International mRCC Database Consortium Risk Research Articles

20 Evaluating intermediate endpoints for overall survival in metastatic renal cell carcinoma treated with immune checkpoint inhibitors: an IMDC study

Abstract Background In Phase 3 trials, the assessment for primary endpoint of overall survival (OS) necessitates extended follow-up periods, a larger pool of events, and higher associated costs. Hence, we sought to determine whether shorter intermediate (IEs) such as Objective Response (OR), Time to Treatment Failure (TTF) and Time to Next Therapy (TTNT) are associated with OS in patients receiving immune checkpoint (ICI)-based therapy. Methods We included all International mRCC Database Consortium (IMDC) patients who received contemporary first line(1L) ICI from 2013 to 2023. IEs were defined from ICI start until drug cessation or death for TTF, and initiation of next line or death for TTNT, or censored at date of last follow-up. OR included investigators-assessed complete or partial response per RECIST1.1 criteria. First, we assessed the endpoint correlations across all follow-up times of individual patient data using Kendall’s Tau (KT) correlation by a Clayton copula. A KT >0.49 indicates a strong correlation (Wicklin R., 2023). Then we evaluated associations of OS with TTF and TTNT status at the 6-month landmark using Cox regression adjusting for IMDC risk groups, metastatic sites, histology, age, and prior nephrectomy, stratified by ICI type and years of ICI start. The KT correlation was estimated by the R GJRM package (https://www.r-project.org/). All other statistical analyses were done with SAS 9.4 software (SAS Institute, Cary, NC). Results The cohort consisted of 1667 patients with a median follow-up of 15.4 months (IQR: 7.1-28.6). For the 6-month landmark analysis in OS, patients who died or had less than 6 months of follow-up were excluded, affecting 278 for OR, 373 for TTF, and 380 for TTNT. Median age at 1L start was 63 years (IQR: 56-70), with 73% being male and 65% undergoing nephrectomy before starting 1L. A total of 1132 patients received dual ICI, while 535 received an ICI+TKI combination. Over the entire follow-up of individual patient data, the Kendall’s Tau correlation was 0.49 (95%CI: 0.45-0.52) for TTF with OS and 0.67 (95%CI: 0.64-0.69) for TTNT with OS. The Kendall’s Tau correlations between endpoints were also similar in subgroup analyses by IMDC risk group and type of regimen and the strongest in the ICI+TKI subgroup with a Kendall’s Tau correlation of 0.73(0.66-0.78). On the 6-month OS landmark analysis (Table), patients who discontinued their 1L regimen had poor OS (adjusted HR: 2.77 (95%CI: 2.16-3.55)). Additionally, those who transitioned to a 2L therapy within the first 6 months showed worse OS, reflected by an HR of 2.82 (2.22-3.59). Patients who did not have an objective response also had worse OS (adjusted HR: 2.74 (95%CI: 2.15-3.49)). On the other hand, patients with an objective response had an 18-month OS rate (equivalent of 12-month OS post the 6-month landmark) of 91% (95%CI: 88%-93%) vs 74% (95%CI: 70%-78%) for those with no response at 6 months. Table. Landmark analysis of OS from 6 months of post therapy initiation, according to OR, TTF and TTNT event status at 6 months, in whole cohort and by IMDC and treatment groups. Conclusions Our study explored TTF, TTNT and OR as clinical IEs for OS. TTNT demonstrated the strongest association with OS, particularly in the ICI+TKI subgroup, making it a potentially clinically meaningful intermediate endpoint for evaluating treatment efficacy in ICI-based regimens.

The role of cytoreductive nephrectomy in metastatic renal cell carcinoma in immune-oncology era (SEVURO-CN): study protocol for a multi-center, prospective, randomized trial

BackgroundThe role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) remains unclear in the immuno-oncology (IO) era. The results of two randomized trials, CARMENA and SURTIME, questioned the role and timing of CN. However, despite the latest advances in the systemic treatment of mRCC, previous trials have only used targeted therapy, and no studies have fully investigated the role of CN in immune checkpoint inhibitor (CPI) settings, and there is an urgent need for future studies to better define the role and timing of CN.MethodsThis study is an open-label, multi-center, parallel, prospective, randomized, interventional clinical study to evaluate the efficacy of CN in combination with CPIs in mRCC patients with International mRCC Database Consortium (IMDC) intermediate- and poor-risk. Synchronous mRCC patients with ≤ 3 IMDC risk features will be randomly allocated to three groups (1, upfront CN; 2, deferred CN; and 3, systemic therapy [ST] only). For ST, the nivolumab plus ipilimumab combination regimen, one of the standard regimens for intermediate- and poor-risk mRCC, is chosen. The primary endpoint is overall survival. The secondary endpoints are progression-free survival, objective response rate, number of participants with treatment-related adverse events, and number of participants with surgical morbidity. We will analyze the genetic mutation profiles of the tumor tissue, circulating tumor DNA, urine tumor DNA, and tumor-infiltrating lymphocytes. The gut and urine microbial communities will be analyzed. The study will begin in 2022 and will enroll 55 patients.DiscussionThis study is one of the few prospective randomized trials to evaluate the benefit of CN in the treatment of synchronous mRCC in the IO era. The SEVURO-CN trial will help identify the role and timing of CN, thereby rediscovering the value of CN.Trial registrationClinicalTrials.gov, NCT05753839. Registered on 3 March 2023.

Evaluating intermediate endpoints (IE) for overall survival (OS) in metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI): An IMDC study.

400 Background: In Ph3 trials, assessment for primary endpoint of OS necessitates extended follow-up (f/u) periods, larger pool of events, and higher associated costs. We sought to determine if shorter IEs like Time to Treatment Failure (TTF) and Time to Next Therapy (TTNT) are associated with OS in patients (pts) receiving ICI-based trt. Methods: We included all International mRCC Database Consortium (IMDC) pts who received contemporary approved first line(1L) ICI from 2013 to 2023. IEs were defined from ICI start until drug cessation or death for TTF, and initiation of next line or death for TTNT, or censored at date of last f/u. Associations of OS with TTF and TTNT status at 6-mo landmark were assessed using Cox regression adjusting for IMDC risk groups, metastatic sites, histology, age, and prior nephrectomy, stratified by treatment (trt) and yrs of ICI start. Endpoint associations across all f/u time were evaluated using Kendall’s Tau (KT) correlation by Clayton copula. A KT >0.49 indicates a strong correlation ( Wicklin R., 2023). Results: The cohort consisted of 1667 pts with a median f/u of 15.4 mo (IQR: 7.1-28.6). Median age at 1L start was 63 yrs (IQR: 56-70), with 73% being male and 65% undergoing nephrectomy before starting 1L. 1132 patients received dual ICI, while 535 received an ICI+TKI combination. Pts who discontinued their 1L regimen within the 6-mo landmark demonstrated poor OS, with a hazard ratio (HR) of 2.74 (95% CI: 2.15-3.49). Additionally, those who transitioned to a 2L therapy within the first 6 mo showed worse OS, reflected by an HR of 2.82 (2.22-3.59). KT correlation with OS across all follow up was 0.49 (0.45, 0.52) for TTF and 0.67 (0.64, 0.69) for TTNT. Consistent results were seen across all subgroups with the strongest association in the ICI+TKI group (Table). Conclusions: TTNT demonstrated the strongest association with OS, particularly in the ICI+TKI subgroup, making it a potentially clinically meaningful intermediate endpoint for evaluating efficacy in ICI-based regimens.[Table: see text]

Uptake and efficacy of immuno-oncology combinations in metastatic renal cell carcinoma in the United States: Evidence from the ASCO CancerLinQ Discovery database.

532 Background: Immuno-Oncology (IO) combinations, either an IO/IO (ipilimumab/nivolumab) or an IO/TKI combination (pembrolizumab/axitinib, avelumab/axitinib, nivolumab/cabozantinib, and pembrolizumab/lenvatinib), have emerged as the standard of care for frontline treatment of metastatic clear cell renal cell carcinoma (mccRCC) since 2018. Here we present uptake trends and efficacy of IO combinations in the United States from 2018 to 2022 using American Society of Clinical Oncology’s (ASCO) CancerLinQ Discovery database (CLQD). Methods: Patients diagnosed with mccRCC treated with frontline IO-based combinations from 2018-2022 were identified in the CLQD kidney dataset. The Kaplan-Meier survival method was used to present time to treatment discontinuation (TTD) and overall survival (OS) stratified by International mRCC Database Consortium (IMDC) risk. Results: There were 515 mccRCC patients who received frontline IO agents in 2018-2022: 228 (44.3%) patients received ipilimumab/nivolumab, 153 (29.7%) patients received IO/TKI (139 out of 153 received pembrolizumab/axitinib), and 122 (23.7%) patients received IO monotherapy (nivolumab or pembrolizumab). 385 (75%) were IMDC intermediate/poor risk and 97 (19%) were favorable risk patients. The median age was 69 (interquartile range: 61-79) and 59% were male. There was an increasing trend of use of IO/TKI from 2019 to 2021 [30.8%, 42.8%, 44.3%, respectively; analysis for 2022 was limited by sample size (n = 8)]. The median follow-up for ipilimumab/nivolumab and pembrolizumab/axitinib was 13.1 and 11.8 months (mos), respectively. The mTTD for ipilimumab/nivolumab and pembrolizumab/axitinib was 8.5 vs 11.0 mos, respectively. The median OS (mOS) was not reached (NR) in either regimen. The TTD and OS stratified by IMDC risk are presented in Table 1. Conclusions: Uptake of frontline IO combinations therapy in mccRCC and in particular IO/TKI combinations increased in the United States since 2018. Compared to progression-free survival (PFS) from the landmark trials, this analysis demonstrated shorter TTD, indicating either underestimation of the true PFS or worse outcomes in a non-clinical trial setting. Integration of radiologic response into this dataset could help clarify outcomes.[Table: see text]

Salvage lenvatinib/everolimus (LE) combination therapy after immune checkpoint inhibitor (ICI) and VEGFR tyrosine kinase inhibitor (TKI) for metastatic renal cell carcinoma (mRCC).

e16520 Background: The optimal treatment for mRCC patients (pts) who have progressed after both ICI and TKI remains uncertain. LE is frequently used as a salvage treatment due to different antitumor mechanisms, but efficacy and toxicity data in this setting are limited. Methods: We retrospectively reviewed charts from two academic centers for 71 adult mRCC pts who received LE after prior ICI and TKI exposure. Collected data included patient demographics, histology, International mRCC Database Consortium (IMDC) risk group, treatment history, and toxicity details using CTCAEv5. Outcomes were objective response rate (ORR) per RECIST 1.1, median time to treatment failure (mTTF), and toxicity. Descriptive statistics, Cox proportional hazards model and Kaplan-Meier method were utilized. Results: The median age was 64 (range: 31–84). Most pts had clear cell histology (84.5%) and had undergone nephrectomy (75%). IMDC risks were favorable (19.7%), intermediate (int) (66.2%), poor (11.3%), and unknown (2.8%). Pts received a median of 3 (range 1-10) prior therapy lines (L) and 42 pts had sequential ICI and TKI, while 29 received ICI/TKI combination therapy. Average ORR was 26.8%, but numerically better when given earlier (2L/3L vs. ≥4L: 28.6% vs. 22%). The mTTF was 5.5 months (m) (95% confidence interval [CI], 3.5–7.6 m), which was not significantly changed by sequential or combinational ICI/TKI treatment exposure. In multivariable Cox analyses, int/poor IMDC risk was associated with a significantly worse TTF compared to favorable risk (HR, 2.2, 95% CI, 1.1-4.1; mTTF: 4.5 vs 12.9 m), and so was ≥4L treatment compared to 2L/3L treatment (HR, 3.2, 95% CI, 1.3-7.6; mTTF: 4.5 vs. 6.6 m). In 57 pts with int/poor IMDC risk, ≥4L treatment was associated with a significantly worse TTF (HR, 2.3, 95% CI, 1.2-4.5; mTTF: 3.6 vs. 6.6 m), while prior nephrectomy was associated with a significantly better TTF (HR, 0.46, 95% CI, 0.22-0.97; mTTF: 5.4 vs. 3.1 m) compared to those without nephrectomy. Of the 71 pts, 64% had ≥ grade 3 adverse events, 60% had treatment interruption, 44.3% had dose reduction, and 21% stopped treatment due to intolerance. Conclusions: LE therapy is feasible but has modest efficacy following ICI/TKI treatment. Pts with favorable risk, prior nephrectomy or early salvage may have a better treatment response. These observations need to be confirmed in prospective studies.

Survival in Metastatic Renal Cell Carcinoma Treated With Immunotherapy and Stereotactic Radiation Therapy or Immunotherapy Alone: A National Cancer Database Analysis

Immunotherapy (IO) has significantly improved outcomes in metastatic renal cell carcinoma (mRCC). Preclinical evidence suggests that responses to IO may be potentiated via immunomodulatory effects of stereotactic radiation therapy (SRT). We hypothesized that clinical outcomes from the National Cancer Database (NCDB) would demonstrate improved overall survival (OS) in patients with mRCC receiving IO+SRT versus IO alone. Patients with mRCC receiving first-line IO ± SRT were identified from the NCDB. Conventional radiation therapy was allowed in the IO alone cohort. The primary endpoint was OS stratified by the receipt of SRT (IO+SRT vs IO alone). Secondary endpoints included OS stratified by the presence of brain metastases (BM) and timing of SRT (before or after IO). Survival was estimated using Kaplan-Meier methodology and compared via the log-rank test. Of 644 eligible patients, 63 (9.8%) received IO+SRT, and 581 (90.2%) received IO alone. Median follow-up time was 17.7 months (range, 2-24 months). Sites treated with SRT included the brain (71.4%), lung/chest (7.9%), bones (7.9%), spine (6.3%), and other (6.3%). OS was 74.4% versus 65.0% at 1 year and 71.0% versus 59.4% at 2 years for the IO+SRT and IO alone groups, respectively, although this difference did not reach statistical significance (log-rank P=.1077). In patients with BM, however, 1-year OS (73.0% vs 54.7%) and 2-year OS (70.8% vs 51.4%) was significantly higher in those receiving IO+SRT versus IO alone, respectively (pairwise P=.0261). Timing of SRT (before or after IO) did not influence OS (log-rank P=.3185). Patients with BM secondary to mRCC had prolonged OS with the addition of SRT to IO. Factors such as International mRCC Database Consortium risk stratification, oligometastatic tumor burden, SRT dose/fractionation, and utilization of doublet therapy should be considered in future analyses to better identify patients who may benefit from combined IO+SRT. Further prospective studies are warranted.

Real-world Treatment Patterns and Clinical Outcomes for Metastatic Renal Cell Carcinoma in the Current Treatment Era

BackgroundImmuno-oncology (IO) agents and tyrosine kinase inhibitors (TKIs) have revolutionized the treatment paradigm for metastatic renal cell carcinoma (mRCC). Data on real-world usage and outcomes are limited. ObjectiveTo examine real-world treatment patterns and clinical outcomes for mRCC. Design, setting, and participantsThis retrospective cohort study included 1538 patients with mRCC who received first-line treatment with pembrolizumab + axitinib (P + A; n = 279, 18%), ipilimumab + nivolumab (I + N; n = 618, 40%), or TKI monotherapy (TKIm; cabozantinib, sunitinib, pazopanib, or axitinib; n = 641, 42%) between January 1, 2018 and September 30, 2020 in US Oncology Network/non-network practices. Outcome measurements and statistical analysisThe relationship with outcomes, time on treatment (ToT), time to next treatment (TTNT), and overall survival (OS) was analyzed using multivariable Cox proportional-hazards models. Results and limitationsThe median age of the cohort was 67 yr (interquartile range 59.5–74.4), 70% were male, 79% had clear cell RCC, and 87% had an intermediate or poor International mRCC Database Consortium risk score. The median ToT was 13.6 for P + A versus 5.8 for I + N versus 3.4 mo for TKIm (p < 0.001) and the median TTNT was 16.4 for P + A versus 8.3 for I + N versus 8.4 mo for TKIm (p < 0.001) . Median OS was not reached for P + A, 27.6 mo for I + N, and 26.9 mo for TKIm (p = 0.237). On adjusted multivariable analysis, treatment with P + A was associated with better ToT (adjusted hazard ratio [aHR] 0.59, 95% confidence interval [CI] 0.47–0.72 vs I + N; 0.37, 95% CI, 0.30–0.45 vs TKIm; p < 0.0001) and better TTNT (aHR 0.61, 95% CI 0.49–0.77 vs I + N; 0.53, 95% CI 0.42–0.67 vs TKIm; p < 0.0001). Limitations include the retrospective design and the limited follow-up for characterization of survival. ConclusionsWe noted substantial uptake of IO-based therapies in the first-line community oncology setting since their approval. In addition, the study provides insights into clinical effectiveness, tolerability, and/or compliance of IO-based therapies. Patient summaryWe examined the use of immunotherapy for patients with metastatic kidney cancer. The findings suggest rapid implementation of these new treatments by oncologists working in the community setting, which is reassuring for patients with this disease.

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

BackgroundThe 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). ObjectiveTo establish real-world clinical benchmarks for IO combination therapies based on the International mRCC Database Consortium (IMDC) criteria. Design, setting, and participantsPatients 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. Outcome measurements and statistical analysisOverall 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. Results and limitationsIn 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. ConclusionsThis 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. Patient summaryThe 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.

Real-world assessment of changing treatment patterns and sequence for patients with metastatic renal cell carcinoma (mRCC) in the first-line (1L) setting.

302 Background: Several immune-oncology (IO) agents and/or tyrosine kinase inhibitors (TKIs) have received approval for treatment of mRCC in 1L setting by Food and Drug Administration (FDA) over last few years. Limited data exists on evolving real-world treatment patterns and sequence in mRCC patients receiving these agents, especially at the community oncology setting. Methods: We used data from The US Oncology Network of over 1,300 providers from over 480 sites across United States from 01/01/2018 to 12/31/2020 (study period). Eligible study population included mRCC patients who received ipilimumab + nivolumab (Ipi+nivo) (IO+IO); pembrolizumab + axitinib (Pembro+axi) (IO+TKI); and axitinib (Axi) or cabozantinib (Cabo) or pazopanib (Pazo) or sunitinib (Suni) (TKIs monotherapy) in 1L setting until 09/30/2020. Descriptive statistics were used for cohort characterization. Results: We identified 3,756 mRCC patients, of which 1,538 were eligible including 42% (n=641) IO+IO, 18% (n=279) IO+TKI, and 40% (n=618) TKI monotherapy. The median age for the entire cohort was 67.1 years (range 25.0, 93.3), 70% (n=1,076) were male, 70% (n=1,081) were white, 38% (n=587) had BMI ≥ 30 and 79% (n=1,208) had clear cell histology. Among entire cohort, 87% (n=1,338) had intermediate/poor risk score as per International mRCC Database Consortium risk model. We noted a trend towards increased utilization of IO+IO and IO+TKI following their respective FDA approvals (IO+IO: April 2018, IO+TKI: April 2019) (Table). During the study period, overall, 35% (n=535), 12% (n=184), and 4% (n=62) mRCC patients received second-line (2L), third-line (3L) and fourth-line (4L) treatments, respectively. Cabo (49%) and pazo (12%); cabo (51%) and ipi+nivo (23%); and nivo (45%) and ipi+nivo (20%) were the most common 2L treatments in IO+IO, IO+TKI, and TKI monotherapy cohorts, respectively. Conclusions: This large real-world study examined use of new FDA approved mRCC treatments and their impact on treatment paradigm. The results show a rapid adaptation of these newer treatments in the community oncology settings. A longer follow-up is needed to assess their clinical impact and optimal treatment strategy in subsequent setting.[Table: see text]

Salvage immune checkpoint inhibitor (ICI) plus tyrosine kinase inhibitor (TKI) combination therapy for metastatic renal cell carcinoma (mRCC).

e16567 Background: ICI/TKI combinations are a new standard of care for the initial treatment (tx) of mRCC. Efficacy and toxicity of such combination regimens beyond the first-line (1L) setting remain unknown. Methods: We retrospectively reviewed charts for adult patients (pts) receiving an ICI/TKI combination in any line of tx for mRCC of any histology at one of two academic centers as of May 1, 2020. ICIs included pembrolizumab (Pm), nivolumab (Ni), ipilimumab (Ip), or avelumab (Av); TKIs included sunitinib (Su), axitinib (Ax), pazopanib (Pz), lenvatinib (Ln), or cabozantinib (Ca). Clinical data including pt demographics, histology, International mRCC Database Consortium (IMDC) risk group, tx history, and ICI/TKI tx and toxicity details were recorded. Outcomes included objective response rate (ORR), median progression-free survival (mPFS), and safety, analyzed via descriptive statistics and the Kaplan-Meier method. Results: Of 85 pts, 69 (81%) were male and 67 (79%) had clear cell histology. IMDC risk was favorable (24%), intermediate (54%), poor (20%), and unknown (2%). 39% had ICI/TKI tx in the 1L setting. ICI/TKI regimens included Pm/Ax (33%), Ni/Ca (25%), Ni/Ax (20%), Av/Ax (11%), Ni/Ip/Ca (8%), Ni/Su (2%), and Ni/Ln (1%). ORR and mPFS stratified by line of tx and prior tx are shown in the table. Of 52 pts who received ICI/TKI tx as salvage (after 1L), 52% had a grade 3 or higher (≥G3) adverse event (AE), of which the most common were anorexia (13.5%), diarrhea and hypertension (11.5% each), and fatigue (9.6%). 65% of pts on salvage ICI/TKI tx stopped tx for progression/death, while 16% stopped tx for ≥G3 AE. ≥G3 AE rates by line of tx were 62.5% (2L), 50% (3L), and 45% (≥4L). Conclusions: ICI/TKI combination therapy is effective and safe beyond the 1L setting. Prior tx history appears to impact efficacy but has less of an effect on safety/tolerability. These observations will need to be confirmed in prospective studies.[Table: see text]

The impact of antibiotic (Ab) exposure on clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI) or VEGF targeted therapy (VEGF-TT).

4552 Background: Retrospective studies have shown an association between Ab exposure and inferior clinical outcomes in patients receiving ICI across various tumor types, including mRCC. However, it is unclear whether Ab exposure has a unique interaction with ICI or is an independent prognostic marker, regardless of treatment. We sought to examine Ab exposure and its association with clinical outcomes in patients with mRCC treated with ICI compared to VEGF-TT. Methods: We identified patients treated with ICI (anti-PD-L1 alone or in combination with VEGF or CTLA4 inhibitor) or VEGF-TT alone in first to fourth line settings from 2009-2020 across 3 academic centers in North America. Ab exposure was defined as administration of Ab within 60 days prior to initiation of systemic therapy. Outcomes of interest were response rate (RR), time to treatment failure (TTF) and overall survival (OS). Multivariable Cox regression was performed to control for imbalances in International mRCC Database Consortium (IMDC) risk factors, histology, and treatment line. Results: We identified 748 patients. Among the ICI (n=427) and VEGF-TT (n=321) cohorts, 13% vs 15% (p=0.47) had Ab exposure and 57% vs 48% (p=0.046) were treated in the first line setting. The proportion of favorable, intermediate, and poor risk disease by IMDC criteria differed between Ab exposed and unexposed patients in the ICI (14% vs 18%, 47% vs 62%, 39% vs 21% p=0.03) and VEGF-TT (7% vs 13%, 43% vs 60%, 50% vs 27%, p=0.01) cohorts. RR, TTF and OS results are displayed in Table 1. Multivariable analysis did not show a significant independent association between Ab exposure and OS in both the ICI (HR 1.13, p=0.62) and VEGF-TT (HR 1.32, p=0.16) cohorts. Treatment modality (ICI vs VEGF-TT) did not modify the effect of Ab exposure on OS (p=0.84). Conclusions: Ab exposure was associated with higher IMDC risk scores in both the ICI and VEGF-TT cohorts as well as inferior OS on univariable analysis. After adjusting for IMDC risk factors, histology and treatment line, we were unable to find an independent association between Ab exposure and OS in multivariable analysis for either cohort.[Table: see text]

Outcomes of first-line (1L) ipilimumab and nivolumab (IPI-NIVO) and subsequent therapy in metastatic renal cell carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC).

4554 Background: IPI NIVO is approved for 1L treatment of IMDC intermediate/poor risk mRCC based on the CHECKMATE 214 trial. Herein, we report the clinical effectiveness of 1L IPI NIVO and second line (2L) therapy in the real-world setting. Methods: Using the IMDC dataset, patients (pts) treated with 1L IPI NIVO were identified. The outcomes of interest were 1L and 2L overall response rate (ORR), treatment duration (TD), time to next treatment (TTNT), and overall survival (OS). Results: 706 pts were included: 9% (57/614), 58% (354/614), and 33% (203/614) were IMDC favorable (fav), intermediate (int), and poor risk, respectively. Median age was 61 years. The majority of pts were males (71%), had clear cell histology (85%), and underwent nephrectomy (61%). 36%, 19%, and 8% of patients had bone, liver, and brain metastases, respectively. The 12-month OS for pts with IMDC fav, int, and poor risk disease was 92%, 79%, and 56%, respectively (p&lt;0.01). The corresponding estimates for 24 months were 80%, 69%, and 38% (p&lt;0.01). Pts who responded (39%) were more likely to have better IMDC risk category (p=0.02), received nephrectomy (p=0.04), normal neutrophil count (p&lt;0.01), and clear cell histology (p=0.01). Pts with progressive disease as best response (27%) were more likely to have not received nephrectomy (p&lt;0.01), worse IMDC risk category (p=0.02), bone metastases (p=0.01), liver metastases (p=0.04), and non-clear cell histology (p=0.01). Of the 66% (466/706) of pts who discontinued 1L IPI NIVO, 51% (236/466) received 2L therapy: sunitinib (40%), cabozantinib (25%), pazopanib (18%), axitinib (8%), and others (9%). The ORR, median TD, and median OS for those who received either sunitinib, cabozantinib, pazopanib or axitinib was 16%, 4.5 months (mo) (95% CI 3.7-5.6), and 14.5 mo (95% CI 10.9-25.9), respectively. 33% (129/386) of pts discontinued IPI NIVO due to irAEs. Conclusions: Our study benchmarks the real-world experience of 1L IPI NIVO in mRCC. IMDC criteria is prognostic for clinical outcome. Tyrosine kinase inhibitors have clinical activity post IPI NIVO.[Table: see text]

Prognostic Significance of Pancreatic Metastases in Patients With Advanced Renal Cell Carcinoma Treated With Systemic Therapy.

Pancreatic metastases (PM) are rare in renal cell carcinoma. It has been suggested that patients with metastases to the pancreas have a more favorable prognosis, but little is known about the long-term outcomes with systemic therapy. We sought to understand the outcomes of patients with metastatic renal cell carcinoma with PM treated with systemic therapy. We conducted a pooled analysis of 4736 patients with metastatic renal cell carcinoma treated on phase II/III clinical trials. Systemic therapies included anti-vascular endothelial growth factor targeted therapy, mammalian target of rapamycin-targeted therapy, and cytokine therapy. The primary end point was overall survival (OS) in patients with versus without PM. Statistical analyses were performed using Kaplan-Meier analysis and Cox regression. Among 4736 patients, 235 (5.0%) were identified to have baseline PM at therapy initiation. The median OS in patients with PM was significantly prolonged with OS of 41.7 months versus 19.0 months (adjusted hazard ratio, 0.52; P < .0001). Similarly, progression-free survival was significantly prolonged in patients with PM (10.9 vs. 6.9 months; adjusted hazard ratio, 0.72; P=.004). The effect of PM on OS and progression-free survival was independent of other sites of metastasis or International mRCC Database Consortium risk group. The presence of PM in RCC is an independent positive predictor for survival and improved response to systemic therapy. These findings suggest RCC with PM is associated with favorable outcomes and further work to understand the underlying disease biology of these patients is warranted.

Clinical Effectiveness of Second-line Sunitinib Following Immuno-oncology Therapy in Patients with Metastatic Renal Cell Carcinoma: A Real-world Study.

Limited data exist on the clinical effectiveness of second-line (2L) vascular endothelial growth factor (receptor) targeted inhibitor (VEGF(R)i) sunitinib after first-line (1L) immuno-oncology (IO) therapy for patients with metastatic renal cell carcinoma (mRCC) in real-world settings. A retrospective cohort study among adult patients with mRCC treated with 2L sunitinib following 1L IO was conducted from select International mRCC Database Consortium (IMDC) centers. All analyses were performed overall and by 1L ipilimumab + nivolumab (IPI+NIVO) or 1L IO+VEGF(R)i. Median overall survival (mOS) and time-to-treatment discontinuation (mTTD) in 2L were estimated using Kaplan-Meier analysis. The 2L objective response rate (ORR) (complete/partial response) was reported. Among 102 patients on 2L sunitinib, mean age was 61.3 years. IMDC risk scores at 2L initiation was available for 83 patients: 8 (9.6%) were favorable, 45 (54.2%) were intermediate, and 30 (36.1%) were poor risk. The 1L consisted of IPI+NIVO in 62 (60.8%), IO+VEGF(R)i therapy in 27 (26.5%), and IO monotherapy in 13 (12.7%) patients. Among all patients, mOS was 15.6 months (95% confidence interval [CI], 9.8-21.7), with a 1-year OS rate of 57.5% (95% CI, 45.2-68.0). mTTD was 5.4 months (95% CI, 4.2-7.2) and ORR was 22.5%. Despite availability of effective 1L therapies in recent years, 2L sunitinib continues to have clinical activity after failure of 1L IO. Further studies on optimal treatment sequencing after 1L IO progression are needed.

Efficacy of immune-checkpoint inhibitors (ICI) in the treatment of older adults with metastatic renal cell carcinoma (mRCC) – an International mRCC Database Consortium (IMDC) analysis

ObjectiveOlder adults with metastatic renal cell carcinoma(mRCC) are underrepresented in immune-checkpoint inhibitor(ICI) registration trials. Here we compare the efficacy of ICI treatments in older vs. younger adults with mRCC. MethodsUsing the International mRCC Database Consortium(IMDC), patients treated with a PD(L)-1 based ICI were identified. Older adult was defined as ≥70-years at the time of treatment. Descriptive statistics were summarized in means, medians, and proportions. Effectiveness endpoints included overall survival (OS), time-to-treatment failure(TTF), time-to-next treatment(TNT), and overall response rate(ORR). Hazards ratios were adjusted(aHR) for IMDC risk factors, histology, line of treatment and older age. ResultsOf 1427 included patients, 397(28%) were older adults. ICI was used as 1st line(1 L) in 40%, 2nd line(2 L) in 49% and 3rd line(3 L) in 11% of patients. In univariable analysis, older adults had inferior OS compared to younger adults(25.1 m vs. 30.8 m, p < 0.01). There were no significant differences in TTF (6.9 m vs. 6.9 m, p = 0.4) or TNT(9.1 m vs 10 m, p = 0.3) between groups. In multivariable analyses, older age was not independently associated with worse OS(aHR = 1.02, p = 0.8), TTF(aHR = 0.95, p = 0.6) or TNT(aHR = 0.93, p = 0.5). Older adults had a lower ORR compared to younger adults(24% vs. 31%, p = 0.01), which was mainly driven by responses in 1 L(31% vs. 44%, p = 0.02) and not observed in 2 L/3 L. ConclusionsAfter multivariable analyses, older adults with mRCC treated with ICI had no difference in OS, TTF or TNT when compared to younger adults. Our data support that chronological older age should not preclude patients from receiving ICI based therapies.

Outcomes of first-line (1L) immuno-oncology (IO) combination therapies in metastatic renal cell carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC).

276 Background: Ipilimumab and nivolumab (IPI-NIVO) and IO/vascular endothelial growth factor (VEGF) inhibitor combinations (IOVE) are now standard of care 1L treatment options for mRCC. However, there is limited head-to-head comparative evidence between these strategies. Methods: Using the IMDC dataset, patients treated with a 1L IOVE combination (pembrolizumab axitinib, avelumab axitinib and nivolumab cabozantinib) were compared with those treated with IPI-NIVO. The outcomes of interest were overall response rate (ORR), treatment duration (TD), time to next treatment (TTNT), and overall survival (OS). A preplanned subgroup analysis of the IMDC intermediate/poor risk population was conducted. Hazard ratios were adjusted for IMDC risk factors. Results: 723 patients were included for analysis (N=571 for IPI-NIVO and N=152 for IOVE). The median age was 60 in both groups. The proportion of patients with IMDC favorable, intermediate and poor risk disease in IPI-NIVO vs. IOVE groups were 9% vs. 33%, 58% vs. 53%, 33% vs. 14%, respectively. In the intermediate/poor risk groups (Table), ORR and median TD were lower and shorter in IPI-NIVO vs IOVE while no difference in median TTNT and OS was detected. The HR for death adjusting for IMDC criteria for IPI-NIVO vs. IOVE was 0.92 (95% CI 0.61-1.40, p=0.71). IMDC risk groups and the presence or absence of sarcomatoid histology, brain, liver or bone metastases were not associated with differences in OS between these treatments (all p&gt;0.2). Patients that had dose delays or steroid use (defined as &gt;40mg of prednisone equivalent/day) for immune related adverse events (irAEs) were associated with longer median TTNT (21.6 vs. 9.5 mons, p=0.02) and OS (NR vs. 44.4 mons, p=0.01) despite similar treatment durations (7.6 vs. 8.9 mons, p=0.77) compared to those without dose delays or steroid use. Conclusions: We were unable to detect any differences in OS between IPI-NIVO and IOVE regimens in the IMDC intermediate/poor risk groups and amongst various subgroups. Patients who experienced irAEs requiring dose delay or steroids had longer overall survival. [Table: see text]

Comparison of nivolumab plus ipilimumab with tyrosine kinase inhibitors as first-line therapies for metastatic renal-cell carcinoma: a multicenter retrospective study.

This study compared real-world outcomes of metastatic renal-cell carcinoma (mRCC) patients treated with tyrosine kinase inhibitors or nivolumab plus ipilimumab. Using the International mRCC Database Consortium (IMDC), we retrospectively evaluated intermediate- and poor-risk mRCC patients who were treated with nivolumab plus ipilimumab (Nivo-Ipi), tyrosine kinase inhibitors (TKIs) as the first-line therapy between August 2015 and January 2020. We compared oncological outcomes between the Nivo-Ipi group and TKIs group using multivariate logistic regression analysis with the inverse probability of treatment weighting (IPTW) method. In this study 278 patients were included. There were 52 and 226 patients in the Nivo-Ipi and TKIs groups (sunitinib 97, axitinib 118, sorafenib 9, pazopanib 2), respectively. The median age in the Nivo-Ipi and TKIs groups were 69and 67years, respectively. There was no significant difference in age, performance status, history of nephrectomy, and the IMDC risk group distribution between the groups. The objective response rate was significantly higher in the Nivo-Ipi group (38%) than in the TKIs group (23%, P = 0.018). The IPTW-adjusted Cox regression analysis showed that a significantly longer progression-free survival (hazard ratio 0.60, P = 0.039) and overall survival (hazard ratio 0.51, P = 0.037) rates in the Nivo-Ipi group than those in the TKIs group. The oncological outcomes of patients receiving the first-line therapy of nivolumab plus ipilimumab in real-world practice were significantly improved in comparison with first-line TKIs therapy.

Application of IMDC criteria across first-line (1L) and second-line (2L) therapies in metastatic renal-cell carcinoma (mRCC): New and updated benchmarks of clinical outcomes.

5063 Background: In patients with mRCC, the International mRCC Database Consortium (IMDC) criteria have been validated as a prognostic tool in patients treated with targeted therapy in the 1-4L settings and with 2L Nivolumab (Nivo). However, it is unknown whether the IMDC criteria can be used to risk stratify in recently approved 1L IO combination therapies, including Ipilimumab + Nivolumab (IOIO) and Axitinib + Pembrolizumab/Avelumab (IOVE). We sought to assess the ability of the IMDC criteria to risk stratify with the use of novel 1L IO combinations and provide updated benchmarks for older 1L and 2L treatments. Methods: Patients with mRCC starting systemic therapy between 2010-2019 were identified through the IMDC. IMDC risk score was calculated at the time of starting the line of therapy of interest. The primary endpoint was overall survival (OS) from time of initiating the treatment of interest. Results: From a total of 6596 unique patients, 5043 treated in the 1L setting and 2498 treated in the 2L setting were included in the analysis. Across the entire cohort, median age was 61, 73% were male, 16% had sarcomatoid features, 79% underwent nephrectomy and 88% had clear-cell histology. IMDC risk groups for 1L and 2L treatment were 17%, 57%, 27% and 10%, 60%, 30% for favourable-, intermediate- and poor-risk disease, respectively. IMDC criteria appropriately risk stratified into 3 prognostic groups in 1L IOIO and 1L IOVE combinations, in addition to older treatments: 1L VEGF TT, 2L VEGF TT, 2L Nivo and 2L Everolimus. Results are displayed in Table. Due to the novelty of 1L IO combinations, median follow up time was shorter and thus landmark OS values are presented. Conclusions: IMDC criteria may be used to risk stratify in recently approved 1L IO combination therapies in addition to older 1L and 2L treatments. These data provide contemporary benchmarks for OS that may be used for patient counseling and trial design. [Table: see text]

Efficacy of immune-checkpoint inhibitors (ICI) in the treatment of older adults with metastatic renal cell carcinoma (mRCC): An international mRCC database consortium (IMDC) analysis.

5068 Background: Anti-PD-1/PD-L1 immune-checkpoint inhibitors (ICI) are now a standard of care in metastatic renal cell carcinoma (mRCC). Older adults were underrepresented in registration trials and given that immunological senescence may affect the anti-tumor activity of ICIs, there is uncertainty about the efficacy of ICIs in this population. Here we provide real world data on outcomes of older adults with mRCC treated with ICIs. Methods: Patients with mRCC treated with a PD-1/PD-L1 ICI either as monotherapy or as a combination treatment from 2000 to 2019 were included. Older adult was defined as ≥ 70-years at the time of ICI treatment. Descriptive statistics were summarized in means, medians and proportions. Efficacy was assessed by survival analysis, including overall survival (OS), time to treatment failure (TTF), and overall response rate (ORR). Multivariate analyses adjusted for imbalances in IMDC risk factors. P &lt; 0.05 was considered statistically significant. Results: Of 1427 patients, 397 (28%) were older adults. Mean age of older vs. younger adults was 74 (70-92) vs. 60 (22-69) years. Groups were comparable in terms of gender (Female 28.5% vs. 26.1%, p = 0.36), rates of nephrectomy (21% vs. 18.3%, p = 0.24) and presence of sarcomatoid features (12.3% vs. 17.8%, p = 0.14). Proportion of IMDC risk-groups between older vs. younger adults were as follows: 15.4% vs. 18.2% for favorable, 61.2% vs. 59.1% for intermediate, and 23.4% vs. 22.7% for poor; there was no statistical difference (p = 0.55). ICI was used as 1st line in 40%, 2nd line in 48.5% and 3rd line in 11.5% patients; older adults were less likely to be treated with ICI in 1st line (32.2% vs. 43%, p &lt; 0.01). In terms of survival, older adults had poorer median OS (25.1m vs. 30.8m, p &lt; 0.01) but similar median TTF (6.9m vs. 6.9m, p = 0.40) compared to younger adults. In multivariate analyses, older age was not a predictor of either worse OS (aHR = 1.02, p = 0.86) or TTF (aHR = 0.95, p = 0.59). Older adults had a lower ORR compared to younger (24% vs. 31%, p = 0.01), which was mainly driven by responses in 1st line (31% vs. 44%, p = 0.02) and not observed in 2nd/3rd line (20% vs. 20%, p = 0.86). Conclusions: On multivariate analyses, older adults with mRCC treated with ICI had no difference in OS and TTF when compared to younger adults, despite having lower ORR in 1st line. Our data supports that older age is not an independent risk factor for survival; thus, treatment selection should not be based solely on chronological age.

Cabozantinib real-world effectiveness in the first through fourth-line settings for the treatment of metastatic renal cell carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC).

639 Background: Cabozantinib (Cabo) is approved for mRCC patients based on the METEOR and CABOSUN trials. The real-world effectiveness of Cabo in mRCC patients in the first- (1L), second- (2L), third- (3L) and fourth-line (4L) settings requires characterization. Methods: This retrospective analysis included mRCC patients who were treated with Cabo and stratified using IMDC risk groups. Overall response rate (ORR), time to treatment failure (TTF), and overall survival (OS) were calculated. Results: A total of 413 patients (82.6% with clear cell and 17.4% non-clear cell) were identified. The median age was 57 years. Overall, 63% of patients had a Karnofsky performance status score of &gt;80 and 82.6% had prior nephrectomy. 23.1%, 75.4% and 88.3% of patients received immunotherapy as a prior line of treatment, before receiving Cabo in the 2L, 3L and 4L settings, respectively. For patients treated with 1L PD(L)1 combination or monotherapy (n=31), 2nd line Cabo had ORR of 20.8%, median TTF of 5.4 months and median OS of 17.4 months. When segregated into IMDC favorable, intermediate, and poor risk groups, the median OS was 34.8 months (95% CI 5.52-NR), 18.0 months (12.3-35.6) and 9.8 months (7.4-20.8), p=0.0088, respectively for 2L Cabo; and 31.5 months (23.6-39.3), 20.5 months (10.1-21.8), and 6.9 months (4.1-10.9), p=&lt;0.0001), respectively for 3L Cabo. Conclusions: The ORR and TTF of Cabo were maintained from the 1L to the 4L therapy settings. In the 2L and 3L settings, the IMDC criteria appropriately stratified patients into favorable, intermediate and poor risk groups for OS. Cabo has activity after first line immunotherapy.[Table: see text]