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Variant allele frequency of the alterations listed in Figure 2

Change in alterations across time points

Purpose:The role of circulating cell-free tumor DNA (ctDNA) as an adjunct to tissue genomic profiling is poorly defined in metastatic renal cell carcinoma (mRCC). In this study, we aim to validate previous findings related to genomic alteration (GA) frequency in ctDNA and determine the concordance between ctDNA and tissue-based profiling in patients with mRCC.Experimental Design:Results of 839 patients with mRCC who had ctDNA assessment with a Clinical Laboratory Improvement Amendments (CLIA)-certified ctDNA assay between November 2016 and December 2019 were collected. Tissue-based genomic profiling was collected when available and concordance analysis between blood- and tissue-based testing was performed.Results:ctDNA was assessed in 839 patients (comprising 920 samples) with mRCC. GAs were detected in 661 samples (71.8%). Tissue-based GAs were assessed in 112 patients. Limiting our analyses to a common 73-/74-gene set and excluding samples with no ctDNA detected, a total of 228 mutations were found in tissue and blood. Mutations identified in tissue (34.7%; 42/121) were also identified via ctDNA, whereas 28.2% (42/149) of the mutations identified in liquid were also identified via tissue. Concordance between ctDNA and tissue-based profiling was inversely related to the time elapsed between these assays.Conclusions:This study confirms the feasibility of ctDNA profiling in the largest mRCC cohort to date, with ctDNA identifying multiple actionable alterations. It also demonstrates that ctDNA and tissue-based genomic profiling are complementary, with both platforms identifying unique alterations, and confirms that the frequency of unique alterations increases with greater temporal separation between tests.

Stereotactic body radiation therapy (SBRT) has been shown to be safe and effective for delaying systemic treatment change among patients with metastatic renal cell carcinoma (mRCC). In this study, we sought to assess the genomic signatures of patients with mRCC who underwent SBRT for oligoprogression. A total of 30 patients with oligoprogressive disease were identified, the majority of whom had clear cell renal cell carcinoma (83.3%) and were receiving first-line treatment (53.3%). Genomic and transcriptomic sequencing were available in 20 and 16 patients, respectively. Duration of systemic treatment (DOT) was categorized as that prior (DOT[P]) and subsequent (DOT[S]) to radiation treatment. The median DOT(P) and DOT(S) were 15.1 and 18.3 mo, respectively, with a median DOT(S)/DOT(P) ratio of 1.4. Patients who had a DOT(S)/DOT(P) ratio of ≥1 had increased expression in pathways related to cell proliferation and development. In contrast, among patients with a ratio of ≤1, the reactive oxygen species pathway was enriched. This study highlights the potential role of genomics and transcriptomics to refine radiation treatment selection in patients with mRCC. PATIENT SUMMARY: In this study, we looked at mutations and genomic expressions among kidney cancer patients who responded better to stereotactic body radiotherapy. We found that enriched expression of certain pathways might play a role in response to radiotherapy.

OBJECTIVES: To better characterize the relay of information about prostate, kidney, and bladder cancer on Twitter in relation to the COVID-19 pandemic. MATERIALS AND METHODS: Tweets containing the joint hashtags “#COVID-19” and either “#bladder cancer”, “#kidney cancer”, or “#prostate cancer” were identified on the Twitter platform from January 1, 2020 to July 30, 2020. The Twitter handle responsible for each tweet was categorized as an Academic, Medical Education, Patient Advocacy Groups/Non-Profits, Pharmaceutical, or Other entity based on content domain. Descriptive statistics were used to summarize data on Twitter handle characteristics stratified by disease category (bladder, kidney, and prostate). Median/interquartile range and percentages were used to summarize continuous and categorical data, respectively. Number of tweets containing the relevant joint hashtags were tracked over time in relation to the cumulative United States case count of COVID-19. RESULTS: The content of 730 total tweets containing the joint hashtags “COVID-19” and either “#bladder cancer” (138 tweets), “#kidney cancer” (137 tweets), or “#prostate cancer” (455 tweets) from January 1, 2020 to July 31, 2020 were analyzed. We identified 326 unique Twitter handles across all disease states (62 bladder, 47 kidney, and 217 prostate-related). Academic Twitter handles accounted for the greatest number of tweets containing the joint hashtags (31%). Temporal tracking of tweets with regard to monthly U.S. COVID cases revealed that communication surged in March of 2020 and peaked in April for both bladder and kidney cancer, whereas related prostate cancer Twitter communication peaked in May of 2020. CONCLUSIONS: As COVID-19 case counts rose in the United States initially, so too did communication surrounding COVID-19 and genitourinary cancers on Twitter. Many of these conversations were driven by academically-associated Twitter accounts.

Previous studies have suggested that the gut microbiome influences the response to checkpoint inhibitors (CPIs) in patients with cancer. CBM588 is a bifidogenic live bacterial product that we postulated could augment CPI response through modulation of the gut microbiome. In this open-label, single-center study (NCT03829111), 30 treatment-naive patients with metastatic renal cell carcinoma with clear cell and/or sarcomatoid histology and intermediate- or poor-risk disease were randomized 2:1 to receive nivolumab and ipilimumab with or without daily oral CBM588, respectively. Stool metagenomic sequencing was performed at multiple timepoints. The primary endpoint to compare the relative abundance of Bifidobacterium spp. at baseline and at 12 weeks was not met, and no significant differences in Bifidobacterium spp. or Shannon index associated with the addition of CBM588 to nivolumab–ipilimumab were detected. Secondary endpoints included response rate, progression-free survival (PFS) and toxicity. PFS was significantly longer in patients receiving nivolumab–ipilimumab with CBM588 than without (12.7 months versus 2.5 months, hazard ratio 0.15, 95% confidence interval 0.05–0.47, P = 0.001). Although not statistically significant, the response rate was also higher in patients receiving CBM588 (58% versus 20%, P = 0.06). No significant difference in toxicity was observed between the study arms. The data suggest that CBM588 appears to enhance the clinical outcome in patients with metastatic renal cell carcinoma treated with nivolumab–ipilimumab. Larger studies are warranted to confirm this clinical observation and elucidate the mechanism of action and the effects on microbiome and immune compartments.

Background Tertiary cancer centers offer clinical expertise and multi‐modal approaches to treatment alongside the integration of research protocols. Nevertheless, most patients receive their cancer care at community practices. A better understanding of the relationships between tertiary and community practice environments may enhance collaborations and advance patient care. Methods A 31‐item survey was distributed to community and tertiary oncologists in Southern California using REDCap. Survey questions assessed the following attributes: demographics and features of clinical practice, referral patterns, availability and knowledge of clinical trials and precision medicine, strategies for knowledge acquisition, and integration of community and tertiary practices. Results The survey was distributed to 98 oncologists, 85 (87%) of whom completed it. In total, 52 (61%) respondents were community practitioners and 33 (38%) were tertiary oncologists. A majority (56%) of community oncologists defined themselves as general oncologists, whereas almost all (97%) tertiary oncologists reported a subspecialty. Clinical trial availability was the most common reason for patient referrals to tertiary centers (73%). The most frequent barrier to tertiary referral was financial considerations (59%). Clinical trials were offered by 97% of tertiary practitioners compared to 67% of community oncologists (p = 0.001). Most oncologists (82%) reported only a minimal‐to‐moderate understanding of clinical trials available at regional tertiary centers. Conclusions Community oncologists refer patients to tertiary centers primarily with the intent of clinical trial enrollment; however, significant gaps exist in their knowledge of trial availability. Our results identify the need for enhanced communication and collaboration between community and tertiary providers to expand patients’ access to clinical trials., Further relationships between community and tertiary medical oncologists are imperative to increasing clinical trial enrollment and successful patient outcomes. This study reports significant gaps in the knowledge of clinical trial availability among oncologists and identifies a need for increased communication and collaboration between the practice settings.

BackgroundCirculating cytokines and angiogenic factors have been associated with clinical outcomes in patients with metastatic renal cell carcinoma (RCC) receiving systemic therapy. However, none have yet examined cytokine concentrations in parallel cohorts receiving either immunotherapy or targeted therapy.MethodsIn this prospective correlative study, we enrolled 56 patients who were planned for treatment with either a vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) or immune checkpoint inhibitor (ICI). Eligibility requirements permitted any RCC histologic subtype, International Metastatic Renal Cell Carcinoma risk classification, and line of therapy. Immunologic profile was assessed at baseline and after 1 month on treatment using a Human Cytokine 30-plex protein assay (Invitrogen). Clinical benefit was defined as complete response, partial response, or stable disease ≥6 months per RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria.ResultsClinical benefit was similar between VEGF-TKI and ICI arms (65% vs 54%). Patients with clinical benefit from VEGF-TKIs had lower pretreatment levels of interleukin-6 (IL-6) (p=0.02), IL-1RA (p=0.03), and granulocyte colony-stimulating factor (CSF) (p=0.02). At 1 month, patients with clinical benefit from ICIs had higher levels of interferon-γ (IFN-γ) (p=0.04) and IL-12 (p=0.03). Among patients on VEGF-TKIs, those with clinical benefit had lower 1 month IL-13 (p=0.02) and granulocyte macrophage CSF (p=0.01) as well as higher 1 month VEGF (p=0.04) compared with patients with no clinical benefit.ConclusionFor patients receiving VEGF-TKI or ICI therapy, distinct plasma cytokines were associated with clinical benefit. Our findings support additional investigation into plasma cytokines as biomarkers in metastatic RCC.

4555 Background: Addition of SBRT to systemic therapy in oligoprogressive mRCC has been shown to prolong the duration of systemic treatment (Cheung et al Eur Urol 2021; De et al BJUI 2021). To date, the genomic predictors of benefit are unknown. We hypothesized that hypoxia-related genes would be associated with lesser benefit from SBRT. Methods: We retrospectively identified patients (pts) with mRCC who had oligoprogressive disease (progression of < 5 sites) while on systemic treatment and received SBRT without any systemic treatment change or interruption. Clinicopathologic characteristics, whole exome and transcriptome sequencing (Ashion Analytics) data were collected. Duration of systemic therapy (DOT) was quantified as systemic treatment duration prior to oligoprogression (DOT[P]) and after completion of SBRT (DOT[S]). The ratio of DOT[S]/DOT[P] was calculated and patients with a ratio ≥ 1.0 were considered to derive greater benefit from SBRT. The frequency of specific DNA alterations and RNA expression of pts above and below a DOT[S]/DOT[P] threshold of 1.0 was compared using a two-tailed Fischer’s exact and student’s t-test, respectively. Results: In this study, 23 mRCC pts who had oligoprogression during systemic treatment and received SBRT were identified. Within this cohort 16 pts (69.6%; M:F, 12:4) had available genomic data. Median age was 70 years and the most common histology was clear cell (87.5%). At the time of oligoprogression 11 pts (68.8%) were on immunotherapy, 4 pts (25.0%) were on targeted therapy. Median DOT[S] and DOT[P] were 12.6 months (range,0.7-46.3) and 13.4 months (range, 0.5-26.9), respectively, with a median DOT[S]/DOT[P] ratio of 1.4 (range,0.01-3.8). The most commonly mutated genes were VHL (56.3%), PBRM1 (37.5%), and SETD2 (37.5%). Alterations in VHL, PBRM1 and SETD2 were seen in 66.7% vs 42.9%, 33.3% vs 43.9%, and 44.4% vs 28.6% in patients with greater vs lesser benefit from SBRT, respectively (p≥0.05for each). Transcriptomic analysis was available in 9 pts and 1580 genes were noted to be differentially expressed between the groups (p < 0.05). Limiting scope to cancer genes in the COSMIC database, pts with lesser benefit from SBRT had higher expression of CDKN1B, CNBP, and FOXO3 whereas pts with greater benefit had higher expression of RNF43, POLD1 and PBRM1 (p < 0.05 for each). Gene set enrichment analysis showed a trend towards increased expression of hypoxia related genes in pts with lesser benefit. Conclusions: Our data align with existing studies supporting the role of SBRT in oligoprogressive mRCC. In addition, while clinical benefit from SBRT appears to be independent of DNA-level alterations, transcriptomic analysis revealed significant differences in gene expression. Hypoxia-associated signatures may be associated with lesser benefit from radiotherapy.

Purpose: The role of circulating cell-free tumor DNA (ctDNA) as an adjunct to tissue genomic profiling is poorly defined in metastatic renal cell carcinoma (mRCC). In this study, we aim to validate previous findings related to genomic alteration (GA) frequency in ctDNA and determine the concordance between ctDNA and tissue-based profiling in patients with mRCC. Experimental Design: Results of 839 patients with mRCC who had ctDNA assessment with a Clinical Laboratory Improvement Amendments (CLIA)-certified ctDNA assay between November 2016 and December 2019 were collected. Tissue-based genomic profiling was collected when available and concordance analysis between blood- and tissue-based testing was performed. Results: ctDNA was assessed in 839 patients (comprising 920 samples) with mRCC. GAs were detected in 661 samples (71.8%). Tissue-based GAs were assessed in 112 patients. Limiting our analyses to a common 73-/74-gene set and excluding samples with no ctDNA detected, a total of 228 mutations were found in tissue and blood. Mutations identified in tissue (34.7%; 42/121) were also identified via ctDNA, whereas 28.2% (42/149) of the mutations identified in liquid were also identified via tissue. Concordance between ctDNA and tissue-based profiling was inversely related to the time elapsed between these assays. Conclusions: This study confirms the feasibility of ctDNA profiling in the largest mRCC cohort to date, with ctDNA identifying multiple actionable alterations. It also demonstrates that ctDNA and tissue-based genomic profiling are complementary, with both platforms identifying unique alterations, and confirms that the frequency of unique alterations increases with greater temporal separation between tests.

Within the past decade, immunotherapy has revolutionized the treatment of advanced non-small lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs) such as pembrolizumab, nivolumab, atezolizumab, and durvalumab have shown superiority over chemotherapy regimens in patients with programmed death-ligand 1 (PD-L1) expression. Several predictive molecular biomarkers, including PD-L1 expression and high tumor mutation burden, have shown utility in discovering lung cancer patient groups that would benefit from ICIs. However, there remains to be a reliable imaging biomarker that would clearly select patients, through baseline or restaging imaging, who would respond or have a prolonged response to ICIs. The purpose of this review is to highlight the role of ICIs in patients with advanced NSCLC and past or current studies in potential biomarkers as well as future directions on the role of imaging in immunotherapy.

Background Immune Checkpoint Inhibitor (ICI) therapies have significantly improved overall survival in numerous cancers, but colitis has emerged as the most frequent dose-limiting toxicity associated with these therapies. Patients experiencing colitis side effects have to discontinue their cancer therapy to treat the colitis, which repositions life-threatening cancer. An ideal therapeutic would offer a colon-restricted approach to treating colitis side effects, while allowing patients to stay on their ICI therapy, an approach unavailable with currently approved therapies. Methods To test this localized approach for the treatment of ICI-mediated colitis, we have developed a new chemical entity as a next-generation candidate therapeutic designed for oral administration. Permeability was tested in predictive epithelial monolayers and confirmed in rodent pharmacokinetic studies. We tested the drug in the preclinical adoptive transfer model for colitis. In this model, immunodeficient mice are hosts for adoptive transfer of naive CD4+ T cells. In the absence of regulatory T cells, the transferred cells drive systemic inflammation and migrate to the colon, causing disease. Without treatment, these mice develop signs of colitis including weight loss, altered crypt architecture and infiltration of the lamina propria by week four. Furthermore, we developed a live biopsy culture system to test drug effects on ICI-colitis patient biopsies obtained via colonoscopy. Results In-vitro studies demonstrate that the drug has minimal toxicity and that it potently suppresses T cell proliferation and cytokine secretion. Permeability studies show a limited ability to cross the colonic mucosa restricting anti-inflammatory effects to sites of ulceration and active colitis. When colitis mice were given drug by oral gavage after colitis had developed, treated mice showed a significant increase in weight over controls and improved histological scores. Importantly, markers of systemic inflammation remained unchained, and the cancer-killing ability of the primary ICI therapy was preserved. Results of the live biopsy culture studies will be presented. Conclusions These preliminary studies demonstrate that the candidate therapeutic has potential to become a novel next-generation oral therapy for ICI-colitis because it effectively limits leukocyte function in-vitro and in-vivo with minimal systemic absorption and minimal expected side effects. Given the favorable drug profile and the rapid growth of ICI therapies, our colon-restricted colitis therapeutic has the potential to improve outcomes in a large number of cancer patients. We anticipate commencing first-in-human studies in Q4 of 2021. Acknowledgements None Ethics Approval The study was approved by City of Hope Cancer Center Institutional Review Board with the approval number of 19304.

Introduction: Focal adhesion kinase (FAK) is a promising target for the treatment of solid tumors because its expression has been linked to tumor progression, invasion, and drug resistance. Several FAK inhibitors have been developed and tested for efficacy in treating advanced cancers. Four FAK inhibitors have shown promising preclinical data and have advanced to clinical development in solid tumors.Areas covered: This article provides a systematic review on FAK inhibitors that have been tested or are currently in clinical trials in advanced solid tumors. We discuss the efficacy of GSK2256098, PF-00562271, VS-6063, and BI 853520 in the preclinical setting and summarize the results of phase I/II clinical trials evaluating these compounds.Expert opinion: The FAK inhibitors examined in clinical trials thus far have been shown to have manageable toxicity profiles and have demonstrated cytostatic effects as single agents, extending progression-free survival without producing a clinical or radiographic response. Trials are currently underway to strengthen the efficacy of treatment by combining FAK inhibitors with cytotoxic chemotherapy, targeted therapy, or immunotherapy. In the future, prognostic markers must be identified to carefully select patients who could benefit from FAK inhibitor treatment alone or in combination strategies.

372 Background: Multiple studies have suggested that the gut microbiome plays a modulatory role in ICI activity and that specific bacteria and/or cumulative microbial diversity may drive response in patients (pts) with mRCC (Routy et al Science 2018; Salgia et al Eur Urol 2020). Even though the tumor microenvironment has substantial bacterial proliferation (Heymann et al Cancer L. 2021), there is a paucity of data assessing the impact of intra-tumoral microbiota in response to ICI therapy. In this study, we sought to explore this association in pts with mRCC. Methods: Pts diagnosed with mRCC who had available RNA sequencing (RNA-seq) data collected in the course of routine clinical care and who were treated with ICIs were retrospectively identified.Intra-tumoral microbiome analysis was performed on formalin-fixed paraffin-embedded samples. Following quality and adapter trimming, RNA-seq reads were mapped to a human genome to filter host reads using the Burrows-Wheeler alignment (BWA) tool. Taxonomic classification was performed using Kraken2 and the absolute abundances of species were estimated using Bracken. The relative abundances among all non-human species were calculated. Statistical testing with Student’s t-test was performed to compare the relative abundance for all species seen within pts who responded to ICIs and those who did not. Results: Among the 28 pts (22:6, M:F) included in this analysis, 24 (86%) had clear cell histology and 20 (71%) were IMDC intermediate/poor risk. All of the samples were collected prior to starting treatment with ICIs and the majority of these (57%) were collected from the primary site. 11 pts (39%) received ICIs as first line treatment and 17 (61%) as second line. Clinical response was seen in 50% of pts included in the study and the most common rendered treatment was nivolumab (17 pts). In the overall cohort, Cutibacterium acne, Moraxella osloensis, and Pasteurella multocida had the highest relative abundances. Additionally, significant differences in relative abundances of specific bacteria were found between ICI responders and non-responders. Among these, Stenotrophomonas maltophilia (p = 0.037) and Corynebacterium sp. zg-917 (p = 0.035) had significantly higher relative abundances in pts who responded to ICIs. Conclusions: This is the first study evaluating the association between intra-tumoral microbiome and response to ICIs in pts with mRCC. Among bacteria associated with response, several have particular relevance – for instance, Corynebacterium spp. have been studied for decades as a possible adjunct to immunotherapeutic agents such as BCG. Efforts are ongoing to validate these findings in a larger cohort.

327 Background: Patients with cancer may possess limited knowledge of emerging modalities in oncology, including genomic profiling (GP) tests, which can create barriers to shared decision making. Effective provider communication can address such barriers but little is understood regarding patients’ perceptions of GP. Methods: In this cross-sectional study, patients who were diagnosed with advanced genitourinary cancers (bladder, renal, and prostate cancers), and were referred for GP responded to a survey to assess reasons to pursue such testing. Clinicopathologic characteristics were collected via chart review. Kolmogorov-Smirnov tests were used to assess associations between reasons to pursue GP and patient characteristics. Results: Data was obtained from a sample of 126 patients (gender: 75% M, 25% F; average age: 67; marital status: 78% married; education: 76% some college; histology: 67% renal cell carcinoma, 19% urothelial, and 14% prostate). The most common reasons to pursue GP by patient response were: to guide treatment (73%), to improve treatment response (32%), to follow physician’s indication (27%), to predict treatment response (23%), to learn about their disease (19%), and to contribute to the science (12%). Notably, older age was significantly associated with three reasons (guide treatment, P = 0.001; physician’s indication, P = 0.03; contribute to the science, P = 0.001). No association was found among younger patients. A higher level of education was associated with the desire to guide treatment (P = 0.001). In contrast, a lower level of education was associated with physician’s indication (P = 0.002). Conclusions: This study highlights important associations between reasons to pursue GP and age and level of education. Differing strategies for information delivery could be considered when communicating GP benefits to older patients and to patients with lower levels of education.

185 Background: Short-term effectiveness of COVID-19 vaccination is widely demonstrated, but the emerging real-world data suggest that immunity may wane over-time (Levin et al. NEJM 2021). Herein we aimed to explore the long-term efficacy of the COVID-19 vaccination among pts with genitourinary cancer. Methods: In this study, pts with genitourinary malignancies (prostate, kidney, and bladder cancers) who had not received COVID-19 vaccination were included. Blood samples were collected prior to and after one dose of either an adenovirus- or mRNA-based COVID-19 vaccine at the 2- and 6-month timepoints. Additional blood samples from pts receiving systemic treatment were collected at 3 consecutive therapy cycles following vaccination. Antibody titers were assessed using the SCoV-2 Detect IgG ELISA assay and results were reported as immune status ratios (ISR). T-cell receptor (TCR) repertoire sequencing was performed using the MiXCR software (MiLabs) and custom strips were used to assess TCR abundance and homology clustering. Results: A total of 183 pts were enrolled, and 136 pts provided baseline blood samples. Among these, 59 (8:51 F:M) provided samples for both the 2- and 6-month timepoints by the 10/6/2021 data cut-off. In this subset of pts, median age was 66 (range 48-85) and 33 (55.9%), 25 (42.4%), and 1 (1.7%) pts had prostate, kidney, and bladder cancer, respectively. A majority of the pts (93.2%) were on systemic treatment with 23.7% on immune checkpoint inhibitors, 18.6% on targeted agents, and 1.7% on chemotherapy. The most commonly administered vaccines were BNT162b2 (61.0%) followed by mRNA-1273 (37.3%) and Ad26.COV2.S (1.7%). The mean (±standard deviation) ISR values at baseline and 2 months were 0.68±1.59 and 6.62±1.75, respectively. At the 6-month timepoint, mean ISR was 5.46±1.61; this was significantly lower than the 2-month antibody titers (p < 0.0001), and reflects a reduction of 17.6%. Further data on TCR sequencing will be presented at the meeting. Conclusions: To our knowledge, this is the first data assessing the long-term serologic outcomes of COVID-19 vaccination in pts with cancer. Our data suggest waning immunity over time in cancer pts. Strategies to prolong host immunity against SARS COV-2 (e.g., booster vaccination) are likely warranted.

386 Background: Aberrant alternative splicing (AS) events have been implicated in the initiation and progression of various cancers; however, the detailed nature of their role in RCC is yet to be fully elucidated. Our study aims to characterize AS events in RCC tumors using a novel AS pipeline (Bisbee). Methods: We retrospectively identified patients (pts) with RCC who had tumor-normal whole exome sequencing and tumor whole transcriptome sequencing (GEMExtra, Ashion Analytics) performed as part of their routine clinical care. AS events from RNA sequencing data were identified and further characterized as (1) alternative splice 3’ site (A3), (2) alternative splice 5’ site (A5), (3) exon skipping (ES), (4) intron retention (IR), and (5) mutually exclusive exons splice events (MUT). The Bisbee outlier analysis was performed against normal kidney tissues from the GTEx tissue library to further identify tumor-associated splice events. Outlier splice events were categorized as either non-coding/protein loss/silent, isoform switch, novel, or unknown. Results: Overall, 147 RCC pts (77% male) with RNA sequencing data were included in this analysis. Median age at diagnosis was 60 (range 31-94) and 97% of pts had metastatic RCC. The distribution of histology was 85% clear cell RCC followed by 11% papillary RCC. The AS analysis identified 25,928 outlier splice events. Approximately 60% of these were predicted to be protein-coding events, with the majority arising from IR and ES. These were followed by A3, A5, and MUT, in descending order of frequency. We also examined tumor-associated novel outlier events where 70% of analyzed RCC tumor samples noted 34 tumor-associated novel events were present, shared in most of the cohort and found an enrichment for IR events leading to frame disruptions. Data of splice variants will be presented at the meeting. Conclusions: In depth examination of this large cohort suggests that IR resulting from AS events occur frequently within RCC. Further efforts to investigate the association of AS events and clinical outcomes are underway.

328 Background: Previous studies have shown that a significant proportion of patients with metastatic genitourinary cancers harbor inaccurate expectations of cure prior to starting treatment with immunotherapy. This study sought to compare changes in perceptions of immunotherapy reported before, and three months after, the start of therapy, as well as treatment side-effects and quality of life. Methods: This longitudinal study enrolled patients diagnosed with advanced genitourinary cancers (bladder, renal, and prostate cancers) prior to commencing immunotherapy. Patients’ perceptions were assessed prior to starting treatment (T0) and three months later (T1). Patients responded to the same survey at both time points assessing expectations of side effects, clinical outcomes (expectation of cure) and quality of life (Functional Assessment of Chronic Illness Therapy-General). Results: Among the 30 patients enrolled, the median age was 67 years old (range, 44-91); most were male (70%), married (80%), and well-educated (70%). Renal cell carcinoma (70%) was the most common form of cancer. Before starting immunotherapy (T0), patients expected (1) fewer side effects (83%) compared with other types of cancer treatment, (2) great efficacy in preventing tumor progression (90%). and (3) increased survival (90%). Notably, the expectation of cure with immunotherapy treatment had changed over time (T0 = 24% vs T1 = 7%; P = 0.001) and overall quality of life had increased (median at T0 = 90 vs T1 = 98; P = 0.01). Three months into treatment (T1), patients perceived themselves as less active (T0 = 70% vs T1 = 63%; P = 0.02), however just 16% reported severe side effects, including fatigue (10%) and diarrhea (10%). In general, patients were satisfied with the management of these side effects (60%). The majority of patients perceived improvement in their condition (50%) and were satisfied with their treatment (60%). Conclusions: This longitudinal study suggests that inaccurate perceptions of cure with immunotherapy may recede over time, with an increased proportion of patients estimating a more accurate (and lower) chance of cure after 3 months of treatment. Patients also reported improved quality of life despite these adjusted expectations of cure.

336 Background: SBRT in indicated for the management of locally recurrent and oligometastatic mRCC as per National Comprehensive Cancer Network guidelines. Our study evaluates both the efficacy of radiotherapy (RT) in prolonging systemic treatment along with RT toxicity in the oligoprogressive RCC setting. Methods: A single institution retrospective data collection was performed in which we identified mRCC patients who experienced oligoprogression (defined as

561 Background: Recently published data suggests that the presence of a TERT promoter mutation is predictive of superior overall survival (OS) in patients (pts) with advanced/metastatic bladder cancer (mUC) treated with an immune checkpoint inhibitor (ICI) (Kouchkovsky et al, JITC 2021). We aim to validate the results of this study in a large independent cohort. Methods: Pts with mUC treated at two tertiary cancer centers with available genomic data collected in the course of routine clinical care were identified retrospectively. Pts that had received at least one line of ICI therapy in the metastatic setting were selected. Demographic and treatment data were collected, with pts divided into two groups based on the presence or absence of TERT mutation status ( TERTm or TERTwt, respectively). We evaluated OS from diagnosis of at least muscle invasive disease, progression free survival (PFS), and objective response rate (ORR) with ICI therapy across the two groups. OS in our cohort was compared with findings from pts with bladder cancer in The Cancer Genome Atlas (TCGA) database. Results: From our combined data sets, a total of 166 pts had available genomic data, with 64 TERTm pts (52:12 M:F) and 58 TERTwt pts (32:26 M:F) meeting criteria for inclusion. Median age at diagnosis was 67 in both groups. The site of primary disease was bladder in 54 (84%) TERTm vs. 41 (71%) in TERTwt; 10 (16%) and 17 (29%) had upper tract disease, respectively. 47 (73%) TERTm pts and 40 (69%) TERTwt pts had pure urothelial disease; 17 (27%) and 18 (31%) pts had mixed/pure variant histology, respectively. 37 (58%) and 42 (72%) pts received first-line ICI therapy whereas 27 (42%) and 16 (28%) received subsequent-line therapy in TERTm and TERTwt, respectively. At the time of analysis, there were 24 (38%) patients alive in TERTm, and 23 (40%) patients alive in TERTwt. OS was 35 vs. 36 mos (95% CI 0.62-1.51, P=0.66) in TERTm and TERTwt, respectively. PFS on ICI therapy was 4.6 vs. 5.3 mos (95% CI 0.58-1.34, P≥0.99) in TERTm and TERTwt, respectively. ORR was 75% in TERTm and 50% in TERTwt (P=.004). OS in the TCGA database was 35 mos in TERTm and 47 in TERTwt (P=0.19) from a total of 311 and 127 pts, respectively. Conclusions: In contrast to previously published data, our data show no difference in OS and PFS on the basis of TERT mutational status in pts with mUC treated with ICI therapy. Further analysis from larger datasets is needed to reconcile the role of TERT mutations within this patient population.

Background: Preliminary studies have characterized potential adverse effects associated with COVID-19 vaccination in pts with cancer. However, biological characterization of vaccine response has yet to be performed. Methods: Eligible pts with advanced GU cancers (metastatic/unresectable prostate, bladder and renal cell carcinoma [RCC]) and had not yet received COVID-19 vaccination. Pts were consented to receive sequential blood draws prior to vaccination and at landmarks of 2, 6, and 12 mos following vaccination. Pts on systemic treatment had additional blood draws coinciding with their first 3 cycles of therapy following vaccination. Ab titers to SARS-CoV-2 were quantified via ELISA and reported as an immune status ratio (ISR). RNA was extracted from PBMC aliquots, converted into cDNA and TCR α/β sequences were selectively amplified. TCR abundance and homology clustering was performed using custom scripts. Results: As of May 14, 2021, 130 pts had consented to the study of whom 126 pts submitted baseline (BL) specimens. The current analysis focuses on 56 pts who submitted cycle 1 (C1) specimens. Among these, 29, 26, and 1 pts had RCC, prostate and bladder cancer, respectively;19 were on checkpoint inhibitor (CPI)-based regimens while 37 were on non-CPI regimens. BNT162b2 (Pfizer) was the most commonly administered vaccine in the cohort (n=29), followed by mRNA-1273 (Moderna;n=26). COVID-19 Ab titers increased significantly from BL to C1 across the cohort from 0.19 (interquartile range [IQR] 0.12-0.18) to 4.37 (IQR 0.2-6.60;P

4513 Background: Recent evidence suggests that the gut microbiome is a potent mediator of immune checkpoint inhibitor (ICI) activity in metastatic renal cell carcinoma (mRCC), with both specific bacterial species and cumulative microbial diversity driving response (Routy et al Science 2018; Salgia et al Eur Urol 2020). We examined whether the butyrate-producing bacterium Clostridium butyricum, the key constituent of CBM-588, could modulate the gut microbiome in patients (pts) with mRCC receiving nivolumab/ipilimumab (N/I) and secondarily improve clinical outcome. Methods: An open-label, randomized study was conducted, with key eligibility criteria including confirmed clear cell and/or sarcomatoid mRCC, intermediate/poor risk by IMDC criteria and no systemic therapy for metastatic disease. Patients were randomized 2:1 to receive either N/I+CBM-588 or N/I alone. N/I was dosed at 3 mg/kg and 1 mg/kg IV every 3 weeks for 12 weeks, followed by N at 480 mg IV every 4 weeks. CBM-588 was dosed orally at 80 mg bid. Stool was collected for bacteriomic profiling at baseline and 12 weeks. Metagenomic sequencing was employed using previously published methods (Dizman et al Cancer Med 2020). The primary endpoint of the study was change in Bifidobacterium spp. from baseline to week 12. Secondary endpoints included change in microbial diversity and clinical outcomes including response rate (RR) and progression-free survival (PFS). Results: 30 pts were randomized between April 2019 and Nov 2020; 1 pt was excluded after genomic sequencing clarified a diagnosis of sarcoma. Among 29 evaluable patients (21:8 M:F), median age was 66, 10 pts (34%) had sarcomatoid features and 24 pts (83%) were intermediate risk. Metagenomic sequencing of paired stool specimens showed an 8-fold increase in B. bifidum and a 6-fold increase in B. adolescentis in pts receiving N/I+CBM-588 from baseline to week 12. C. butyricum was detected only in pts receiving CBM-588. Pathogenic species (e.g., Escherichia. coli and Klebsiella spp.) were more prevalent in pts not receiving CBM-588. RR was significantly higher among pts receiving N/I+CBM-588 vs N/I alone (59% vs 11%; P = 0.024). Median PFS was also prolonged with the addition of CBM-588 to N/I (NR vs 11 weeks; P < 0.001). No significant difference in grade 3/4 toxicities were observed between study arms. Conclusions: This is the first randomized, prospective study to suggest enhancement of ICI response with a live bacterial product. The observed clinical impact is corroborated by biologic findings supporting gut modulation by CBM-588. Clinical trial information: NCT03829111.

1538 Background: Although many tertiary cancer centers offer access to myriad research protocols, the majority of patients nevertheless receive treatment at community practices. We sought to examine the barriers that hamper clinical collaboration between tertiary and community practice environments in Southern California. Methods: A 31-item survey was distributed to community and tertiary oncologists using REDCap, a browser-based electronic data capture system. Survey questions assessed the following attributes: demographics and features of clinical practice, referral patterns, availability and knowledge pertaining to clinical trials, strategies for knowledge acquisition, and integration of community and tertiary practices. Results: The survey was distributed to 98 oncologists, 85 (87%) of whom completed it in full. The most common institutional affiliations were City of Hope Comprehensive Cancer Center (58%), University of California, Los Angeles (10%), and Cedars Sinai Medical Center (8%). In total, 52 (61%) respondents were community practitioners and 33 (38%) were tertiary oncologists. A majority (56%) of community oncologists defined themselves as general oncologists whereas almost all (97%) tertiary oncologists reported a subspecialty. Clinical trial availability was the most common reason for pt referrals to tertiary centers (73%). The most frequent barrier to tertiary referral was financial considerations (59%). Clinical trials were offered by 97% of tertiary practitioners as compared to 67% of community oncologists (p = 0.001). Of note, while a majority of tertiary center providers (52%) described the primary value of community practices to be a source of referrals for clinical trials, most community oncologists (82%) reported only a minimal-to-moderate understanding of clinical trials available at regional tertiary centers. Conclusions: Community oncologists refer patients to tertiary centers primarily with the intent of clinical trial enrollment; however, significant gaps exist in their knowledge of trial availability. Our results identify the need for enhanced communication and collaboration between community and tertiary providers to expand patients’ access to clinical trials.

282 Background: TERT and BAP1 mutations are associated with poor clinical outcome in patients (pts) with metastatic renal cell carcinoma (mRCC) (Dizman et al JITC 2020; Joseph et al J Urol 2016). In this study we explore radiogenomics as a non-invasive method to identify these alterations. Methods: Pts with mRCC who had genomic testing in the course of routine clinical care were included in the current analysis. Pts were assessed with the GEM Extra assay, a CAP-accredited, CLIA-certified test encompassing paired tumor-normal whole exome sequencing (WES) and tumor whole transcriptome sequencing (TGen; Phoenix, AZ). Pts underwent CT imaging; radiomic analysis was performed on the segmented metastatic and primary lesions. Features were independently correlated with TERT and BAP1 mutation status to generate Pearson correlation values (PCVs). Results: 92 pts (65:27 M: F) were included in the analysis; of these, the majority of pts (84%) had clear cell histology. Alterations in the TERT gene were seen in 12 pts. In these pts 1,325 radiomic features of the primary tissue were examined and 251 features correlated with a PCV ≥ |0.2|. Of these, 42 features were correlated with a PCV ≥ |0.3|. Highest correlation with TERT mutation was seen with Gray Level Cooccurrence Matrix (GLCM) and First Order Features (FOF). 9 pts had BAP1 mutation with 5 detected in primary tumor and 4 in metastatic sites. Analysis of primary tumor imaging yielded no significant associations between radiomic features and BAP1 mutation. However, out of approximately 1,500 radiomic features noted in metastatic sites, 111 features correlated with BAP1 mutation with a PCV ≥ 0.2. Of these, 15 features correlated with a PCV ≥ 0.3. The radiomic features with the highest correlation with BAP1mt were Gray Level Dependence Matrix (GLDM) and GLCM. Conclusions: By identifying a correlation between radiomic features of TERT mutation in primary tumors and BAP1 mutation in metastatic sites, our work may ultimately yield a non-invasive method of discerning mutational status in patents with mRCC. Efforts are ongoing to validate our findings within The Cancer Imaging Archive.

We present a patient with leptomeningeal carcinomatosis from breast cancer treated with intrathecal topotecan and intravenous eribulin. The regimen was well tolerated and provided clinical stability in a patient with progression on a prior intrathecal chemotherapy regimen.