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Purpose: There are case reports of patients with both primary breast cancer (BC) and renal cell carcinoma (RCC). We explore the association between these two malignancies using SEER population data and our institutional records.Methods: We studied the association between BC and RCC in the 2000-2016 Surveillance, Epidemiology and End Results (SEER) database. We then reviewed our hospital records of patients with both BC and RCC and collected information including personal and family history of cancers, genetic testing, and patient outcomes.Results: Of the 813,477 females diagnosed with BC in the SEER database, 1,914 later developed RCC. The risk of developing RCC was significantly increased within the first six months, 7-12 months, and 1-5 years following BC diagnosis with standardized incidence ratios (SIRs) of 5.08 (95% CI, 4.62- 5.57), 2.09 (95% CI, 1.8-2.42), and 1.15 (95% CI, 1.06-1.24), respectively. Of 56,200 females with RCC, 1,087 later developed BC. The risk of developing BC following RCC was elevated within the first six months (SIR of 1.45 [95% CI, 1.20-1.73]). For our hospital patients, 437 had both BC and RCC. 427 (97.71%) were female, and 358 (81.92%) were white, and breast cancer was diagnosed before RCC in 246 (61.5%) patients. There were 15 germline mutations in those with genetic testing. Conclusion:Our findings suggest that BC patients are at higher risk of developing RCC and vice versa. BC tended to precede RCC, and patients frequently had personal histories of other malignancies and a family history of cancer, particularly BC.

Metastatic renal cell carcinoma (mRCC) is associated with a high risk of thromboembolism (TE). We investigated whether immunotherapy (IO) increases the hypercoagulable state in this high-risk population. Patients with mRCC treated with IO between 1 January 2015 and 31 December 2019 at the Cleveland Clinic were identified. Cumulative incidence analysis calculated TE rates over time and Gray’s test determined differences in TE rates among groups. The Kaplan–Meier method estimated survival, while Cox proportional hazard regression evaluated the impact of TE on OS. Of 351 patients, 75% were men with clear cell mRCC (81%) and International Metastatic Renal Cell Carcinoma (IMDC) intermediate- to poor-risk disease (77%). Patients received single-agent IO (52%), doublet IO (31%), or IO with non-IO therapy (17%). The median number of IO doses was 8 (range 1–81). At a median follow-up of 12.8 months, 12% of patients (n = 43) had a TE event (venous n = 37 [11%], arterial n = 6 [2%]). The cumulative TE incidence at 6 months was 4.4% (95% confidence interval [CI] 2.6–6.9) and 9.8% (95% CI 6.8–13.4) at 12 months. No factors, including IMDC or Khorana score, were identified to predict TE development. Seventy-two percent of TE resulted in hospitalization (9% TE-related mortality and 21% TE-related dose delay). TE (p

There have been significant advances in the treatment of metastatic renal cell carcinoma (mRCC), with immunotherapy (IO)-based combinations as the standard-of-care treatment in the front-line setting. IO in this setting is paired with another IO agent or with a vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitor (TKI). One IO/IO combination and four IO/TKI combinations are currently approved. However, the role of the salvage IO in patients with disease progression on TKI monotherapy is uncertain. Here, we present a case series of five patients who were on single-agent TKI therapy for treatment-refractory mRCC and upon disease progression had an IO agent added to their TKI. The median duration of TKI monotherapy was 11.2 months (range, 1.7–31.1 months), and the median duration of response after the addition of IO was 4 months (range, 2.8–10.5 months). Although IO salvage therapy has a plausible rationale, this case series did not show a clear benefit to this approach. Further clinical trials are needed to determine the clinical utility of IO salvage therapy in mRCC.

PD1/L1 inhibitors are approved by FDA as first-line therapy for patients with advanced urothelial carcinoma (aUC) who are cisplatin-ineligible with high tumor PD-L1 expression or are platinum-ineligible regardless of PD-L1 expression. However, the outcomes when employing PD1/L1 inhibitors for platinum-ineligible patients are unclear. This retrospective analysis evaluates the clinical outcomes of first-line PD1/L1 inhibitors in patients with aUC deemed to be platinum-ineligible.Data were retrospectively collected from 8 academic institutions. The following criteria were used to define platinum ineligibility: creatinine clearance (CrCl)30 mL/min; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 3; CrCl 30 to 59 mL/min and ECOG PS 2; elderly and/or comorbidities. Patient characteristics, responses and treatment-related toxicities were identified. Survival curves were estimated by the Kaplan-Meier method. A Cox regression analysis was conducted to explore the association of baseline variables with response and survival.A total of 79 platinum-ineligible patients with aUC were eligible. Patients were treated with atezolizumab (51.9%), pembrolizumab (35.5%), nivolumab (8.9%), or durvalumab (3.8%). The objective response rate was 27.9%. The median overall survival was 45 weeks (95% confidence interval [CI], 32-80), and the median treatment failure-free survival was 16 weeks (95% CI, 9-18). Treatment-related toxicity of any grade and grade ≥ 3 was seen in 41.8% and 31.7% of patients, respectively. Anemia and liver metastasis were associated with worse survival.The efficacy of first-line PD1/L1 inhibitors for platinum-ineligible patients with aUC in the real world appears comparable to those reported in trials of unselected cisplatin-ineligible patients, whereas grade ≥ 3 toxicities appear more common. Further validation is required including data based on PD-L1 status and other biomarkers. Platinum-ineligible patients with aUC warrant evaluation of novel, safe, and effective agents.

BACKGROUND: Bone metastases (BM) in renal cell carcinoma (RCC) patients are associated with poor outcomes. There are limited published data on outcomes in these patients with immunotherapy agents. We present a multi-institutional, retrospective analysis of metastatic RCC patients with BM treated with ipilimumab and nivolumab (I + N). OBJECTIVE: Patient, tumor, and treatment-related variables were retrospectively collected from electronic medical records of patients with a histologically confirmed diagnosis of RCC and at least one radiographically confirmed BM prior to initiation of I + N. Best objective response was assessed by clinical chart review, imaging reports, and treating physician evaluation; progression-free survival (PFS) and overall survival (OS) were recorded as of 31 December 2020. Descriptive statistics were used to summarize patient characteristics and BM-related variables. Kaplan-Meier method and Mantel-Haenszel log-rank test were used to compare survival among groups. Cox regression univariable and multivariable models were used to correlate patient- and treatment-related variables to outcomes. RESULTS: Eighty patients with RCC and BM treated with I + N were identified. Patients were predominantly male and Caucasian presenting primarily with IMDC intermediate or poor-risk clear-cell RCC. Best response to I + N was progressive disease (46%), stable disease (28%), partial response (21%), and not evaluable (5%). Median PFS was 6.1 months (95% CI 3.8–8.9 months) with the majority of patients (65%) discontinuing I + N due to disease progression. Median OS was 25.6 months (95% CI 14.9–NA) with median follow-up of 25.2 months. A multivariable regression model for PFS showed several variables to be significantly associated with worse PFS including female gender [p = 0.02; hazard ratio (HR) 2.16; 95% CI 1.14–4.12], metastases to other sites (p = 0.006; HR 2.12; 95% CI 1.24–3.62) and presence of BM to ribs (p = 0.0007; HR 2.61; 95% CI 1.50–4.52). A multivariable Cox model of OS showed no prior radiation therapy to BM (p = 0.02; HR 2.17; 95% CI 1.13–4.17) and presence of liver metastases (p = 0.0006; HR 3.19; 95% CI 1.65–6.19) to be significantly associated with worse OS. CONCLUSION: RCC patients with ≥ 1 BM who received I + N therapy had a relatively low response rate, PFS, and OS. Strategies to improve outcomes in this subset of patients are needed.

Prostate-specific antigen screening is controversial. In 2008, the United States Preventive Services Task Force recommended against screening men aged ≥ 75 years, and in 2012, expanded this to include all men. The impact of these changes continues to unfold. We hypothesized that these screening changes could delay the diagnosis of advanced prostate cancer.The Surveillance, Epidemiology, and End Results database was used to identify men (age, 55-69 years) diagnosed with prostate cancer in 2004 to 2008 (group 1), 2009 to 2012 (group 2), and 2013 to 2015 (group 3). Groups reflect United States Preventive Services Task Force guideline changes. Descriptive statistics were used to present baseline statistics and the number of patients diagnosed in aforementioned groups. Data was adjusted for population growth.A total of 328,586 men were identified (group 1, 135,625; group 2, 117,979; group 3, 74,982). The average number of men diagnosed annually with N1M0 (group 1, 381; group 2, 477; group 3, 660) and M1 (group 1, 523; group 2, 761; group 3, 1037) disease increased. With group 1 as control, there was a decrease in the incidence of localized disease (group 2, 9.2%; group 3, 33.2%). However, the incidence of N1M0 (group 2, 5.3%; group 3, 30.1%) and M1 disease (group 2, 22.6%; group 3, 49.2%) increased. Separate analyses of patients (age 50-75 years) and African Americans showed similar trends.With each recommendation, there was increased incidence of de novo metastatic prostate cancer. The sequelae of advanced disease include financial, emotional, and physical burden. Future studies are needed to identify screening strategies that reduce the risk of developing metastatic disease without over-diagnosing indolent cancers.

Cribriform (CF) and/or intraductal carcinoma (IDC) are associated with more aggressive prostate cancer (CaP) and worse outcomes.The transcriptomic features that typify CF/IDC are not well described and the capacity for clinically utilized genomic classifiers to improve risk modeling for CF/IDC remains undefined.We performed a retrospective review of CaP patients who had Decipher testing at a single high-volume institution. Index lesions from radical prostatectomy specimens were identified by genitourinary pathologists who simultaneously reviewed prostatectomy specimens for the presence of CF and IDC features. Patients were grouped based on pathologic features, specifically the absence of CF/IDC (CF-/IDC-), CF positive only (CF+/IDC-), and CF/IDC positive (CF+/IDC+).Clinical, pathologic, and genomic categorical variables were assessed using the Pearson chi-square test, while quantitative variables were assessed with the Kruskal-Wallis test. Multivariable logistic regression was used to identify the predictors of high-risk Decipher scores (0.60). A gene set enrichment analysis was performed to identify genes and gene networks associated with CF/IDC status.A total of 463 patients were included. Patients who were CF+/IDC+ had the highest Decipher risk scores (CF+/IDC+: 0.79 vs CF+/IDC-: 0.71 vs CF-/IDC-: 0.56, p 0.001). On multivariate logistic regression, predictors of high-risk Decipher scores included the presence of CF, both alone (CF+/IDC-; odds ratio [OR]: 5.45, p 0.001) or in combination with positive IDC status (CF+/IDC+; OR: 6.87, p 0.001). On the gene set enrichment analysis, MYC pathway upregulation was significantly enriched in tumor samples from CF/IDC-positive patients (normalized enrichment score [NES]: 1.65, p = 0.046). Other enriched pathways included E2F targets (NES: 1.69, p = 0.031) and oxidative phosphorylation (NES: 1.68, =0 .033).This is the largest series identifying an association between a clinically validated genomic classifier and the presence of CF and IDC at radical prostatectomy. Tumors with CF and intraductal features were associated with aggressive transcriptomic signatures.Genomic-based tests are becoming readily available for the management of prostate cancer. We observed that Decipher, a commonly used genomic test in prostate cancer, correlates with unfavorable features in tissue specimens.

The past 30 years have borne witness to a gradual evolution in the treatment landscape of advanced renal cell carcinoma (aRCC). Early immunotherapy approaches such as interferon-α and high-dose interleukin-2 (IL-2) therapy in this immunogenic tumor provided durable responses in only a minority of patients and came with toxic side effects. A growing understanding of the tumor biology elucidated pathways of tumorigenesis, which in turn revealed novel targets amenable to targeted therapies. Inhibition of angiogenesis and cell signaling emerged as cornerstones of treatment with the approval of bevacizumab and several pan-kinase and tyrosine kinase inhibitors. Though effective, their use has been limited by low rates of durable response, resistance, and side effects. The immunotherapy revolution of the past decade has led to immunotherapy-based combination regimens such as ipilimumab plus nivolumab, pembrolizumab plus axitinib, and avelumab plus axitinib, displacing single agent anti-angiogenic therapy in the first-line setting by demonstrating durable responses and improved survival over sunitinib. These immunotherapy-based combinations define first-line standard of care for aRCC today. The pipeline of second-line agents for consideration in patients who have disease progression despite immunotherapy regimens is robust but still in early stages of development.

PURPOSE Immune checkpoint inhibitors (ICIs) are standard therapy in metastatic renal cell carcinoma (RCC). The safety and activity of the combination of ipilimumab and nivolumab in patients who have received prior ICI targeting the programmed death 1 (PD-1) pathway remains unknown. We evaluated ipilimumab and nivolumab in patients with metastatic RCC after prior treatment with anti–PD-1 pathway–targeted therapy. PATIENTS AND METHODS Patients with metastatic RCC who received prior anti–PD-1 pathway-targeted therapy and subsequently received ipilimumab and nivolumab were reviewed. Objective response rate and progression-free survival per investigator assessment were recorded. Toxicity of ipilimumab and nivolumab was also assessed. RESULTS Forty-five patients with metastatic RCC were included. All patients (100%) received prior ICIs targeting the PD-1 pathway. The median age was 62 years (range, 21-82 years). At a median follow-up of 12 months, the objective response rate to ipilimumab and nivolumab was 20%. The median progression-free survival while on ipilimumab and nivolumab was 4 months (range, 0.8-19 months). Immune-related adverse events (irAEs) of any grade with ipilimumab and nivolumab were recorded in 29 (64%) of the 45 patients; grade 3 irAEs were recorded in 6 (13%) of the 45 patients. CONCLUSION Ipilimumab and nivolumab demonstrated antitumor activity with acceptable toxicity in patients with metastatic RCC who had prior treatment with checkpoint inhibition.

Non-clear cell renal cell carcinoma (nccRCC) accounts for approximately 25% of RCC diagnoses. Although broadly labeled as "nccRCC," they comprised a host of histologies that include papillary, chromophobe, unclassified, and others. Moreover, these histological variants are further subclassified on the basis of genomic profiling, thereby highlighting nccRCC to be anything but a homogenous cohort of RCC. The heterogeneity of nccRCC has proved challenging in developing therapeutics for this population. Although ccRCC therapeutic data have been commonly extrapolated for the treatment of nccRCC, the overall poor outcome of these patients highlights an unmet need. In an era of precision medicine, genomic analysis, and predictive biomarkers, novel approach to drug design and development is necessary to optimize treatment outcomes in nccRCC patients. Herein, we provide an overview of the nccRCC histologies, clinical trial data, and future opportunities for treatment options and development in nccRCC.

Despite treatment with abiraterone acetate and prednisone (AA/P), most patients with metastatic hormone sensitive prostate cancer (mHSPC) will develop castration-resistant disease (metastatic castration-resistant prostate cancer [mCRPC]). The early identification of who will progress on AA/P is limited. This study investigates the role of prostate surface antigen (PSA) kinetics as a predictor of progression in mHSPC patients treated with AA/P. All patients with mHSPC who initiated androgen deprivation therapy (ADT) and AA/P from June 2017 to February 2019 at the Cleveland Clinic were eligible. PSA-mCRPC was defined as a PSA rise at two consecutive time points. Patients were followed until first mCRPC or last contact after AA/P. Patterns of PSA change were evaluated using a longitudinal mixed model at time 0, 3, 6, 9, and 12 months from AA/P initiation. The association between PSA profile at 3 months and PSA-mCRPC was examined using survival analysis. Radiographic progression (Rad-mCRPC) was also analyzed. A total of 130 men with follow-up were included. The median (interquartile range [IQR]) follow-up time was 15.3 (10.5, 22.5) months. Eighty-two percent were Caucasian (median age 68.5 years); participants had a median (IQR) PSA of 16.8 (5.3, 48.0) ng/mL. Half of the patients had de novo disease, and 46.2% had high-risk disease (61% had a Gleason score ≥ 8, 16% had visceral disease, and 54% had three or more bony lesions). The greatest PSA percentage reduction from baseline after AA/P initiation occurred at the first 3 months (median 98.3%). The reduction at 6–12 months from baseline was small (99.7–100%). Patients without PSA-mCRPC had a significantly greater 3-month reduction of PSA values compared to patients who developed PSA-mCRPC (p interaction = 0.0002). 50.8% of patients were able to achieve a non-detectable PSA (median 13.1 months). PSA-mCRPC (n = 20) was observed from 4 to 24 months after AA/P, with the majority of events occurring within the first 12 months. Patients with PSA

Immunotherapy has revolutionized the management of metastatic renal cell carcinoma with four checkpoint inhibitors (nivolumab, ipilimumab, avelumab, and pembrolizumab) approved either as monotherapy or as combination therapy. The use of ipilimumab and nivolumab for treatment-naive, intermediate to poor risk, metastatic renal cell carcinoma was the first checkpoint inhibitor-based combination therapy and remains the only dual checkpoint inhibitor combination approved in mRCC. In this article, we review the trials that led to the approval of ipilimumab and nivolumab in this setting. We also highlight the ongoing trials using this combination, its use in special populations, and clinically relevant unanswered questions.

Immune checkpoint inhibitors have improved clinical outcomes in many malignancies, including renal cell carcinoma (RCC). Awareness of potential adverse events and effective management of these toxicities is critical to maximizing clinical outcomes. Pembrolizumab plus axitinib is approved as front-line treatment of advanced renal cell carcinoma (aRCC), making it the first checkpoint inhibitor and tyrosine kinase inhibitor combination approved for any malignancy. Given overlapping toxicities with this combination, the toxicity profile of each drug must be considered when assessing and managing toxicities in patients treated with pembrolizumab and axitinib. Use of online resources, including published guidelines from ASCO, the Immuno-Oncology Essentials Web site, and other organizations, can assist oncology and nononcology health care professionals to more effectively manage toxicities, maximize clinical outcomes, and improve quality of life for patients with aRCC. Herein, we describe a case of a patient with aRCC treated with pembrolizumab and axitinib, highlighting a systematic approach to toxicity management.

666 Background: Activation of the GAS6/AXL pathway promotes tumor cell proliferation; high levels of GAS6 and AXL have been associated with drug resistance and decreased survival. Batiraxcept is an ultra-high affinity decoy protein that captures GAS6, preventing it from activating AXL signaling. Serum soluble AXL (sAXL)/GAS6 ratio correlates with response to batiraxcept in advanced ovarian cancer. Batiraxcept in combination with cabozantinib is being evaluated in patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC) in this study. Prior studies of cabozantinib in similar pt populations have shown an overall response rate (ORR) ranging from 15 – 32.5% and progression-free survival (PFS) from 3.7-7.2 months (mo). Methods: Key eligibility criteria include previously treated ccRCC pts, excluding prior cabozantinib. Objectives were to determine the safety of batiraxcept plus cabozantinib 60 mg, the recommended phase 2 dose (RP2D), ORR, PFS, duration of response. Correlative endpoints included assessment of baseline serum sAXL/GAS6 with ORR and PFS. Results: In Phase 1b (P1b), 26 pts received at least one dose of batiraxcept with cabozantinib (16 pts - 15 mg/kg; 10 pts - 20 mg/kg). Median age was 60 (range 40-81), male 85% (n=22), IMDC intermediate/poor risk 77% (n=20). All pts received prior immuno-oncology (IO) therapy, 54% (n=14) also received VEGF-TKI; 85% (n=22) received 1 to 2 prior lines of therapy (range 1-6). Median follow-up time was 11.6 mo (range 3.7-18). The RP2D is 15 mg/kg. Related adverse events (AE) any grade and grade ≥ 3 were 100% and 39% (n=10), respectively. Cabozantinib dose reductions occurred in 54% (n=14). AEs of special interest were grade 1 or 2 infusion related reactions, 27% (n=7). Batiraxcept was discontinued due to disease progression 62% (n=16) or toxicity 12% (n=3). The table shows P1b efficacy, ORR of 42%, median PFS of 9.3 mo, and DCR of 84%. Twenty (77%) pts had high baseline sAXL/GAS6 levels; ORR was 55% (11/20) with mPFS of 9.3 mo, compared to 0% ORR and mPFS 6.4 mo in the low sAXL/GAS6 pts. Conclusions: Batiraxcept was well tolerated when combined with cabozantinib. No new safety signals were noted. Efficacy for the combination is encouraging compared to historical cabozantinib monotherapy data. Higher GAS6 levels were predictive for treatment response. The P2 accrual is complete and efficacy data are maturing. A P3 trial plans to evaluate the efficacy in ccRCC patients who have progressed on IO-based and VEGF-TKI therapies. Clinical trial information: NCT04300140 . [Table: see text]

547 Background: Despite recent therapeutic advancements for patients with mUC, including checkpoint inhibitors (CPIs), anti-FGFR and antibody-drug conjugates (ADCs), biomarker data to predict therapeutic response and identify mechanisms of resistance remain limited. Ongoing randomized clinical trials evaluating the combination of CPIs and ADCs in these pts underscore the need to develop biomarkers to better understand who might best respond to these therapies. Here, we employ a liquid biopsy approach to molecularly characterize circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), including those isolated with Trop-2, the target of the novel drug Sacituzumab Govitecan and Datopotamab Deruxtecan. Methods: 104 blood samples serially collected from pts being treated for mUC were used for CTC collection using anti-EpCAM and Trop-2 antibodies in parallel. CTCs were isolated and stained for immune markers PD-L1 and HLA I using the VERSA (Versatile Exclusion-based Rare Sample Analysis) platform. Plasma was isolated for paired analysis of CTC and ctDNA content. CTCs were analyzed for enumeration and single-cell protein analysis. Overall survival (OS) was defined from time of sample collection, and survival analyses were performed using the Kaplan-Meier method. Results: We observed significantly shorter OS in pts with higher CTC burden (≥ 20 CTCs/7.5 mL blood) in samples captured with either EpCAM (median 34.1 vs 3.1 mo, P < 0.01) or Trop-2 (median 34.1 vs 6.2 months, P < 0.01). Furthermore, EpCAM and Trop-2 CTC burdens were higher at progression timepoints relative to responding or stable timepoints, when stratified according to treatment modality (table). Inter and intra-patient heterogeneous PD-L1 and HLA I expression and co-expression was observed on CTCs although no significant differences were seen globally between EpCAM and Trop-2 CTCs. In a cohort of pts treated with CPIs, we observed dynamic phenotypic changes in the ratio of HLA:PD-L1 that differed between EpCAM and Trop-2 CTCs. ctDNA analysis identified concordant increases in tumor fraction and acquired genomic mutations. When examined longitudinally across individual pts, these findings in tandem with changes in enumeration, suggest the emergence of different CTC subpopulations that may serve as biomarkers of resistance. Conclusions: We identify the prognostic significance of CTC enumeration with parallel EpCAM and Trop-2 CTC isolation and demonstrate the utility of a liquid biopsy assay that can detect pharmacodynamic changes in CTC burden and immune marker expression throughout the course of treatment. [Table: see text]

604 Background: Treatment with immunotherapy can be associated with prolonged disease control after discontinuation without the need for further anticancer therapy. Toxicity from therapy can also persist after cessation. TFS with and without toxicity can characterize survival time. Significant TFS was reported for CheckMate 067 trial in pts with metastatic melanoma (Regan et al JITC 2021) and CheckMate 214 trial for pts with aRCC (Regan et al CCR 2021), but treatment was often halted for toxicity rather than a pre-defined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16 260 trial, which was designed to reduce toxicity and to cap immunotherapy duration (Atkins et al JCO 2022). Methods: Data were analyzed from 128 patients (pts) with clear-cell aRCC treated with first-line nivolumab (NIVO) monotherapy for up to 2 years. As part of the protocol, salvage nivolumab/ipilimumab (NIVO/IPI) for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (28% of pts). TFS was defined as the area between Kaplan-Meier curves for time from registration to protocol therapy cessation and for time from registration to subsequent therapy initiation or death, estimated from 36-month (mo) mean times. The time on treatment or off treatment with grade 3+ treatment-related adverse events (TRAEs) was also captured. Results: At 36 mos from enrollment, 68.3% of pts were alive: 96.8% of IMDC favorable-risk (FAV) pts and 56.6% of those with intermediate/poor-risk (I/P), respectively. The 36-mo mean time on protocol therapy was 11.5 mos (16.0 mos for FAV pts and 9.6 mos for I/P pts). The 36-mo mean TFS for the whole population was 9.4 mos. For FAV pts the mean TFS was 12.9 mos, of which TFS with grade 3+ TRAEs was 1.5 mos. For I/P pts, the mean TFS was 8.0 mos, of which TFS with grade 3+ TRAEs was 1.0 mos. At 36 mos, 65.6% of FAV pts and 27.1% of I/P pts were alive and second-line treatment-free. Conclusions: NIVO monotherapy with salvage NIVO/IPI in non-responders is an active treatment approach in treatment-naïve pts with aRCC and results in substantial TFS and toxicity-free TFS. TFS was particularly noted in pts with FAV disease, further supporting the use of an immunotherapy-only regimen in this population. Clinical trial information: NCT03117309 . [Table: see text]

672 Background: The combination of ipilimumab and nivolumab (Ipi/Nivo) is approved for patients (pts) with treatment-naïve, intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), but duration of therapy and safety/efficacy of re-induction at progression is unknown. A phase II trial of intermittent Ipi/Nivo with re-induction at progression was conducted (NCT03126331). Methods: Patients with treatment-naïve mRCC were treated with induction Ipi/Nivo followed by up to 24 weeks (+/- 8 weeks) of maintenance Nivo. Pts who achieved a complete response (CR) or partial response (PR) were eligible for inclusion and entered a treatment-free observation period. Pts were restaged every 12 weeks. Pts with no disease progression (PD) remained off therapy. Upon PD, pts were re-challenged with 2 doses of Ipi/Nivo every 3 weeks, with 1 or 2 more doses at physician discretion. The study objectives were to estimate success rate of observation in pts who achieve a CR/PR (defined by 50% of CR/PR pts sustaining a treatment-free interval of at least 9 months), and to assess toxicity in pts undergoing re-induction. The study was closed early given poor accrual in the rapidly changing mRCC treatment landscape. Results: Nine pts were included; 89% male, median age 57, 78% prior nephrectomy, 67% clear-cell histology, all had KPS ≥ 80%, and 78% were intermediate-risk by IMDC criteria. All pts had 4 doses of induction Ipi/Nivo. Response to Ipi/Nivo and Nivo maintenance prior to enrollment was 33% CR and 67% PR. Most (78%) pts patients have remained off therapy, with a median treatment-free interval (TFI) of 34.3 months (range, 8.7-41.8). The success rate of 0.78 (95% CI: 0.40-0.97) exceeded the pre-specified threshold of 50%. Two pts had PD off therapy (3 and 8 months after therapy cessation; both with best initial response of PR). Both received 2 cycles of re-induction Ipi/Nivo. No grade 3 or greater toxicities occurred with re-induction, but both pts developed PD at their first scans after re-induction. Conclusions: This pilot prospective study demonstrates that patients with a radiographic response to Ipi/Nivo can have prolonged treatment-free intervals. Further studies of de-escalation strategies are warranted. Correlative investigations for this trial are ongoing. Clinical trial information: NCT03126331 .

TPS742 Background: The first-line treatment for metastatic clear cell renal cell carcinoma (mccRCC) includes an immuno-oncology (IO) based combination. The current standard regimens include a PD-1 inhibitor plus either (1) an anti-CTLA-4 inhibitor (IO/IO), or (2) an anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) (IO/TKI). Currently, there is no level 1 evidence to guide physician’s choice between an IO/IO versus IO/TKI combination. The phase III IMmotion 151 trial performed RNA-seq from 823 ccRCC tumors and established seven biologically distinct gene expression clusters of ccRCC (Motzer and Rini et al., Cancer Cell 2020). The seven clusters showed differential responses to immune checkpoint inhibitor and may serve as a predictive biomarker to select frontline treatment. Methods: This trial is a phase II, multicenter study using the established biologic clusters to assign patients with mccRCC to either an IO/IO (ipilimumab/nivolumab) or an IO/TKI (nivolumab/cabozantinib) regimen. Patients diagnosed with mccRCC without prior systemic therapy (including in the neoadjuvant or adjuvant setting) and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. RNA-seq will be performed on metastatic tumor specimens and used to assign tumor clusters. Patients with cluster 1/2 tumors will be assigned to the nivolumab/cabozantinib arm; patients with cluster 4/5 tumors will be assigned to the ipilimumab/nivolumab arm. Cluster 3/6/7 will be excluded. The primary endpoint is overall response rate (ORR) per RECIST 1.1. The hypothesis is that use of tumor clusters to assign front-line therapy to either nivolumab/cabozantinib or ipilimumab/nivolumab will lead to a 20% greater ORR compared to unselected historical controls in CheckMate 9ER (ORR: 55%) or CheckMate 214 (ORR: 40%). This trial adopts Simon’s MiniMax two-stage design (power: 80%, one-sided α: 0.1). For the nivolumab/cabozantinib arm, stage I will enroll 12 eligible patients. If there are 7 or more responders in the first 12 patients, the trial will continue for stage II to enroll additional 14 patients (total n=26). The primary endpoint will be met if there are 18 or more responders (ORR ≥75%). For the ipilimumab/nivolumab arm, stage I will enroll 16 eligible patients. If there are 7 or more responders in the first 16 patients, the trial will continue for stage II to enroll additional 12 patients (total n=28). The primary endpoint will be met if there are 15 or more responders (ORR ≥60%). Key secondary endpoints include progression-free survival (PFS), depth of response>80%, and rate of immune-related adverse events (irAEs). This trial is funded by the Department of Defense Kidney Cancer Research Program Clinical Trial Award (W81XWH-22-1-1033) (NCT05361720). Clinical trial information: NCT05361720 .

103 Background: Androgen deprivation therapy (ADT) has been the backbone of treatment for mHSPC for decades. In recent years, multiple randomized controlled trials demonstrating an overall survival (OS) benefit of combination treatment (e.g. ADT + novel hormonal agent and/or chemotherapy) has made this the current SOC. Large real-world reports have shown a significant number of patients are still being treated below the SOC with ADT alone, but these databases do not include patient level data to help understand the rationale for treatment decisions. We reviewed our institution’s treatment patterns for mHSPC to better understand why some patients are being treated with ADT alone. Methods: We conducted a retrospective analysis on patients who initiated treatment for mHSPC from 2017-2021 at Cleveland Clinic. Patient characteristics were recorded, including age and histology. Treatment characteristics, including location of treatment, treatment regimen, and treatment rationale (if not treated with SOC) were noted. Results: Four hundred forty-nine patients were included, with diagnosis of metastatic disease made at a median of 63 years, of which 446 started treatment with systemic therapy. The vast majority of patients were managed by a medical oncologist (95.5%). About half of the patients (49.8%) received treatment at the main campus, with the remaining patients being treated at an affiliated regional hospital (28.7%) or outpatient medical center (21.5%). Additional characteristics are shown. Out of the 446, 40 (9.0%) patients received ADT alone. Reasons for ADT monotherapy included patient preference (n = 13), cost (n = 2), and poor functional status/comorbidities (n = 4). Twenty (50%) of the patients who got ADT alone had no documented rationale for why this treatment plan was elected. One patient was lost to follow-up. For patients who received only ADT, 12 were treated at main campus, 20 were treated at a regional hospital, and 8 were treated at an outpatient medical center. Conclusions: At our institution, adherence to treatment up to SOC for mHSPC was better than previous real-world reports. There were documented reasons for not treating mHSPC up to SOC combination therapy for half of the patients who got ADT monotherapy. It remains unclear why the remaining half did not get combination therapy up to the SOC. [Table: see text]

630 Background: The introduction of immunotherapies has changed the first-line treatment landscape for advanced/metastatic renal cell carcinoma (aRCC). This study examines patient preferences in this rapidly changing environment to better understand the tradeoffs patients with aRCC are willing to make when choosing treatment. Methods: Patients with self-reported aRCC in the United States completed an online, cross-sectional survey. A discrete choice experiment was used to assess preferences for attributes of aRCC treatments. Patients completed a series of choice tasks showing 2 treatment profiles that varied in 7 important attributes identified through literature and qualitative research: overall survival, progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), risk of adverse events, quality of life (QOL) changes, and treatment administration. Descriptive statistics were reported, and a hierarchical Bayesian logistic model was used to calculate preference weights. Relative importance estimates (mean ± standard error) were computed for each attribute; these represent the mean percentage of the variation in preferences explained by the attribute. Results: Survey results from a total of 299 patients were analyzed (male, 50%; mean age, 56 years). All 7 attributes were statistically significant for influencing the choice of treatment. Key attributes included treatment regimen convenience and QOL improvement, which ranked similarly to increasing survival time. Among the efficacy attributes, increasing survival time was most important, followed by ORR, PFS, and DOR. Reducing the risk of serious adverse events from 82% to 65% was prioritized after the efficacy parameters. Conclusions: Patients with aRCC highly value less burdensome treatment regimens and improved QoL in addition to improvement in survival. This highlights the need for a broader context beyond efficacy and safety when discussing treatment options with patients. Funding: This study was supported by Bristol Myers Squibb.

683 Background: In renal cell carcinoma (RCC), partial nephrectomy (PN) is indicated for patients with solitary kidney, chronic kidney disease, or bilateral tumors. A subset of these patients, however, may have large and complex renal masses not initially suitable for PN. Neoadjuvant Tyrosine Kinase Inhibitor therapy has shown promising results in cytoreducing renal tumors and may permit PN in circumstances not otherwise feasible. Methods: This was a single arm phase II clinical trial of neoadjuvant axitinib in patients with complex (RENAL nephrometry score 10-12 and cT1b-cT3M0) biopsy-proven clear cell RCC with strong indications for partial nephrectomy (PN), and in whom radical nephrectomy may result in dialysis dependence. Axitinib 5 mg was administered orally twice daily for 8 weeks prior to surgery. Primary outcome was reduction in longest tumor diameter; secondary outcomes included tumor response (RECIST), change in RENAL score, feasibility of PN, change in estimated glomerular filtration rate (DeGFR), and post-surgical complications. Results: 26 patients were enrolled. 19 (73.1%) patients had ≥ clinical T3a staged tumors. Post therapy, 17 (65.4%) patients had ≥T3a staged tumors. Axitinib resulted in reductions in tumor size (7.7 vs. 6.3 cm, p

691 Background: The perioperative safety of cabozantinib and nivolumab in mccRCC, and the optimal timing to hold cabozantinib prior to surgery, are unknown. Methods: In this phase 2 trial, patients with mccRCC are given cabozantinib (40mg daily) and nivolumab (480mg q4 weeks) for 12 weeks prior to cytoreductive nephrectomy. Post-operatively, patients resume treatment with cabozantinib and nivolumab until disease progression. A 3+3 design was used to evaluate the safety of the interval (21 or 14 days) between the discontinuation of cabozantinib and nephrectomy. Evaluable patients completed at least 10 of 14 cabozantinib doses prior to the pre-specified period of stopping pre-operative cabozantinib. Surgical complications assessed using the Clavien-Dindo classification system is a secondary endpoint of this study. Results: 16 patients have been enrolled and 14 completed nephrectomy to date. 12 (75%) of patients are male, 4 (25%) female, ages 44-77 years old with median age at diagnosis 58.5 years old. BMIs ranged from 17.8 kg/m2 to 39.3 kg/m2 with median BMI of 28.7kg/m2. 63% of patients were classified by IMDC as intermediate-risk and 37% as poor-risk disease. Dose reductions of cabozantinib occurred in 14% of patients who completed nephrectomy and cabozantinib held in 42% of nephrectomy patients during the course of treatment. Three evaluable patients completed nephrectomy within the 21-day interval and 5 within the 14-day interval after discontinuation of cabozantinib. There were no treatment-related surgical complications in patients who completed nephrectomy and there were no delays in resuming combination systemic therapy after surgery. Conclusions: Combination cabozantinib and nivolumab can be safely administered up to 14 days prior to cytoreductive nephrectomy. Clinical Trial Information: NCT04322955 Clinical trial information: NCT04322955 .

While immune checkpoint inhibitors (ICI) can lead to sustained responses in metastatic renal cell carcinoma (mRCC), the optimal duration of therapy remains unknown. We aimed to examine treatment-free survival (TFS) in objective responders who discontinued ICI and to explore factors that may impact objective response rate (ORR) and TFS. MEDLINE/PubMed, Embase, and the Cochrane Library were searched for prospective studies reporting individual outcomes after ICI discontinuation in patients with mRCC. Pooled ORR and TFS were estimated using random-effects meta-analyses, and associations between ICI regimen type or treatment line and ORR or TFS were evaluated. Sixteen cohorts comprising 1833 patients treated with ICI were included. The pooled ORR was 43% (95% CI 33% to 53%), and significant differences in summary estimates existed among patients who received ICI monotherapy (22%, 95% CI 18% to 26%), ICI plus a vascular endothelial growth factor (VEGF) pathway inhibitor (57%, 95% CI 48% to 65%), and dual ICI (40%, 95% CI 36% to 44%). Of 572 responders who had available data, 327 stopped ICI, with 86 (26%) continuing to respond off-treatment. Pooled TFS rates at 6 and 12 months were 35% (95% CI 20% to 50%) and 20% (95% CI 8% to 35%), respectively, and were highest for responders treated with dual ICI and lowest for those treated with ICI plus a VEGF pathway inhibitor. Thus, a subset of patients with mRCC who are treated with ICI-based therapy can have durable TFS after therapy discontinuation. Prospective clinical trials and biomarkers are needed to identify patients who can discontinue ICI therapy without compromising clinical outcomes.

Renal cell carcinomas vary considerably in their tumor biology and disease course, which is reflected in the range of treatment paradigms in localized and metastatic renal cell carcinoma (mRCC). Active surveillance remains an important component of all renal cell carcinoma management. In mRCC, the rapid evolution from cytokine-based therapy to targeted therapy to immunotherapy with checkpoint blockade has revolutionized the field and drastically altered treatment outcomes. More recently, combination therapies have become a standard of care for most patients with mRCC. In this review, we highlight recent critical data that led to changes in treatment paradigms and provide a practical framework for the management of patients with mRCC.

The combination of ipilimumab plus nivolumab (I+N) has greatly improved outcomes in patients with intermediate or poor-risk untreated metastatic renal cell carcinoma (mRCC). However, little is known about the outcomes of patients with brain metastasis (BrM) treated with I+N. A search was performed to retrospectively identify all patients with mRCC treated with I+N in the Duke Cancer Institute and the Cleveland Clinic Taussig Cancer Center, followed by a chart review. Patients were included if they had BrM at the time of I+N initiation. Cohort characteristics are summarized with descriptive statistics. Kaplan-Meier method was used to estimate overall survival (OS) and global, intracranial, and extracranial progression-free survival (PFS) for the cohort and log rank test was used to compare OS and PFS between patient groups. Radiographic response was categorized by RECIST. Fisher’s exact test was used to correlate patient factors with radiographic response. From October 2017 to December 2020, 19 patients with BrM received I+N for mRCC with a median follow-up time of 27.1 months (range 15.0–35.6). By International Metastatic RCC Database Consortium (IMDC) risk criteria, 16% had favorable, 58% had intermediate, and 26% had poor-risk disease. 68% were systemic therapy naïve, and 77% of patients had clear cell histology. 95% had received local CNS directed therapy with surgery, radiotherapy, or both. The objective response rate was 44% (0% complete response) with three of six patients treated in the second line or greater setting experiencing a partial response. The median PFS was 7.6 months (95% CI 5.6 to 14.9). The median extracranial PFS was 8.5 months (95% CI 5.6 to 19.7), and median intracranial PFS was 14.7 months (95% CI 7.2 to not reached). No variables assessed were significantly associated with radiographic response (gender, IMDC risk, presence of bone metastasis, line of therapy, or presence of immune related adverse events). In our retrospective cohort of patients with mRCC with BrM, I+N, in combination with CNS-directed local therapy, appears to have clinical efficacy as previously described with responses seen beyond the first-line setting. Further investigation is warranted in this population given exclusion from prior clinical trials.

Background Nivolumab is approved for mRCC patients who have received prior anti-angiogenic therapy but the duration of therapy required for sustained clinical benefit is unknown. A phase II clinical trial to investigate the feasibility of intermittent nivolumab dosing was conducted. Methods Patients ≥18 years of age with mRCC who were previously treated with at least one antiangiogenic therapy were eligible. Patients were treated with nivolumab for twelve weeks. Patients who had RECIST PD were removed from the trial. Patients who did not initially achieve ≥10% reduction in tumor burden (TB) continued nivolumab per standard of care. Patients with ≥10% TB reduction entered a treatment-free observation phase with re-imaging every 12 weeks. Nivolumab was restarted in patients with a ≥ 10% TB increase and again held with TB reduction ≥10%. This intermittent nivolumab dosing continued until RECIST PD while on nivolumab. The primary objective was feasibility of intermittent nivolumab, defined as the proportion of patients eligible for intermittent therapy who elect to receive intermittent nivolumab. Intermittent nivolumab would be considered “feasible” if the acceptance rate was ≥80%. Forty patients provides > 95% power with 0.05 type I error, assuming a null acceptance rate of 50%. With the approval of the combination of ipilimumab/nivolumab (April 2018) in front-line mRCC, this cohort was closed prior to completed pre-planned approval. Results Of the 14 patients enrolled, 13 (93%) were male with a median age 65. All had a prior nephrectomy and 12 (86%) were intermediate-risk by IMDC criteria. Five patients (36%) met the criteria for the intermittent phase of the trial (median TB decrease 46%) and all agreed to intermittent therapy. With a median follow-up of 48 weeks, only one patient restarted therapy. The four remaining patients have a sustained response for a median of 34 weeks (range, 16–53) off therapy. No patients developed RECIST PD while off therapy. Conclusions This prospective experience of intermittent nivolumab dosing in mRCC supports further investigation of intermittent immunotherapy dosing strategies in RCC. Trial registration NCT03126331 (Intermittent Nivolumab in Metastatic Renal Cell Carcinoma Patients; Date of registration 4/27/2017; https://clinicaltrials.gov/ct2/show/NCT03126331).

Purpose: Transcriptomic profiling can shed light on the biology of small-cell bladder cancer (SCBC), nominating biomarkers, and novel therapeutic targets. Experimental Design: Sixty-three patients with SCBC had small-cell histology confirmed and quantified by a genitourinary pathologist. Gene expression profiling was performed for 39 primary tumor samples, 1 metastatic sample, and 6 adjacent normal urothelium samples (46 total) from the same cohort. Protein levels of differentially expressed therapeutic targets, DLL3 and PDL1, and also CD56 and ASCL1, were confirmed by IHC. A SCBC PDX model was utilized to assess in vivo efficacy of DLL3-targeting antibody–drug conjugate (ADC). Results: Unsupervised hierarchical clustering of 46 samples produced 4 clusters that correlated with clinical phenotypes. Patients whose tumors had the most “normal-like” pattern of gene expression had longer overall survival (OS) compared with the other 3 clusters while patients with the most “metastasis-like” pattern had the shortest OS (P = 0.047). Expression of DLL3, PDL1, ASCL1, and CD56 was confirmed by IHC in 68%, 30%, 52%, and 81% of tissue samples, respectively. In a multivariate analysis, DLL3 protein expression on >10% and CD56 expression on >30% of tumor cells were both prognostic of shorter OS (P = 0.03 each). A DLL3-targeting ADC showed durable antitumor efficacy in a SCBC PDX model. Conclusions: Gene expression patterns in SCBC are associated with distinct clinical phenotypes ranging from more indolent to aggressive disease. Overexpression of DLL3 mRNA and protein is common in SCBC and correlates with shorter OS. A DLL3-targeted ADC demonstrated in vivo efficacy superior to chemotherapy in a PDX model of SCBC.

4593 Background: Upper tract urothelial carcinoma (UTUC) is a rare and heterogeneous disease accounting for approximately 5-10% of UC. While tumor grade and stage are known prognostic factors, data on other factors affecting outcomes in UTUC patients (pts) undergoing surgery is scant. We studied effect of various clinical factors and treatment on outcomes in UTUC. Methods: This is a single-institution retrospective study of 607 pts with UTUC undergoing surgery (nephroureterectomy (NU) or ureterectomy (U)) between Jan 2000 and Dec 2020. We studied effect of demographics, clinicopathological features, tumor location, preoperative Neutrophil-to-Lymphocyte ratio (NLR) and Albumin-to-Globulin ratio (AGR) and use of neoadjuvant or adjuvant chemotherapy on overall survival (OS) and recurrence free survival (RFS). Results: Of the 607 pts 401 (66.06%) were males and 355 (58.48%) were > 70 yrs; 232 pts (38.22%) had UTUC of renal pelvis, 242 (39.87%) of ureter and 133 (21.91%) of both. 542 pts (89.29%) underwent radical NU and 65 (10.71%) segmental U; 328 patients (54.04%) were diagnosed with muscle invasive UC (MIUC) ( > / = pT2) and 276 (45.47%) with non-MIUC ( < / = pT2). Only 51 (8.4%) pts had lymph node positive (N+) disease. Lymphovascular invasion (LVI) was identified in 163 (26.85%) and carcinoma- in-situ (CIS) in 163 (26.85%) pts. Surgical margins were positive in 92 pts (15.16%). Median NLR cutoff was 3.25 and AGR cutoff was 1.25 (dichotomized based on literature). 44 pts (7.2%) received Neoadjuvant chemotherapy and 49 pts (8%) received adjuvant chemotherapy. Tumor recurrence occurred in 216 pts (35.58%) of which 65% were at urothelial and 35% at non-urothelial sites. With median follow up of 35.2 mos, median OS was 82.69 mos and 5-yr OS rate was 60%; median RFS was 29.47 mos and 5-yr RFS rate was 40%. High grade, age > / = 70 yrs, high NLR, low AGR, presence of LVI, positive margins, CIS, MIUC, N+ disease were associated with worse outcomes. Pts with only renal pelvis involvement had better OS. Conclusions: In this large, long term follow-up series of UTUC pts, we identified several prognostic factors besides grade and stage that impact outcomes. These findings warrant further validation for use in clinical practice. [Table: see text]

TPS4599 Background: In clear cell renal cell carcinoma (ccRCC) the constitutive expression of hypoxia induced factor 1-α leads to increased expression of AXL. AXL overexpression has been associated with the development of resistance to VEGF inhibitors and suppression of the innate immune response through inhibition of macrophage-driven inflammation. Batiraxcept is a recombinant fusion protein dimer containing an extracellular region of human AXL combined with the human immunoglobulin G1 heavy chain (Fc), which demonstrates highly potent, specific AXL inhibition. In preclinical studies using the 786-O, M62, and SN12L1 tumors, batiraxcept monotherapy resulted in a significant reduction of tumor growth compared to control. In healthy volunteer and ovarian cancer clinical studies, batiraxcept was well tolerated with no dose-related adverse events, and a maximum tolerated dose was not reached. Therefore, batiraxcept could be tested as either a monotherapy or in combination with standard of care drugs in patients with metastatic ccRCC. The Phase 1b dose-escalation portion of this study evaluated batiraxcept in combination with standard of care cabozantanib in patients who progressed on or after first line therapy. No DLT was observed at either of two batiraxcept doses evaluated. The recommended Phase 2 dose of batiraxcept has been identified as 15 mg/kg every 2 weeks (q2w) with cabozantinib 60 mg based upon safety, PK/PD, and preliminary efficacy data. Methods: This Phase 2, multi-center, open-label study includes three parts: Part A) batiraxcept 15 mg/kg q2w in combination with cabozantinib 60 mg daily for ccRCC subjects who have progressed on or after one line of therapy, n=25. Part B) batiraxcept 15 mg/kg q2w with cabozantinib 40 mg daily and nivolumab at the investigator’s choice (240 mg q2w or 480 mg q4w) for first line treatment of advanced or metastatic ccRCC subjects, n=20. If no safety signals are observed in the first 6 subjects enrolled, 10 subjects will be enrolled in the first stage of a Simon 2-stage minmax statistical design. If ≥ 6/10 subjects achieve PR or CR, stage 2 will open to enroll up to 20 total subjects. Part C) batiraxcept 15 mg/kg q2w monotherapy for subjects with advanced/metastatic ccRCC ineligible for curative intent therapies, n=10. The primary objective for each arm is objective response rate by RECIST v1.1. Secondary objectives include safety, duration of response, clinical benefit rate, progression free survival by RECIST v1.1, and overall survival. Exploratory objectives include pharmacokinetic and pharmacodynamic assessments. The Phase 2 portion of this Ph1b/2 study is currently enrolling. Clinical trial information: NCT04300140.

4511 Background: AXL is up-regulated by hypoxia-inducible factor-1 signaling in both VHL-deficient and hypoxic tumor cells and plays a critical role in the metastatic phenotype of ccRCC. Batiraxcept is a recombinant fusion protein containing an extracellular region of human AXL combined with the human immunoglobulin G1 heavy chain (Fc), demonstrating highly potent, specific AXL inhibition. Methods: Batiraxcept at doses of 15 and 20 mg/kg, plus cabozantinib 60 mg daily, was evaluated using a 3+3 dose escalation study design. The primary objective was safety; secondary and exploratory objectives included identification of the recommended phase 2 dose (RP2D), overall response rate (ORR), and duration of response (DOR). Correlation of serum soluble AXL (sAXL)/GAS6 with ORR was evaluated. Key eligibility criteria include previously treated (2L+) ccRCC patients; prior treatment with cabozantanib was not allowed. sAXL/GAS6 was evaluated at baseline. Results: Data as of 4-February-2022, Phase 1b enrolled 26 patients, 16 patients treated with 15 mg/kg and 10 patients with 20 mg/kg dose of batiraxcept. Baseline characteristics: median age 60 (40-81); male 22 (85%); median prior line of therapy 1 (1-5); IMDC risk group of favorable 6 (23%); prior VEGF inhibitor 15 (58%); 100% with prior immunotherapy. At median follow up of 4.9 months, 92% (n=24) patients remained on the study. No dose limiting toxicities were observed at either 15 mg/kg or 20 mg/kg dose. Batiraxcept and cabozantinib related adverse events (AEs) occurred in 17 subjects (65%). Most common related AE include decreased appetite 31% (n=8), diarrhea and fatigue 23% (n=6). Grade 3 related AEs occurred in 4 patients (15%) including diarrhea, thromboembolism, hypertension, small bowel obstruction, and thrombocytopenia (n=1, 4% each) being most common. No grade 4 or 5 related AEs were observed. The ORR was 46% (n=12, partial response [PR]; Table). No patients had primary progressive disease. Among the patients who had baseline sAXL/GAS6 ratio of ≥ 2.3, the ORR was 67% (12/18). Regardless of baseline sAXL/GAS6 ratio, 3-month DOR was 100%; and 6-month progression free survival was 79%. Batiraxcept PK levels were similar across both doses and GAS6 levels suppressed through the dosing period. Conclusions: Batiraxcept plus cabozantinib is well tolerated. The RP2D of batiraxcept was identified as 15 mg/kg. Early efficacy signals were observed including 100% DOR at 3 months. Baseline sAXL/GAS6 may serve as a potential biomarker to enrich the population. Clinical trial information: NCT04300140. [Table: see text]

4529 Background: Immune checkpoint blockade has revolutionized mRCC Tx, but primary and acquired resistance continues to result in poor patient outcomes. OX40 (CD-134) mediates IO resistance. Co-stimulatory OX40 (CD-134) activates exhausted T-cells. OX40 activation in dendritic cells increases the proliferation, effector function, and survival of T cells. PFOX is an agonist for OX40. We hypothesized that PFOX + the VEGFR inhibitor Axi would improve outcomes vs. Axi in patients (pts) with mRCC after IO Tx. Methods: Pts with predominantly clear cell mRCC were stratified for MSKCC risk groups then randomized 1:1 to Axi 5mg po bid plus PFOX 0.3mg/kg iv (Arm 1) or placebo (PL) iv (Arm 2) on Day 1 of a 2-week cycle. The primary endpoint was progression free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR) per RECIST v1.1, and safety/tolerability. A prespecified interim analysis (IA) tested PFS at a 1-sided P < 0.02 when ≥ 33 events were observed. Results: Between February 2018 and October 2021 a total of 59 pts were randomly assigned and treated with Axi+PFOX (N = 29) or Axi+PL (N = 30). Pt and disease characteristics are summarized in the table. As of October 2021, 38 PFS events had occurred, 19 on each arm. The IA rejected the hypothesis of added efficacy for PFOX with a p of 0.0089. Subsequently the study was closed to new accrual. At a median follow up of 13.4 mo, median PFS was 13.1 (6-15.8) months (mo) for Arm 1 and 8.5 (5.5-11) mo for Arm 2 (HR = 0.85 [95% CI: 0.45-1.60] p = 0.61). After adjusting by MSKCC risk group and prior lines of Tx, HR = 0.74 [95% CI: 0.38-1.46] p = 0.39. Median OS was not reached (adjusted HR = 0.71 [95% CI: 0.24-2.12] p = 0.54). ORR Arm 1: 31% PR, 52% SD, 14% PD, and Arm 2: 37% PR, 50% SD, 13% PD. Median DOR 9.1 (3.3-23.9) mo for Arm 1, and 7.5 (1.8-32.7) mo. for Arm 2. Rates of any grade Tx related adverse events (TRAEs; 93% vs 100%), including grade 3 or 4 TRAEs (66% vs 47%), in Arm 1 and Arm 2, respectively. 4 pts discontinued Tx due to TRAE, 3 in Arm 1 (1 grade 3 hypertension, 1 grade 2 stroke, 1 grade 3 bullous dermatitis) and 1 in Arm 2 (grade 4 ALT elevation). The most common TRAEs were diarrhea 52%, hypertension 52%, fatigue 41%, nausea 41% for Arm 1 and hypertension 67%, diarrhea 53%, fatigue 50% for Arm 2. Conclusions: In IO-pretreated mRCC pts, Axi + PFOX did not improve outcomes compared to Axi alone. Clinical trial information: NCT03092856. [Table: see text]

2501 Background: The immunoregulatory cytokine IL-27 upregulates inhibitory immune checkpoint receptors (eg, PD-L1, TIGIT) and downregulates proinflammatory cytokines (eg, IFNγ, TNFα). SRF388 is a fully human IgG1 blocking antibody to IL-27 with potential to promote immune activation in the tumor microenvironment. A phase 1 study was conducted to establish the preliminary safety of SRF388 and to identify recommended phase 2 doses (RP2D) suitable for monotherapy and combination expansions (NCT04374877). Methods: The dose-escalation study (accelerated single patient followed by standard 3+3) enrolled patients (pts) with advanced treatment-refractory solid tumors. Upon RP2D selection, monotherapy and combination expansions opened for treatment-refractory clear cell renal cell cancer (ccRCC), hepatocellular cancer (HCC), and non-small cell lung cancer. SRF388 was administered IV every 4 weeks (wks) as monotherapy and every 3 wks with pembrolizumab. Tumor response was assessed by RECIST1.1. Results: The monotherapy dose-escalation enrolled 29 pts with doses ranging from 0.003 to 20 mg/kg. Median age was 64 years. Most pts were female (62%) with ECOG PS of 1 (72%). Approximately 80% had prior PD-(L)1 blockade, and 48% had ≥4 prior therapies. Treatment-related adverse events (TRAEs) occurred in 21%, and all were low grade. Fatigue was the only TRAE reported in ≥10% (n = 3). No dose-limiting toxicities (DLTs) or Grade ≥3 TRAEs were observed. Median time on study was 9 wks (range 0–59). One patient with highly treatment-refractory NSCLC experienced a confirmed partial response (PR) at 8 wks that was durable for 20 wks. Nine pts (31%) experienced disease stabilization at 8 wks, with 6 of 9 exhibiting durable disease control at 6 months. Of the 7 pts with ccRCC in the dose-escalation portion of the trial, 3 (43%) experienced durable disease control for ≥20 wks (range: 20-32). With doses up to 20 mg/kg, SRF388 PK remain linear with an estimated T1/2 of 10-12 days. PK characteristics and safety profile support dosing every 3 or 4 wks. Based on safety, tolerability, PK, peripheral pSTAT1 inhibition, and preliminary efficacy, 10 mg/kg was selected as the RP2D. Both the pembrolizumab safety cohort (n = 10) and Stage 1 of the ccRCC monotherapy expansion (n = 17) have fully enrolled. Of the 10 evaluable pts with ccRCC, 1 confirmed monotherapy PR has been reported, enabling Stage 2 initiation. Changes in several serum cytokines and chemokines were observed after SRF388 administration, including expected increase in circulating IL-27 levels. Conclusions: Results of IL-27 pathway blockade with a first-in-class therapeutic demonstrates that SRF388 has good tolerability with encouraging preliminary antitumor activity as a monotherapy. Updated data, including safety and clinical outcomes as well as correlative biomarker analyses, will be presented. Clinical trial information: NCT04374877.

Neoadjuvant chemotherapy (NAC) has been increasingly adopted in the management of high-grade upper tract urothelial carcinoma (UTUC), largely extrapolating from level I evidence in urothelial carcinoma of the bladder. Studies examining pathologic outcomes in patients with UTUC receiving NAC are mostly limited to retrospective, single-center studies with limited sample size, with results of a phase II trial recently presented. Hypothesizing that NAC is associated with improved pathologic response (PR), we compared pathologic outcomes in patients with high-grade UTUC who did and did not receive NAC before extirpative surgery.A total of 6174 patients with nonmetastatic, high-grade UTUC who underwent extirpative surgery from 2006 to 2014 were identified from the National Cancer Database. Patients were stratified by NAC status. PR was defined as pathologic stage less than clinical stage. Univariate and multivariable logistic regression analysis was employed to identify predictors of PR.Two hundred sixty (4.2%) patients received NAC. A higher incidence of PR was observed in patients receiving NAC (25.2% vs. 1.8%; P .001), with complete PR observed in 6.1% of patients receiving NAC and 0.4% of patients undergoing surgery alone. NAC (odds ratio [OR], 19.8; 95% confidence interval [CI], 11.8-33.5), nonwhite race (OR, 3.2; 95% CI, 1.7-6.3), and ureteral tumor location (OR, 1.6; 95% CI, 1.02-2.6) were independently associated with PR.Examining a large national cancer registry, we observed a higher incidence of PR in patients with UTUC receiving NAC, validating findings of prior studies. Our findings support consideration of NAC in high grade UTUC. Prospective trials will better define the impact of NAC on pathologic and survival outcomes.

PURPOSE Neuroendocrine (NE)-like carcinoma is a newly recognized molecular subtype of conventional urothelial carcinoma of the bladder with transcriptomic profiles and clinical outcomes highly similar to histological NE carcinoma. The identification of NE-like tumors is challenging, as these tumors often appear histologically like urothelial carcinoma and can be missed by routine morphological criteria. We previously developed a single-sample classifier to identify NE-like tumors, which we aimed to validate in an independent cohort. MATERIALS AND METHODS A single-sample genomic classifier was performed on transurethral specimens from a retrospective multicenter cohort of 234 patients who underwent cisplatin-based neoadjuvant chemotherapy and subsequent radical cystectomy. Outcomes were compared for NE-like vs. non-NE-like. RESULTS We identified 10 patients with urothelial tumors of the NE-like subtype, all of which had robust gene expression of neuronal markers, but did not express markers associated with basal or luminal tumors. The cancer-specific mortality rates were significantly higher compared to non-NE-like tumors (P < 0.001), with 5 of the 10 patients dying within 12 months from surgery. CONCLUSIONS The single-sample classifier was able to identify urothelial carcinomas with NE-like subtype. These NE-like tumors have demonstrated transcriptomic profiles and clinical behavior similar to histological NE tumors across multiple patient cohorts. We propose that NE-like tumors should be managed similarly to histological NE tumors, and that standard treatments for small cell lung cancer as well as novel strategies may be evaluated in these patients.

268 Background: Invasive cribriform and intraductal carcinoma (CF/IDC) portends an unfavorable prognosis for patients diagnosed with prostate cancer (CaP). Limited studies with small sample sizes have explored whether genomic classifiers are associated with IDC and/or CF status. We investigated the correlation between Decipher genomic risk score and IDC/CF status and assessed PCa transcriptomic features. Methods: We performed a retrospective review of CaP patients who had Decipher testing at a single high volume center between 2009-2020. The highest grade index lesion from radical prostatectomy specimens was identified by GU pathologists and used for Decipher testing. Genitourinary pathologists reviewed prostatectomy specimens for the presence of CF and IDC features. Patients were divided into three groups based on pathologic features, absent CF/IDC (CF-/IDC-), CF positive only (CF+/IDC-), and CF/IDC positive (CF+/IDC+). Categorical clinical, genomic, and pathologic variables were assessed using the Pearson Chi-Square test, quantitative with the Kruskal-Wallis test. Multivariable logistic regression was used to identify predictors of high-risk Decipher GC scores. The Kaplan-Meier method with log-rank was used to compare biochemical recurrence free survival. Differential gene expression and gene network analysis was used to identify genes and pathways associated with IDC/CF features. Results: 463 patients were included with a median follow-up of 25 months. Patients who were CF+/IDC+ had higher GC scores (CF+/IDC+: 0.77 vs. CF+/IDC-: 0.71 vs. CF-/IDC-: 0.61, p3 (CF+/IDC+: 79% vs. CF+/IDC-: 52% vs. CF-/IDC-: 52%, p3 (OR: 1.58, p=0.04). Transcriptomic analysis revealed that the hallmark androgen response pathway was significantly upregulated in CF+/IDC+ patients (Log fold change: 15.7, p

288 Background: Nivolumab (nivo) is FDA approved for patients (pts) with VEGFR TKI-resistant RCC and the nivo + ipilimumab (nivo/ipi) combination is FDA approved for treatment naïve pts with IMDC intermediate and poor risk renal cell carcinoma (RCC). Little information was available on the efficacy and toxicity of nivo monotherapy in treatment naïve RCC or the efficacy of nivo/ipi salvage in pts with tumors resistant to initial nivo monotherapy. Methods: Eligible pts with treatment naïve RCC received nivo 240mg IV q2 wk x 6 doses followed by 360mg IV q3 wk x 4 doses followed by 480 mg q4 wk until progressive disease (PD), toxicity, or completion of 96 wks of treatment (Part A). Pts with PD prior to, or stable disease (SD) at 48 wks (pSD) were potentially eligible to receive salvage nivo (3mg/kg)/ipi (1 mg/kg) q3 wk x 4 doses followed by q4 wk nivo maintenance for up to 48 wks (Part B). All pts were required to submit tissue from a metastatic lesion obtained within 12 months (mos) prior to study entry and prior to Part B for correlative studies. Results: 123 pts with clear cell(cc) RCC were enrolled between 5/2017 and 12/2019 at 12 participating HCRN sites. Data lock was 04/07/2021. Median Follow-up 26.9 mos. Median age 65 (32-86) years; 72% male. IMDC risk: favorable (Fav) 35 (28%), intermediate (I) 76 (62%) and poor (P) 12 (10%). 22 (18%) had a component of sarcomatoid histology (SARC). RECIST defined ORR was: 34.1% (25.8-43.2%) (CR 6.5%, PR 27.6%), SD 47 (35.8%). ORR by irRECIST was 39%. ORR by IMDC was: Fav 20/35 (57.1%) (39-74%), (I/P) 22/88 (25%) and for SARC 36.4%. ORR by PD-L1 status was 21/78 (27%), 8/16 (50%) and 6/8 (75%) for pts with tumor PD-L1 of 0, 1-20 or > 20%, respectively (trend test p-value 0.002). 5/7 (71.4%) Fav pts with PD-L1 > 1 responded. Median DOR was 27.6 (13.7, NA) mos with 26/42 responders including 17/20 (85%) with Fav Risk remaining progression free. Median PFS was 8.2 (5.5, 10.9) mos; (30.3 for IMDC Fav and 5.4 for I/P). 91 pts remain alive with 24 mos OS rate of 78%. 65 patients (59 PD, 6 pSD) were potentially eligible for salvage nivo/ipi (Part B), but 25 did not enroll due to symptomatic PD (6), grade 3-4 toxicity on nivo (17), or other (2) and 5 were not treated due to inability to confirm residual disease on a biopsy. ORR for Part B by RECIST was 11.4% (4/35) and by irRECIST 17.2%. Grade 3-5 treatment-related AEs (TrAE) (not including asymptomatic amylase/lipase) were seen in 20.3% in Part A and 14.2% in Part B with 1 death in each cohort. Conclusions: Nivo monotherapy is active in treatment naïve ccRCC across all IMDC groups. Although efficacy appears less than combination nivo/ipi in I/P pts, Fav pts had a notably high ORR and DOR. Efficacy appeared to correlate with tumor PD-L1 status, although at least half the responders had a tumor PD-L1 of 0. Salvage treatment with nivo/ipi after nivo was frequently not feasible and of limited benefit. Clinical trial information: NCT03117309.

526 Background: Myeloid derived suppressors cells (MDSC) are immune cells that create an immunosuppressive microenvironment. Increased expression of MDSC subsets is associated with worse overall survival in ICI-treated mUC pts, but their role in immune-related adverse events (irAE) is unknown. Immune profiles associated with irAE are also unknown. We investigated associations of MDSC and –omics profiles with response and irAE in ICI-treated mUC pts. Methods: Baseline (B) and on-treatment (Tx) blood samples were collected from ICI-treated mUC pts. MDSC were measured in fresh unfractionated whole blood (WB) and in peripheral blood mononuclear cells (PBMC). MDSC were identified by flow cytometry in WB, defined as LinloCD33+/HLADR-, and subclassified as polymorphonuclear (PMN)-MDSC (CD15+/CD14-), monocytic (M)-MDSC (CD15-/CD14+), and uncommitted (UC)-MDSC (CD15-/CD14-). MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. irAE severity was graded by CTCAE v5. In a subcohort of 17 pts, proteomics and transcriptomics were analyzed via Olink and Bulk RNAseq, respectively. Wilcoxon rank sum test compared MDSC and –omics among response and irAE groups. Kruskal-Wallis test compared –omics results between irAE responders (irAE-R), irAE non-responders (irAE-NR), and no irAE/non-responders (noAE-NR). Results: 41 ICI-treated mUC pts (25 anti-PD-L1, 16 anti-PD-1) had at least 1 MDSC sample: 28 pts at B, 30 pts at Tx, and 17 pts at both B and Tx. Primary UC sites were bladder (78%) and upper tract (22%); 73% male; median age 72 (range, 28-82); 85% had KPS > 80%; 51% had visceral metastasis. ICI was first and second-line therapy in 37% and 63% of pts, respectively. 13 pts were responders (R); 26 pts were non-responders (NR); 2 pts were not evaluable. 22 pts developed irAE. Median time to irAE was 84 days (range, 21-145); 10 pts required steroids; 3 required ICI discontinuation. UC-MDSC was predominant in WB and PMN-MDSC in PBMC in both B and Tx. Between B and Tx, WB UC-MDSC and PB UC-MDSC increased in R (n = 13; p = 0.04), but decreased in NR (n = 26; p = 0.02). In the subcohort of 17 pts, 11 had irAE (7 irAE-R; 4 irAE-NR), 6 had noAE-NR. Proteomic analysis showed increased expression of CXCL12 in noAE-NR pts (p = 0.006) and increased expression of IL-8 (p = 0.016), IL-18 (p = 0.012), and IL-18R1 (p = 0.016) in all irAE pts. At the transcriptome level, upregulation of IFN-γ was associated with response, whereas upregulation of both IFN-γ and IFN-α differentiated irAE-R from irAE-NR. Conclusions: In ICI-treated mUC pts, WB & PB UC-MDSC increased in R and decreased in NR between B and Tx. Increased expression of pro-inflammatory chemokines was observed in irAE pts, independent of response. A distinct inflammatory pathway was observed in irAE-R. Prospective investigation of blood-based biomarkers of response and irAE development is warranted.

Purpose Standard frontline treatment of patients with metastatic renal cell carcinoma currently includes sunitinib. A barrier to long-term treatment with sunitinib includes the development of significant adverse effects, including diarrhea, hand-foot syndrome (HFS), and fatigue. This trial assessed the effect of an alternate 2 weeks on, 1 week off (2/1) schedule of sunitinib on toxicity and efficacy in previously untreated patients with metastatic renal cell carcinoma. Methods Patients started with oral administration of 50 mg sunitinib on a 2/1 schedule and underwent schedule and dose alterations if toxicity developed. The primary end point was < 15% grade ≥ 3 fatigue, diarrhea, or HFS. With 60 patients, the upper bound of the CI would fall below the published 4/2 schedule grade ≥ 3 toxicity rate of 25% to 30%. Results Fifty-nine patients were treated between August 2014 and March 2016. Seventy-seven percent were intermediate or poor risk per Memorial Sloan Kettering Cancer Center criteria. With a median follow-up of 17 months, 25% of patients experienced grade 3 fatigue, HFS, or diarrhea; 37% required a dose reduction, and 10% discontinued because of toxicity. The overall response rate was 57%, median progression-free survival was 13.7 months, and median overall survival was not reached. At 12 weeks, Functional Assessment of Cancer Therapy–General scores dropped between 0% and 10% from baseline, with less reduction in patients who continued treatment longer. Conclusion The primary end point of decreased grade 3 toxicity was not met; however, treatment with a 2/1 sunitinib schedule is associated with a lack of grade 4 toxicity, a low patient discontinuation rate, and high efficacy.

Bladder cancer is the sixth most common cancer in the US and most tumors have urothelial (transitional cell) histology. Platinum-based chemotherapy has long been the standard of care in advanced disease, but long-term outcomes have largely remained poor. Since the peak incidence of bladder cancer is in the eighth decade of life and beyond, medical comorbidities may often limit the use of chemotherapy. Immune checkpoint inhibitors with their favorable toxicity profiles and notable antitumor activity have ushered in a new era in the treatment of advanced urothelial cancer (UC) with five agents targeting the PD-1/PD-L1 pathway being recently approved by the US Food and Drug administration. A plethora of clinical trials are ongoing in diverse disease settings, employing agents targeting PD-1/PD-L1 and related immune checkpoint pathways. While reactivating anti-tumor immunity, these agents may lead to a unique constellation of immune-related adverse events, which may warrant discontinuation of therapy and potential use of immunosuppression. Novel combinations with various treatment modalities and optimal sequencing of active therapies are being investigated in prospective clinical trials and retrospective registries. At the era of precision molecular medicine, and since patients do not respond uniformly to these agents, there is a growing need for identification and validation of biomarkers that can accurately predict treatment response and assist in patient selection. This review discusses current updates and future directions of immunotherapy in advanced UC.

BACKGROUND The outcome of patients who progress on front-line immune-based combination regimens (IC) including immune checkpoint inhibitors (CPI) and receive subsequent systemic therapy is unknown. Methods Retrospective analysis of consecutive patients with clear-cell mRCC who progressed on one of seven clinical trials investigating an IC and received ≥1 line of subsequent VEGFR TKI therapy. Results Thirty-three patients [median age 57 (37–77), 85% male, 73% ECOG 0] were included. For evaluable patients (N = 28), the best response to first subsequent therapy was 29% partial response, 54% stable disease, and 18% progressive disease. The median PFS (mPFS) for first subsequent therapy was 6.4 months (95% CI, 4.4–8.4); no difference in mPFS by prior type of IC (VEGFR TKI-CPI vs. CPI-CPI) was noted (p = 0.310). Significant AEs were observed in 30% of patients, more frequently transaminitis (9%). Conclusions VEGFR TKIs have clinical activity in mRCC refractory to IC therapy, possibly impacted by the mechanism of prior combination therapy.

Little is known about the outcomes, safety, and response to subsequent therapies of patients with metastatic urothelial carcinoma (mUC) treated with atezolizumab outside clinical trials. The objectives of the study include to report the clinical efficacy and safety of atezolizumab, and the response to future therapies in clinical practice outside clinical trials. This is a retrospective, single-center study including consecutive patients with confirmed mUC who received at least one dose of atezolizumab 1200 mg every 3 weeks between May 2016 and April 2017. Seventy-nine patients, median age 72 years (range 29–93), 71% men and 76% ECOG PS 0–1, were identified. Most patients (79%) had primary cancer in the bladder, 62% had prior surgery, and 75% received at least one prior line of treatment (34 patients had prior cisplatin-based chemotherapy). Best response included 18% partial response, 29% stable disease, and 53% progressive disease. Patients were on atezolizumab for a median of 2.7 months (95%CI, 1.8–3.6) and median PFS was 3.2 months (95%CI, 1.6–4.8). A total of 33 (42%) patients had significant (any cause) AEs, including grade 4 hyperbilirubinemia in two patients; no toxic deaths were reported. At time of data analysis, only 18% of patients received at least one subsequent line of treatment for a median of 1.8 months (95%CI, 0.0–5.0) while 42% were referred to palliative care/hospice or died. Patients with mUC who progressed on atezolizumab were unlikely to receive subsequent systemic treatments and the benefit of those treatments appeared limited in our cohort. The findings may impact timing and designs of clinical trials in mUC.

Background Squamous cell carcinoma (SCC) is an uncommon histologic subtype of bladder cancer with limited data on treatment patterns, outcomes, and prognostic factors. “Real world” information might inform decision-making, prognostic estimates, and clinical trial designs. Patients and Methods A retrospective review of patients with tissue-confirmed bladder SCC treated at Cleveland Clinic from 2007 to 2016 was performed. Data on patient characteristics, treatment patterns, and clinical follow-up were extracted. Univariate analysis was used to identify predictors of overall survival (OS), recurrence-free survival (RFS) and time to recurrence. Results Of 58 identified patients, 42 had complete data available. Median age at diagnosis was 67 years (range, 37-90). Hematuria was the most common (71%) presenting symptom; 32 patients had pure SCC and 10 predominant/extensive squamous differentiation without major differences noted in clinicopathologic variables or outcomes among those 2 groups. Overall, 35 patients underwent cystectomy with 5 receiving neoadjuvant and 1 adjuvant chemotherapy, whereas 3 had chemotherapy for recurrent disease. Of patients with cystectomy, most had locally advanced disease (75% pT3/4, 35% pN+). Overall, 10 patients progressed and 14 died; median OS was not reached. The 2-year estimated OS, RFS, and cumulative incidence of recurrence were 61% ± 9%, 50% ± 9%, and 32% ± 9%, respectively. Hydronephrosis, older age (70 years or older), lymphovascular invasion, nodal metastases, and advanced T stage were associated with 1 or more poor outcomes. Conclusion In patients with resectable bladder SCC, radical cystectomy remains the main treatment modality. The role of perioperative chemotherapy remains unclear. The identified prognostic factors might be helpful for prognostication, treatment discussion, and trial eligibility/stratification.

BackgroundAs most of the patients previously enrolled in trials had nephrectomy before starting systemic treatment (syst-Rx), the response of the intact-Rmass to novel ICI and tyrosine kinase inhibitor (TKI) combination regimens is not well described.MethodsA retrospective review of 227 patients with mRCC who were treated with ICI (single agent or combinations) in the 1st- or 2nd-line was conducted. Following the appropriate regulatory process, collaborators from 6 US sites collected clinical, pathological, and outcome data via chart review. Overall response was investigator-assessed for all patients with at least one post-treatment scan or evidence of clinical progression after treatment initiation. Overall radiographic response (ORR) represents any radiographic response in the metastatic disease per investigator’s assessment. To accurately assess response in intact-Rmass, 3-dimensional measurement of the intact-Rmass was performed and Rmass volume was calculated at baseline and at the time of best overall response for 1st- and 2nd-line therapy. Radiographic response in intact-Rmass is defined as >30% decrease in the Rmass volume.ResultsMedian age at diagnosis was 62 years, 69% were male, 82% had clear cell histology. 15% and 12% had sarcomatoid and rhabdoid features, respectively. Overall, 82 patients (36%) had a measurable intact-Rmass while receiving syst-Rx. 63 (28%) patients never had a nephrectomy, and 10 (4%) patients had delayed nephrectomy after a good overall response to syst-Rx. 108 (48%) received ICI in 1st-line (88/108 received ipilimumab/nivolumab combination). 91 (40%), and 18 (8%) patients received TKI, or ICI+TKI in 1st-line. 161 (71%) and 86 (38%) of the patients received 2nd-line and 3rd-line therapy, respectively. 104 (46%) received ICI in 2nd-line (75/104 treated with single-agent ICI). 48 (21%), and 4 (2%) patients received TKI, or ICI+TKI in 2nd-line. Radiographic response in intact-Rmass for evaluable patients is summarized in table 1. The highest response rates in intact-Rmass were seen with ICI+TKI combinations. Higher rates of radiographic response in intact-Rmass were seen in patients treated with ICI in 1st-line compared to 2nd-line, possibly related to higher usage of ICI combinations (ipilimumab/nivolumab) in 1st-line. Overall metastatic disease response to different regimens in the 1st-line or 2nd-line was not different based on the history of nephrectomy prior to syst-Rx (table 2).Abstract 294 Table 1Radiographic response (≥30% decrease in volume) in the intact renal massAbstract 294 Table 2Overall radiographic response (ORR) per investigator assessmentConclusionsHigher radiographic response rates in the intact-Rmass were seen in patients treated with ICI+TKI and ICI in the 1st-line. There was no significant difference in overall metastatic disease response to 1st- or 2nd-line treatment based on the history of nephrectomy prior to syst-Rx.Ethics ApprovalEach of the 6 participating centers had their IRB approved protocol for retrospective study and data collection. Data Use Agreements were obtained for each center to share limited data set data with University of Wisconsin - Madison (IRB protocol UW17148 # 2018–0213). Final analysis was performed at University of Wisconsin.Consent not applicable to retrospective studies.

BackgroundIn clear cell renal cell carcinoma (ccRCC) the constitutive expression of hypoxia induced factor 1-α leads to increased expression of AXL. AXL overexpression has been associated with the development of resistance to VEGF inhibitors and suppression of the innate immune response through inhibition of macrophage-driven inflammation. AVB-S6-500 (AVB-500) is recombinant fusion protein dimer containing an extracellular region of human AXL combined with the human immunoglobulin G1 heavy chain (Fc), which demonstrates highly potent, specific AXL inhibition. In mouse ccRCC xenograft models, AVB-500 showed significantly more tumor reduction in combination with pazopanib versus pazopanib alone. In a Ph1b study of AVB-500 plus chemotherapy in platinum-resistant ovarian cancer (NCT03639246), no dose limiting toxicity (DLT) or treatment discontinuation due to adverse events was observed. The recommended phase 2 dose (RP2D) of 15 mg/kg was established by a model-informed drug development (MIDD) approach.MethodsThe P1b portion of this trial is a 3+3 dose escalation study to evaluate safety, pharmacokinetics, and pharmacodynamics of AVB 500 in combination with cabozantinib 60 mg daily. Dose levels of AVB-500 may include 15, 20, and 25 mg/kg every two weeks. The primary objective is to evaluate safety and tolerability. Secondary objectives include identification of the RP2D of AVB-500 and clinical activity. Key eligibility criteria include clear cell histology RCC and at least one prior line of therapy administered in the advanced or metastatic setting.ResultsAs of July 21, 2021, seven patients have received at least one dose of AVB-500 15 mg/kg and cabozantinib, with six patients ongoing treatment. No DLTs were observed. Trough levels at C1D15 were above the minimally efficacious concentration (MEC) identified from MIDD and GAS6 (AXL ligand) levels were suppressed prior to C2D1. Partial responses were observed in 3 of 5 patients (table 1); all patients demonstrated tumor decrease from baseline.Abstract 424 Table 1Preliminary clinical activity in NCT04300140ConclusionsAVB-500 in combination with cabozantanib demonstrates promising preliminary clinical activity and tolerability in patients with ccRCC. AVB-500 15 mg/kg is the presumptive RP2D with C1D15 AVB-500 troughs consistently above MECs observed. Safety, PK/PD and clinical activity will be updated at the time of presentation. (NCT04300140)Ethics ApprovalThis study has obtained ethics approval from WIRB Institutional Review Board®, Protocol ID #20200159, and all subjects provided informed consent prior to taking part in this study.

Despite significant changes in the therapeutic landscape of renal cell carcinoma, the majority of patients with metastatic disease eventually progress after first-line treatment with vascular endothelial growth factor receptors (VEGFR) tyrosine kinase inhibitor (TKI) therapy. Understanding existing data on subsequent therapies is crucial to define an optimal treatment sequence following first-line failure. This review examines the data supporting currently approved agents in this setting and provides a framework for decision-making regarding treatment sequencing beyond first-line therapy with VEGFR TKIs.

Background: Patients with renal cell carcinoma (RCC) are at a higher risk of thromboembolism (TE) compared to other cancers. Immunotherapy (IO) is a mainstay in the treatment of advanced or metastatic RCC (aRCC). It is still unknown whether IO further increases the hypercoagulable status in this already high risk population. We present the first analysis of the incidence and outcomes of venous (VTE) and arterial (ATE) events in patients with aRCC treated with immunotherapy. Methods: All patients with aRCC treated with IO at the Cleveland Clinic from 1/2015 to 12/2019 were identified. Cumulative incidence analysis was done to calculate rates of TE over time, and Gray's test was used to determine difference in rates of TE among groups. Factors associated with overall survival (OS) were identified using Cox proportional hazards regression, and the impact of TE on OS was evaluated with TE analyzed as a time dependent covariate. Results: Of 351 pts, 75% were men (median age 65 years, 92% white). 81% had clear cell histology and 77% had International Metastatic RCC Database Consortium intermediate to poor risk disease. Median follow up 12.8 months (range 0.1-53 months). From RCC diagnosis to IO initiation, the cumulative incidence of TE was 6.1% (95%CI 3.3-9.1) at 6 months and 6.1% (95%CI 3.8-9.1 months) at 12 months. At the time of IO start, 12% of patients were on anticoagulation, not specifically for TE related events. IO was used as first line therapy in 43% of patients (median doses 8, range 1-81) and included single agent (54% nivolumab, 13% pembrolizumab, 0.6% durvalumab, 1% atezolizumab, 0.2% avelumab) or doublet (30% ipilimuamb and nivolumab). VTE occurred in 11% (n=37), of which 62% were DVT, 27% PE, or 11% both. DVT locations were 74% lower limb, 7% upper limb, 19% visceral vein. ATE occurred in 2% (n=6), 4 had cerebral vascular events and 2 had myocardial infarctions. There was no difference in TE rates in patients receiving single versus doublet IO (p= 0.7475) For all patients, the incidence of TE after initiation of IO was 4.4% (95%CI 2.6%-6.9%) at 6 months and 9.8% (95%CI 6.8%-13.4%) at 12 months. Of all TE events, 72% resulted in hospitalization (mean duration of hospitalization 4 days), 9% of which resulted in clot related mortality. TE related dose delay occurred in 21% of patients (mean delay of 13 days). There were no TE-related IO discontinuations. The impact of IMDC score and Khorana score with respect to OS were evaluated in separate multivariable models given overlap in variables for score calculation. TE (HR 3.23, 95% CI 2.07-5.03, p Conclusion: Patients treated with IO therapy had a high incidence of TE at 12 months from treatment initiation. TE is associated with risk of treatment delay, hospitalization and mortality. TE, IMDC poor risk, and Khorana score ≥ 2 are associated with poorer survival. Further investigations into IO-associated TE are needed to identify benefit from primary thromboprophylaxis. Disclosures Gupta: Astra Zeneca: Consultancy; BMS: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Exelixis: Other; Janssen: Other. Khorana:Leap: Research Funding; BMS: Honoraria, Research Funding; Merck: Research Funding; Array: Other: Research funding (to institution); Janssen: Honoraria; Bayer: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Medscape: Honoraria; Leo Pharma: Honoraria; Seattle Genetics: Honoraria; Pharmacyte: Honoraria; Pharmacyclics: Honoraria.

Summary Background Checkpoint inhibitor therapy is a standard of care for patients with metastatic renal cell carcinoma. Treatment options after checkpoint inhibitor therapy include vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitors, although no prospective data regarding their use in this setting exist. Axitinib is a VEGF-R inhibitor with clinical data supporting increased activity with dose titration. We aimed to investigate the activity of dose titrated axitinib in patients with metastatic renal cell carcinoma who were previously treated with checkpoint inhibitor. Methods We did a multicentre, phase 2 trial of axitinib given on an individualised dosing algorithm. Patients at least 18 years of age with histologically or cytologically confirmed locally recurrent or metastatic renal cell carcinoma with clear cell histology, a Karnofsky Performance Status of 70% or more, and measurable disease who received checkpoint inhibitor therapy as the most recent treatment were eligible. There was no limit on number of previous therapies received. Patients received oral axitinib at a starting dose of 5 mg twice daily with dose titration every 14 days in 1 mg increments (ie, 5 mg twice daily to 6 mg twice daily, up to 10 mg twice daily maximum dose) if there was no axitinib-related grade 2 or higher mucositis, diarrhoea, hand-foot syndrome, or fatigue. If one or more of these grade 2 adverse events occurred, axitinib was withheld for 3 days before the same dose was resumed. Dose reductions were made if recurrent grade 2 adverse events despite treatment breaks or grade 3–4 adverse events occurred. The primary outcome was progression-free survival. Analyses were done per protocol in all patients who received at least one dose of axitinib. Recruitment has been completed and the trial is ongoing. This trial is registered with ClincalTrials.gov , number NCT02579811 . Findings Between Jan 5, 2016 and Feb 21, 2018, 40 patients were enrolled and received at least one dose of study treatment. With a median follow-up of 8·7 months (IQR 3·7–14·2), the median progression-free survival was 8·8 months (95% CI 5·7–16·6). Fatigue (83%) and hypertension (75%) were the most common all-grade adverse events. The most common grade 3 adverse event was hypertension (24 patients [60%]). There was one (3%) grade 4 adverse event (elevated lipase) and no treatment-related deaths occurred. Serious adverse events that were likely related to therapy occurred in eight (20%) patients; the most common were dehydration (n=4) and diarrhoea (n=2). Interpretation Individualised axitinib dosing in patients with metastatic renal cell inoma previously treated with checkpoint inhibitors did not meet the prespecified threshold for progression free survival, but these data show that this individualised titration scheme is feasible and has robust clinical activity. These prospective results warrant consideration of axitinib in this setting. Funding Pfizer.

Synchronous tumors are defined as two tumors arising concurrently or within six months of each other. Reports of synchronous RCC and breast cancer are limited to nonmetastatic renal cell carcinoma (RCC) and hormone receptor-positive infiltrative ductal carcinoma. We present the first case of synchronous metastatic renal cell carcinoma and metastatic triple-negative breast cancer, managed with a novel combination of immunotherapy and chemotherapy.

In 2018, the results of multiple phase III trials in metastatic renal cell carcinoma (mRCC) were presented. A phase III noninferiority trial demonstrated the importance of careful patient selection before cytoreductive nephrectomy. Additionally, three randomized phase III trials demonstrated the superiority of combination therapy with an immune-checkpoint inhibitor backbone versus sunitinib in patients with treatment-naive mRCC.