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BACKGROUND Immune checkpoint inhibitors (ICIs) represent an appealing treatment for patients with advanced urothelial cancer (aUC) and a poor performance status (PS). However, the benefit of ICIs for patients with a poor PS remains unknown. It was hypothesized that a poor Eastern Cooperative Oncology Group (ECOG) PS (≥2 vs 0-1) would correlate with shorter overall survival (OS) in patients receiving ICIs. METHODS In this retrospective cohort study, clinicopathologic, treatment, and outcome data were collected for patients with aUC who were treated with ICIs at 18 institutions (2013-2019). The overall response rate (ORR) and OS were compared for patients with an ECOG PS of 0 to 1 and patients with an ECOG PS ≥ 2 at ICI initiation. The association between a new ICI in the last 30 and 90 days of life (DOL) and death location was also tested. RESULTS Of the 519 patients treated with ICIs, 395 and 384 were included in OS and ORR analyses, respectively, with 26% and 24% having a PS ≥ 2. OS was higher in those with a PS of 0 to 1 than those with a PS ≥ 2 who were treated in the first line (median, 15.2 vs 7.2 months; hazard ratio [HR], 0.62; P = .01) but not in subsequent lines (median, 9.8 vs 8.2 months; HR, 0.78; P = .27). ORRs were similar for patients with a PS of 0 to 1 and patients with a PS ≥ 2 in both lines. Of the 288 patients who died, 10% and 32% started ICIs in the last 30 and 90 DOL, respectively. ICI initiation in the last 30 DOL was associated with increased odds of death in a hospital (odds ratio, 2.89; P = .04). CONCLUSIONS Despite comparable ORRs, ICIs may not overcome the negative prognostic role of a poor PS, particularly in the first-line setting, and the initiation of ICIs in the last 30 DOL was associated with hospital death location.

Objective To evaluate the relationship between dynamic changes in the modified Glasgow Prognostic Scale (mGPS) and postnephrectomy survival among localized clear cell renal cell carcinoma (ccRCC) patients. Methods We retrospectively identified patients who underwent nephrectomy for localized ccRCC with preoperative mGPS = 0 from 2005 to 2018. The primary exposure of interest was ΔmGPS between 2 points – 60 days prior to surgery and 1 year after surgery. We assessed the relationship between ΔmGPS and survival outcomes. Kaplan-Meier curves were generated to determine survival estimates and Cox proportional hazards models were fit to estimate hazard ratios (HRs). Multivariable models were constructed using both ΔmGPS and clinical variables known to be associated with differences in survival. Results We identified 313 patients for our analytic cohort with a median follow-up time of 20.2 months. Thirty-seven (11.9%) patients died and 39 (12.54%) showed recurrence during follow-up. Two hundred sixty-three (84.6%) patients had unchanged mGPS before and after surgery, while 48 (15.4%) patients showed an increase in postoperative mGPS from preoperative mGPS. Compared to patients with unchanged mGPS, patients with a higher postoperative mGPS had an increased risk of death (HR = 3.05 [1.39-6.68], P = .005) and recurrence (HR = 2.98 [1.34-6.64], P = .008). Conclusion Patients with an increase in mGPS following nephrectomy for ccRCC were more likely to die and experience cancer recurrence. Assessing dynamic changes in this cheap, validated, and reproducible test may be useful in identifying patients at higher risk for more aggressive disease or for counseling patients regarding risk of cancer recurrence.

BACKGROUND: Biomarkers to guide treatment in metastatic renal cell carcinoma (mRCC) are lacking. We aimed to investigate the association between pretreatment neutrophil-to-lymphocyte ratio (NLR) and outcome of patients with mRCC receiving nivolumab. METHODS: Through retrospective chart review, we identified 38 patients with mRCC treated with standard of care nivolumab between 2015 – 2016 at Winship Cancer Institute of Emory University. NLR was determined from complete blood count collected prior to starting treatment and imaging was performed to assess progression. The NLR cutoff value of 5.5 was determined by log rank test, and the univariate association with overall survival (OS) or progress free survival (PFS) was assessed by Cox proportional hazard model and Kaplan-Meier method. RESULTS: The 38 patients had a median age of 68.5 years. The PFS and OS for all patients at 12 months was 54% and 69%, respectively. The median PFS was 2.6 months in the high NLR group but not reached in the low NLR group. Low NLR was strongly associated with increased PFS with hazard ratio of 0.20 (95%CI 0.07–0.64; p=0.006). The median OS was 2.7 months in the high NLR group but not reached in the low NLR group. Low NLR was significantly associated with a prolonged OS with hazard ratio of 0.06 (95% CI 0.01–0.55; p=0.012). CONCLUSION: Pre-treatment NLR less than 5.5 is associated with superior PFS and OS. NLR is a biomarker that can inform prognosis for patients with mRCC and should be further validated in larger cohorts and in prospective studies.

Importance Patients with brain metastases from renal cell carcinoma (RCC) have been underrepresented in clinical trials, and effective systemic therapy is lacking. Cabozantinib shows robust clinical activity in metastatic RCC, but its effect on brain metastases remains unclear. Objective To assess the clinical activity and toxic effects of cabozantinib to treat brain metastases in patients with metastatic RCC. Design, Setting, and Participants This retrospective cohort study included patients with metastatic RCC and brain metastases treated in 15 international institutions (US, Belgium, France, and Spain) between January 2014 and October 2020. Cohort A comprised patients with progressing brain metastases without concomitant brain-directed local therapy, and cohort B comprised patients with stable or progressing brain metastases concomitantly treated by brain-directed local therapy. Exposures Receipt of cabozantinib monotherapy at any line of treatment. Main Outcomes and Measures Intracranial radiological response rate by modified Response Evaluation Criteria in Solid Tumors, version 1.1, and toxic effects of cabozantinib. Results Of the 88 patients with brain metastases from RCC included in the study, 33 (38%) were in cohort A and 55 (62%) were in cohort B; the majority of patients were men (n = 69; 78%), and the median age at cabozantinib initiation was 61 years (range, 34-81 years). Median follow-up was 17 months (range, 2-74 months). The intracranial response rate was 55% (95% CI, 36%-73%) and 47% (95% CI, 33%-61%) in cohorts A and B, respectively. In cohort A, the extracranial response rate was 48% (95% CI, 31%-66%), median time to treatment failure was 8.9 months (95% CI, 5.9-12.3 months), and median overall survival was 15 months (95% CI, 9.0-30.0 months). In cohort B, the extracranial response rate was 38% (95% CI, 25%-52%), time to treatment failure was 9.7 months (95% CI, 6.0-13.2 months), and median overall survival was 16 months (95% CI, 12.0-21.9 months). Cabozantinib was well tolerated, with no unexpected toxic effects or neurological adverse events reported. No treatment-related deaths were observed. Conclusions and Relevance In this cohort study, cabozantinib showed considerable intracranial activity and an acceptable safety profile in patients with RCC and brain metastases. Support of prospective studies evaluating the efficacy of cabozantinib for brain metastases in patients with RCC is critical.

We present the first reported work that explores the potential of radiomics to predict patients who are at risk for developing immunotherapy-induced pneumonitis. Despite promising results with immunotherapies, immune-related adverse events (irAEs) are challenging. Although less common, pneumonitis is a potentially fatal irAE. Thus, early detection is critical for improving treatment outcomes; an urgent need to identify biomarkers that predict patients at risk for pneumonitis exists. Radiomics, an emerging field, is the automated extraction of high fidelity, high-dimensional imaging features from standard medical images and allows for comprehensive visualization and characterization of the tissue of interest and corresponding microenvironment. In this pilot study, we sought to determine whether radiomics has the potential to predict development of pneumonitis. We performed radiomic analyses using baseline chest computed tomography images of patients who did (N = 2) and did not (N = 30) develop immunotherapy-induced pneumonitis. We extracted 1860 radiomic features in each patient. Maximum relevance and minimum redundancy feature selection method, anomaly detection algorithm, and leave-one-out cross-validation identified radiomic features that were significantly different and predicted subsequent immunotherapy-induced pneumonitis (accuracy, 100% [p = 0.0033]). This study suggests that radiomic features can classify and predict those patients at baseline who will subsequently develop immunotherapy-induced pneumonitis, further enabling risk-stratification that will ultimately lead to better treatment outcomes.

Objective Several inflammatory markers have been studied as potential biomarkers in renal cell carcinoma (RCC), however few reports have analyzed their prognostic value in aggregate and in non-clear cell histologies. We hypothesize that a combination of specific inflammatory markers into an RCC Inflammatory Score (RISK) could serve as a rigorous prognostic indicator of overall survival (OS) in patients with clear cell and non-clear cell RCC. Methods Patients undergoing nephrectomy for RCC were queried from our institutional database. Primary outcome was OS. Our exposure was RISK, based on a combination of preoperative C-reactive protein (CRP), albumin, erythrocyte sedimentation rate (ESR), corrected calcium, and aspartate transaminase to alanine transaminase (AST)/(ALT) ratio. RISK was developed using grid-search methodology, receiver-operating-characteristic (ROC) analysis, and sensitivity-specificity trade-off analysis. Prognostic value of RISK was analyzed using the Kaplan–Meier method and Cox proportional regression models. ROC and chi-square analyses were performed to compare the predictive accuracy of RISK to Size, Size, Grade, and Necrosis (SSIGN) score, UCLA Integrated Staging System (UISS), and Leibovich Prognosis Score (LPS). Results Among 391 RCC patients treated with nephrectomy, area under the curve (AUC) for RISK was 0.783, which was comparable to SSIGN (AUC 0.776, p = 0.82) and UISS (AUC 0.809, p = 0.317). Among patients with localized disease, AUC for RISK and Leibovich Prognosis Score was 0.742 and 0.706, respectively (p = 0.456). On multivariate analysis, we observed a step-wise statistically significant inverse relationship between increasing RISK group and OS (all p

4510 Background: The HCRN GU16-260 trial reported on the efficacy and toxicity of nivo monotherapy in treatment naïve clear cell RCC (Cohort A) and the efficacy of nivo/ipi salvage therapy in pts with tumors resistant to initial nivo monotherapy (Atkins JCO 2020.38.15_suppl.5006). Limited information is available on the effects of such an approach in pts with advanced nccRCC. Methods: Eligible pts with treatment-naïve nccRCC 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 (mo) prior to study entry and prior to enrolling on Part B for correlative studies. Results: 35 pts with nccRCC were enrolled between 5/2017 and 12/2019 at 12 participating HCRN sites. Median age 63 (range 35-84 years); 89% male. IMDC favorable 8 (23%), intermediate 18 (51%) and poor risk 9 (26%). Of the 35 pts 19 (54%) had papillary, 6 (17%) chromophobe and 10 (29%) unclassified histology. RECIST defined ORR was 5 of 35 (14.3%) [CR 2 (5.7%), PR 3 (8.6%)], SD 16 (45.7%), PD 14 (40.0%). Immune-related ORR was 8 of 35 (22.9%). RECIST ORR by histology was: papillary - 1/19 (5%); chromophobe - 1/6 (17%); unclassified - 3/10 (30%). 9 pts (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified, 1 papillary) responding. Median PFS was 4.0 (2.7, 4.3) mo. 21 pts remain alive. None of the responders have progressed or died. 28 pts (25 PD, 3 pSD) were potentially eligible for salvage nivo/ipi (Part B), but 12 did not enroll due to symptomatic PD (2), grade 3-4 toxicity on nivo (3), or other including no biopsy tissue (7). In the 16 Part B pts, best response to nivo/ipi was: PR (1, 6%) – (unclassified/non-sarcomatoid); SD (7, 44%); PD (8, 50%). Grade 3 Treatment-related adverse events (TrAEs) were seen in 7/35 (20%) on nivo. Grade 3-5 TrAEs were seen in 7/16 (44%) on nivo/ipi with 1 pt experiencing sudden death. Correlative studies including PD-L1 status, WES and RNAseq are pending. Conclusions: Nivo monotherapy has limited activity in treatment naïve nccRCC with most responses (4 of 5) seen in pts with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivo studies. Salvage treatment with nivo/ipi was provided in 16 of 28 (57%) pts with PD/pSD on nivo monotherapy, with 1 response observed. Clinical trial information: NCT03117309.

e18638 Background: Immunotherapy terminology is often complex and can be difficult for patients to understand, threatening both informed consent and patient-centered communication. Improving patient-centered communication is fundamental to fostering a quality provider-patient relationship and has been shown to positively impact the length of time to initiating treatment and to optimize patient outcomes. The aim of this study is to determine whether patients understand basic immunotherapy terminology and if a provider defining the term improves patient understanding. Methods: Conversations between oncology providers and patients discussing immunotherapy for the first time, either as standard of care or as part of a clinical trial, were observed, audio recorded and transcribed (n = 39). Technical terms used in the conversation were noted by the research assistant. With consent, patients were interviewed post-conversation to assess their understanding of these technical terms used by the provider (n = 39). Comparisons of the terms (correct vs. incorrect) were conducted using chi-square tests or Fisher’s exact tests, where appropriate, for categorical variables, and using ANOVA for continuous variables. Results: Participants were mostly white (79.5%), had some college education (55.3%), had a personal income of > = $50k (56.7%), and had a family member with cancer (54.1%). The term ‘immunotherapy’ was the most difficult term for participants to understand with less than half (19/39; 48.7%) correctly defining it. The only demographic characteristic that was significantly correlated with understanding ‘immunotherapy’ was having a family member with cancer (p = 0.031). Immunotherapy agents, such as Pembro and Nivolumab, were defined correctly by patients 65% (19/29) of time). Interestingly ‘immune system’ was well understood (23/26; 88.5%). Providers defined immunotherapy in 97.4% of conversations. However, there was no correlation between having a provider define immunotherapy in the conversation, and the likelihood of participants correctly defining the term in the post-conversation interview (p = 0.487).The immune system was defined in 92.3% of conversations (n = 26), and defining immune system in the conversation was correlated with increased patient understanding (p = 0.009). Conclusions: Analysis of patient-provider conversations shows that patients have difficulty understanding some immunotherapy terminology. Since immunotherapy is a relatively new therapy, it may be more difficult for providers to translate it into lay language, which could be why patients lack understanding of ’immunotherapy’, even when provided with a definition. Since patient understanding of key terminology is essential for not only enhancing patient-centered communication, but for improving informed consent and optimizing patient outcomes, educational interventions should be developed to improve understanding.

e16542 Background: Immune checkpoint inhibitors (ICIs) are commonly used as first-line treatment for pts with advanced RCC. In the recent phase 3 CLEAR trial, LEN + PEMBRO showed improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) vs sunitinib in first-line treatment of advanced RCC (Motzer R et al. NEJM. 2021). Additional treatment options are needed for pts with disease progression on ICIs. A phase 1b trial of LEN + PEMBRO was performed in multiple tumor types and included an expansion part into a phase 2 cohort of ICI-pretreated, treatment-naïve, or previously treated ICI-naïve pts with metastatic RCC (NCT02501096). We report the final results of the RCC cohort with an extended follow-up. Methods: Eligible pts were ≥18 years old and had measurable disease. Efficacy analyses were conducted by prior therapy grouping. The primary endpoint was ORR at week 24 (ORRwk24) per immune-related (ir) RECIST by investigator assessment. Secondary endpoints included ORR, duration of response (DOR), PFS, OS, and safety. Exploratory endpoints included tumor response assessed per RECIST v1.1 by independent review committee (IRC). Subgroup analyses of the ICI-pretreated group will be included in the poster. Results: The recommended doses determined in phase 1b were LEN 20 mg daily + PEMBRO 200 mg once every 3 weeks (Taylor M et al. JCO. 2020). The study enrolled 145 pts (efficacy analysis, n=143; safety analysis, n=145). At data cutoff (August 18, 2020), the median follow-up time was 19.8 months. The ORRwk24 was 55.8% (95% CI 45.7–65.5) for ICI-pretreated pts (n=104), 72.7% (95% CI 49.8–89.3) for treatment-naïve pts (n=22), and 41.2% (95% CI 18.4–67.1) for previously treated ICI-naïve pts (n=17). The median OS for the previously treated ICI-naïve pts was 30.3 months and was not reached in the other groups. Additional efficacy analyses are shown in the table. Treatment-related adverse events occurred in 99.3% of pts; the most common were fatigue (58.6%), diarrhea (55.2%), and hypertension (40.0%). Most pts (69%) maintained the LEN starting dose or were reduced to LEN 14 mg daily (dose level −1). Conclusions: LEN + PEMBRO demonstrated promising antitumor activity with a manageable safety profile in pts with metastatic RCC, including pts who were ICI-pretreated. Clinical trial information: NCT02501096. [Table: see text]

e16526 Background: ICIs have altered the therapeutic landscape in pts with aUC and new biomarkers are needed to better predict response and outcomes with ICIs. It is unclear whether demographics, such as race, age, sex and history of smoking, are associated with outcomes with ICIs. We hypothesized that specific demographic groups (sex, age, race, smoking history) would be associated with outcomes with ICIs in aUC. Methods: We performed a retrospective cohort study across 25 institutions. Data collected included demographic and clinicopathologic factors, response and outcomes. We calculated observed response rate (ORR), Progression-Free Survival (PFS) and overall survival (OS) for specific demographic groups. We built multivariable models (logistic regression for ORR; Cox regression for PFS and OS) with all demographic groups to assess outcomes. Analysis was done for the overall population and stratified by treatment line (first line [1L]; salvage [2+L]). The stratified analysis was also adjusted for known prognostic risk scores (internally developed for 1L; Bellmunt for 2+L); p-value < 0.05 was significant. Results: We identified 1026 pts; 754, 744 and 780 were included in OS, ORR and PFS analysis. Overall, median age at ICI initiation was 70; 26% female; 75% White, 11% Hispanic, 5% Black, 8% other; 69% had smoking history; 28% with mixed histology; 17% with upper tract UC. In the unstratified analysis, age 65-74 (vs < 65) was significantly associated with higher ORR (32% vs 22%) and median PFS (5 vs 3 mo HR 0.8); otherwise no significant difference was noted among groups for ORR, PFS, OS in both the stratified and unstratified analyses (Table). Conclusions: We did not identify significant associations between age, sex, race or smoking history and ORR, PFS, OS with ICIs in pts with aUC. Limitations include retrospective nature, lack of randomization, possible selection and confounding factors. Further research is required to identify prognostic and predictive biomarkers for ICI therapy in aUC.[Table: see text]

TPS4592 Background: Despite advances in therapy of clear cell renal cell carcinoma, outcomes for patients with aRCCVH remain poor and these patients have typically been excluded from pivotal phase III studies. COSMIC-313 (NCT03937219) exploring C/N/I vs N/I excludes those with aRCCVH. Given responses seen with C as well as N/I in aRCCVH, there is reason to explore this triplet combination in this population. Methods: NCT04413123 is single arm phase 2 trial multi-institutional study involving Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center, Winship Cancer Institute, Karmanos Cancer Center, University of California in San Diego and University of Texas Southwestern. The primary objective is to assess the objective response rate (ORR) by investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 of C in combination with N/I in aRCCVH. Key secondary endpoints are progression-free survival (PFS), overall survival (OS) and toxicity by Common Terminology Criteria for Adverse Events (CTCAE) version 5. Mandatory pretreatment biopsy (unless medically infeasible) is required for correlative analysis to define the composition and transcriptional states of tumor and immune cells within the aRCCVH microenvironment in addition to determining the number and state of tumor-infiltrating T cell clones in aRCCVH and relation to response. Any variant histology is allowed, including clear-cell RCC with over 80% sarcomatoid features. Patients may be treatment naïve or received prior therapy including up to one anti-vascular endothelial growth factor agent not including C; prior therapy with immune checkpoint inhibitors is exclusionary. All International Metastatic RCC Database Consortium risk classifications are allowed; patients should have adequate organ function with performance status 0-1. C will be administered at a starting dose of 40 mg daily. N will be dosed at 3 mg/kg with I 1 mg/kg every 3 weeks followed by maintenance N 480 mg IV every 4 weeks and will be continued until progressive disease or unacceptable toxicity. C can be reduced to. 20 mg daily or 20 mg every other day as needed for toxicity. Dose reductions of N or I are not permitted but delays up to 12 weeks are allowed; N may be continued without I if toxicity can be directly attributed to I. Radiographic imaging is performed at baseline with first scheduled assessment at 12 weeks then every 8 weeks thereafter. A one-stage design is employed to enroll 40 eligible patients, which provides 93% power at 1-sided alpha of 0.09 to distinguish an ORR of 40% versus 20%. 12 or more responses are required to deem treatment promising. Seven of the planned 40 patients have been enrolled as of 2/1/2021. Clinical trial information: NCT04413123.

4585 Background: Adrenocortical Carcinoma (ACC) is a rare and aggressive malignancy with poor prognosis and limited treatments in the advanced setting. Molecular pathways with tumor suppressor genes (e.g. TP53, CDKN2A) and oncogenes (e.g. CTNNB1 and RAS) are implicated in oncogenesis. To our knowledge, the genomic landscape of ctDNA alterations for ACC has not been described in a large cohort. We report plasma-based ctDNA alterations in patients with advanced ACC. Methods: We retrospectively evaluated genomic data from 102 patients with ACC who had ctDNA testing between 12/2016 – 10/2020 using Guardant360 (Guardant Health, CA). ctDNA analysis interrogated single nucleotide variants (SNV), fusions, indels and copy number variations (CNV) of up to 83 genes. We evaluated the frequency of genomic alterations, the landscape of co-occurring mutations, and pathogenic or likely pathogenic alterations with potential targeted therapies. The prevalence of alterations identified in ctDNA were compared to those detected in tissue using a publicly available database (cBioPortal). Results: The median age was 54 years (range 24-81), and 55% of patients were male. Among the entire cohort, 84 pts (82.4%) had ≥1 somatic alteration detected. Mutations were most frequently detected in TP53 (52%), EGFR (23%), CTNNB1 (18%), MET (18%), and ATM (14%). The frequencies detected in ctDNA were similar to the results detected in tissue. Pathogenic and/or likely pathogenic mutations in therapeutically relevant alterations were observed in 36 patients (35%), including EGFR, BRAF, MET, CDKN2A, and CDK4/6 (Table 1). The most frequently co-occurring mutations were EGFR + TP53 (14%), EGFR + MET (11%), BRAF + MET (10%). Conclusions: Blood-based ctDNA profiling in advanced ACC provided comprehensive genomic data in most patients, with a similar profile to tumor tissue analyses. Over one third of patients had actionable mutations with approved therapies in other cancers. This approach might inform the development of personalized treatment options for this aggressive malignancy.[Table: see text]

4528 Background: Significant unmet need remains for people with cisplatin-ineligible (cis-ineligible) locally advanced or metastatic urothelial carcinoma (la/mUC). In the first-line (1L) setting, carboplatin-based regimens have demonstrated poor tolerability, modest objective response rate (ORR) and limited durability. PD-1/PD-L1 inhibitors demonstrate durable responses; however, only a minority of pts achieve a response (ORR 24-29%). Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) delivering the microtubule-disrupting agent monomethyl auristatin E (MMAE) to targeted tumor cells expressing Nectin-4. EV has shown an overall survival benefit versus chemotherapy in previously treated la/mUC. Preclinical studies show that ADCs utilizing MMAE can induce immunogenic cell death and may enhance antitumor immunity. Clinical data suggests the combination of EV + pembrolizumab (P) may have the potential to induce greater antitumor activity compared to either agent alone. Preliminary data on EV + P was previously presented, and the FDA granted breakthrough therapy designation to EV + P for the treatment of pts with 1L cis-ineligible la/mUC in Feb 2020. Here we report updated data with 24.9 months median follow-up. Methods: This multi-cohort EV-103 study (NCT03288545) evaluates the safety/activity of EV + P (Dose Escalation/Cohort A). This report highlights 1L cis-ineligible pts treated with 3-week cycles of EV 1.25 mg/kg (Days 1, 8) and P (Day 1). Endpoints include safety/tolerability, investigator response per RECIST v1.1, DOR, PFS, and OS. Results: As of 13 Oct 2020, the median follow-up for the 45 1L la/mUC pts (median age 69 yrs [51-90]) was 24.9 months. The median number cycles of EV + P was 9 (range 1-34). The most common treatment-related adverse events were peripheral sensory neuropathy (56%, 4% ≥G3), fatigue (51%, 11% ≥G3), and alopecia (49%). There was one death reported as possibly related to study treatment (multiple organ dysfunction syndrome) per investigator assessment. Confirmed ORR is 73.3% (95% CI: 58.1, 85.4) including 17.8% CR and an ORR of 57.1% (8/14) in pts with liver metastasis. The median DOR was 25.6 months (95% CI: 8.3, -). Fifty-three percent of the responders had DOR at 24 months. Additionally, the DCR is 93.3%, the median PFS is 12.3 months (95% CI: 8.0, -), and the median OS is not reached. The OS rate at 24 months is 56.3% (95% CI: 39.8, 69.9). Conclusions: EV + P, a platinum-free option, continues to demonstrate promising activity with a durable response profile in 1L cis-ineligible pts with la/mUC. The safety profile is manageable and stable over time with no new safety signals. Cohort K of EV-103 in cis-ineligible pts with la/mUC is actively randomizing pts to EV monotherapy or EV + P to evaluate the contribution of each agent. Clinical trial information: NCT03288545.

5058 Background: Emerging data suggest differences in the tumor genomic profile of AA compared with CA men with aPC. We hypothesized that there will be significant differences in the tumor genomic landscape between AA and Ca pts as detected by cfDNA CGP. Methods: Pts with aPC and available cfDNA CGP by the Guardant (G360) 73 gene panel were included. In addition, G360 74 gene panel was used to identify CDK12 mutation (not detected in 73 gene panel) in an independent cohort of aPC pts. Barnard’s test was used to evaluate the association between genetic mutation and gene. Genomic landscape was also compared by a Bayesian Network (BN) machine learning approach. Results: A total of 552 pts (125 AA, 427 CA) tested by G360 73 gene panel were included. Multiple genomic aberrations were enriched in AA patients (Table). In the independent cohort of 261 aPC patients (AA=106 pts, CA=155 pts) tested by G360 74 gene panel, CDK12 mutation was significant enriched in AA pts. (9.4% vs. 1.9%, p=0.006). Machine learning analysis supported these results, and will be presented at the meeting. Conclusions: These hypothesis generating data suggest significant differences in the tumor genomic profile between AA and CA pts with aPC. Identification of molecular drivers of tumor progression enriched in AA pts may allow development of tailored systemic therapy for these men, and decrease disparities in disease related outcomes. Data need external validation. PB,RR,MAB contributed equally to this work.[Table: see text]

4549 Background: Baseline NER has been reported to be associated with outcomes of immuno-oncology based combination treatment in advanced renal cell carcinoma (aRCC). We report outcomes by baseline NER of patients with aRCC in the JAVELIN Renal 101 trial who received avelumab + axitinib (A + Ax) or sunitinib (S). Methods: We calculated the median NER (mNER) for patients in the A + Ax and the S arms at the data cutoff (April 20, 2020) for the 3rd interim analysis (IA3). Progression-free survival (PFS), overall survival (OS), and objective response (OR) by NER are reported. Multivariate Cox regression analyses of PFS and OS were also conducted. Results: At the IA3 cutoff date, the mNERs for the A + Ax arm (n = 383) and S arm (n = 396) were 29.2 and 27.0, respectively. OR, PFS and OS for both arms are summarized in the table below. Better observed treatment outcomes in OR (63.9% vs 55.2%) and median PFS (15.5 vs, 11.1 months) were observed for patients with a NER < median vs. NER ≥ median in the A + Ax arm, while there were not major differences in outcome based on NER in the S arm. The stratified hazard ratio (HR) for PFS in patients with a NER < median compared with those with a NER ≥ median in the A + Ax arm was 0.81 (95% CI, 0.630-1.035) and 0.93 (95% CI, 0.728-1.181) in the S arm. Patients with a NER < median had improved OS compared with those with a NER ≥ median in the A + Ax arm (stratified HR, 0.67; 95% CI, 0.481-0.940) and the S arm (stratified HR, 0.57; 95% CI, 0.424-0.779). Multivariate analysis showed that a low NER was associated with longer PFS and OS by treating baseline NER as either a continuous variable or a binary variable (dichotomized by median). Conclusions: Baseline NER may be predictive of OR and PFS in aRCC patients treated with A + Ax, and prognostic for overall survival regardless of therapy. Clinical trial information: NCT02684006. [Table: see text]

e16570 Background: The CheckMate 9ER trial showed that the combination of nivolumab and cabozantinib (nivo-cabo) in first line setting for treatment of mRCC was superior to sunitinib in terms of objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) and led to its FDA approval. We report outcomes of cohort of patients with mRCC treated with nivo-cabo in the salvage setting. Methods: We retrospectively reviewed 17 patients with mRCC treated at Winship Cancer Institute who progressed through at least one line of prior therapy. These patients were then treated with either sequences: [1] cabozantinib and then add nivolumab upon progression (n = 8) and [2] nivolumab/ipilimumab or nivolumab and then add cabozantinib upon progression (n = 9) with two with nivolumab and ipilimumab. Median PFS and OS rates, and clinical benefit (defined as complete response or partial response, or stable disease) were described. Results: Thirteen patients had clear cell histology and four patients had non-clear cell histology. For sequence [1], the mPFS for cabozantinib alone was 9.9 months and combination of nivolumab added to cabozantinib was 8.9 months. For sequence [2], the mPFS for nivolumab with or without ipilimumab was 5.9 months and combination of cabozantinib added to nivolumab was 10.4 months. The 12-month OS rate was 88% for sequence [1] and 89% for sequence [2]. The 24-month, OS rate was 50% for sequence [1] and 89% for sequence [2]. 5/8 (63%) patients in sequence [1] and 7/9 (78%) patients in sequence [2] had clinical benefit. 3/8 (37.5%) patients in sequence [1] and 2/9 (22%) patients in sequence [2] experienced immune-related adverse effects such as hypothyroidism (grade II for two patients), pneumonitis (grade II), hepatic transaminase elevations (grade II), and pancreatitis (grade III). No patients in sequence [1] needed dose reduction in cabozantinib once nivolumab was added. 3/9 (33%) patients had dose reduction in cabozantinib in sequence [2] due to diarrhea. Conclusions: Nivo-cabo demonstrates activity in the salvage setting but there is still need to understand the optimal sequencing of both agents in the treatment of mRCC. Outcomes from this combination treatment are to be further validated from ongoing phase III trial, PDIGREE (NCT03793166).

e17049 Background: There is limited biomarker data available for metastatic hormone sensitive prostate cancer (mHSPC). Inflammatory markers found on routine clinical lab data, including leukocyte to lymphocyte ratios calculated from complete blood counts (CBC), is associated with clinical outcomes (CO) in different malignancies. We investigated the association between basophil-to-lymphocyte ratio (BLR) and CO in a racially diverse patient population with mHSPC. Methods: We performed a retrospective multicenter review from Winship Cancer Institute at Emory University and Georgia Cancer Center for Excellence at Grady Memorial Hospital (2014 – 2020). Demographics, disease characteristics, and laboratory data were collected at the start of upfront therapy with either docetaxel (DOC) or abiraterone (ABI). Overall survival (OS) and progression-free survival (PFS) were used to measure CO. Results: Included were 165 patients with mHSPC with a median follow-up time of 22.6 months. 89 (53.9%) were Black and 76 (46.1%) were Non-Black (White, Asian, or Hispanic). 106 (63%) had Gleason scores of 8-10 and 105 (63.6%) were classified as high-volume disease (per CHAARTED trial criteria). 92 (55.8%) received DOC and 73 (44.2%) received ABI. Worse CO were associated with high BLR at an optimal cut of 0.0265 (range 0 – 0.81 , mean of 0.03, standard deviation 0.09). Elevated BLR is associated with decreased OS (HR 3.51, 1.79 – 6.91, p

3040 Background: Pembrolizumab was recently FDA approved across solid tumors for TMB scores ≥ 10mut/Mb as assessed by next-generation sequencing (NGS) of tissue (tTMB). A prior study of advanced cancer patients treated with immunotherapy found that higher somatic TMB, as defined by the 80th percentile in each histology, was associated with better overall survival. Previously, bTMB assessed by ctDNA from patients with newly diagnosed advanced NSCLC at a score of 16 mut/MB correlated with a tTMB score of 10 mut/MB. TMB levels vary by cancer type, line of treatment, and therapy received; the distribution of bTMB scores across solid tumor types has not been well characterized. Here we report the distribution of bTMB scores in patients with advanced malignancies. Methods: We queried 5,610 samples from patients with different cancer types undergoing clinical cell-free DNA testing (Guardant360; Redwood City, CA) and assessed bTMB scores from October 2020 - January 2021. bTMB score was derived via a previously described computational algorithm examining the total number of synonymous and non-synonymous SNVs and indels across a 1.0MB genomic footprint. We assessed the success rate of bTMB evaluation, overlap with microsatellite instability (MSI) status, and defined the distribution of bTMB levels across indications in this dataset. Results: bTMB score was successfully assessed in 4,275/5,610 (76.3%) samples (Table). The majority of samples (58%) were tested at disease progression as compared to initial diagnosis (42%). The median turnaround time from sample receipt to clinical reporting was 11 days and decreased to 9 days over the course of the study. For the majority of cancer types the 80th percentile TMB was ≥ 16 mut/MB tissue equivalency. Conclusions: Our analysis demonstrates the feasibility of measuring bTMB using a commercially available liquid biopsy assay. bTMB scores trended higher than tTMB previously reported in these cancer types, reflecting the ability of ctDNA to better capture tumor heterogeneity. cfDNA may allow for exploration of bTMB evolution throughout treatment. TMB should be interpreted in the context of disease, treatment, and method; these data establish a pan-cancer benchmark for bTMB which will serve as a resource for further studies.[Table: see text]

6500 Background: Racial/ethnic minorities have disproportionately increased risk of contracting COVID-19 and experiencing severe illness; they also have worse breast cancer (BC) outcomes. COVID-19 outcomes among racial/ethnic minorities with BC are currently unknown. We sought to compare clinicopathologic characteristics and COVID-19 outcomes stratified by race/ethnicity. Methods: The COVID-19 and Cancer Consortium registry (NCT04354701) was used to identify patients with invasive BC and laboratory-confirmed SARS-CoV-2 diagnosed in the U.S. between 2020-03-06 and 2021-02-04. The primary analysis was restricted to women who self-identified as non-Hispanic White (NHW), non-Hispanic Black (NHB), or Hispanic (H). Demographic, cancer characteristics, and COVID-19 outcomes were evaluated. COVID-19 outcomes included: hospital admission, intensive care unit (ICU) admission, mechanical ventilation, death within 30 days of COVID-19 diagnosis and death from any cause during follow-up. Descriptive statistics were used to compare clinicopathologic characteristics and Fisher exact tests were used to compare COVID-19 outcomes across the 3 racial/ethnic groups. Results: A total of 1133 patients were identified of which 1111 (98%) were women; of which 575 (52%) NHW, 243 (22%) NHB, 183 (16%) H, and 110 (10%) other/unknown. Baseline characteristics differed among racial/ethnic groups. H were younger (median age: NHW 63y; NHB 62y; H 54y) and more likely to be never smokers (NHW 62%; NHB 62%; H 78%). NHB had higher rates of obesity (NHW 40%; NHB 54%; H 46%), diabetes (NHW 16 %; NHB 32%; H 20%) and combined moderate and severe baseline COVID-19 at presentation (NHW 28%; NHB 42%; H 28%). Cancer characteristics are as shown (Table). Significant differences were observed in outcomes across racial/ethnic groups including higher rates of hospital admission (NHW 34%; NHB 49%; H 34%; P

e16546 Background: The IMDC and MSKCC risk models for mRCC were validated before the era of ICI. The mGPS incorporates albumin and C-reactive protein and reflects systemic inflammation. mGPS may be a useful prognostic biomarker of particular relevance in mRCC given the current, largely ICI-based treatment paradigm and hypothesis that systemic inflammation may contribute to ICI resistance. Methods: We retrospectively assessed mRCC patients treated with ICI (including anti-PD-1 and anti-PD-L1 agents) in any line of therapy at Winship Cancer Institute of Emory University from 2015-2018. Primary outcomes assessed included overall survival (OS) and progression-free survival (PFS). mGPS was calculated by giving 1 point for CRP > 10 mg/L and/or albumin < 3.5 g/dL with 0 points awarded for solitary low albumin. The relationship between mGPS and survival outcomes was assessed in UVA and MVA using Cox proportional hazard model and in Kaplan-Meier analysis. Results: We assessed 156 eligible patients. Median follow up was 24.2 months. Median age was 64 years, 69% were male, 20% were Black, and 78% had clear cell histology. 57.1% received anti-PD-1 monotherapy whereas all others received dual ICI or ICI combined with an antiangiogenic agent or experimental therapy in trial. Higher baseline mGPS was significantly associated with worse OS and PFS (Table). The median OS of patients with baseline mGPS of 0, 1 and 2 was 44.5 (CI 27.3, NA), 15.3 (CI 11, 24.2) and 10 (CI 4.6, 17.5) months, respectively (p

Simple Summary Inflammation has been recognized to be linked to tumor development. Several markers of inflammation can be detected via blood such as variety of blood cells, which can be readily and easily obtained. These markers have been studied as ways to predict and prognosticate tumor response to chemotherapy. With the development of immunotherapy, namely immune checkpoint inhibitors (ICIs) such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PDL-1) PDL-1 inhibitors, several markers have also been studied in assessing tumor response. In this review, we will discuss the various inflammatory markers that have been studied in several tumors treated with ICIs. Abstract Chronic inflammation is considered a major risk factor for cancer formation. Inflammation within the tumor environment plays a role in its response to therapy, growth, and prognosis. Cancer associated inflammation is known to occur in the tumor microenvironment and in the systemic circulation, and is correlated with disease progression and prognosis in many cancers. Blood cells such as neutrophils, lymphocytes, platelets, and circulating proteins such as C-reactive protein, and interleukins, such as IL-6, have been associated with inflammatory responses, which contribute to tumorigenesis. Cancer has found ways to evade the immune response; a pathway that can attenuate the innate immune response is via blocking immune checkpoints. Development of monoclonal antibodies against inhibitory immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have given rise to immunotherapy, which has shown remarkable responses in anti-tumor activity resulting in several U.S. Federal and Drug Administration (FDA)-approved checkpoint inhibitors. Various inflammatory markers and their prognostic and predictive implications in malignancies treated with immunotherapy will be discussed in this review.

Answer questions and earn CME/CNE The concept of frailty has become increasingly recognized as one of the most important issues in health care and health outcomes and is of particular importance in patients with cancer who are receiving treatment with surgery, chemotherapy, and radiotherapy. Because both cancer itself, as well as the therapies offered, can be significant additional stressors that challenge a patient's physiologic reserve, the incidence of frailty in older patients with cancer is especially high-it is estimated that over one-half of older patients with cancer have frailty or prefrailty. Defining frailty can be challenging, however. Put simply, frailty is a state of extreme vulnerability to stressors that leads to adverse health outcomes. In reality, frailty is a complex, multidimensional, and cyclical state of diminished physiologic reserve that results in decreased resiliency and adaptive capacity and increased vulnerability to stressors. In addition, over 70 different measures of frailty have been proposed. Still, it has been demonstrated that frail patients are at increased risk of postoperative complications, chemotherapy intolerance, disease progression, and death. Although international standardization of frailty cutoff points are needed, continued efforts by oncology physicians and surgeons to identify frailty and promote multidisciplinary decision making will help to develop more individualized management strategies and optimize care for patients with cancer. CA Cancer J Clin 2017;67:362-377. © 2017 American Cancer Society.

Osteoblasts communicate both with normal cells in the bone marrow, and with tumor cells that metastasized to bone. Here we show that osteoblasts release exosomes, we termed osteosomes, which may be a novel mechanism by which osteoblasts communicate with cells in their environment. We have isolated exosomes from undifferentiated/proliferating (D0 osteosomes) and differentiated/mineralizing (D24 osteosomes) primary mouse calvarial osteoblasts. The D0 and D24 osteosomes were found to be vesicles of 130–140 nm by dynamic light scattering analysis. Proteomics profiling using tandem mass spectrometry (LC-MS/MS) identified 206 proteins in D0 osteosomes and 336 in D24 osteosomes. The proteins in osteosomes are mainly derived from the cytoplasm (~47%) and plasma membrane (~31%). About 69% of proteins in osteosomes are also found in Vesiclepedia, and these canonical exosomal proteins include tetraspanins and Rab family proteins. We found that there are differences in both protein content and levels in exosomes isolated from undifferentiated and differentiated osteoblasts. Among the proteins that are unique to osteosomes, 169 proteins are present in both D0 and D24 osteosomes, 37 are unique to D0, and 167 are unique to D24. Among those 169 proteins present in both D0 and D24 osteosomes, 10 proteins are likely present at higher levels in D24 than D0 osteosomes, based on emPAI ratios of more than 5. These results suggest that osteosomes released from different cellular state of osteoblasts may mediate distinct functions. Using live-cell imaging, we measured the uptake of PKH26-labeled osteosomes into C4-2B4 and PC3-mm2 prostate cancer cells. In addition, we showed that cadherin-11, a cell adhesion molecule, plays a role in the uptake of osteosomes into PC3-mm2 cells as osteosome uptake was delayed by neutralizing antibody against cadherin-11. Together, our studies suggest that osteosomes could have a unique role in the bone microenvironment under both physiological and pathological conditions.

Mücahid Yılmaz,1 Mustafa Necati Dağlı,2 Ökkeş Uku,1 Mehmet Nail Bilen,1 Hasan Korkmaz,2 Kenan Erdem,3 Ertuğrul Kurtoğlu1 1Department of Cardiology, Elazığ Education and Research Hospital, 2Department of Cardiology, FIRAT University School of Medicine, Elazığ, 3Department of Cardiology, Sivas Hospital State, Sivas, Turkey Background: The relationship between increased mean platelet volume (MPV) and atherosclerosis is well known. In the present study, MPV in patients with coronary slow flow (CSF) and in cases with normal coronary anatomy (NCA) was investigated and compared with the aim of identifying the relationship between CSF and MPV. Patients and methods: We studied 40 patients previously determined via coronary angiography as having NCA and 40 patients with CSF in the coronary blood stream, as identified by thrombolysis in myocardial infarction square. Thus, a total of 80 patients from the Elaziğ Education and Research Hospital (Elaziğ, Turkey) were included in the present study retrospectively and laboratory and anamnesis information was scanned into their files. The relationship between MPV and CSF was studied. Results: MPV levels were observed to be significantly higher in the CSF group compared to the NCA group (10.05±1.3 and 8.6±0.6, p9.05 measured in CSF patients at application had a predictive specificity of 77.5% and sensitivity of 77.5% for CSF (area under the curve: 0.825, 95% confidence interval [CI]: 0.726–0.924, p

Although myeloid growth factors are commonly used to treat metastatic castration-resistant prostate cancer (mCRPC), the optimal timing of administration has not been well studied. We assessed the effects of same-day pegfilgrastim, a neutrophil stimulator, after cabazitaxel treatment with or without carboplatin in patients with mCRPC. We also evaluated the frequency of urinary tract inflammation during treatment.Between September 2010 and September 2014, 151 consecutive patients with mCRPC underwent cabazitaxel treatment with or without the addition of carboplatin at a single institution. We assessed absolute neutrophil count recovery, incidence of neutropenia, neutropenic fever, antibiotic usage, treatment delays or discontinuation, dose reduction, and hospitalization with pegfilgrastim administration. Radiologists blinded to therapy reviewed computed tomography scans to detect urinary tract inflammation.The median patient age was 69 years (range, 41-88 years); 78% of patients were white, and 54% had a Gleason score ≥ 9. Median overall survival was 9 months (95% confidence interval, 8-11 months). One patient (1%) had neutropenia; 38 patients (25%) had infection. During cycle 1, a significantly higher proportion of patients receiving pegfilgrastim after 24 hours developed infection than did those receiving pegfilgrastim the same day (26% vs. 6%; P = .01).Same-day pegfilgrastim administration after cabazitaxel treatment with or without carboplatin in patients with mCRPC is feasible. The urinary tract inflammation rate (21%) was higher than that reported anecdotally. Results need to be prospectively validated.

PURPOSE OF REVIEW In the present review, we summarize the recent developments in the management of germ cell tumors (GCTs). RECENT FINDINGS Treatment-related acute and late-onset toxicity remains a key challenge in the management of GCTs. Recent data show that patients with large retroperitoneal lymph node metastases are at increased risk of venous thromboembolism and may benefit from prophylactic anticoagulation. Predictive models have been developed to identify patients with residual retroperitoneal lymph node masses who are more likely to benefit from surgical resection. However, their clinical use remains hampered by relatively low accuracy. There are currently multiple conventional-dose chemotherapy (CDCT) options for salvage therapy in patients with refractory or recurrent disease. In addition, more efficacious high-dose chemotherapy (HDCT) regimens continue to be developed. The role of salvage CDCT versus HDCT is currently being prospectively investigated.Finally, intratumoral heterogeneity is a common finding in cancer and an obvious observation in GCTs. Despite intratumoral heterogeneity, recent studies on nonseminomatous GCT have identified distinct histological subgroups and a potentially lethal clinical phenotype. Importantly, comprehensive molecular profiling so far has not elucidated the biologic basis or the clinical underpinnings of intratumoral heterogeneity in GCTs. SUMMARY Remaining challenges to be addressed include minimizing therapeutic toxicity and improving outcomes in patients with refractory/recurrent GCTs or malignant transformation of teratomas.

Giris: Bu calismada koroner yavas akim (KYA) tespit edilen hastalar ile normal koroner anatomi (NKA) tespit edilen hastalar arasinda P dalga dispersiyonu ve QTc dispersiyonu karsilastirildi ve KYA ile P dalga dispersiyonu ve QTc dispersiyonu arasindaki iliskinin belirlenmesi amaclandi. Hastalar ve Yontem: Calismaya 40 NKA ve 42 KYA olmak uzere toplam 82 hasta alindi. Koroner kan akimi TIMI kare sayisina gore hesaplandi. Elektrokardiyografi cekimleri her derivasyon icin en az 3 QRS kompleksi icerecek sekilde, 50 mm/saniye hizinda, 20 mV amplitudunde ve standart 12 derivasyonda cekildi. En uzun p dalgasi Pmax ve en kisa p dalgasi Pmin olarak kabul edildi. En uzun P dalgasi ile en kisa p dalgasi arasindaki farki P dispersiyonu kabul edildi. QTc dispersiyonu olcumleri icin oncelikle kalp hizina gore Bazzet formulu (QT/√R-R) ile duzeltilmis QT araligi hesaplandi. En uzun QTc araligi (QTcmax) ile en kisa QTc (QTcmin) araligi arasindaki fark hesaplanarak olculdu. Butun olcumler manuel olarak yapildi. Bulgular: Bu calisma KYA grubunda P dispersiyonu (sirasi ile 53.2 ± 5.35 ve 46.07 ± 4.12, p< 0.0001), Pmax (sirasi ile 106.2 ± 10.11 ve 97.7 ± 8.17, p< 0.0001), maksimum QTc (sirasi ile 438.96 ± 16.77 ve 426.13 ± 10.01, p< 0.0001) ve QTc dispersiyonu (sirasi ile 68.99 ± 4.34 ve 61.64 ± 4.15, p< 0.0001) surelerinin NKA grubuna gore istatistiksel olarak anlamli derecede uzun oldugunu gostermektedir. Sonuc: Bu calisma koroner yavas akim da P dalga dispersiyonu ve QTc dispersiyonu surelerinin arttigini gostermektedir.

// Mehmet Asim Bilen 1 , Kenneth R. Hess 2 , Matthew T. Campbell 3 , Jennifer Wang 3 , Russell R. Broaddus 4 , Jose A. Karam 5 , John F. Ward 5 , Christopher G. Wood 5 , Seungtaek L. Choi 6 , Priya Rao 4 , Miao Zhang 4 , Aung Naing 7 , Rosale General 3 , Diana H. Cauley 3 , Sue-Hwa Lin 8 , Christopher J. Logothetis 3 , Louis L. Pisters 5 , Shi-Ming Tu 3 1 Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA 2 Department of Biostatistics the University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 Department of Genitourinary Medical Oncology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA 4 Department of Pathology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA 5 Department of Urology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA 6 Department of Radiation Oncology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA 7 Department of Investigational Cancer Therapeutics the University of Texas MD Anderson Cancer Center, Houston, Texas, USA 8 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Correspondence to: Shi-Ming Tu, email: stu@mdanderson.org Keywords: testicular cancer, intratumoral heterogeneity, chemoresistance, nonseminomatous germ cell tumor, next-generation sequencing Received: August 15, 2016 Accepted: November 07, 2016 Published: November 16, 2016 ABSTRACT Background: Nonseminomatous germ cell tumor of the testis (NSGCT) is largely curable. However, a small group of patients develop refractory disease. We investigated the hypothesis that intratumoral heterogeneity contributes to the emergence of chemoresistance and the development of refractory tumor subtypes. Results: Our institution’s records for January 2000 through December 2010 included 275 patients whose primary tumor showed pure embryonal carcinoma (pure E); mixed embryonal carcinoma, yolk sac tumor, and teratoma (EYT); or mixed embryonal carcinoma, yolk sac tumor, seminoma, and teratoma (EYST). Patients with EYST had the highest cancer-specific mortality rate ( P = .001). They tended to undergo somatic transformation ( P = .0007). Two of 5 patients with clinical stage I EYST who had developed recurrence during active surveillance died of their disease. Materials and Methods: In this retrospective study, we evaluated consecutive patients who had been diagnosed with the three most common histological phenotypes of NSGCT. Chemoresistance was defined as the presence of teratoma, viable germ cell tumor, or somatic transformation in the residual tumor or the development of progressive or relapsed disease after chemotherapy. In a separate prospective study, we performed next-generation sequencing on tumor samples from 39 patients to identify any actionable genetic mutations. Conclusions: Our data suggest that patients with EYST in their primary tumor may harbor a potentially refractory NSGCT phenotype and are at increased risk of dying from disease. Despite intratumoral heterogeneity, improved patient selection and personalized care of distinct tumor subtypes may optimize the clinical outcome of patients with NSGCT.

Objective To determine whether neutrophil/lymphocyte ratio (NLR) differed between patients with isolated coronary artery disease (CAD), isolated coronary artery ectasia (CAE), coronary slow flow and normal coronary anatomy. Methods Patients who underwent coronary angiography were consecutively enrolled into one of four groups: CAD, coronary slow flow, CAE and normal coronary anatomy. Results The CAD ( n = 40), coronary slow flow ( n = 40), and CAE ( n = 40) groups had similar NLRs (2.51 ± 0.7, 2.40 ± 0.8, 2.6 ± 0.6, respectively) that were significantly higher than patients with normal coronary anatomy ( n = 40; NLR, 1.73 ± 0.7). Receiver operating characteristics demonstrated that with NLR > 2.12, specificity in predicting isolated CAD was 85% and sensitivity was 75%, with NLR > 2.22 specificity in predicting isolated CAE was 86% and sensitivity was 75%. With NLR > 1.92, specificity in predicting coronary slow flow was 89% and sensitivity was 75%. Multivariate logistic regression analyses identified NLR as an independent predictor of isolated CAE (β = −0.499, 95% CI −0.502, −0.178; P Conclusions NLR was higher in patients with CAD, coronary slow flow and CAE versus normal coronary anatomy. NLR may be an indicator of CAD, CAE and coronary slow flow.

While Wilms’ tumor (WT), or nephroblastoma, is the most common pediatric tumor, it is rarely seen in adults and represents less than 1% of all renal neoplasms. The diagnosis of WT during pregnancy is rarer yet and requires a multidisciplinary approach between surgery, radiation, obstetrics/maternal fetal medicine, pediatrics and medical oncology with special consideration for the safety of both the patient and the fetus. We report a clinical case of a pregnant patient with a localized WT who underwent nephrectomy, chemotherapy during pregnancy, Cesarean section followed by post-partum chemotherapy and radiation therapy without evidence of disease recurrence in the year since completing therapy. We also conducted a review of the sparse published data on the optimal treatment of WT in pregnancy. Our case demonstrates a treatment plan for WT diagnosed during pregnancy when the patient requires systemic therapy prior to delivery.

INTRODUCTION AND OBJECTIVES:The inflammation-based modified Glasgow Prognostic Score (mGPS) is widely used as a prognostic indicator before surgery; however, little information is available on its ...

We aimed to compare the power of the HAS-BLED and CRUSADE risk scores in predicting in-hospital bleeding events in patients with stable coronary artery disease undergoing elective coronary angiography. A total of 405 consecutive patients were included in the study. The mean HAS-BLED score was significantly higher (p < 0.001) in the in-hospital bleeding group. In patients with a HAS-BLED score ≥ 3, the in-hospital bleeding rate was significantly higher than in those with a HAS-BLED score < 3 (p < 0.001). Receiver operating characteristic curve analysis revealed that the HAS-BLED score was superior in predicting in-hospital bleeding events compared to the CRUSADE score [area under the curve (AUC) = 0.684 vs 0.569, respectively, p = 0.002]. Also in the percutaneous coronary intervention subgroup, the HAS-BLED score was superior to the CRUSADE score (AUC = 0.722 vs 0.520, respectively, p = 0.002). We showed that the HAS-BLED and CRUDASE scores are helpful in stable patients undergoing elective coronary angiography. Our results suggest that as a practical, easy-to-implement and more predictive scoring system, the HAS-BLED score was more useful for predicting in-hospital bleeding in patients who did not present with acute coronary syndrome.

Sarcopenia is associated with poor outcomes in a variety of conditions, including malignancy. Abdominal skeletal muscle area (SMA) segmentation using computed tomography (CT) has been shown to be an accurate surrogate for identifying sarcopenia. While magnetic resonance imaging (MRI) segmentation of SMA has been validated in cadaver limbs, few studies have validated abdominal SMA segmentation using MRI at lumbar level mid-L3. Our objective was to assess the reproducibility and concordance of CT and MRI segmentation analyses of SMA at mid-L3. This retrospective analysis included a random sample of 10 patients with renal cell carcinoma (RCC) and CT abdomen/pelvis, used to assess intra-observer variability of SMA measurements using CT. An additional sample of 9 patients with RCC and both CT and T2-weighted (T2w) MRI abdomen/pelvis was used to assess intra-observer variability of SMA using MRI and concordance of SMA between MRI and CT. SMA was segmented using Slice-O-Matic. SMA reproducibility was assessed using intraclass correlation coefficient (ICC). SMA concordance was analyzed using Bland–Altman plot and Pearson correlation coefficient. The intra-observer variability of CT and MRI SMA at mid-L3 was low, with ICC of 0.998 and 0.985, respectively. Bland–Altman analysis revealed bias of 0.74% for T2w MRI over CT. The Pearson correlation coefficient was 0.997 (p < 0.0001), demonstrating strong correlation between CT and T2w MRI. Abdominal SMA at mid-L3 is reproducibly segmented for both CT and T2w MRI, with strong correlation between the 2 modalities. T2w MRI can be used interchangeably with CT for assessment of SMA and sarcopenia. This finding has important clinical implications.

Background Given the increasing number of available immunotherapeutic agents, more patients are presenting after failing immunotherapy in need of new treatment options. In this study, we investigated the clinical outcomes of patients treated with sequential immunotherapy. Methods We performed a retrospective review of 90 advanced stage cancer patients treated on immunotherapy-based phase 1 clinical trials at Winship Cancer Institute from 2009 to 2017. We included 49 patients with an immune checkpoint inhibitor (ICI)-indicated histology. Patients were analyzed based on whether they had received prior ICI. Clinical outcomes were overall survival (OS), progression-free survival (PFS), and clinical benefit (best response of complete response, partial response, or stable disease). Univariate analysis (UVA) and multivariate analysis (MVA) were performed using Cox proportional hazard or logistic regression model. Covariates included age, liver metastases, number of prior lines of therapy, histology, and Royal Marsden Hospital (RMH) risk group. Results The most common histologies were melanoma (61%) and lung/head and neck cancers (37%). More than half of patients (n = 27, 55%) received at least one ICI prior to trial enrollment: ten received anti-PD-1, two received anti-CTLA-4, five received anti-PD-1/CTLA-4 combination, and ten received multiple ICI. In MVA, ICI-naive patients had significantly longer OS (HR: 0.22, CI: 0.07–0.70, p = 0.010) and trended towards higher chance of CB (HR: 2.52, CI: 0.49–12.97, p = 0.268). Patients who received prior ICI had substantially shorter median OS (10.9 vs 24.3 months, p = 0.046) and PFS (2.8 vs. 5.1 months, p = 0.380) than ICI-naive patients per Kaplan-Meier estimation. Within the ICI-naive group, 78% (7 of 9) of patients who received prior interleukin (IL-2) or interferon gamma (IFNγ) experienced disease control for at least 6 months, compared to a disease control rate of 15% (2 of 13) in patients who had received chemotherapy, targeted therapy, or no prior treatment. Conclusions ICI-naive patients may experience improved clinical outcomes on immunotherapy-based phase 1 clinical trials than patients who have received prior ICI. This may be particularly true for patients who received prior IL-2 or IFNγ. Further development of immunotherapy combination therapies is needed to improve clinical outcomes of these patients. These results should be validated in a larger study.

Background Microphthalmia Transcription Factor (MITF)family translocation renal cell carcinoma (tRCC) is a rare RCC subtype harboring TFE3/TFEB translocations. The prognosis in the metastatic (m) setting is poor. Programmed death ligand-1 expression was reported in 90% of cases, prompting us to analyze the benefit of immune checkpoint inhibitors (ICI) in this population. Patients and methods This multicenter retrospective study identified patients with MITF family mtRCC who had received an ICI in any of 12 referral centers in France or the USA. Response rate according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed. Genomic alterations associated with response were determined for 8 patients. Results Overall, 24 patients with metastatic disease who received an ICI as second or later line of treatment were identified. Nineteen (82.6%) of these patients had received a VEGFR inhibitor as first-line treatment, with a median PFS of 3 months (range, 1–22 months). The median PFS for patients during first ICI treatment was 2.5 months (range, 1–40 months); 4 patients experienced partial response (16,7%) and 3 (12,5%) had stable disease. Of the patients whose genomic alterations were analyzed, two patients with mutations in bromodomain-containing genes (PBRM1 and BRD8) had a clinical benefit. Resistant clones in a patient with exceptional response to ipilimumab showed loss of BRD8 mutations and increased mutational load driven by parallel evolution affecting 17 genes (median mutations per gene, 3), which were enriched mainly for O-glycan processing (29.4%, FDR = 9.7 × 10− 6). Conclusions MITF family tRCC is an aggressive disease with similar responses to ICIs as clear-cell RCC. Mutations in bromodomain-containing genes might be associated with clinical benefit. The unexpected observation about parallel evolution of genes involved in O-glycosylation as a mechanism of resistance to ICI warrants exploration.

291 Background: Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer. Despite cabo improving RCC outcomes, VTE management in these patients remains a challenge, partly due to poor understanding of cabo safety profile and drug interactions with anticoagulants. Recent anti-Xa DOAC studies demonstrated comparable efficacy and safety with LMWH for VTE treatment in patients with cancer. Thus far, cabo clinical trials have largely allowed concurrent LMWH use but not DOACs. Herein, we investigated the hemostasis safety profile of cabo with different anticoagulants in patients with RCC. Methods: We performed a retrospective multicenter study (7 sites) of patients with advanced RCC receiving treatment with cabo. Patients were allocated into three groups: cabo with concomitant use (at least 1 week) of 1) DOACs (anti-Xa inhibitors), 2) LMWH, or 3) no anticoagulant. Primary endpoint was to evaluate the rate of major bleeding events (defined per the International Society of Hemostasis and Thrombosis criteria) in the above groups. Secondary endpoint was rate of new/recurrent VTE while on anticoagulation. Overall comparison between groups was analyzed by Fisher exact test. If a difference was found, then pairwise comparison was done. Results: Between 2016-2020, 172 patients with RCC received cabo (DOAC 50, LMWH 18, and no anticoagulant 104). At initiation, cabo median dose was 60 mg but 45% had dose reduction. Median age was 63 [IQR 57-69]. Most were males (77%), had clear cell histology (81.5%), underwent nephrectomy (76.7%), and had intermediate IMDC risk disease (59%). Cabo was first, second, and subsequent line of therapy in 19.8%, 34.9%, and 45.3% of patients, respectively. The table below shows major bleeding and VTE events between groups. An overall difference of major bleeding was found between the three groups comparison ( p=0.009). There was no difference in major bleeding events between patients who received DOAC vs LMWH ( p=0.28) and DOAC vs no anticoagulant ( p=0.1) but there was a difference between LMWH vs no anticoagulant ( p=0.02). Two patients died from bleeding (one in LMWH and one in DOAC group). Conclusions: This study highlights the first reported real world experience of cabo with different anticoagulants in patients with advanced RCC. Cabo use with a DOAC had a similar bleeding risk in comparison to patients not receiving any anticoagulation. In carefully selected patients, DOACs can be considered as concurrent medications in those receiving cabo. Given the low number of patients receiving LMWH, it is difficult to draw conclusions from this group. Data are currently being updated to expand subjects receiving DOAC and LMWH in our cohort. [Table: see text]

444 Background: It is unclear whether prior RS of primary tumor is associated with response and outcomes with ICI in aUC. We hypothesized that such response and outcomes would not differ based on prior RS. Methods: We performed a retrospective cohort study including patients (pts) with aUC who received ICI. We compared overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) between pts with vs without RS [cystectomy or (nephro)-ureterectomy]. Analysis was stratified based on ICI therapy line (first-line vs salvage). A separate comparison between pts with prior RS or radiation (RT) only or none was also pursued. ORR was compared between groups using logistic regression, as well OS and PFS using cox regression analysis; a multivariable model was built adjusting for calculated Bellmunt score. P

156 Background: AA have substantially higher prostate cancer incidence rates, are diagnosed at a younger age and with a more advanced stage as compared to Ca. However, after adjusting for known prognostic factors, AA have an increased overall survival. We hypothesized that these differences might be due to the underlying changes in the genomic landscape which can be revealed by liquid biopsy. Methods: Real world comprehensive genomic profiling of ctDNA from aPCa patients from two institutions. The first ctDNA results as reported by Guardant 360 panel (Redwood City, CA) were included. Association between genetic mutation and gene were tested using Barnard’s test. To account for multiple testing, we used Benjamini-Hochberg’s False Discovery Rate adjustment across all tests to determine thresholds for false discovery rates. Same analysis was performed using a Bayesian Network Machine learning approach. Results: Overall, 361 patients with aPCa (81 AA and 280 Ca) were included in the analysis. Pathogenic genomic alterations were found in 87.0% of the cases, more frequently TP53 (42.4%), AR (34.1%), PIK3CA (13.9%), BRAF (12.7%), NF1 (10.8%) and MYC (10.0%). Targetable alterations of interest included DNA repair genes [BRCA 2 (7.8%), BRCA 1 (4.4%), ATM (6.4%), CDK12 (2.2%)], PIK3CA/mTOR/AKT (19.1%), PTEN (3.3%) and NTRK (1.9%). MSI-high was found in 4 patients. AA as compared to Ca had a significantly higher prevalence of CDK12 (20.7% vs. 3.8%, p=0.016) and GNA11 mutations (3.7% vs. 0.4%, p=0.0225). BayesNet analysis also supported these results (table). Conclusions: In this dataset, liquid biopsy of ctDNA was useful for genetic characterization of aPCa and reveal differences in the molecular phenotype of AA and Ca in aPCa with potential clinical implications. These findings support ongoing research on the clinical utility of non-invasive genotyping and therapeutic response monitoring with a focus on AA population. [Table: see text]

443 Background: Enfortumab vedotin (EV) is an antibody-drug conjugate targeting Nectin-4, which is FDA approved for patients (pts) with treatment-refractory advanced urothelial cancer (aUC). The activity of EV in pt subsets of interest such as those with distinct histological variants has not been well defined. Methods: A retrospective study of pts with aUC treated with ≥1 dose of EV as standard of care (SOC) or on a clinical trial (if trial results already reported) at 12 US sites was undertaken. Objective response rate (ORR) was investigator-assessed for pts with at least one post-baseline scan or clear evidence of clinical progression. ORR was compared across subsets of interest using proportion test. Results: A total of 184 patients with aUC were included; median age at diagnosis 70, 20% women and 60% with definitive surgery. Most common primary sites included bladder (70%) and upper tract (28%). Majority of pts (72%) had pure urothelial histology (UH) per local review, but 26% had at least a component of variant histology (VH), most commonly squamous (14%), micropapillary (8%) or plasmacytoid (3%). EV was given as monotherapy in 84% and as SOC in 58%; and 81% had ≥ 1 prior treatment in the metastatic (met) setting. ECOG PS was ≥2 in 15%; 37% had baseline neuropathy, 15% diabetes and 9% had GFR≤30. At median follow-up of 37.0 (IQR: 20.5-60.2) months from initial diagnosis, median time from met diagnosis to EV start was 11.7 (IQR: 4.3 – 20.5) months. Median duration of EV was 5.5 (IQR: 1.4 – 6.7) months, and 84% of pts were evaluable for response. ORR for evaluable pts was 53% (8% CR, 45% PR); 25% had SD and 21% PD. Median PFS and OS were not yet reached. At data cutoff in 9/2020, 55% had stopped EV (36% due to PD, 19% intolerance) and 65% were alive. Comparison of ORR in subgroups of interest for 127 evaluable pts treated with EV monotherapy is shown in the table below. Notably, among 31 pts with FGFR3 alterations, 26 were evaluable and ORR was 46%. Conclusions: In a large, retrospective, multi-institutional cohort, responses to EV were observed across a broad range of aUC pts, including pts with variant histology component, FGFR3 alterations and also in populations previously excluded from clinical trials such as pts with GFR

256 Background: PARP inhibitors, olaparib and rucaparib recently improved survival outcomes (in the Profound and Triton-2 trials) in pts with aPC harboring HRRm. Notably, ~35% of pts screened for the PROfound trial did not meet eligibility solely due to the lack of adequate quality/quantity of tumor tissue required for CGP (De Bono, NEJM, 2020). cfDNA analysis non-invasively assesses tumor-derived genomic alterations. We evaluated the prevalence of HRRm in a real-world aPC population, who had commercially available cfDNA assay results available. Methods: cfDNA based CGP (using a clinically-validated 73- to 74-gene panel i.e. Guardant360 or G360) from consecutive aPC pts between 11/2016–8/2020 were used for detection of HRRm. Frameshift and nonsense mutations were included as pathogenic. Variants of unknown significance were excluded. In this unmatched study, the prevalence of each HRRm was compared with those reported in literature using the chi square test. Results: cfDNA CGP from 7701 aPC pts were available for interrogation of BRCA1/BRCA2 mutations, & from 4671 aPC pts for ATM mutations. Prevalence of BRCA1 and 2 as detected by cfDNA was similar to historical CGP of primary tissue. Prevalence of BRCA1 was higher than historical CGP of metastatic tissue. Prevalence of ATM in cfDNA was higher than historic tumor tissue CGP but similar to prior reports from cfDNA testing (Table). Conclusions: In this large real-world population of pts with aPC undergoing routine cfDNA CGP by a CLIA certified lab, prevalence of HRRm was similar (or higher for BRCA1 and ATM) to what has been previously reported from the tumor tissue. These data provide the rationale for utilizing cfDNA CGP as a routine test for detection of HRRm in men with aPC to identify men who are candidates for PARPi. [Table: see text]

274 Background: MiT family translocation renal cell carcinomas (TRCC) represent a rare and aggressive subgroup of RCC harboring high expression of c-MET. While response rates of VEGF receptor-tyrosine kinase inhibitor and immune checkpoint inhibitors are limited, efficacy of cabozantinib (a TKI that inhibits VEGFR, MET, and AXL) in this subgroup is unclear. Methods: We performed a multicentre, retrospective, international cohort study of patients with TRCC treated with cabozantinib regardless the line of treatment at 7 centers (3 in France and 4 in the US). The main objectives were to estimate response rate according to RECIST criteria, and to analyze progression-free survival (PFS) and overall survival (OS). Results: Among 31 metastatic patients treated in the participating centers, 24 were evaluable for response and were included in this study (21 with TFE3 and 3 with TFEB translocations). Median age at diagnosis was 43.5 years (range, 22–70). Most frequent metastatic sites at diagnosis were lungs (62.5%), retroperitoneal lymph nodes (45.8%) and bone (37.5%). Patient’s IMDC risk group at diagnosis was favourable (20,8%), intermediate (62,5%) and poor (16,7%). Seven (29%) patients received cabozantinib at first line, 9 (37.5%) at second line and 8 (33%) at third line and beyond. The proportion of patients who achieved an objective response was 16.6%, including 1 complete response and 3 partial responses. For 11 (45.8%) patients, stable disease was the best response. With a median follow-up of 14 months (IQR 5-23), median PFS was 8.4 months (range, 1-34+) and median OS was 17 months (range, 2-43). No PFS difference was detected overall or in any subgroup except in patients with bone metastasis which harbored a median PFS of 3.6 months as compared to 9.1 months for those without (p=0.03). Conclusions: This real-world study provides evidence supporting activity of cabozantinib in TRCC, with more durable responses to therapy than those observed with of VEGF receptor-tyrosine kinase inhibitor and immune checkpoint inhibitors. International collaborations and prospective studies are necessary to identifies efficacious therapies for this rare disease that lacks evidence-based treatment options.