International Metastatic Database Consortium Research Articles

1704P Potential surrogate endpoints for overall survival (OS) in immunotherapy (IO)-treated metastatic renal cell carcinoma (mRCC): An International Metastatic Database Consortium (IMDC) study

1704P Potential surrogate endpoints for overall survival (OS) in immunotherapy (IO)-treated metastatic renal cell carcinoma (mRCC): An International Metastatic Database Consortium (IMDC) study

35 Efficacy of treatments post-lenvatinib in patients with advanced renal cell carcinoma (aRCC)

Abstract Background Lenvatinib is a tyrosine kinase inhibitor (TKI) that targets both vascular endothelial growth factor (VEGF) receptor and fibroblast growth factor receptor. It has demonstrated efficacy both in the upfront and refractory disease settings. However, there is a lack of data surrounding the efficacy of TKIs post-lenvatinib exposure. In this study, we investigate the activity of therapies post-lenvatinib in patients with aRCC. Methods We conducted a retrospective analysis utilizing the International Metastatic Database Consortium (IMDC). Patients having received treatment post-lenvatinib exposure were eligible and divided into two cohort: patients post-1st line lenvatinib (2nd line cohort) and patients post-2nd line lenvatinib (3rd line cohort). The primary objective was objective response rate (ORR) and time to treatment failure (TTF). ORR was summarized with 95% two-sided exact binomial confidence interval. TTF was defined as time from treatment initiation to drug cessation for any reason censored at the date of last follow-up. Results Overall, 84 patients received 1st line lenvatinib of whom 43 (51%) remain on therapy, 20 (24%) received 2nd line treatment, and 21 (25%) received no subsequent treatment. The median duration of prior lenvatinib was 9.7 months. All patients received 1st line pembrolizumab + lenvatinib (ORR 50%, median TTF 19.7 months). Reason for lenvatinib discontinuation was progression (50%), progression + toxicity (20%), toxicity (15%), or other (15%). For the 2nd line cohort, median age was 61 years, most patients were male (85%), had prior nephrectomy (75%), clear cell histology (85%), and were IMDC intermediate/poor risk (55%). 2nd line therapy regimens included TKI monotherapy (80%), TKI-IO (5%), and other (15%). The median follow up from 2nd-line treatment initiation was 4.9 months. The ORR to 2nd line treatment was 5% (95% CI 0.2-25) and median TTF was 5.8 months (95% CI 1.9-14.9). Of 2nd line lenvatinib-exposed patients (n=84), 24 (29%) remain on treatment, 34 (40%) received 3rd line treatment, and 26 (31%) did not receive additional therapy. The median duration of prior lenvatinib was 5.9 months. Most patients received 2nd line everolimus + lenvatinib (97%) (ORR 31%, median TTF 9.2 months). Reason for lenvatinib discontinuation was progression (59%), progression + toxicity (9%), toxicity (12%), or other (21%). For the 3rd line cohort, median age was 67 years, most patients were male (68%), had prior nephrectomy (88%), clear cell histology (68%), and were IMDC intermediate/poor risk (77%). 3rd line treatments included TKI alone (50%), IO-TKI (38%), and other (12%). The median follow up from 3rd-line treatment initiation was 14.9 months. The ORR to 3rd line treatment was 12% (95% CI 3.3-27) and median TTF was 2.8 months (95% CI 1.9-7.4). Conclusions In this analysis, we demonstrate modest activity of TKI-based therapy post-lenvatinib exposure. Our study highlights the need for improved treatment options for patients progressing on lenvatinib-based therapies.

Efficacy of post-lenvatinib treatments in patients (pts) with advanced renal cell carcinoma (aRCC).

4538 Background: Lenvatinib is a tyrosine kinase inhibitor (TKI) that targets both vascular endothelial growth factor (VEGF) receptor and fibroblast growth factor receptor. It has demonstrated efficacy both in the upfront and refractory disease settings. However, there is a lack of data surrounding the efficacy of TKIs post-lenvatinib exposure. In this study, we investigate the activity of post-lenvatinib therapies in pts with aRCC. Methods: We conducted a retrospective analysis utilizing the International Metastatic Database Consortium (IMDC). Pts having received treatment post lenvatinib exposure were eligible and divided into two cohort: pts post-1st line lenvatinib (2nd line cohort) and pts post-2nd line lenvatinib (3rd line cohort). The primary objective was objective response rate (ORR) and time to treatment failure (TTF). ORR was summarized with 95% two-sided exact binomial confidence interval. TTF was defined as time from treatment initiation to drug cessation for any reason censored at the date of last follow-up. Results: Overall, 84 pts received 1st line lenvatinib of whom 43 (51%) remain on therapy, 20 (24%) received 2nd line treatment, and 21 (25%) received no subsequent treatment. All pts received 1st line pembrolizumab + lenvatinib (ORR 50%, median TTF 9.7 months). Reason for lenvatinib discontinuation was progression (50%), progression + toxicity (20%), toxicity (15%), or other (15%). For the 2nd line cohort, median age was 61 years, most pts were male (85%), had prior nephrectomy (75%), clear cell histology (85%), and were IMDC intermediate/poor risk (55%). 2nd line therapy regimens included TKI monotherapy (80%), TKI-IO (5%), and other (15%). The ORR to 2nd line treatment was 5% (95% CI 0.2-25) and median TTF was 5.8 months (95% CI 1.9-14.9). Of 2nd line lenvatinib-exposed pts (n=84), 24 (29%) remain on treatment, 34 (40%) received 3rd line treatment, and 26 (31%) did not receive additional therapy. Most pts received 2nd line everolimus + lenvatinib (97%) (ORR 39%, median TTF 5.9 months). Reason for lenvatinib discontinuation was progression (59%), progression + toxicity (9%), toxicity (12%), or other (21%). For the 3rd line cohort, median age was 67 years, most pts were male (68%), had prior nephrectomy (88%), clear cell histology (68%), and were IMDC intermediate/poor risk (77%). 3rd line treatments included TKI alone (50%), IO-TKI (38%), and other (12%). The ORR to 3rd line treatment was 12% (95% CI 3.3-27) and median TTF was 2.8 months (95% CI 1.9-7.4). Conclusions: In this analysis, we demonstrate modest activity of TKI-based therapy post-lenvatinib exposure. Our study highlights the need for improved treatment options for pts progressing on lenvatinib-based therapies.

Abstract 928: Real-world comparison of first-line treatments for metastatic clear cell renal cell carcinoma (mccRCC)

Abstract Multiple regimens are available for management of mccRCC including either immuno-oncology doublet (IO/IO) or combinations of IO and tyrosine kinase inhibitors (TKI). Clinical trials have compared these regimens to sunitinib, with no direct comparison between them. As such, there is ambiguity among physicians about preferred first-line for mccRCC. We performed a single-institution retrospective study of adults treated in first-line for mccRCC between 1/1/2017 and 1/1/2023. Regimens included IO/IO (ipilimumab/nivolumab [I/N]) or IO/TKI (pembrolizumab/axitinib [P/A], nivolumab/cabozantinib [N/C], or pembrolizumab/lenvatinib [P/L]). We compared efficacy and toxicity endpoints, using Kruskal-Wallis test for medians and Chi-square for categorical variables. 42 patients with median age of 61 (range: 36-95) were included. Patient distribution in IO/IO vs IO/TKI group was 20.0% vs 30.8% in International Metastatic Database Consortium (IMDC) favorable risk, 46.7% vs 38.5% in intermediate-risk, and 33.3% vs 30.8% in poor-risk group. 78.6% vs 66.6% of patients had WHO grade 3/4 ccRCC, 18.8% vs 15.4% had sarcomatoid features in the IO/IO vs IO/TKI, respectively. 38% (16/42) received I/N, 7% (3/42) N/C, 52% (22/42) P/A, and 2% (1/42) P/L. Median follow-up was 109 weeks. Table-1 compares the efficacy of IO/IO vs IO/TKI. IO-related toxicity, TKI-related toxicity, treatment interruptions, dose reductions, and need for steroids were not significantly different between IO/IO and IO/TKI (p= 0.240, p=0.372, p=0.923, p=1.00, and p=0.248, respectively). Genomic characteristics will be reported in poster. Despite small sample size, our real-world data showed that patients treated with IO/IO had significantly worse outcomes compared to those treated with IO/TKI. While this difference may stem from a more aggressive disease in IO/IO group but further insights needs to be obtained through future prospective studies comparing IO/IO and IO/TKI regimens. Variable IO/IO IO/TKI p-value Median treatment duration (weeks) 8.3 59.4 <0.001 Disease control rate (complete response + partial response + stable disease) (%) 50.0 91.7 0.024 Time from 1st line to 2nd line therapy (weeks) 14.6 57.1 0.001 Median overall survival (weeks) 63.6 Not reached 0.001 Citation Format: Omid Yazdanpanah, Sami Dwabe, Garrett Harada, Steven Seyedin, Nataliya Mar. Real-world comparison of first-line treatments for metastatic clear cell renal cell carcinoma (mccRCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 928.

Efficacy of subsequent immunotherapy-tyrosine kinase inhibitor combinations after TKI monotherapy failure in patients with intermediate/poor risk metastatic clear cell renal cell carcinoma: A real-world retrospective study.

e16537 Background: The randomized phase 3 trials KEYNOTE-426, CheckMate 9ER, and CLEAR have demonstrated the efficiency of immunotherapy-based drug combinations as first-line treatment for metastatic clear cell renal cell carcinoma (mccRCC). Immunotherapy-tyrosine kinase inhibitor (IO-TKI) has shown significant benefits over sunitinib monotherapy with respect to overall survival in mccRCC patients with intermediate/poor international metastatic database consortium (IMDC risk group). However, most of the patients received second-line TKI or immune checkpoint inhibitors therapy after TKI monotherapy failure in those clinical trials. The role of IO-TKI after disease progression in sunitinib monotherapy cohort was not fully investigated. We sought to evaluate the efficacy of second-line IO-TKI for mccRCC patients with IMDC intermediate/poor risk who had previously received at least one line of TKI monotherapy. Methods: We conducted retrospective analysis of IMDC intermediate/poor risk mccRCC patients treated with IO-TKI during any treatment line at our center from June 2019 to April 2022. Demographic, clinicopathological, and systemic therapy data were collected. The primary end point was overall survival (OS), defined as the time from initiation of treatment to death from any cause or last follow-up. The secondary end point was progression-free survival (PFS), defined as the time to the first documented disease progression. Results: Overall, 81 IMDC intermediate/poor risk mccRCC patients were enrolled, with a median follow-up of 17 months. 49 patients received first-line IO-TKI therapy, 32 patients who had previously received at least one line of TKI monotherapy received second-line IO-TKI after disease progression. The objective response rate (ORR) and median PFS of second-line IO-TKI after TKI monotherapy failure was 28.6% and 9 months, respectively. OS between first-line IO-TKI therapy and second-line IO-TKI after TKI monotherapy failure was not statistic significant (30 months vs. 26 months, p = 0.630). Conclusions: In this real-world retrospective study, we observed antitumor activity of second-line IO-TKI for mccRCC patients with IMDC intermediate/poor risk after disease progression. Notably, first-line IO-TKI therapy did not have superior OS when TKI monotherapy patients received second-line IO-TKI therapy. Randomized trials are needed to evaluate optimal combination strategies and sequencing of therapies in mccRCC.

Immune checkpoint inhibitors combined with tyrosine kinase inhibitors or immunotherapy for treatment-naïve metastatic clear-cell renal cell carcinoma-A network meta-analysis. Focus on cabozantinib combined with nivolumab.

Introduction: The combination of immunotherapy and targeted therapy is currently marking a new era in the treatment of renal cancer. The latest clinical guidelines recommend the use of drug combinations for the first-line treatment of advanced renal cancer. The aim of this review is to compare the efficacy of combined cabozantinib + nivolumab therapy with other immune checkpoint inhibitors combined with tyrosine kinase inhibitors or monoclonal antibodies blocking the CTLA-4 (cytotoxic T cell antigen 4) in the first-line treatment of metastatic clear-cell renal cell carcinoma (RCC). Methodology: A systematic literature search was carried out in the PubMed and EMBASE databases. Randomized controlled trials (RCTs) on therapies recommended by the latest EAU and ESMO guidelines for treatment-naïve metastatic RCC (i.e., lenvatinib + pembrolizumab, axitinib + pembrolizumab and nivolumab + ipilimumab) were searched. A network meta-analysis (NMA) was performed for data synthesis. The methodology of included RCTs was assessed using the Cochrane RoB two tool. The data were analyzed in the overall population as well as in risk subgroups defined according to the International Metastatic Database Consortium (IMDC) i.e., patients with a favorable and intermediate or poor prognoses. The most recent cut-off dates from included studies were analyzed. Results: Four RCTs (CheckMate 9 ER, KEYNOTE-426, CLEAR and CheckMate 214) were included in the review. No studies directly comparing cabozantinib + nivolumab with any of the drug combinations included in this review were available. NMA showed that cabozantinib + nivolumab was superior compared to axitinib + pembrolizumab and nivolumab + ipilimumab in all analyzed comparisons (overall population and IMDC risk subgroups), both in terms of overall survival and progression-free survival (PFS). The advantage of cabozantinib + nivolumab was statistically significant only for PFS when compared to nivolumab + ipilimumab in the overall population. The results for the comparison of cabozantinib + nivolumab with lenvatinib + pembrolizumab showed numerical superiority of lenvatinib + pembrolizumab combination in terms of overall survival, but none of the results were statistically significant. The advantage of lenvatinib + pembrolizumab over cabozantinib + nivolumab in terms of PFS was statistically significant in the overall and favorable prognosis population. Conclusion: Inclusion of the most recent cut-off data from CheckMate 9 ER did not affect the role of the cabozantinib + nivolumab combination for treatment-naïve metastatic RCC. Cabozantinib + nivolumab is an effective therapeutic option for the first-line treatment of advanced renal cancer that is recommended both in the latest European and American guidelines for all IMDC risk groups.

Tumor diameter response in patients with metastatic clear cell renal cell carcinoma is associated with overall survival.

Tumor shrinkage of at least 10% after presurgical targeted molecular therapy (TMT) in renal cell carcinoma (RCC) patients has been associated with better overall survival (OS) outcomes. We characterized primary and metastatic tumor diameter response and OS in patients with metastatic clear cell RCC (ccRCC) who received preoperative TMT, immunotherapy, or both followed by deferred cytoreductive nephrectomy (dCN). Patients with metastatic ccRCC (n = 198) who underwent preoperative therapy and dCN from 2005 to 2019 were identified retrospectively. Longest primary and metastatic tumor diameters were calculated using cross-sectional images obtained before systemic therapy and dCN using the Response Evaluation Criteria in Solid Tumors. Patients were stratified by tumor shrinkage of at least 10% in the primary and/or metastatic tumors after systemic therapy. The Kaplan-Meier method was used to estimate OS, and Cox proportional hazards models were used to assess the association of patient characteristics with OS. In total, 31.31% of patients had only metastatic tumor shrinkage (MTS) ≥ 10%, 8.08% had only primary tumor shrinkage (PTS) ≥ 10%, 32.32% had PTS and MTS ≥ 10%, and 28.28% had PTS/MTS < 10%. The median OS, number of patients with tumor shrinkage ≥ 10%, and International Metastatic Database Consortium (IMDC) scores were similar among the 3 systemic therapy groups (all P ≥ 0.80). Patients with MTS ≥ 10%, PTS ≥ 10%, and PTS/MTS ≥ 10% had significantly longer median OS compared to patients with PTS/MTS < 10% (P < 0.01). Patients with intermediate-risk IMDC scores had significantly longer median OS compared to patients in the poor-risk group. After adjusting for preoperative therapy and IMDC risk group, MTS ≥ 10%, PTS ≥ 10%, and PTS/MTS ≥ 10% were associated with better OS outcomes (HR 0.48 95% CI 0.32-0.73, P < 0.001; HR 0.48, 95% CI 0.23-0.98, P = 0.04; HR 0.44, 95% CI 0.29-0.67, P < 0.001, respectively). Intermediate risk score and shrinkage of at least 10% in the primary tumor, metastases, or both were associated with better OS outcomes in patients with metastatic ccRCC who underwent dCN independent of the type of preoperative systemic therapy.

First-Line Treatment of Metastatic Clear Cell Renal Cell Carcinoma: What Are the Most Appropriate Combination Therapies?

Simple SummaryFirst-line treatment options for metastatic clear cell renal cell carcinoma have significantly increased. The current recommended therapeutic strategy is based on a combination, but monotherapy remains an alternative. However, the choice of the type of combination, i.e., dual immunotherapy or immunotherapy combined with an antiangiogenic drug, has not been clearly standardized. A strategy based on the International Metastatic Database Consortium (IMDC) classification is currently recommended with pembrolizumab + axitinib, cabozantinib + nivolumab, and lenvatinib + pembrolizumab (for all patients) or nivolumab + ipilimumab (for patients with intermediate or poor risk), which are the first-line treatment standards of care. This review summarizes all recent data from the main combinations evaluated in first-line treatment and discusses the choice of drugs according to the patient’s profile and the benefit/risk balances of each combination.The development of antiangiogenic treatments, followed by immune checkpoint inhibitors (ICI), has significantly changed the management of metastatic clear cell renal cell cancer. Several phase III trials show the superiority of combination therapy, dual immunotherapy (ICI-ICI) or ICI plus tyrosine kinase inhibitors (TKI) of the vascular endothelium growth factor (VEGF) over sunitinib monotherapy. The question is therefore what is the best combination for a given patient? A strategy based on the International Metastatic Database Consortium (IMDC) classification is currently recommended with pembrolizumab + axitinib, cabozantinib + nivolumab, and lenvatinib + pembrolizumab (for all patients) or nivolumab + ipilimumab (for patients with intermediate or poor risk), which are the first-line treatment standards of care. However, several issues remain unresolved and require further investigation, such as the PD-L1 status, the relevance of possible options based on the patient’s profile, and consideration of second-line and subsequent treatments.

Prognostic biomarkers of systemic inflammation in patients on active surveillance for metastatic renal cell carcinoma (mRCC): A biobank analysis.

348 Background: A subset of patients with metastatic renal cell carcinoma (mRCC) follow an indolent disease course. Given the toxicity and non-curative nature associated with systemic anti-cancer therapy (SACT), some patients may benefit from initial active surveillance (AS). However, selecting patients suitable for this approach is challenging. Biomarkers of systemic inflammation predict survival in mRCC, both independently and as part of the International Metastatic Database Consortium (IMDC) risk score. We sought to use these biomarkers to characterise the time to initiation of SACT (tSACT) in mRCC patients on AS. Methods: 126 mRCC patients clinically assessed and commenced on AS prior to any systemic therapy were retrospectively identified from a regional mRCC clinical database. Patients who underwent metastasectomy for oligometastatic disease at any time were excluded. The primary endpoint, tSACT, was defined as the time from radiological diagnosis of mRCC until SACT initiation, or death, or censorship if continuing AS at follow-up date. Inflammatory biomarkers from routine blood tests (haemoglobin, white cell count, neutrophil count, platelets, C-reactive protein (CRP), albumin) and the IMDC score, measured at the time of diagnosis of mRCC, were recorded. The relationship between these and tSACT was examined using Kaplan-Meier and Cox-regression methods. Results: 66 (52%) patients had commenced SACT. 17 (13.5%) had died without commencing SACT (median survival of the 17 was 40.4 months, range 9.1-130.2 months, and comorbidities may have affected fitness for starting therapy or led to all-cause mortality). 43 patients remained on AS, with minimum and median follow-up of 12.6 months and 39.6 months respectively. The median tSACT was 17.2 months (IQR 8.8-34.8 months). On univariate analysis, CRP and albumin were predictive of time on AS ( p= 0.01 and p= 0.049 respectively). On multivariate analysis, only CRP was independently associated with tSACT ( p= 0.035), stratifying tSACT from 9.1 months (CRP &gt; 10) to 20.9 months (CRP≤10) ( p= 0.009). 111 (88.1%) patients were IMDC 0-1, while 12 (9.5%) and 3 (2.4%) were IMDC 2 or 3 and may have had comorbidities that influenced the initial AS decision. In our cohort the IMDC risk score did not predict time on AS. Conclusions: These results highlight that some patients with mRCC may undergo active surveillance for a marked time period before SACT initiation. We identify routine biomarkers of the systemic inflammatory response that predict time to systemic therapy. In particular CRP, a simple measure of inflammation, stratifies the time to initiation of SACT across a clinically significant time period. This simple, widely available test may help to objectively inform clinical decisions about AS in patients in mRCC. Additional experience is necessary to further define the risks and benefits of this approach.

Prognostic Value of Plasma hPG80 (Circulating Progastrin) in Metastatic Renal Cell Carcinoma.

Simple SummaryMetastatic renal cell carcinoma (mRCC) accounts for one-third of all newly diagnosed renal cell cancers. A better understanding of the biology and molecular basis of disease progression has resulted in several drug targets being identified and led to approval of several new drugs for treating mRCC in the past decade. A growing need has emerged for identifying novel molecular tumor biology based and stage-specific prognostic and predictive biomarkers in mRCC reflective of biology beyond the currently available prognostic models which are solely based on clinical characteristics. We investigated hPG80 (circulating progastrin), which is associated with kidney cancer biology and found that hPG80 levels is both an independent prognostic marker in mRCC and also improves current clinical prognostic models. This will help stratify mRCC patients more accurately in future and improve the management of mRCC patients.Precise management of kidney cancer requires the identification of prognostic factors. hPG80 (circulating progastrin) is a tumor promoting peptide present in the blood of patients with various cancers, including renal cell carcinoma (RCC). In this study, we evaluated the prognostic value of plasma hPG80 in 143 prospectively collected patients with metastatic RCC (mRCC). The prognostic impact of hPG80 levels on overall survival (OS) in mRCC patients after controlling for hPG80 levels in non-cancer age matched controls was determined and compared to the International Metastatic Database Consortium (IMDC) risk model (good, intermediate, poor). ROC curves were used to evaluate the diagnostic accuracy of hPG80 using the area under the curve (AUC). Our results showed that plasma hPG80 was detected in 94% of mRCC patients. hPG80 levels displayed high predictive accuracy with an AUC of 0.93 and 0.84 when compared to 18–25 year old controls and 50–80 year old controls, respectively. mRCC patients with high hPG80 levels (>4.5 pM) had significantly lower OS compared to patients with low hPG80 levels (<4.5 pM) (12 versus 31.2 months, respectively; p = 0.0031). Adding hPG80 levels (score of 1 for patients having hPG80 levels > 4.5 pM) to the six variables of the IMDC risk model showed a greater and significant difference in OS between the newly defined good-, intermediate- and poor-risk groups (p = 0.0003 compared to p = 0.0076). Finally, when patients with IMDC intermediate-risk group were further divided into two groups based on hPG80 levels within these subgroups, increased OS were observed in patients with low hPG80 levels (<4.5 pM). In conclusion, our data suggest that hPG80 could be used for prognosticating survival in mRCC alone or integrated to the IMDC score (by adding a variable to the IMDC score or by substratifying the IMDC risk groups), be a prognostic biomarker in mRCC patients.

Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Nivolumab plus Cabozantinib Joins Immune Checkpoint Inhibition Combination Therapies for Treatment-naïve Metastatic Clear-Cell Renal Cell Carcinoma

Longer follow-up and new trial data from phase 3 randomised controlled trials investigating immune checkpoint blockade (PD-1 or its ligand PD-L1) in advanced clear-cell renal cell carcinoma (RCC) have recently become available. The CheckMate 9ER trial demonstrated an improved progression-free survival (PFS) and overall survival (OS) benefit for the combination of cabozantinib plus nivolumab. A Keynote-426 update demonstrated an ongoing OS benefit for pembrolizumab plus axitinib in the intention-to-treat population, with a PFS benefit seen across all International Metastatic Database Consortium (IMDC) subgroups, while an update of CheckMate 214 confirmed the long-term benefit of ipilimumab plus nivolumab in IMDC intermediate and poor risk patients. The RCC Guidelines Panel continues to recommend these tyrosine kinase inhibitors + immunotherapy (IO) combination across IMDC risk groups in advanced first-line RCC and dual immunotherapy of ipilimumab and nivolumab in IMDC intermediate and poor risk. Patient summaryNew data from trials of immune checkpoint inhibitors for advanced kidney cancer confirm a survival benefit with the combination of cabozantinib plus nivolumab and pembrolizumab plus axitinib and ipilimumab plus nivolumab. These combination therapies are recommended as first-line treatment for advanced kidney cancer.

Prediction of watchful waiting in newly diagnosed metastatic clear cell renal cell carcinoma patients with a good or intermediate prognosis.

5079 Background: In metastatic clear cell renal cell carcinoma (mccRCC), the number of International Metastatic Database Consortium (IMDC) risk factors plus metastatic sites may identify patients with rapid or slow disease progression in a period of watchful waiting (WW) (median WW of 8.4 vs 22.2 months; Rini et al. Lancet Oncol. 2016). We aimed to validate this and prospectively assess the added value of baseline PET with [18F]FDG and [89Zr]Zr-DFO-girentuximab to predict the WW-period in the multicenter IMaging PAtients for Cancer drug selecTion (IMPACT)-RCC cohort study. (NCT02228954). Methods: Between February 2015 and March 2018, 40 treatment-naïve mccRCC patients with a good (n=13) or intermediate prognosis (n=25) according to IMDC, were enrolled. Following baseline CT, [18F]FDG and [89Zr]Zr-DFO-girentuximab-PET, CT scans (RECIST1.1) were acquired at 2, 4, 6, 9, 12 months and thereafter every 4 months. Primary endpoint was time to radiological and/or clinical disease progression, requiring systemic treatment. Patients were assigned to a favorable (&lt;2 IMDC risk factors and &lt;3 metastatic sites) or unfavorable for WW-group (all others; Rini et al). Maximum standardized uptake values (SUVmax) were measured in PET-positive lesions measuring ≥10mm, or 15mm in lymph nodes. High and low-uptake groups were defined based on median geometric mean (gm) SUVmax across patients. A one-sided test was used to validate observations by Rini et al; other tests were two-sided. Results: The median WW-period was 9.3 months in the unfavorable WW-group (n=19) vs 20.4 months in the favorable WW-group (n=21) (HR 1.89 95%CI 0.94-3.89; p=0.037), confirming observations of Rini et al. Patients with high [18F]FDG uptake had a median WW-period of 8.5 months compared to 25.2 months in the low-uptake group (HR 4.08 95%CI 1.89-9.28; p=0.0002). Patients with high [89Zr]Zr-DFO-girentuximab uptake had a median WW-period of 10.7 versus 16.4 months in the low-uptake group (HR 1.37; 95%CI 0.69-2.76; p=0.37). [18F]FDG uptake groups improved a Cox-model for WW based on the prognostic groups of Rini et al (p=0.0015); [89Zr]Zr-DFO-girentuximab did not (p=0.98). Conclusions: The IMPACT-RCC study validated the observations by Rini et al. and shows that adding baseline [18F]FDG PET further improves the prediction of the duration of the WW-period in mccRCC patients. Clinical trial information: NCT02228954 .

Axitinib plus pembrolizumab in patients with advanced renal cell carcinoma: Long-term efficacy and safety from a phase Ib study.

5080 Background: Axitinib (AXI) plus pembrolizumab (pembro) showed superior overall survival (OS), progression-free survival (PFS) and response rate compared with sunitinib in a randomized Phase 3 trial in advanced renal cell carcinoma (RCC). Here, we report long-term efficacy and safety data of the combination AXI/pembro from the Phase 1 trial, with almost 5 years of follow-up. Methods: 52 treatment-naïve patients with advanced RCC were enrolled between 23 September 2014 and 13 October 2015, and were treated with oral AXI 5 mg twice daily and intravenous pembro 2 mg/kg every 3 weeks. Planned treatment duration was 2 years for pembro and not limited for AXI. Based on International Metastatic Database Consortium (IMDC) criteria, 46.2%, 44.2% and 5.8% of patients were reported as having favourable, intermediate and poor risk. Results: At data cut-off date (July 3, 2019), median OS was not reached; 38 (73.1%) patients were alive. 14 (26.9%) patients had died, none were related to treatment. The probability of being alive was 96.1% (95% CI 85.2–99.0) at 1 year, 88.2% (95% CI 75.7– 94.5) at 2 years, 82.2 % (95% CI 68.5– 90.3) at 3 years, and 66.8 % (95% CI 49.1–79.5) at 4 years. Median PFS was 23.5 (95% CI 15.4–30.4) months. Median duration of response was 22.1 (95% CI 15.1–not evaluable) months. Median time on treatment with the combination AXI/pembro was 14.5 months (n=52), median time on pembro after AXI discontinuation was 9.0 months (n=10), and median time on AXI after pembro discontinuation was 7.5 months (n=11). After stopping study treatment, 22 patients received subsequent systemic therapy, including nivolumab and cabozantinib (n=6 each). Grade 3/4 AEs were reported in 38 (73.1%) patients. 20 (38.5%) patients discontinued either drug due to AEs: 17 (32.7%) patients discontinued AXI, and 13 (25.0%) patients discontinued pembro with 10 (19.2%) discontinuing both drugs. Dose reduction of AXI due to AEs was reported in 16 (30.8%) patients. The most common AEs reported were diarrhea (84.6%), fatigue (80.8%), hypertension (53.8%), cough (48.1%), and dysphonia (48.1%). Increased alanine aminotransferase and aspartate aminotransferase occurred in 44.2% and 36.5% of patients, respectively. With this longer follow-up, there were no cumulative AEs or new AEs. OS by IMDC risk group will be presented. Conclusions: In patients with advanced RCC with almost 5 years of follow-up, the combination of AXI/pembro continues to demonstrate clinical benefit with no new safety signals. Clinical trial information: NCT02133742 .

Identification and validation of dichotomous immune subtypes based on intratumoral immune cells infiltration in clear cell renal cell carcinoma patients

BackgroundIncreasing evidence has elucidated the clinical significance of tumor infiltrating immune cells in predicting outcomes and therapeutic efficacy. In this study, we comprehensively analyze the tumor microenvironment (TME) immune cell...

Clinical Activity of Ipilimumab Plus Nivolumab in Patients With Metastatic Non-Clear Cell Renal Cell Carcinoma.

Ipilimumab plus nivolumab has been approved for intermediate- and poor-risk metastatic renal cell carcinoma (RCC). However, the activity in non-clear cell RCC (nccRCC) is unknown. Patients from Cleveland Clinic and the University of Texas Southwestern who had received ipilimumab plus nivolumab for metastatic nccRCC from October 2017 to May 2019 were retrospectively identified. Ipilimumab plus nivolumab was administered in accordance with the CHECKMATE 214 trial. Imaging was obtained at baseline and every 12 weeks. The baseline patient characteristics, objective response per Response Evaluation Criteria in Solid Tumors, version 1.1, and treatment-related adverse events (TRAEs) per Common Terminology Criteria for Adverse Events, version 5.0, were analyzed. Eighteen patients were identified. The median age was 59 years (range, 32-81 years), 77.8% were men, and the Eastern Cooperative Oncology Group performance status was 0 (38%) or 1 (50%). The median treatment duration was 2.4 months (range, 0.7-12.3 months). The non-clear cell histologic types included 6 papillary, 5 chromophobe, 3 unclassified, 2 adenocarcinoma of renal origin, 1 translocation, and 1 medullary. Most had an intermediate (66%) or poor (22%) International Metastatic Database Consortium risk. The best objective response included 6 partial responses (PRs; 33.3%) and 3 with stable disease (16.7%). Of the patients with a PR, the median time to the best response was 3.0 months, and median duration of the PR was 4.3 months. The median progression-free survival was 7.1 months. All-grade TRAEs were noted in 11 patients (61.1%) and included colitis (22%), hepatotoxicity (16%), rash (11%), and fatigue (11%). Eleven patients (61%) had TRAEs requiring high-dose glucocorticoids (> 40 mg of prednisone equivalent daily). Ipilimumab plus nivolumab demonstrated objective responses and notable toxicity in patients with nccRCC.

The Association Between Small Primary Tumor Size and Prognosis in Metastatic Renal Cell Carcinoma: Insights from Two Independent Cohorts of Patients Who Underwent Cytoreductive Nephrectomy

BackgroundOne of the main challenges in the management of renal cell carcinoma (RCC) is risk-stratifying patients who present with metastatic disease. Tumor size is an important predictor of survival in the localized setting; however, this feature has not been explored fully in patients presenting with M1 RCC. ObjectiveTo assess the impact of tumor size on survival in patients with metastatic RCC who underwent cytoreductive nephrectomy (CN). Design, setting, and participantsWe queried the Memorial Sloan Kettering (MSK) nephrectomy database for patients who presented with M1 disease and underwent CN between 1989 and 2016 (n=304). Primary tumor size was obtained from pathology reports. Data from the International Metastatic Database Consortium (IMDC) were used for validation purposes (n=778). Outcome measurements and statistical analysisOverall survival (OS) estimates were computed using the Kaplan-Meier method. Cox regressions were used to test the association between tumor size and OS in univariate and multivariable analyses. Tumors ≤4cm were compared with larger masses. Secondary analyses were performed to assess the robustness of these findings. Results and limitationsClear cell tumors ≤4cm were significantly associated with improved OS in both the MSK (hazard ratio [HR]: 0.35, 0.17–0.72, p= 0.004) and IMDC (HR 0.54, 0.36–0.83, p= 0.004) cohorts. The association was observed even after adjusting for known prognostic factors (HR 0.40, 0.14–1.14, p= 0.09 and HR: 0.54, 0.33–0.90, p= 0.02 in the MSK and IMDC cohorts, respectively). Limitations of this study include the absence of patients who were considered poor surgical candidates as well as potential selection bias. ConclusionsThe primary tumor size ≤4cm was independently associated with improved OS in patients with metastatic clear cell RCC who underwent CN. Additionally, the association between primary size and survival was found to be nonlinear. These findings suggest that there is a group of small metastatic RCCs that can convey a better overall prognosis. The potential role of primary tumor size when risk stratifying patients with M1 RCC should be explored further to determine its utility during clinical decision making. Patient summaryWe evaluated the impact of small tumor size on prognosis in patients with metastatic kidney cancer who undergo removal of the primary tumor. Very small masses (≤4cm) were associated with better prognosis in patients with clear cell tumors.

Lesion detection by [89Zr]Zr-DFO-girentuximab and [18F]FDG-PET/CT in patients with newly diagnosed metastatic renal cell carcinoma

PurposeThe main objective of this preliminary analysis of the IMaging PAtients for Cancer drug selecTion (IMPACT)-renal cell cancer (RCC) study is to evaluate the lesion detection of baseline contrast-enhanced CT, [89Zr]Zr-DFO-girentuximab-PET/CT and [18F]FDG-PET/CT in detecting ccRCC lesions in patients with a good or intermediate prognosis metastatic clear cell renal cell carcinoma (mccRCC) according to the International Metastatic Database Consortium (IMDC) risk model.MethodsBetween February 2015 and March 2018, 42 newly diagnosed mccRCC patients with good or intermediate prognosis, eligible for watchful waiting, were included. Patients underwent CT, [89Zr]Zr-DFO-girentuximab-PET/CT and [18F]FDG-PET/CT at baseline. Scans were independently reviewed and lesions of ≥10 mm and lymph nodes of ≥15 mm at CT were analyzed. For lesions with [89Zr]Zr-DFO-girentuximab or [18F]FDG-uptake visually exceeding background uptake, maximum standardized uptake values (SUVmax) were measured.ResultsA total of 449 lesions were detected by ≥1 modality (median per patient: 7; ICR 4.25–12.75) of which 42% were in lung, 22% in lymph nodes and 10% in bone. Combined [89Zr]Zr-DFO-girentuximab-PET/CT and CT detected more lesions than CT alone: 91% (95%CI: 87–94) versus 56% (95%CI: 50–62, p = 0.001), respectively, and more than CT and [18F]FDG-PET/CT combined (84% (95%CI:79–88, p < 0.005). Both PET/CTs detected more bone and soft tissue lesions compared to CT alone.ConclusionsThe addition of [89Zr]Zr-DFO-girentuximab-PET/CT and [18F]FDG-PET/CT to CT increases lesion detection compared to CT alone in newly diagnosed good and intermediate prognosis mccRCC patients eligible for watchful waiting.

Consistent efficacy of nivolumab plus ipilimumab across number of International Metastatic Database Consortium (IMDC) risk factors in CheckMate 214.

4575 Background: The IMDC prognostic model was created based on anti-VEGF treatments for advanced renal cell carcinoma (aRCC), and may not be relevant for immunotherapy. Methods: In a post hoc analysis of CheckMate 214, we compared efficacy with nivolumab + ipilimumab (N+I) vs sunitinib (S) by number of IMDC risk factors present. Results: Among 1096 intent-to-treat (ITT) patients (pts) in both arms, 21%, 61%, and 18% had favorable, intermediate (int), or poor-risk, respectively. Of int-risk pts, 58% had 1 factor (most commonly &lt;1 y from diagnosis [Dx], 52%; Hb &lt; LLN, 27%; or KPS ≤70%, 10%); and 42% had 2 factors (of these pts, the most common combination of 2 factors was &lt;1 y from Dx and Hb &lt; LLN, 59%). Of poor-risk pts, 58% had 3 factors, 29% had 4 factors, and few had 5 (10%) or 6 (3%) factors. Due to small numbers, pts with 4–6 factors were pooled. At 30-mo minimum follow-up, RECIST v1.1-confirmed objective response rate (ORR) and complete response (CR) rate per investigator remained consistently higher with N+I vs S across pts with 1–4 factors, although with S, ORR decreased with increasing number of factors (Table). Improved progression-free survival (PFS) and overall survival (OS) were seen with N+I over S irrespective of the number of factors present, including in pts with only 1 risk factor (Table). Conclusions: N+I showed consistent efficacy across number of IMDC risk factors, while S decreased in efficacy with increasing number of factors. Efficacy of N+I was superior to S in all int- and poor risk pts. These CheckMate 214 results along with prior CheckMate 025 data showing consistent OS benefit with N monotherapy across IMDC risk categories show a need for improved prognostic models for immunotherapies in aRCC. Clinical trial information: NCT02231749. [Table: see text]

Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors

BackgroundImmune checkpoint inhibitors (ICIs) are being increasingly utilised in the front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) vascular endothelial growth factor–receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy after 1L ICI therapy. Patients and methodsThis is a retrospective study of mccRCC patients treated with 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Patients were treated at MD Anderson Cancer Center or Memorial Sloan Kettering Cancer Center between December 2015 and February 2018. Objective response was assessed by blinded radiologists' review using Response Evaluation Criteria in Solid Tumours v1.1. Descriptive statistics and Kaplan–Meier method were used. ResultsSeventy patients were included in the analysis. Median age at mccRCC diagnosis was 59 years; 8 patients (11%) had international metastatic database consortium favourable-risk disease, 48 (69%) had intermediate-risk disease and 14 (20%) had poor-risk disease. As 1L therapy, 12 patients (17%) received anti–programmed death ligand-1 (PD-(L)1) monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab and 25 (36%) received combination anti–PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib and cabozantinib. On 2L TKI therapy, one patient (1.5%) achieved a complete response, 27 patients (39.7%) a partial response and 36 patients (52.9%) stable disease. Median progression-free survival (mPFS) was 13.2 months (95% confidence interval: 10.1, NA). Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity. ConclusionsIn this retrospective study of patients with mccRCC receiving 2L TKI monotherapy after 1L ICI, we observed 2L antitumour activity and tolerance comparable to historical data for 1L TKI.

Rates of occult brain metastases in patients (pts) with advanced renal cell carcinoma (RCC): A cohort study from patients treated across 22 clinical trials.

673 Background: National guidelines for RCC management only recommend brain imaging ‘if clinically indicated’; the rate of occult brain metastases is not defined. Early detection of CNS disease has major implications as it typically triggers early intervention with the aim to limit morbidity, including major complications of local progression. In an effort to define the utility of brain screening, we investigated the rate of occult brain metastasis in a large cohort of metastatic RCC pts. Methods: We performed a retrospective review of completed and actively accruing metastatic RCC clinical trials conducted at Memorial Sloan Kettering Cancer Center. Individual charts of pts screening for those studies with mandatory brain imaging at baseline were reviewed to identify subjects harboring occult brain metastases. We collected patient demographics, International Metastatic Database Consortium (IMDC) risk status, sites of metastatic disease, and tumor histology. Patients with neurologic symptoms were excluded. Descriptive statistics were applied to analyze findings across the cohort. Results: A total of 22 clinical trials for metastatic RCC conducted from 2004-2017 required brain imaging at baseline, and a total of 535 pts were screened in this context. A total of 25/535 pts were found to have occult brain metastasis (4.67%), which was multi-focal in 10/25 (40%) and sub-cm in 15/25 (60%). For these 25 pts, the mean age at diagnosis was 56 years (38-77), and IMDC risk score at enrollment was: 1/24 favorable (4%), 21/24 intermediate (88%), and 2/24 poor-risk (8%) patients. 18/25 patients presented with de novo metastatic disease; 13/25 had received prior therapies; and 24/25 patients (96%) had &gt; 2 additional non-CNS sites of metastatic disease at time of screening. 21/23 pts and 2/23 pts were then treated with radiation and surgical resection, respectively. Conclusions: This retrospective cohort study shows a 5% rate of occult CNS disease in asymptomatic patients with advanced RCC. These findings can inform current screening guidelines for full disease assessment in metastatic RCC patients.