 3.52-NR) for intermediate and poor risk population, respectively, (p < 0.0002). Only 34/78 (43.5%) received a second line treatment that was TKI (ORR 8.3% and DCR 41.6%) or IO (ORR 18.1% and DCR 40.9%). ConclusionWe report one of the largest case series regarding PM from RCC. Characteristics of patients suggest a more aggressive behavior of PM from mRCC. Outcome data suggest that TKI-IO as first line treatment, and TKI as second line, confirm their activity for these patients with dismal prognosis.

Efficacy, Safety, and Tolerability of Tivozanib in Heavily Pretreated Patients With Advanced Clear Cell Renal Cell Carcinoma.

Tivozanib has been approved as a third-line or later therapy for advanced renal cell carcinoma based on the TIVO-3 trial, which was conducted before immune checkpoint therapies (ICT), cabozantinib, and lenvatinib/everolimus became incorporated in the current sequential treatment paradigm for advanced clear cell RCC (ccRCC). We performed a retrospective study of patients with advanced ccRCC treated with tivozanib at MD Anderson Cancer Center during 6/2021-7/2023. A blinded radiologist assessed tumor response by RECIST v1.1. We assessed overall response rate (ORR), clinical benefit rate (CBR) [percentage of all treated patients who achieved radiologic response or stable disease (SD) for ≥ 6 months], progression-free survival (PFS), overall survival (OS), and safety. Of 30 analyzed patients, 23% had performance status ≥ 2; 47% had International Metastatic RCC Database Consortium (IMDC) poor-risk disease. Median number of prior therapies was 4 (range 1-8). All patients received prior ICT, 87% cabozantinib and 60% lenvatinib ± everolimus. Of 26 evaluable patients, 2 patients had confirmed partial response (ORR 7.7%); 5 patients had SD for ≥ 6 months (CBR 23.3%). Median PFS was 3.8 months (range 0.7-13.9); median OS was 14.1 months (range 0.3-28.5). Fifteen patients (50%) had ≥ 1 treatment-related adverse event (TRAE). There were 6 grade ≥ 3 TRAEs [hypertension, congestive heart failure (3), mucositis, and GI perforation (grade 5)]. In this cohort of heavily pretreated patients with advanced ccRCC, tivozanib yielded a modest clinical benefit in a minority of patients who received prior ICT, cabozantinib, and lenvatinib ± everolimus. TRAEs were consistent with previously published reports.

Impact of immunotherapy time-of-day infusion on survival and immunologic correlates in patients with metastatic renal cell carcinoma: a multicenter cohort analysis

BackgroundRecent studies have demonstrated that earlier time-of-day infusion of immune checkpoint inhibitors (ICIs) is associated with longer progression-free survival (PFS) and overall survival (OS) among patients with metastatic melanoma and...

Survival by depth of response and efficacy by International Metastatic Renal Cell Carcinoma Database Consortium Subgroup with lenvatinib plus pembrolizumab versus sunitinib in advanced renal cell carcinoma: analysis of the phase 3 randomized CLEAR study

Background: The extent of tumor shrinkage has been deemed a predictor of survival for advanced/metastatic renal cell carcinoma (RCC), a disease with historically poor survival.Objective: To perform an exploratory analysis of overall survival (OS) by tumor response by 6 mo, and to assess the efficacy and survival outcomes in specific subgroups.Design, setting, and participants: CLEAR was an open-label, multicenter, randomized, phase 3 trial of first-line treatment of advanced clear cell RCC.Intervention: Patients were randomized 1:1:1 to lenvatinib 20mg orally daily with pembrolizumab 200 mg intravenously once every 3 wk, lenvatinib plus everolimus (not included in this analysis), or sunitinib 50 mg orally daily for 4 wk on treatment/2 wk of no treatment.Outcome measurements and statistical analysis: Landmark analyses were conducted to assess the association of OS with tumor shrinkage and progressive disease status by 6 mo. Progression-free survival, duration of response, and objective response rate (ORR) were analyzed by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk subgroup and by the presence of target kidney lesions. Efficacy was assessed by an independent review committee as per Response Evaluation Criteria in Solid Tumors version 1.1.Results and limitations: Landmark analyses by tumor shrinkage showed that patients enrolled to lenvatinib plus pembrolizumab arm with a confirmed complete response or &gt;75 % target-lesion reduction by 6 mo had a 24-mo OS probability of 91.7 %. A landmark analysis by disease progression showed that patients with no progression by 6 mo had lower probabilities of death in both arms. Patients with an IMDC risk classification of intermediate/poor had longer median progression-free survival (22.1 vs 5.9 mo) and a higher ORR (72.4 % vs 28.8 %) with lenvatinib plus pembrolizumab versus sunitinib. Similarly, results favored lenvatinib plus pembrolizumab in IMDC-favorable patients and those with/without target kidney lesions. Limitations of the study are that results were exploratory and not powered/stratified.Conclusions: Lenvatinib plus pembrolizumab showed improved efficacy versus sunitinib for patients with advanced RCC; landmark analyses showed that tumor response by 6 mo correlated with longer OS.Patient summary: In this report of the CLEAR trial, we explored the survival of patients with advanced renal cell carcinoma by assessing how well they initially responded to treatment. We also explored how certain groups of patients responded to treatment overall. Patients were assigned to cycles of either lenvatinib 20 mg daily plus pembrolizumab 200 mg every 3 wk or sunitinib 50 mg daily for 4 wk (followed by a 2-wk break). Patients who either had a ‘‘complete response’’ or had their tumors shrunk by &gt;75 % within 6 mo after starting treatment with lenvatinib plus pembrolizumab had better survival than those with less tumor reduction by 6 mo. Additionally, patients who had more severe disease (as per the International Metastatic Renal Cell Carcinoma Database Consortium) at the start of study treatment survived for longer without disease progression with lenvatinib plus pembrolizumab than with sunitinib.

Natural history of bone-only metastasis in renal cell carcinoma

BackgroundBone metastasis (BM) is considered a poor prognostic factor of renal cell carcinoma (RCC). Confusion exists regarding how to deal with RCC patients with bone-only metastasis. Patients and MethodsThe clinical data of consecutive RCC patients with bone-only metastasis at Peking University Cancer Hospital between 2006 and 2018 were retrospectively collected and analyzed. ResultsFifty-four eligible patients were screened from an RCC database of 1,878 metastatic patients. After a median follow-up of 43.6 m, 61.1% of the patients were presented with progression of prior BM or new BM. The progression-free survival (PFS) and overall survival (OS) was 16.2 m (95%CI: 11.4–21.0) and 65.2 m, respectively. For the 30 patients with oligo-metastasis (≤3 loci) and 24 ones with multiple-metastasis (>3 loci), the median OS was not reached and 42.0m (95%CI: 12.7–71.2) with statistical difference (P < 0.001). In the oligo-metastasis group, the median PFS of the 15 patients treated with local therapy and of the 13 patients treated with systemic therapy was 14.2 m (95%CI: 5.3–23.3) and 18.0 m (95%CI:15.4–20.6), respectively. In the multiple-metastasis group, the median PFS and OS of the 18 patients treated with systemic therapy was 16.6 m (95%CI: 7.5–25.7) and 63.9 m (95%CI: 21.8–106.0), respectively. Univariate analysis and multivariate analysis showed that the number of metastatic sites (oligo/multiple) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score, RCC pathological subtype were significantly associated with prognosis (P < 0.05). ConclusionRCC patients with bone-only metastases have a favorable prognosis. The number of metastatic sites, IMDC, RCC pathological subtype could serve as survival predictors, which might provide clue of treatment modality.

Impact of Complete Surgical Resection of Metastatic Lesions in Patients with Advanced Renal Cell Carcinoma in the Era of Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors.

Complete metastasectomy (CM) in metastatic renal cell carcinoma (mRCC) has demonstrated efficacy in the cytokine era, but its effectiveness in the era of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) remains unclear. A multi-institutional database included clinicopathological data of 367 patients with mRCC. Patients were divided into two groups: the CM group and the non-CM group. These two groups were compared before and after propensity score matching (PSM). Cox proportional hazard models were used to detect factors associated with disease-free survival (DFS) and overall survival (OS) from mRCC diagnosis. The CM group showed a significant association with longer overall survival compared to the non-CM group in the PSM-unadjusted cohorts (p < 0.001, hazard ratio 0.49, 95% confidence interval 0.35-0.69), but no superiority was noted in the adjusted cohorts. The median DFS after CM was 24 months, with no significant differences based on relapse timing. Notably, the international metastatic RCC database consortium risk categories and metastatic burden were associated with DFS. This study supports the potential of CM in mRCC management during the TKI/ICI era, although limitations including sample size and selection bias need to be considered.

Time to strategy failure and treatment beyond progression in pretreated metastatic renal cell carcinoma patients receiving nivolumab: post-hoc analysis of the Meet-URO 15 study.

Immunotherapies exhibit peculiar cancer response patterns in contrast to chemotherapy and targeted therapy. Some patients experience disease response after initial progression or durable responses after treatment interruption. In clinical practice, immune checkpoint inhibitors may be continued after radiological progression if clinical benefit is observed. As a result, estimating progression-free survival (PFS) based on the first disease progression may not accurately reflect the actual benefit of immunotherapy. The Meet-URO 15 study was a multicenter retrospective analysis of 571 pretreated metastatic renal cell carcinoma (mRCC) patients receiving nivolumab. Time to strategy failure (TSF) was defined as the interval from the start of immunotherapy to definitive disease progression or death. This post-hoc analysis compared TSF to PFS and assess the response and survival outcomes between patients treatated beyond progression (TBP) and non-TBP. Moreover, we evaluated the prognostic accuracy of the Meet-URO score versus the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score based on TSF and PFS. Overall, 571 mRCC patients were included in the analysis. Median TSF was 8.6 months (95% CI: 7.0 - 10.1), while mPFS was 7.0 months (95% CI: 5.7 - 8.5). TBP patients (N = 93) had significantly longer TSF (16.3 vs 5.5 months; p < 0.001) and overall survival (OS) (34.8 vs 17.9 months; p < 0.001) but similar PFS compared to non-TBP patients. In TBP patients, a median delay of 9.6 months (range: 6.7-16.3) from the first to the definitive disease progression was observed, whereas non-TBP patients had overlapped median TSF and PFS (5.5 months). Moreover, TBP patients had a trend toward a higher overall response rate (33.3% vs 24.3%; p = 0.075) and disease control rate (61.3% vs 55.5%; p = 0.31). Finally, in the whole population the Meet-URO score outperformed the IMDC score in predicting both TSF (c-index: 0.63 vs 0.59) and PFS (0.62 vs 0.59). We found a 2-month difference between mTSF and mPFS in mRCC patients receiving nivolumab. However, TBP patients had better outcomes, including significantly longer TSF and OS than non-TBP patients. The Meet-URO score is a reliable predictor of TSF and PFS.

Pembrolizumab plus lenvatinib (P+L) versus alternative therapies in first-line (1L) advanced renal cell carcinoma (aRCC) by IMDC risk status: A network meta-analysis (NMA).

421 Background: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk criteria is a widely used prognostic model in advanced RCC. Pembrolizumab plus lenvatinib (P+L) demonstrated a significant improvement in ORR, PFS, and OS versus sunitinib in subjects with cc aRCC in the KEYNOTE-581/CLEAR trial. This NMA indirectly compared the efficacy of P+L to other therapies in 1L aRCC subjects within IMDC risk groups using data from randomized clinical trials (RCTs). Methods: A systematic literature review was conducted to identify systemic therapies in 1L aRCC. Trials reporting results for IMDC favorable risk and/or intermediate+poor risk groups were included. A Bayesian NMA with fixed-effect models was performed to indirectly compare P+L to alternate therapies using sunitinib as the common comparator. Hazard ratios (HRs) for OS and PFS were calculated with 95% credible intervals (CrIs). The NMAs assuming constant hazard ratios (HRs) for OS and PFS were performed for all IMDC risk group categories. For the proportion of patients experiencing response, a binomial likelihood and logit link were used, and relative effects were expressed as odds ratios (OR). Results: For the IMDC favorable risk subgroup, P+L demonstrated statistically significant increase in ORR compared to nivolumab + ipilimumab (N+I) (OR=5.35; 95% CrI: 2.59, 11.41) and nivolumab (OR=8.41; 95% CrI: 1.84, 43.77). For PFS, P+L resulted in a statistically significant improvement in PFS compared to N+I (HR=0.31, 95% CrI: 0.17-0.56). For OS, no significant differences were observed compared to other alternatives in the network. For the IMDC intermediate+poor risk subgroup, P+L demonstrated statistically significant increase in ORR compared to nivolumab + cabozantinib (N+C) (OR=1.77; 95% CrI: 1.02, 3.10), N+I (OR=3.15; 95% CrI: 1.94, 5.10), and nivolumab + ipilimumab + cabozantinib (N+I+C) (OR=2.34; 95% CrI: 1.34, 4.12), pembrolizumab + axitinib (P+A) (OR=2.65; 95% CrI: 1.57, 4.44) and nivolumab (OR=4.68; 95% CrI: 1.84, 12.02). For PFS, P+L resulted in a statistically significant improvement compared to N+I (HR=0.59; 95% CrI: 0.41, 0.84) (P+A) (HR=0.64; 95% CrI: 0.44, 0.93), and avelumab + axitinib (A+A) (HR=0.65; 95% CrI: 0.46, 0.93). For OS, no significant differences were observed compared to other alternatives in the network. Conclusions: PFS analysis favored P+L over all alternative therapies in the network in favorable or intermediate+poor IMDC risk groups. ORR analysis favored P+L over all alternative therapies in the network in intermediate+poor IMDC risk groups. No significant difference in OS was observed between P+L and other alternative therapies in the network.

Phase III randomized trial of stereotactic ablative radiotherapy (SAbR) for oligometastatic advanced renal carcinoma (EA8211-SOAR).

TPS489 Background: Optimal strategies for managing oligometastatic renal cell carcinoma (RCC) are unclear. While systemic therapy is the accepted standard, Stereotactic Ablative Radiation (SAbR) is a promising alternative based on retrospective and limited prospective data1-3. SAbR may spare patients from systemic therapy toxicity, but progression of occult micrometastasis remains a concern. This prospective ECOG-ACRIN phase 3 randomized trial will compare SAbR to systemic therapy for oligometastatic RCC. Co-primary endpoints are overall survival (OS) and toxicity. Methods: Patients with RCC (any histology except for sarcomatoid) with an ECOG performance 0-2, International Metastatic RCC Database Consortium (IMDC) favorable and intermediate-risk, and 2-5 extracranial metastases are eligible. The exclusion criteria include prior systemic therapy (except for adjuvant therapy) and brain metastases. Patients with intact primary are eligible after definitive treatment of the primary site. Stratification factors include 1) number of metastases (2-3 vs 4-5), 2) histology (clear cell vs non-clear cell), 3) IMDC (0 vs 1-2), 4) prior adjuvant systemic therapy (yes vs no), and 5) time from treatment of primary disease (&lt;1yr vs &gt;1yr). Patients will be randomized to up front systemic therapy (the type of systemic therapy will be chosen at the discretion of the investigator) versus SAbR (and additional SAbR of up to a total of 6 metastasis while disease remains amenable) followed by systemic therapy. Co-primary endpoints are OS and toxicity (≥grade 3). Target accrual goal is 472 patients which will provide 85% power to test non-inferiority in OS from a non-inferiority hybrid design, assuming a null hazard ratio of 1.24 and alternative hazard ratio of 0.85. If it is concluded that SAbR arm has non-inferior OS, superiority in toxicity will be tested. Secondary endpoints include health-related quality of life (QOL) as measured with NFKSI-19 and EQ-5D-5L and progression free survival (PFS). Exploratory endpoints include PFS of 1st line systemic therapy, local control with SAbR and cost-effectiveness. The trial has been open for enrollment since September 2023.

Anemia in patients ≥ 75 years with metastatic clear cell renal cell carcinoma: an important poor prognostic factor in the international metastatic renal cell carcinoma database consortium model

BackgroundDue to an increase in life expectancy, the incidence of metastatic renal cell carcinoma (mRCC) in patients aged ≥75 years has been increasing. In this study we investigated the characteristics before treatment and the outcomes of systemic therapies for patients aged ≥75 years with mRCC and compared the results with those for patients aged < 75 years in order to determine whether differences in age influenced survival.MethodsA total of 206 consecutive Japanese patients with mRCC, including 47 patients aged ≥75 years, who received systemic therapy were included. Clinical data from medical records were retrieved and analyzed retrospectively. Survival analyses were determined using a Kaplan–Meier method, and analyzed with a log-rank test.ResultsElderly patients categorized as favorable risk group based on the International Metastatic RCC Database Consortium (IMDC) stratification system were significantly lower. Among IMDC risk factors, the rate of anemia was significantly higher in elderly patients. No statistically significant benefit in progression free survival for first and second line treatment was observed, whereas improvements in overall survival as well as cancer specific survival were seen in patients aged < 75 years.ConclusionsFor mRCC patients aged ≥75 years, a higher proportion of base line anemia, which resulted in higher rates of IMDC intermediate/poor risk, would be responsible for shorter OS/CSS. Furthermore, mRCC patients aged ≥75 years tend to receive BSC instead of second line active treatment. Overcoming under-treatment in elderly patients might help to prolong survival in mRCC.

Efficacy of Sunitinib in Patients With Favorable and Intermediate Risk Metastatic Renal Cell Carcinoma - Lithuanian National Cancer Institute Experience.

According to the European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) recommendations, sunitinib is one of the recommended regimens for favorable and intermediate-risk metastatic renal cell carcinoma (mRCC) patients. The objective of this study was to evaluate sunitinib efficacy as a first-line treatment for mRCC patients with favorable/intermediate prognostic risk in a real-world setting. Patients diagnosed with mRCC and confirmed as appropriate candidates for the first-line systemic treatment were included in this retrospective study. The prognostic risk was evaluated according to the model of the International Metastatic RCC Database Consortium (IMDC). Patients received sunitinib as a first-line treatment. A total of 94 patients were enrolled from 2019 to the 2020and 67 of them were included in the detailed analysis. Median progression-free survival (PFS) was 23.4 (95%CI=17.3-29.5), and median overall survival (OS) was 66 months (95%CI=44.9-87.1). The age over 60 years was a significant negative predictor for PFS and OS. Regarding the IMDC model for disease risk prediction, the number of two risk factors in the intermediate risk group was a significant predictor for a shorter response to the first-line therapy. Sunitinib is an effective tyrosine kinase inhibitor, which can be used as a first-line treatment in favorable/intermediate-risk groups of patients with mRCC, especially in countries where novel systemic treatment modalities are not yet available.

Abstract C136: VHL, PBRM1, and BAP1 mutation variants and response to first-line therapies in patients with metastatic clear-cell renal cell carcinoma (mRCC)

Abstract Background VHL, PBRM1, and BAP1 are common mutations in clear-cell renal cell carcinoma (ccRCC). VHL and PBRM1 mutations result in downstream dysregulation of vascular endothelial growth factor receptor (VEGFR) that cause angiogenesis and uncontrolled cell growth. VEGFR tyrosine kinase inhibitors (TKI) are the mainstay of ccRCC treatment. The current first-line (1L) therapies for mRCC include combination anti-VEGFR TKI + anti-PD-1 immune checkpoint inhibitors (CPI), or combination CPI targeting PD-1 and CTLA-4. It is unknown whether VHL and PBRM1 mutations are predictive for response to 1L anti-VEGFR TKI, anti-VEGFR TKI + CPI, or combination CPI immunotherapy. In this retrospective observational study, we evaluated the real-world outcomes of 1L therapies in patients with mRCC with or without VHL, PBRM1, or BAP1 mutations. Methods This study used the nationwide de-identified Flatiron Health-Foundation Medicine RCC clinico-genomic database, originating from approximately 280 cancer clinics (~800 sites of care). Patients with metastatic ccRCC, diagnosed from 8/1996-8/2022, who received 1L therapy with anti-VEGFR TKI, anti-VEGFR TKI + PD-1/PD-L1, or anti-PD-1 + anti-CTLA-4 therapy, and who had comprehensive genomic profiling were included. The primary endpoint was real-world overall survival (rwOS) in mRCC patients with VHL mutations. Secondary endpoints included rwOS and real-world progression-free survival (rwPFS) in patients with BAP1 and PBRM1 mutations, and rwPFS in patients with VHL mutations. The cox proportional hazard model was used to conduct the multivariable analysis adjusting for demographic/clinical factors for rwOS and rwPFS. The Kaplan-Meier method were used to estimate the median survival time. Results149 patients with complete data sets were included, of whom 99 had VHL mutations, 65 had PBRM1 mutations, and 31 had BAP1 mutations. Eight patients (5%) had favorable International Metastatic RCC Database Consortium (IMDC) risk, 110 (74%) had intermediate IMDC risk, and 31 (21%) had poor IMDC risk. The adjusted hazard ratio (HR) for rwOS in patients with VHL mutations compared to those without who received 1L anti-VEGFR TKI, anti-VEGFR TKI + PD-1/PD-L1, or PD-1/PD-L1 + CTLA-4 therapy were 1.53 (95% CI: 0.78-3.00, p=0.221), 0.87 (95% CI: 0.29-2.61, p=0.798), and 1.64 (95% CI: 0.71-3.75,p=0.245), respectively. The median rwOS for patients with PBRM1 mutations who received anti-VEGFR TKI was 50.1 months (95% CI: 34.62-NR) and 30.6 months (95% CI: 19.4-63.2) in patients without PBRM1 mutations (adjusted HR 0.54, 95% CI: 0.29-1.00, p=0.049). The median rwPFS for BAP1 mutations with anti-VEGFR TKI therapy was 5.2 months (95% CI: 3.6-9.1) and 6.4 (95% CI: 4.7-10.8) in patients without BAP1 mutations (adjusted HR 2.45, 95% CI: 1.35-4.44, p=0.003). Conclusion No significant difference was observed in rwOS in mRCC patients with VHL mutations treated with first-line anti-VEGFR TKI, anti-VEGFR TKI + PD-1/PD-L1, or PD-1/PD-L1 + CTLA-4 therapy, compared to patients without VHL mutations. Additional studies are needed to confirm this finding. Citation Format: Jessica Zhu, Junxiao Hu, Elaine T Lam. VHL, PBRM1, and BAP1 mutation variants and response to first-line therapies in patients with metastatic clear-cell renal cell carcinoma (mRCC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C136.

Assessing the prognostic value of IMDC risk score for nivolumab-treated patients with renal cancer and malignant melanoma.

The response of Renal Cell Cancer (RCC) to tyrosine kinase inhibitors (TKI) has been well established. Although these stratifications have been established for TKI response and prognosis, these parameters have recently been used to predict immunotherapy response in RCC. We aimed to use a combination of clinical parameters of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups and metastatic sites at the time of diagnosis to predict the effectiveness of immune checkpoint inhibitors in malignant melanoma (MM). In this cross-sectional study, we retrospectively analyzed the demographic information, metastatic sites, and IMDC risk group data. The blood parameters were included in the first cycle of nivolumab treatment. The OS was statistically different between the RCC and MM groups in terms of the IMDC. In univariate analysis of stage at diagnosis, CRP levels and bone and bone marrow metastases were confirmed to be prognostic factors in the MM population in terms of OS. Brain metastasis was a prognostic factor for RCC, whereas sex, line of treatment, LDH, bone, and splenic metastasis remained significant in patients with MM in terms of OS. Brain metastasis was prognostic in both cancer types in multivariate analysis in terms of PFS. In addition to brain metastasis, LDH levels and lung, liver, and splenic metastases also affect PFS in patients with MM undergoing nivolumab treatment. In our study, the IMDC was confirmed to be a prognostic factor for MM. The IMDC groups were similar, except for the favorable RCC and MM groups. Different metastatic sites were prognostic, similar to the IMDC risk group in the MM group.

NCMP-01. TREATMENT STRATEGIES IN PATIENTS WITH RENAL CELL CANCER AND BRAIN METASTASES

Abstract BACKGROUND Brain metastases (BM) significantly impact quality of life and survival in patients with metastatic renal cell cancer (mRCC). Based on the International Metastatic RCC Database Consortium (IMDC) risk classification, treatment strategies for patients with mRCC vary from systemic treatment with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) and/or immune checkpoint inhibitors (ICIs) to active surveillance (AS). Here, we describe the impact of treatment strategies on survival in patients with RCC and BM. METHODS We conducted a single-center, retrospective cohort study at Erasmus MC Cancer Institute (Rotterdam, Netherlands). All consecutive patients with RCC BM between 2011-2022 were included. Primary outcome was the BM-free survival, i.e. the time between diagnosis of extracranial metastases (ECM) and BM. Secondary outcome was overall survival (OS). RESULTS 46 patients with RCC BM were included: 25 (54.3%) had received prior systemic treatment for ECM, and 21 (45.7%) were treatment naive at diagnosis of BM. IMDC scores (favorable 12% resp. 0%, intermediate 48% resp. 64%, poor 24% resp. 0%, unknown 16% resp. 36%) were not significantly different (p=0.07) between these groups. In 39 (84.8%) of 46 patients, BM were metachronous ( &amp;gt;1 month) after ECM. In these patients (n=39), the median BM-free survival was 22.3 (IQR 5.7-46.7) months and was significantly longer (p=0.02) in previously treated patients (29.0 [IQR 12.6-57.0] months) as compared to treatment naive patients (6.8 [IQR 1.0-7.0] months). However, median OS since ECM diagnosis (39.1 [IQR 16.5-111.5] months) was not significantly different (p=0.62) between previously treated and treatment naive patients. CONCLUSION Patients with RCC who received systemic treatment for ECM prior to BM diagnosis, had a longer BM-free survival as compared to patients without previous systemic treatment. These results emphasize the need for careful evaluation of AS in patients with mRCC, even in patients with a favorable prognostic profile.

213P Prognostic significance of absolute lymphocyte count in patients with metastatic renal cell carcinoma treated with first-line combination immunotherapies: Results from the International metastatic renal cell carcinoma database consortium (IMDC)

213P Prognostic significance of absolute lymphocyte count in patients with metastatic renal cell carcinoma treated with first-line combination immunotherapies: Results from the International metastatic renal cell carcinoma database consortium (IMDC)

Genomic ancestry in kidney cancer: Correlations with clinical and molecular features.

Genetic ancestry (GA) refers to population hereditary patterns that contribute to phenotypic differences seen among race/ethnicity groups, and differences among GA groups may highlight unique biological determinants that add to our understanding of health care disparities. A retrospective review of patients with renal cell carcinoma (RCC) was performed and correlated GA with clinicopathologic, somatic, and germline molecular data. All patients underwent next-generation sequencing of normal and tumor DNA using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, and contribution of African (AFR), East Asian (EAS), European (EUR), Native American, and South Asian (SAS) ancestry was inferred through supervised ADMIXTURE. Molecular data was compared across GA groups by Fisher exact test and Kruskal-Wallis test. In 953 patients with RCC, the GA distribution was: EUR (78%), AFR (4.9%), EAS (2.5%), SAS (2%), Native American (0.2%), and Admixed (12.2%). GA distribution varied by tumor histology and international metastatic RCC database consortium disease risk status (intermediate-poor: EUR 58%, AFR 88%, EAS 74%, and SAS 73%). Pathogenic/likely pathogenic germline variants in cancer-predisposition genes varied (16% EUR, 23% AFR, 8% EAS, and 0% SAS), and most occurred in CHEK2 in EUR (3.1%) and FH in AFR (15.4%). In patients with clear cell RCC, somatic alteration incidence varied with significant enrichment in BAP1 alterations (EUR 17%, AFR 50%, SAS 29%; p=.01). Comparing AFR and EUR groups within The Cancer Genome Atlas, significant differences were identified in angiogenesis and inflammatory pathways. Differences in clinical and molecular data by GA highlight population-specific variations in patients with RCC. Exploration of both genetic and nongenetic variables remains critical to optimize efforts to overcome health-related disparities.

Efficacy of avelumab plus axitinib versus sunitinib by numbers of IMDC risk factors and target tumor sites at baseline in advanced renal cell carcinoma: long-term follow-up results from JAVELIN Renal 101

In the phase III JAVELIN Renal 101 trial, first-line avelumab+ axitinib improved progression-free survival (PFS) and objective response rate versus sunitinib in patients with advanced renal cell carcinoma across all International Metastatic RCC Database Consortium (IMDC) risk groups (favorable, intermediate, and poor); analyses of overall survival (OS) remain immature. Here, we report post hoc analyses of efficacy from the third interim analysis (data cut-off, April 2020) by the numbers of IMDC risk factors and target tumor sites at baseline. Efficacy endpoints assessed were PFS, objective response, and best overall response per investigator assessment (RECIST v1.1) and OS. Best percentage change and percentage change from baseline in target tumor size over time during the study were also assessed. In patients with 0, 1, 2, 3, or 4-6 IMDC risk factors, hazard ratios [HRs; 95% confidence interval (CIs)] for OS with avelumab+ axitinib versus sunitinib were 0.660 (0.356-1.223), 0.745 (0.524-1.059), 0.973 (0.668-1.417), 0.718 (0.414-1.248), and 0.443 (0.237-0.829), and HRs (95% CIs) for PFS were 0.706 (0.490-1.016), 0.709 (0.540-0.933), 0.711 (0.527-0.960), 0.501 (0.293-0.854), and 0.395 (0.214-0.727), respectively. In patients with 1, 2, 3, or ≥4 target tumor sites, HRs (95% CIs) for OS with avelumab+ axitinib versus sunitinib were 0.912 (0.640-1.299), 0.715 (0.507-1.006), 0.679 (0.442-1.044), and 0.747 (0.346-1.615), and HRs (95% CIs) for PFS were 0.706 (0.548-0.911), 0.552 (0.422-0.723), 0.856 (0.589-1.244), and 0.662 (0.329-1.332), respectively. Across all subgroups, analyses of objective response rate and complete response rate favored avelumab+ axitinib versus sunitinib, and a greater proportion of patients treated with avelumab+ axitinib had tumor shrinkage. In post hoc analyses, first-line treatment with avelumab+ axitinib was generally associated with efficacy benefits versus treatment with sunitinib in patients with advanced renal cell carcinoma across subgroups defined by different numbers of IMDC risk factors or target tumor sites.