International mRCC Database Consortium Research Articles

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]

Real world outcomes of first line (1L) nivolumab and ipilimumab (NIVO IPI) in metastatic renal cell carcinoma (mRCC): An update from the International mRCC Database Consortium (IMDC).

Real world outcomes of first line (1L) nivolumab and ipilimumab (NIVO IPI) in metastatic renal cell carcinoma (mRCC): An update from the International mRCC Database Consortium (IMDC).

The Relationship Between Health-Related Quality of Life and Overall Survival in Patients With Advanced Renal Cell Carcinoma in CheckMate 214.

In CheckMate 214 (median follow-up, 25.2 months), nivolumab plus ipilimumab yielded greater overall survival (OS) benefit than sunitinib in patients with intermediate-/poor-risk advanced renal cell carcinoma (aRCC). Health-related quality of life (HRQoL) assessed by the Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 (FKSI-19) was also more favorable for the nivolumab plus ipilimumab group than the sunitinib group. We investigated whether HRQoL scores can predict OS of patients with 5 years follow-up in CheckMate 214. CheckMate 214 was an open-label, phase III trial in previously untreated aRCC (N = 1096). Patients with intermediate-/poor-risk disease (International mRCC Database Consortium prognostic score ≥ 1; n = 847) were randomized to either nivolumab plus ipilimumab or sunitinib monotherapy. Pooled data for OS and FKSI-19 total and subscales (disease-related symptoms [DRS], DRS-physical [DRS-P], and function/well-being [FWB]) were analyzed. Relationships between HRQoL and OS were assessed using Cox proportional hazard models with baseline and longitudinal scores. Associations between HRQoL changes and OS were assessed by landmark analyses. Patients with higher FKSI-19 total and subscale scores at baseline had longer OS than patients with lower scores (HR ≤ 0.834; P < .0001). Longitudinal models indicated stronger associations between HRQoL and OS (HR ≤ 0.69; P < .001 for each). At 3 months after randomization, patients with stable/improved HRQoL versus baseline had longer median OS than patients with worsened/unobserved HRQoL versus baseline (55.9 and 26.0 months, respectively; HR = 0.56; 95% CI, 0.46-0.67; P < .0001). Results at 6-, 9-, and 12-month landmarks were consistent with these findings. In aRCC, patient-reported outcomes are important for HRQoL and prognostic evaluation. NCT02231749; https://clinicaltrials.gov/ct2/show/NCT02231749.

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

Background and objectiveMetastatic renal cell carcinoma (mRCC) patients have been reported to have better outcomes when treated with immunotherapies (IO) compared to targeted therapies (TT). This study aims to evaluate the impact of first-line systemic therapies on survival of mRCC patients with or without sarcomatoid features using real-world data. MethodsMetastatic RCC patients of International mRCC Database Consortium (IMDC) intermediate or high risk, diagnosed from January 2011 to December 2022, treated with first-line systemic therapies, and with histological documentation of the presence or absence of sarcomatoid features in nephrectomy specimens were identified using the Canadian Kidney Cancer information system. Patients were classified by initial treatment: (1) targeted therapy (TT) used alone or (2) immunotherapy (IO)-based systemic therapies used in combination of either IO-IO or IO-TT. The inverse probability of treatment weighting using propensity scores was used to balance for covariates. Cox proportional hazard models were used to assess the impact of initial treatment received on overall survival (OS). Key findings and limitationsOf the 1202 eligible patients, 791 were treated with TT and 411 with IO combinations. Of the patients, 76% were male, and the majority (91%) had a nephrectomy before systemic therapy. In nonsarcomatoid patients (639 TT and 320 IO patients), treatment with IO was associated with improved OS compared with patients treated with TT (median of 72 vs 48 mo, hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.50–0.80, objective response rate [ORR] of 38.5% for IO and 23.5% for TT). In sarcomatoid patients (152 TT and 91 IO patients), treatment with IO was associated with improved OS (median of 48 vs 18 mo, HR 0.41, 95% CI 0.26–0.64, ORR of 49.5% for IO and 13.8% for TT). Similar results were observed in patients with synchronous metastatic disease only. Conclusions and clinical implicationsIO treatment was associated with improved survival in mRCC patients. The magnitude of benefit is increased in patients with sarcomatoid mRCC, consequently, identifying the sarcomatoid status early on could help healthcare providers make a better treatment decision. Patient summaryMetastatic renal cell carcinoma (mRCC) patients of International mRCC Database Consortium intermediate and high risk, diagnosed from January 2011 to December 2022, treated with first-line systemic therapies, and with histological documentation of the presence or absence of sarcomatoid features in nephrectomy specimens were identified using the Canadian Kidney Cancer information system (CKCis). In this study, treatment with immunotherapy was associated to an improved survival and response rates for mRCC patients with and without sarcomatoid features. The magnitude of benefit is increased in patients with sarcomatoid mRCC.

Cytoreductive nephrectomy and its effect on prognosis in patients with disseminated renal cell carcinoma receiving treatment in wide clinical practice

Aim. To evaluate the effect of cytoreductive nephrectomy (CN) on overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) and to identify a group of patients who are candidates for cytoreductive surgical treatment.Materials and methods. We retrospectively analyzed a database of 403 patients with mRCC treated at the Moscow City Oncological Hospital No. 62 and the City Clinical Oncological Dispensary (Saint Petersburg) between 2006 and 2022. In total, 330 (81.9 %) patients underwent CN. All patients received systemic anti-tumor therapy: targeted anti-angiogenic therapy - 317 (78.6 %), cytokines - 61 (15.1 %), checkpoint inhibitors - 25 (6.2 %). The groups of operated and non-operated patients were unbalanced: CN was more often not performed in patients with multiple metastases, bone and liver lesions, laboratory abnormalities (anemia, increased serum alkaline phosphatase and lactate dehydrogenase) and unfavorable prognosis per IMDC (International mRCC Database Consortium) classification (p &gt;0.05 for all). Results. CN was associated with a significant increase in OS compared with primary tumor preservation in situ: median OS was 36 months with 95 % confidence interval 29.1-37.1, and 11 months with 95 % confidence interval 8.1-21.3, respectively (p &lt;0.0001). The benefit for OS in the CN group was also observed in clear-cell mRCC (p &lt;0.0001), grade G3 (p &lt;0.0001), multiple metastases (p &lt;0.0001) groups, and in the IMDC poor prognosis group (p &lt;0.0001). Conclusion. CN in selected mRCC patients results in a significant increase in OS. Further research is needed to determine selection criteria for surgical treatment candidates.

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]

1902P Comparison of cabozantinib (CABO) versus sunitinib (SUN) following first-line (1L) nivolumab plus ipilimumab (NIVO+IPI) for metastatic renal cell carcinoma (mRCC): A target trial emulation using real-world data from the International mRCC Database Consortium (IMDC)

1902P Comparison of cabozantinib (CABO) versus sunitinib (SUN) following first-line (1L) nivolumab plus ipilimumab (NIVO+IPI) for metastatic renal cell carcinoma (mRCC): A target trial emulation using real-world data from the International mRCC Database Consortium (IMDC)

Characterization of Patients with Metastatic Renal Cell Carcinoma Undergoing Deferred, Upfront, or No Cytoreductive Nephrectomy in the Era of Combination Immunotherapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

BackgroundThe role of cytoreductive nephrectomy (CN) has not yet been well characterized in the era of combination immunotherapy. ObjectiveTo evaluate characteristics and outcomes for patients with metastatic renal cell carcinoma (mRCC) who received immuno-oncology (IO)-based combination therapy according to CN status. Design, setting, and participantsUsing the International mRCC Database Consortium (IMDC), patients with mRCC who received frontline IO-based combinations were included. Upfront CN was defined as CN up to 3 mo before diagnosis of metastatic disease but before systemic therapy initiation. Deferred CN was defined as CN after systemic therapy initiation. Outcomes measurements and statistical analysisOverall survival (OS) from initiation of systemic therapy was estimated via Cox proportional-hazards regression. A 12-mo landmark time and a time-varying covariate for CN status were used to mitigate potential bias. Results and limitationsOf the 385 patients eligible for landmark analysis, 24, 182, and 179 underwent deferred CN, upfront CN, and no CN, respectively. Patients in the no CN subgroup were older (63 yr vs 57 yr in the deferred CN subgroup and 60 yr in the upfront CN subgroup; p = 0.001) and a higher proportion had bone metastases (44% vs 26% in the deferred CN subgroup and 23% in the upfront CN subgroup; p < 0.001). A lower proportion of patients in the upfront CN subgroup had IMDC poor risk (23% vs 43% in the no CN subgroup and 47% in the deferred CN subgroup; p < 0.001). On multivariable analysis, CN receipt was an independent favorable prognostic factor (hazard ratio 0.45, 95% confidence interval 0.26–0.78; p = 0.005). The study is limited by the lack of randomization and its retrospective nature. ConclusionsDespite changes in practice patterns with the advent of novel therapeutic agents, CN may still serve as an effective surgical intervention in carefully selected patients. Patient summaryFor patients with metastatic kidney cancer, surgery to remove the primary tumor was traditionally the treatment of choice, but immunotherapy drugs are now another option for these patients. We analyzed data for contemporary patients with metastatic kidney cancer who received combination immunotherapy as their first treatment. We found that in selected patients receiving immunotherapy, surgery to remove the primary tumor as well can result in better prognosis.

Indications and Outcomes for Deferred Cytoreductive Nephrectomy Following Immune Checkpoint Inhibitor Combination Therapy: Can Systemic Therapy be Withdrawn in Patients with No Evidence of Disease?

BackgroundUpfront cytoreductive nephrectomy (CN) is no longer the standard of care for patients with metastastic renal cell carcinoma (mRCC) with intermediate or poor prognosis according to the International mRCC Database Consortium categories. ObjectiveTo investigate indications for CN following first-line ipilimumab-nivolumab, and assess management and outcomes for patients achieving no evidence of disease (NED) after CN. Design, setting, and participantsThis was a retrospective cohort study among 125 patients with synchronous mRCC who received ipilimumab-nivolumab treatment between March 2019 and June 2022 at four European centres. At one of the four centres, nivolumab was stopped following NED. Outcome measurements and statistical analysisWe measured complete response of metastases (mCR) according to Response Evaluation Criteria in Solid Tumours 1.1; near-complete response of mestastases (mnCR) was defined as a >80% reduction in cumulative metastatic volume. Treatment-free survival (TFS), disease-free survival (DFS), progression-free survival (PFS), and cancer-specific survival (CSS) were determined. Results and limitationsAt median follow-up of 25 mo, 23/125 patients (18%) had undergone deferred CN. Of 26 patients (21%) with mCR or mnCR, 19 (73%) underwent CN to achieve NED, of whom 11 (58%) discontinued nivolumab, with median TFS of 21 mo. For patients who continued (n = 8, 42%) versus discontinued nivolumab following NED, 2-yr DFS was 83% versus 60% (p = 0.675) and 3-yr CSS was 100% versus 70% (p = 0.325). Four patients underwent CN because of a dissociated response of the primary tumour and were still alive at median follow-up of 5 mo. ConclusionsCN can result in NED, durable DFS, and substantial time off systemic therapy. More collaborative data are required to ascertain the benefits of treatment discontinuation versus oncologic safety. Patient summaryIn our study using real-world data, 18% of patients treated with immunotherapy underwent deferred kidney surgery. The majority were free of disease after 3 years. Half of the patients who stopped immunotherapy after surgery have been off therapy for 21 months or longer. Larger studies are needed to investigate the effect of kidney surgery and discontinuation of immunotherapy on survival.

Salvage lenvatinib/everolimus combination therapy after immune checkpoint inhibitor and VEGFR tyrosine kinase inhibitor for metastatic renal cell carcinoma.

The optimal treatment for metastatic renal cell carcinoma (mRCC) patients who have progressed after both immune checkpoint inhibitor (ICI) and VEGFR tyrosine kinase inhibitor (TKI) remains uncertain. Lenvatinib and everolimus (LE) are frequently used in combination as salvage therapy because of their different antitumor mechanisms, but efficacy and toxicity data in this setting are lacking. We retrospectively reviewed charts from two academic centers for 71 adult mRCC patients who received LE after prior ICI and TKI exposure. We evaluated patient demographics, histology, International mRCC Database Consortium (IMDC) risk group, treatment history, and toxicity details. Outcomes of interest included objective response rate (ORR), time to treatment failure (TTF), overall survival (OS), ≥grade 3 toxicities, and schedule or dosage changes, which were evaluated using descriptive statistics, chi-square test, Cox proportional hazards model, and the Kaplan-Meier method. The median age was 64 (range 31-84). Most patients had clear cell histology (84.5%) and had undergone nephrectomy (80.3%). IMDC risks were favorable (19.7%), intermediate (int) (66.2%), poor (11.3%), and unknown (2.8%). The average ORR was 26.8%, while the median TTF was 5.5 months (95% confidence interval [CI], 3.5-7.6) and the median OS was 9 months (95% CI, 7.6-12.9). Intermediate and poor IMDC risks were independently associated with a significantly worse TTF compared to favorable risk (hazard ratio (HR), 3.03, 95% CI, 1.18-7.79), as was ≥4L treatment vs. 2L/3L treatment (HR, 2.02, 95% CI, 1.08-3.8). Of the 71 patients, 57.7% had ≥grade 3 adverse events, 60% had treatment interruption, 44.3% had dose reduction, and 21% stopped treatment due to intolerance. LE therapy is feasible but has modest efficacies following ICI/TKI treatment. Patients with favorable risk or treated earlier may have a better treatment response. These observations need to be confirmed in prospective studies.

Analysis of the effect of clinical and laboratory parameters on survival in patients with metastatic renal cell cancer with intermediate prognosis according to IMDC (International mRCC Database Consortium)

Introduction. Most patients with metastatic renal cell carcinoma (mRCC) who received systemic therapy are classified into as intermediate risk group according to the International mRCC Database Consortium (IMDC) assessment. However, survival differs in patients with one and two unfavourable prognostic risk factors.Objective. To analyze the impact of possible clinical and laboratory parameters on survival in mRCC patients with intermediate prognosis according to IMDC in the presence of one or two unfavourable prognostic risk factors.Materials &amp; methods. A retrospective analysis of data from 316 mRCC patients with intermediate prognosis receiving systemic therapy was carried out. The presence and effect on survival of the following laboratory parameters were compared: hemoglobin, neutrophil count, LDH, platelet count, alkaline phosphatase, serum calcium level, ESR, and emphasis was also placed on the time of metastases appearance. Overall survival (OS), post-progression survival (PPS), and 3- and 5-year survival were evaluated.Results. The overall 3- and 5-year survival rate for subgroups with one and two unfavourable prognostic risk factors were 85.2% ± 1.8% and 58.1 ± 1.6%; 79.1% ± 1.7% and 35.6  1.6%, respectively (p &lt; 0.001). Three- and 5-year PPS for both subgroups amounted to 66.1% ± 1.6% and 21.8% ± 1.4%; 45.2% ± 1.5% and 12.2% ± 1.3%, respectively (p &lt; 0.001). Median for OS was 61 and 51 months and PPS was 50 and 32 months respectively (p &lt;0.001). No statistically significant difference was found in the frequency of gradations of the investigated laboratory indicators with a predictive effect on prognosis, depending on the number of a unfavourable prognostic risk factors. There were also no significant differences in survival rates when laboratory parameters deviated from the normal, except for hemoglobin: OS in patients with one prognostic factor is significantly higher with normal hemoglobin (p &lt; 0.05). In the future, considering the absence of influence of the selected factors on survival rates with their obvious significant differences in patients with one and two prognostic factors, the influence of the time of appearance of metastases (synchronous / metachronous) was analysed: all survival parameters were significantly worse in patients with synchronous metastases. Furthermore, OS in patients with metachronous metastases with the same relapse-free period was significantly better in patients with one prognostic factor according to IMDC.Conclusions. The presence of one or two prognostic factors significantly affects the indicators of 3 and 5-year overall survival and PPS in patients with an intermediate prognosis of mRCC, while laboratory parameters do not affect survival, except for hemoglobin levels, the time of metastases appearance has a significant effect, and the time of metastases appearance has a significant effect.

The Selection for Cytoreductive Nephrectomy (SCREEN) Score: Improving Surgical Risk Stratification by Integrating Common Radiographic Features

BackgroundCareful patient selection is critical when considering cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) but few studies have investigated the prognostic value of radiologic features that measure tumor burden. ObjectiveTo develop a prognostic model to improve CN selection with integration of common radiologic features with known prognostic factors associated with mortality in the first year following surgery. Design, settings, and participantsData were analyzed for consecutive patients with mRCC treated with upfront CN at five institutions from 2006 to 2017. Univariable and multivariable models were used to evaluate radiographic features and known risk factors for associations with overall survival. Relevant factors were used to create the SCREEN model and compared to the International mRCC Database Consortium (IMDC) model for predictive accuracy and clinical usefulness. Results and limitationsA total of 914 patients with mRCC were treated with upfront CN during the study period. Seven independently predictive variables were used in the SCREEN score: three or more metastatic sites, total metastatic tumor burden ≥5 cm, bone metastasis, systemic symptoms, low serum hemoglobin, low serum albumin, and neutrophil/lymphocyte ratio ≥4. Predictive accuracy measured as the area under the receiver operating characteristic curves was 0.76 for the SCREEN score and 0.55 for the IMDC model. Decision curve analysis showed that the SCREEN model was useful beyond the IMDC classifier for threshold first-year mortality probabilities between 15% and 70%. ConclusionsThe SCREEN score had higher predictive accuracy for first-year mortality compared to the IMDC scheme in a multi-institutional cohort and may be used to improve CN selection. Patient summaryThis study provides a model to improve selection of patients with metastatic kidney cancer who may benefit from surgical removal of the primary kidney tumor. We found that radiographic measurements of the tumor burden predicted the risk of death in the first year after surgery. The model can be used to improve decision-making by these patients and their physicians.

Global Real-World Outcomes of Patients Receiving Immuno-Oncology Combinations for Advanced Renal Cell Carcinoma: The ARON-1 Study.

Immuno-oncology combinations have achieved survival benefits in patients with metastatic renal cell carcinoma (mRCC). The ARON-1 study (NCT05287464) was designed to globally collect real-world data on the use of immuno-combinations as first-line therapy for mRCC patients. Patients aged ≥ 18 years with a cytologically and/or histologically confirmed diagnosis of mRCC treated with first-line immuno-combination therapies were retrospectively included from 47 International Institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall clinical benefit (OCB). A total of 729 patients were included; tumor histology was clear-cell RCC in 86% of cases; 313 patients received dual immuno-oncology (IO + IO) therapy while 416 were treated with IO-tyrosine kinase inhibitor (IO + TKI) combinations. In the overall study population, the median OS and PFS were 36.5 and 15.0 months, respectively. The median OS was longer with IO+TKI compared with IO+IO therapy in the 616 patients with intermediate/poor International mRCC Database Consortium (IMDC) risk criteria (55.7 vs 29.7 months; p=0.045). OCB was 84% for IO+TKI and 72% for IO + IO combination (p<0.001). Our study may suggest that immuno-oncology combinations are effective as first-line therapy in the mRCC real-world context, showing outcome differences between IO + IO and IO + TKI combinations in mRCC subpopulations. NCT05287464.

Characterizing progression to subsequent lines of therapy in metastatic renal cell carcinoma (mRCC) after nivolumab plus ipilimumab (Nivo+Ipi): Results from the International mRCC Database Consortium (IMDC).

4538 Background: Treatment patterns and number of lines of therapy for patients with mRCC are not well characterized in the era of immunoncology-based combinations. We aimed to quantify the attrition rates by line of therapy and to examine predictors of receiving second-line (2L) treatment. Methods: Using the IMDC, patients with mRCC who received first-line (1L) Nivo+Ipi were included. Clinical and pathologic characteristics and outcomes were extracted. Chi-square tests were used to compare categorical variables between patients who received 2L and those who did not. A logistic regression model was used to assess predictors of 2L therapy initiation in eligible patients. Results: 995 patients treated with 1L Nivo+Ipi were identified, of whom 704 stopped 1L and were thus eligible for 2L therapy. Reasons for stopping 1L included progressive disease (PD) in 39.5%, toxicity in 25.0%, death in 4.3%, complete response in 1.6% and other in 29.7%. Among 2L eligible patients, 410 (58.2%) received 2L whereas 294 (41.8%) did not. Patients who stopped 1L for PD were more likely to initiate 2L than those who stopped for other reasons (81.7% vs 43.0%, p &lt;0.001). Patients who received 2L were more likely to have clear-cell histology (75.1 vs 62.9%, p=0.02), bone metastases (39.8 vs 29.6%, p=0.01), and only one site of metastases (18.3 vs 10.5%, p=0.01) and less likely to be poor risk by IMDC criteria (27.1 vs 34.4%, p=0.03). After adjusting for IMDC criteria, no predictors of receiving 2L therapy remained significant. The overall response rate to 1L therapy was lower in patients who received 2L than in those who did not: 18.5% (76/366) and 33.7% (99/245), respectively (p&lt;0.001). Among 258 patients who stopped 2L, 145 (56.2%, overall 20.6%) started third-line (3L) therapy. Of the 98 patients who stopped 3L, 52 (53.1%, overall 7.4%) started fourth-line therapy. Conclusions: In our study, we found that over half of eligible patients received the subsequent line of therapy. We were unable to identify predictors of 2L therapy initiation. Attrition rates between lines of therapy have important implications for patient counseling, cost analyses, and clinical trial design. [Table: see text]

The emerging use of immunotherapy as a treatment option in metastatic renal cell carcinoma: Real-world evidence from a single UK tertiary cancer centre.

e16509 Background: The landscape of systemic anticancer therapy (SACT) options for the treatment of metastatic renal cell carcinoma (mRCC) has recently evolved following results from the CheckMate 214 trial in 2018 which demonstrated improved overall survival in patients with International mRCC Database Consortium (IMDC) intermediate- and poor-risk mRCC clear cell histological subtype receiving combination immunotherapy (Ipilimumab/Nivolumab) in the first-line setting compared to Sunitinib. This is in addition to other treatment options including: vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) (e.g. Sunitinib, Pazopanib, Tivozanib, Cabozantinib, etc.), combination immunotherapy/TKI (e.g. Avelumab/Axitinib), VEGF/mammalian target of Rapamycin (mTOR) inhibitors (e.g. Lenvatinib/Everolimus) and single-agent immunotherapy (e.g. Nivolumab) in both first- and second-line settings. Methods: An audit of SACT prescribing practices in mRCC between 2019-2022 in a single UK tertiary cancer centre (Castle Hill Hospital, Hull, UK) was conducted as part of a national collaboration multi-centre UK audit looking into the real-world landscape and treatment choices in mRCC. Information was derived from the Somerset Cancer Registry and a dataset containing 87 patients with a coded diagnosis of ‘malignant neoplasm of kidney, except renal pelvis (CX64X)’ and ‘secondary malignant neoplasm of kidney &amp; renal pelvis (C790)’ was generated. Results: Of the 81 patients included in the final analysis, 65% (n = 53) were male and 81% (n = 66) had a clear cell histological subtype. The main sites of metastases were lung (n = 58) and lymph nodes (n = 45). Most of the patients (n = 72) received either one or two lines of SACT. Of those with clear cell mRCC, 74% (n = 51/69) were classed as having IMDC intermediate- or poor-risk features with almost half (n = 34/69) receiving combination Ipilimumab/Nivolumab. Comparing overall survival (OS) and progression-free survival (PFS) to the published Kaplan-Meier curves in the CheckMate 214 trial, no significant differences in OS (p = 0.6) and PFS (p = 0.13) were observed, although there was an overall trend towards improved PFS in the first 6 months (82.4% vs 63.3%) in our local dataset. Conclusions: The results of our real-world evaluation of prescribing practices in mRCC favoured the use of combination immunotherapy in the first-line setting for the treatment of IMDC intermediate- and poor-risk clear cell mRCC with similar outcomes to the published data in the CheckMate 214 trial. The overall trend towards improved PFS in the first 6 months in our local dataset highlights the importance of patient selection when using immunotherapy.

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.

Prognostic Factors for Survival in Patients Undergoing Surveillance After Cytoreductive Nephrectomy.

The clinical course of patients being placed on surveillance in a cohort of systemic therapy-naïve patients who undergo cytoreductive nephrectomy is not well documented. Thus, we evaluated the clinical course of patients placed on surveillance following cytoreductive nephrectomy and identified predictors of survival. In this large single-institution study, we retrospectively analyzed metastatic renal cell carcinoma patients who underwent cytoreductive nephrectomy followed by surveillance. Predictors of survival were evaluated using the Kaplan-Meier method with a log-rank test. Patients were risk stratified based on IMDC (International mRCC Database Consortium) and number of metastatic sites (Rini score), with IMDC score ≤1 and ≤2 metastatic organ sites considered favorable risk. Primary end point was systemic therapy-free survival. Secondary end points included intervention-free survival, cancer-specific survival, and overall survival. Median systemic therapy-free survival was 23.6 months (95% CI: 15.1-40.6), intervention-free survival was 11.8 months (95% CI: 8.0-18.4), cancer-specific survival was 54.2 months (95% CI: 46.2-71.4), and overall survival 52.4 months (95% CI: 40.3-66.8). Favorable-risk patients compared to unfavorable-risk patients had longer systemic therapy-free survival (50.6 vs 11.1 months, P < .01), survival (25.2 vs 7.3, P < .01), and cancer-specific survival (71.4 vs 46.2 months, P = .02). Using risk stratification based on IMDC and number of metastatic sites, surveillance in favorable-risk patients can be utilized for a period without the initiation of systemic therapy. This approach can delay patients' exposure to the side effects of systemic therapy.

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.

Optimal sequential therapy using tyrosine kinase inhibitors as the first-line treatment in patients with metastatic renal cell carcinoma: A nationwide multicenter study

ObjectiveThe purpose of the study was to identify the best sequence of therapy beginning with a tyrosine kinase inhibitor (TKI) as the first-line therapy for patients with metastatic renal cell carcinoma (mRCC) in terms of overall survival (OS), progression-free survival (PFS), and rates of discontinuation and adverse effects during the treatment period. MethodsThis is a retrospective, nationwide multi-center study of patients with mRCC after diagnosis at 10 different tertiary medical centers in Korea from January 1992 to December 2017. We focused on patients at either “favorable” or “intermediate” risk according to the International mRCC Database Consortium criteria, and they were followed up (median 335 days). Finally, a total of 1409 patients were selected as the study population. We generated a Cox proportional hazard model adjusted for covariates, and the different therapy schemes were statistically tested in terms of OS as well as PFS. In addition, frequencies of discontinuation and adverse events were compared among the therapy schemes. ResultsOf the primary patterns of treatment sequences (24 sequences), “sunitinib–pazopanib” and “sunitinib–everolimus–immunotherapy” showed the most beneficial results in both OS and PFS with significantly lower hazards than “sunitinib”, which is the most commonly treated agent in Korea. Considering that the “TKI–TKI” structure showed relatively higher discontinuation rates with higher adverse effects, the overall beneficial sequence would be “sunitinib–everolimus–immunotherapy”. ConclusionAmong several sequential therapy starting with TKIs, “sunitinib–everolimus– immunotherapy” was found to be the best scheme for mRCC patients with “favorable” or “intermediate” risks.

Real-world outcomes in patients with metastatic renal cell carcinoma (mRCC) receiving dual immune checkpoint inhibitor (ICI-ICI) regimens or immune checkpoint inhibitor and tyrosine kinase inhibitor (ICI-TKI) combinations as first-line therapy: A British Columbia (BC) population-based analysis.

646 Background: Currently available first-line treatment regimens for mRCC include pembrolizumab-axitinib (ICI-TKI) and ipilimumab-nivolumab (ICI-ICI). Although both regimens are superior to sunitinib, direct comparisons between ICI-ICI and ICI-TKI are lacking and real-world data are sparse. Methods: Through BC Cancer pharmacy data and patient access programs queries, we identified 319 mRCC patients who were treated with first line ICI-TKI or ICI-ICI between May 2019 and March 2022. Patients’ charts were reviewed for baseline characteristics, including International mRCC Database Consortium (IMDC) risk criteria, pharmacy data, pathology and radiology reports, treatment toxicity, rationale for treatment choice when available, progression and survival outcomes. Treatment groups were compared using standard descriptive statistics; survival outcomes were compared using Kaplan Meier and Cox Regression analyses. Results: Among the first 214 patients, 64.9% and 35.1% received first line ICI-ICI and ICI-TKI, respectively. The most commonly cited reason for choosing ICI-ICI was unavailability of a publicly funded alternative at the time of prescription. IMDC risk group distribution was markedly different between regimens; in ICI-TKI patients, favorable, intermediate and poor-risk patients respectively represented 60.3%, 28.8% and 10.9%, versus 10.2%, 56.9% and 32.9% in ICI-ICI patients (p&lt;0.001). Response rates in ICI-TKI compared favorably to ICI-ICI in the overall population with objective response rates (ORR) of 69% vs 50.4% (p=0.012) and primary progression rates of 12.7% vs 33.1% (p=0.001). However, in the intermediate-poor risk patients, survival outcomes were similar between ICI-TKI and ICI-ICI, with median progression-free survival (mPFS) of 7.5 versus 4.5 months respectively (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.41 to 1.09, p=0.107) and median overall survival (mOS) of not reached (NR) vs 22.6 months (HR 0.86, 95% CI 0.44 to 1.69, p=0.665). Of interest, in patients treated with ICI-ICI, more ipilimumab infusions in the induction phase was associated with improved mOS, rising from 3.9 to 13.6, 21.8 and 37.5 months for 1, 2, 3 or 4 infusions respectively (statistically significant by Log Rank [Mantel-Cox], p&lt;0.001). Conclusions: In the real-world mRCC experience from BC, Canada, ICI-TKI was associated with statistically significantly improved ORR over ICI-ICI although the treated population was comparatively enriched for favorable risk patients by IMDC. PFS and OS did not differ between the two regimens in the intermediate-poor risk population. Updated results on all 319 patients will be presented.