Search

Background In this multicenter, single-arm, multicohort, phase 2 trial, the efficacy of nivolumab and ipilimumab was evaluated in patients with advanced rare genitourinary cancers, including bladder and upper tract carcinoma of variant histology (BUTCVH), adrenal tumors, platinum-refractory germ cell tumors, penile carcinoma, and prostate cancer of variant histology (NCT03333616). Methods Patients with rare genitourinary malignancies and no prior immune checkpoint inhibitor exposure were enrolled. Patients received nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg intravenously every 3 weeks for 4 doses, and this was followed by 480 mg of nivolumab intravenously every 4 weeks. The primary endpoint was the objective response rate (ORR) by the Response Evaluation Criteria in Solid Tumors (version 1.1). Results Fifty-five patients were enrolled at 6 institutions between April 2018 and July 2019 in 3 cohorts: BUTCVH (n = 19), adrenal tumors (n = 18), and other tumors (n = 18). The median follow-up was 9.9 months (range, 1 to 21 months). Twenty-eight patients (51%) received 4 doses of nivolumab and ipilimumab; 25 patients received nivolumab maintenance for a median of 4 cycles (range, 1-18 cycles). The ORR for the entire study was 16% (80% confidence interval, 10%-25%); the ORR in the BUTCVH cohort, including 2 complete responses, was 37%, and it was 6% in the other 2 cohorts. Twenty-two patients (40%) developed treatment-related grade 3 or higher toxicities; 24% (n = 13) required high-dose steroids (≥40 mg of prednisone or the equivalent). Grade 5 events occurred in 3 patients; 1 death was treatment related. Conclusions Nivolumab and ipilimumab resulted in objective responses in a subset of patients with rare genitourinary malignancies, especially those with BUTCVH. An additional cohort exploring their activity in genitourinary tumors with neuroendocrine differentiation is ongoing. Lay summary Patients with rare cancers are often excluded from studies and have limited treatment options. Fifty-five patients with rare tumors of the genitourinary system were enrolled from multiple sites and were treated with nivolumab and ipilimumab, a regimen used for kidney cancer. The regimen showed activity in some patients, particularly those with bladder or upper tract cancers of unusual or variant histology; 37% of those patients responded to therapy. Additional studies are ongoing to better determine who benefits the most from this combination.

Objectives: The pathophysiology of isolated coronary artery ectasia (CAE) involves atherosclerosis and inflammation. Eosinophils and lymphocytes have been found to play a significant role in inflammation, atherosclerosis and endothelial dysfunction. Many studies have explored the relationship between isolated CAE and systemic inflammation. However, there are no data regarding the relationship between eosinophil-to-lymphocyte ratio (ELR) and isolated CAE. Therefore, this study analysed the relationship between ELR and isolated CAE. Methods: All patients who underwent coronary angiography between January 2009 and June 2018 were investigated retrospectively. Of 16 240 patients, 232 patients with isolated CAE (141 males) and 247 age- and gender-matched control subjects (130 males) with normal coronary angiography (NCA) were enrolled in this study. Baseline demographic and laboratory data were obtained from the hospital database. The severity of isolated CAE was determined according to the Markis classification, vessel count and diffuseness of ectasia. Results: Patients with angiographic isolated CAE had significantly elevated white blood cell (WBC) and eosinophil counts and ELR values compared to patients with NCA [8.11 ± 1.75 vs 7.49 ± 1.80 × 109 cells/l, p < 0.0001; 0.22 (0.13-0.32) vs 0.19 (0.12-0.28) × 109 cells/l, p = 0.02; 0.11 (0.06-0.17) vs 0.08 (0.05-0.12), p < 0.0001. The ELR value for Markis I was significantly higher than for Markis IV (p = 0.04), and three-vessel isolated CAE was significantly higher than onevessel isolated CAE (p = 0.04). Additionally, the ELR value for diffuse ectasia (Markis class I, II and III) was significantly higher compared to focal (Markis class IV) ectasia (p = 0.02). In receiver operating characteristics (ROC) analyses, it was determined that an ELR value > 0.099, measured in isolated CAE patients at application, had a predictive specificity of 60.3% and a sensitivity of 56.5% (area under the curve: 0.604, 95% confidence interval: 0.553-0.655, p < 0.0001). Conclusions: Patients with isolated CAE had higher blood eosinophil counts and ELR. Furthermore, the ELR was significantly correlated with severity of isolated CAE. These findings demonstrate that ELR may have a significant role in the aetiopathogenesis of isolated CAE. WOS:000587657400003 Q4

To assess comparative effectiveness of adjuvant therapies for renal cell carcinoma and quantify the absolute benefit of adjuvant treatments by clinicopathological risk groups.This 'living' review was conducted using Living Interactive Evidence (LIvE) synthesis framework.The 'living' results are available on an interactive website. This network meta-analysis, including six RCTs with 7525 participants, showed that pembrolizumab (rank 1) significantly improved disease-free survival and overall survival compared with sunitinib but not when compared to pazopanib, and axitinib. The risk of treatment-related grade 3 or higher adverse events was increased with pembrolizumab as compared to placebo and axitinib but not when compared to sunitinib. The absolute benefit of adjuvant pembrolizumab increases substantially with larger tumor size, nodal positivity and higher Leibovich scores.Current evidence suggests that pembrolizumab delays disease progression compared to sunitinib. A risk-adapted strategy should be used in patients undergoing consideration for treatment with adjuvant pembrolizumab.

BackgroundImmune checkpoint inhibitor-based combinations have expanded the treatment options for patients with renal cell carcinoma (RCC); however, tolerability remains challenging. The aim of this study was to evaluate the safety and efficacy of the immunostimulatory interleukin-2 cytokine prodrug bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) as first-line therapy in patients with advanced clear-cell RCC.MethodsThis was an open-label multicohort, multicenter, single-arm phase 1/2 study; here, we report results from the phase 1/2 first-line RCC cohort (N=49). Patients received BEMPEG 0.006 mg/kg plus NIVO 360 mg intravenously every 3 weeks. The primary objectives were safety and objective response rate (ORR; patients with measurable disease at baseline and at least one postbaseline tumor response assessment). Secondary objectives included overall survival (OS) and progression-free survival (PFS). Exploratory biomarker analyses: association between baseline biomarkers and ORR.ResultsAt a median follow-up of 32.7 months, the ORR was 34.7% (17/49 patients); 3/49 patients (6.1%) had a complete response. Of the 17 patients with response, 14 remained in response for >6 months, and 6 remained in response for >24 months. Median PFS was 7.7 months (95% CI 3.8 to 13.9), and median OS was not reached (95% CI 37.3 to not reached). Ninety-eight per cent (48/49) of patients experienced ≥1 treatment-related adverse event (TRAE) and 38.8% (19/49) had grade 3/4 TRAEs, most commonly syncope (8.2%; 4/49) and increased lipase (6.1%; 3/49). No association between exploratory biomarkers and ORR was observed. Limitations include the small sample size and single-arm design.ConclusionsBEMPEG plus NIVO showed preliminary antitumor activity as first-line therapy in patients with advanced clear-cell RCC and was well tolerated. These findings warrant further investigation.

Introduction There are three combination immune checkpoint inhibitor (ICI)–based regimens in the first-line setting for metastatic renal cell carcinoma (mRCC). Currently, there is limited real-world data for clinical outcomes and toxicity in mRCC patients treated with first-line ICI-based regimens. Methods We performed a retrospective review of 49 mRCC patients treated with ICI-based combination regimens in the standard of care setting at the Winship Cancer Institute of Emory University from 2015–2020. We collected baseline data from the electronic medical record including demographic information and disease characteristics. Immune-related adverse events (irAEs) were collected from clinic notes and laboratory values. The primary clinical outcomes measured were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Results The median age was 65 years, and most patients (80%) were males. The majority were White (86%) and had clear cell RCC (83%). Most patients had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 (43%) or 1 (45%). Approximately one-half (49%) had at least three sites of distant metastatic disease. Most patients (88%) received nivolumab and ipilimumab. More than one-half (53%) of patients experienced an irAE, with 13 (27%) patients having treatment delayed and 18% discontinuing treatment for toxicity. The median OS was not reached, and the median PFS was 8.0 months per a Kaplan-Meier estimation. More than half of patients (53%) had a PFS > 6 months, and 22% had PFS > 1 year. The ORR was 33% for the entire cohort, and 7% of patients had a complete response. Conclusion We presented real-world efficacy and toxicity data for front-line ICI combination treatment regimens. The ORR and median PFS were lower in our cohort of patients compared to the available data in the clinical trial setting. This was likely because of more advanced disease in this study. Future studies should provide additional data that will allow comparisons between different ICI combination regimens for untreated mRCC.

The COVID-19 pandemic has had a distinct spatiotemporal pattern in the United States. Patients with cancer are at higher risk of severe complications from COVID-19, but it is not well known whether COVID-19 outcomes in this patient population were associated with geography.To quantify spatiotemporal variation in COVID-19 outcomes among patients with cancer.This registry-based retrospective cohort study included patients with a historical diagnosis of invasive malignant neoplasm and laboratory-confirmed SARS-CoV-2 infection between March and November 2020. Data were collected from cancer care delivery centers in the United States.Patient residence was categorized into 9 US census divisions. Cancer center characteristics included academic or community classification, rural-urban continuum code (RUCC), and social vulnerability index.The primary outcome was 30-day all-cause mortality. The secondary composite outcome consisted of receipt of mechanical ventilation, intensive care unit admission, and all-cause death. Multilevel mixed-effects models estimated associations of center-level and census division-level exposures with outcomes after adjustment for patient-level risk factors and quantified variation in adjusted outcomes across centers, census divisions, and calendar time.Data for 4749 patients (median [IQR] age, 66 [56-76] years; 2439 [51.4%] female individuals, 1079 [22.7%] non-Hispanic Black individuals, and 690 [14.5%] Hispanic individuals) were reported from 83 centers in the Northeast (1564 patients [32.9%]), Midwest (1638 [34.5%]), South (894 [18.8%]), and West (653 [13.8%]). After adjustment for patient characteristics, including month of COVID-19 diagnosis, estimated 30-day mortality rates ranged from 5.2% to 26.6% across centers. Patients from centers located in metropolitan areas with population less than 250 000 (RUCC 3) had lower odds of 30-day mortality compared with patients from centers in metropolitan areas with population at least 1 million (RUCC 1) (adjusted odds ratio [aOR], 0.31; 95% CI, 0.11-0.84). The type of center was not significantly associated with primary or secondary outcomes. There were no statistically significant differences in outcome rates across the 9 census divisions, but adjusted mortality rates significantly improved over time (eg, September to November vs March to May: aOR, 0.32; 95% CI, 0.17-0.58).In this registry-based cohort study, significant differences in COVID-19 outcomes across US census divisions were not observed. However, substantial heterogeneity in COVID-19 outcomes across cancer care delivery centers was found. Attention to implementing standardized guidelines for the care of patients with cancer and COVID-19 could improve outcomes for these vulnerable patients.

The past decade has witnessed a revolution in the development of immune checkpoint inhibitors for the treatment of multiple tumor types, including genitourinary cancers. Immune checkpoint inhibitors have notably improved the treatment outcomes of patients with metastatic renal cell carcinoma and metastatic urothelial carcinoma. In prostate cancer, the role of immunotherapy with checkpoint inhibitors is not yet established except for microsatellite instability high (MSI-H) tumors. Other immunotherapeutic approaches that have been explored in these malignancies include cytokines, vaccines, and cellular therapy. Ongoing studies are exploring the use of immunotherapy combinations as well as combination with chemotherapy and targeted therapy in these types of tumors. The use of immunotherapy beyond the metastatic setting is an active area of research. Moreover, there is great interest in biomarker development to predict response to immunotherapy and risk of toxicity. This book chapter is a comprehensive review of immunotherapeutic approaches, both approved and investigational, for the treatment of renal cell carcinoma, urothelial carcinoma, and prostate cancer.

Background Cabozantinib is approved for the first and subsequent line treatment of metastatic clear-cell renal cell carcinoma (ccRCC) based on trials in which most patients were immune checkpoint blockade (ICB) naive. With an expanding role of ICB in earlier lines of therapy, we assessed activity of cabozantinib in patients with metastatic ccRCC after progressing on anti-PD-1/PD-L1–based ICBs. Methods We retrospectively analysed the clinical outcomes of 86 patients from 2 academic centres who received cabozantinib after progression on ICB alone, ICB in combination with vascular endothelial growth factor inhibitors (VEGFis) or ICB in combination with other therapies. Overall response rate (ORR, investigator assessed), time to treatment failure (TTF), overall survival (OS) and toxicities leading to dose reductions or cessation were evaluated. Results Eighty-six patients were included in the analysis; the median age was 63 years (range 33–84) and the median number of prior therapies was 2 (range 1–10). The type of prior ICB therapy was ICBs alone (64%), an ICB in combination with a VEGFi (29%) or ICBs in combination with other therapies (7%). At the time of cabozantinib treatment, 71% of patients were in the International Metastatic RCC Database Consortium good- or intermediate-risk groups. Approximately half of patients (52%) were started on cabozantinib at the full 60 mg daily dose. The ORR was 36% (95% confidence interval [CI] = 26–47%) with no complete response and 43% achieving stable disease; 21% had primary progressive disease. The median TTF was 6.5 months (95% CI = 5.3–8.5.). The median OS was 13.1 months (95% CI = 8.7-NR) with 55% (95% CI = 41–66%) OS rate at 12 months. Most common reasons for dose reductions were fatigue (27%), palmar-plantar erythrodysesthesia (16%) and diarrhoea (10%). Conclusions Cabozantinib is active in patients treated with prior ICB-based therapies, with no new safety signals. This study supports the use of cabozantinib after ICB-based therapies.

About one-third of advanced renal cell carcinoma (RCC) patients have bone metastases, which subsequently leads to the development of skeletal-related events (SREs), broadly defined to include surgery and radiation to bone, bone pain, pathological fracture, spinal cord compression, or hypercalcemia. The cumulative impact of SREs in RCC has not been well studied. SREs increase morbidity and mortality of RCC patients, although many interventions do significantly reduce their rates of development and improve prognosis. We performed a systematic review from the existing literature in PubMed from January 2002 through September 2019 and summarized the body of evidence regarding the development, prevention, prognosis and treatment of SREs in advanced RCC patients.

Urinary tract cancer can be pure urothelial carcinoma, pure nonurothelial carcinoma or variant urothelial carcinoma (defined here as mixed urothelial carcinoma). Little is known regarding outcomes for patients with variant urothelial carcinoma receiving immune checkpoint inhibitors. We hypothesized that variant urothelial carcinoma does not compromise immune checkpoint inhibitor efficacy in patients with advanced urothelial carcinoma.We performed a retrospective cohort study across 18 institutions. Demographic, clinicopathological, treatment and outcomes data were collected for patients with advanced urothelial carcinoma who received immune checkpoint inhibitors. Patients were divided into pure vs variant urothelial carcinoma subgroups, with variant urothelial carcinoma further divided by type of variant (ie squamous, neuroendocrine etc). We compared overall response rate using univariate and multivariate logistic regression and progression-free survival and overall survival using Kaplan-Meier and univariate and multivariate Cox proportional hazards.Overall 519 patients were identified, with 395, 406 and 403 included in overall response rate, overall survival and progression-free survival analyses, respectively. Overall response rate to immune checkpoint inhibitors between patients with pure vs variant urothelial carcinoma was comparable (28% vs 29%, p=0.90) without significant differences for individual subtypes vs pure urothelial carcinoma. Median overall survival for patients with pure urothelial carcinoma was 11.0 months vs 10.1 months for variant urothelial carcinoma (p=0.60), but only 4.6 months for patients with neuroendocrine features (9 patients, HR 2.75, 95% CI 1.40-5.40 vs pure urothelial carcinoma, p=0.003). Median progression-free survival was 4.1 months for pure vs 5.2 months for variant urothelial carcinoma (p=0.43) and 3.7 months for neuroendocrine features (HR 1.87, 95% CI 0.92-3.79 vs pure urothelial carcinoma, p=0.09).Overall response rate to immune checkpoint inhibitors was comparable across histological types. However, overall survival was worse for patients with tumors containing neuroendocrine features. Variant urothelial carcinoma should not exclude patients from receiving immune checkpoint inhibitors.

Background Purpose: The combination of a mammalian target of rapamycin inhibitor and lenalidomide showed enhanced preclinical cytotoxicity. We conducted a phase 1 study in advanced solid tumour patients to assess safety, efficacy and pharmacodynamic (PD) outcomes. Methods We employed a 3+3 dose escalation design to establish the safety and recommended phase 2 doses (RP2D) of daily everolimus and lenalidomide in patients with advanced solid tumours. The starting doses were 5 and 10 mg, respectively, with planned escalation to maximum single-agent doses of 10 and 25 mg in the absence of dose-limiting toxicity. PD endpoints of lymphocyte subsets and immune cytokines were assessed in peripheral blood using multiparameter flow cytometry and LUMINEX assay. Efficacy was evaluated by cross-sectional imaging after every two cycles of treatment. Results The study enrolled 44 patients, median age of 58 years and 28 males (63.6%). The RP2D was established as 10 and 25 mg daily continuously for everolimus and lenalidomide. Common (>5%) grade ≥3 adverse events included rash (19%), neutropenia (19%), hypokalaemia (11%) and fatigue (9%). Best efficacy outcomes in 36 evaluable patients were partial response in 5 (13.8%), stable disease in 24 (55.8%) and progressive disease in 7 (19.4%) patients. PD assessment revealed significant association of cytokine levels (interleukin-2 (IL2), IL21 and IL17), baseline activated and total CD8+ lymphocytes and change in B cell lymphocytes and activated NK cells with clinical benefit. Conclusions The study demonstrated the safety of everolimus and lenalidomide with promising efficacy signal in thyroid and adenoid cystic cancers. Clinical Trial Registration NCT01218555

Summary Background Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness. Methods In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. Findings Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57–76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53–2·21), male sex (1·63, 1·07–2·48), smoking status (former smoker vs never smoked: 1·60, 1·03–2·47), number of comorbidities (two vs none: 4·50, 1·33–15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11–7·18), active cancer (progressing vs remission: 5·20, 2·77–9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79–4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07–0·84) or the US-Midwest (0·50, 0·28–0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. Interpretation Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments. Funding American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

Purpose: Concurrent inhibition of mTOR and PI3K led to improved efficacy in preclinical models and provided the rationale for this phase I study of everolimus and buparlisib (BKM120) in patients with advanced solid tumor. Patients and Methods: We used the Bayesian Escalation with Overdose Control design to test escalating doses of everolimus (5 or 10 mg) and buparlisib (20, 40, 60, 80, and 100 mg) in eligible patients. Pharmacokinetic assessment was conducted using blood samples collected on cycle 1, days 8 and 15. Pharmacodynamic impact on mTOR/PI3K pathway modulation evaluated in paired skin biopsies collected at baseline and end of cycle 1. Results: We enrolled 43 patients, median age of 63 (range, 39–78) years; 25 (58.1%) females, 35 (81.4%) Caucasians, and 8 (18.6%) Blacks. The most frequent toxicities were hyperglycemia, diarrhea, nausea, fatigue, and aspartate aminotransferase elevation. Dose-limiting toxicities observed in 7 patients were fatigue (3), hyperglycemia (2), mucositis (1), acute kidney injury (1), and urinary tract infection (1). The recommended phase II dose (RP2D) for the combination was established as everolimus (5 mg) and buparlisib (60 mg). The best response in 27 evaluable patients was progressive disease and stable disease in 3 (11%) and 24 (89%), respectively. The median progression-free survival and overall survival were 2.7 (1.8–4.2) and 9 (6.4–13.2) months. Steady-state pharmacokinetic analysis showed dose-normalized maximum concentrations and AUC values for everolimus and buparlisib in combination to be comparable with single-agent pharmacokinetic. Conclusions: The combination of everolimus and buparlisib is safe and well-tolerated at the RP2D of 5 and 60 mg on a continuous daily schedule.

Nonbacterial thrombotic endocarditis (NBTE) is a rare entity most commonly diagnosed postmortem with rates in autopsy series ranging from 0.9 to 1.6%. A 63-year-old female with past medical history of hypertension and mitral valve prolapse presented to the hospital with shortness of breath, headache, and necrotic skin lesions on her hands and feet. Computed tomography (CT) scan of her chest demonstrated a pulmonary embolus in the right lower lung segmental artery and right upper lobe lobar to segmental pulmonary artery, a mass-like consolidation in the left upper lung field impeding the hilum. CT scan of the abdomen demonstrated metastatic disease in liver and bone and bilateral femoral deep vein thrombosis. Transesophageal echocardiography revealed severe mitral regurgitation with two small mobile plaques on the mitral valve and two immobile plaques on the descending aorta. Magnetic resonance imaging of the brain was consistent with subacute infarcts and metastatic disease. Bronchoscopy was performed and pathology revealed primary adenocarcinoma of the lung. She was treated with anticoagulation and systemic chemotherapy. The patient and family elected to proceed with hospice due to her clinical decline, poor performance status, and poor prognosis after a prolonged hospital stay. Underlying malignancy is detected in approximately 40–85% of patients with NBTE. Lung cancer is the most frequently associated malignancy followed by pancreatic, stomach, breast, and ovarian cancer. Widespread necrotic skin lesions as presenting symptoms of primary lung adenocarcinoma are rare. In the present case, the diagnosis of necrotic skin lesions and NBTE preceded that of the neoplastic disease. Necrotic skin lesions and NBTE can be the first manifestations of an occult malignancy causing extensive multi-organ infarcts. NBTE can present with such extensive skin lesions as a first presenting sign of malignancy. To the best of our knowledge, this is the first case to present with such extensive skin lesions as the first presenting symptom of lung adenocarcinoma.

Introduction Immune-related adverse event (IRAE) onset may represent a clinical biomarker for anti-programmed cell death protein 1 (PD-1) antibody response based on emerging evidence from patients with various advanced malignancies. This phenomenon has not been previously reported in a multidisease cohort of patients with gastrointestinal (GI) cancer with Food and Drug Administration (FDA)-approved indications to receive immune checkpoint inhibitor therapy. Materials and Methods The study was a multicenter retrospective cohort analysis of 76 patients with GI cancer who had received anti-PD-1 antibodies for FDA-approved indications. The primary and secondary outcomes of the study were progression-free survival (PFS) and overall survival (OS) in patients based upon IRAE presence, respectively. PFS and OS were estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusted for IRAE onset, patient age, and enrolling institution was used to analyze outcomes. Results Median PFS and OS were prolonged in patients who experienced IRAEs compared with those who did not experience them (PFS: not reached [NR] vs. 3.9 months [hazard ratio (HR) 0.13, 95% confidence interval (CI) 0.05–0.3, p < .001]; OS: NR vs. 7.4 months [HR 0.11, 95% CI 0.03–0.36, p < .001]). Among patients who experienced IRAEs, there were no significant differences in PFS and OS by either initial IRAE severity, management, or time to onset. Conclusion Patients with gastrointestinal cancer who experienced IRAEs while on anti-PD-1 antibodies demonstrated significant improvements in PFS and OS compared with their counterparts who did not develop IRAEs. Although these findings add to results from studies in other tumor types, larger prospective studies are needed prior to clinical adoption of IRAE onset as a biomarker for immune checkpoint inhibitor response. Implications for Practice Predictive clinical biomarkers for immune checkpoint inhibitor response have been understudied in the field of immuno-oncology. Immune-related adverse event onset appears to be one such biomarker. Across tumor types, immune-related adverse event onset has been associated with response to anti-programmed cell death protein 1 (PD-1) antibodies. The results of this study demonstrate this for the first time in patients with gastrointestinal cancer receiving anti-PD-1 antibodies. Before immune-related adverse event onset can be adopted clinically as a predictive biomarker for immune checkpoint inhibitor response, however, larger prospective studies are needed to better understand the nuances between immune-related adverse event characteristics (severity, site, management, timing of onset) and immune checkpoint inhibitor effectiveness.

Metastatic urothelial carcinoma (mUC) has a poor prognosis with a 5-year survival probability of 4.8%. The mainstay of first-line treatment is platinum-based chemotherapy. Second-line therapy involves immune checkpoint inhibitors or a fibroblast growth factor receptor (FGFR) inhibitor, erdafitinib, for patients harboring selected FGFR alterations. Several additional agents are under development for the treatment of mUC. Recent studies demonstrate that ramucirumab and docetaxel have clinical activity in mUC. We report two patients with metastatic upper tract urothelial cancer (mUTUC) with FGFR alterations who were heavily pretreated with FGFR inhibitors that later showed response to ramucirumab and docetaxel. Preclinical studies indicate that FGF and VEGF pathways work synergistically, which could explain the observations in our patients. Our findings may represent another treatment option for patients with mUC and FGFR alterations who have progressed on multiple lines of therapy.

Background The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria are the gold standard for risk‐stratifying patients with metastatic renal cell cancer (mRCC). We developed a novel risk scoring system for patients with mRCC treated with immune checkpoint inhibitors (ICIs). Methods We performed a retrospective analysis of 100 ICI‐treated patients with mRCC at Winship Cancer Institute from 2015 to 2018. Several baseline variables were collected, including markers of inflammation, body mass index (BMI), and sites of metastatic disease, and all were considered for inclusion in our risk scoring system. Upon variable selection in multivariable model, monocyte‐to‐lymphocyte ratio (MLR), BMI, and number and sites of metastases at baseline were used for risk score calculation. Patients were categorized using four‐level risk groups as good (risk score = 0), intermediate (risk score = 1), poor (risk score = 2), or very poor (risk score = 3–4). Cox's proportional hazard model and the Kaplan‐Meier method were implemented for survival outcomes. Results Most patients were male (66%) with clear cell renal cell carcinoma (72%). The majority (71%) received anti–programmed cell death protein‐1 monotherapy. Our risk scoring criteria had higher Uno's concordance statistics than IMDC in predicting overall survival (OS; 0.71 vs. 0.57) and progression‐free survival (0.61 vs. 0.58). Setting good risk (MLR, Considering the increasing number of treatment options for patients with metastatic renal cell carcinoma, it is becoming more important to identify factors that increase the likelihood of responses to systemic therapy. This article describes a novel risk scoring system for patients with metastatic renal cell carcinoma treated with ICI, focusing on risk from systemic inflammation, number and sites of metastatic disease, and body composition.

Background Sarcopenia and inflammation have been associated with poor survival in patients with cancer. We explored the combined effects of these variables on survival in patients with cancer treated with immunotherapy. Methods We performed a retrospective review of 90 patients enrolled on immunotherapy‐based phase I clinical trials at Emory University from 2009 to 2017. Baseline neutrophil‐to‐lymphocyte ratio, monocyte‐to‐lymphocyte ratio, and platelet‐to‐lymphocyte ratio (PLR) were used as surrogates of inflammation. The skeletal muscle index (SMI) was derived from the skeletal muscle density calculated from baseline abdominal computed tomography images. Optimal cutoffs for continuous inflammation biomarkers and SMI were determined by bias‐adjusted log‐rank test. A four‐level risk stratification was used to create low‐risk (PLR, The interaction between chronic inflammation and body composition is particularly important in the era of immunotherapy, considering that immune checkpoint inhibitors rely on the host immune system for their efficacy. This article reports on the combined effects of inflammation and sarcopenia on clinical outcomes in patients with solid tumors treated with immunotherapy‐based regimens.

The pathophysiology of isolated coronary artery ectasia (CAE) takes in inflammation and atherosclerosis. It is clear that basophils have a critical role in endothelial dysfunction, atherosclerosis and inflammation. In this study, it was aimed to examine the association between isolated CAE and basophilia. All cases who underwent coronary angiography between January 2013 and April 2018 evaluated retrospectively. Of 10985 cases, 173 (107 males) with isolated CAE and 220 with normal coronary angiography (NCA) that age and gender matched subjects (119 males) were recorded. Hospitals database was used to derive the biochemical and hematological test results, and baseline characteristics. White blood cell (WBC) count and basophil count were significantly elevated for the cases that have angiographic isolated CAE when compared to the subjects with NCA [ 7.87 (6.83-9.42)109/ L vs 7.48 (6.27-8.67) 109/ L, p=0.01; 0.04 (0.03-0.05) 109/ L vs 0.03 (0.02-0.05) 109/ L, p=0.03, respectively]. According to receiver operating characteristics curve analyses (ROC); the specificity of a basophil value > 0.037 109/ L (measured prior to coronary angiography) in predicting isolated CAE was 57,3% and the sensitivity was 57.2% (area under the curve [AUC] 0.562, 95% CI 0.505, 0.618; p=0.03). Patients with isolated CAE have higher blood basophil count. Elevated blood basophil count may have a substantial mission in the pathogenesis of isolated CAE. [Med-Science 2019; 8(4.000): 800-6]

Papillary renal cell carcinoma (PRCC) is a subtype of renal cell carcinoma (RCC) accounting for approximately 15–20% of cases and further divided into Type 1 and Type 2. Type 1 PRCC tends to have more alterations in the MET tyrosine kinase receptor than Type 2 PRCC. Treatment for RCC patients is based on studies with minimal participation from patients with PRCC; consequently, conventional therapies tend to be less effective for RCC patients with a subtype other than ccRCC (non-ccRCC). Since MET is a known alteration in PRCC, it is potential target for directed therapy. There have been many attempts to develop MET inhibitors for use in solid tumors including PRCC. The following review will discuss the current research regarding MET-targeted therapy, MET inhibitors in clinical trials, and future directions for MET inhibitors in PRCC.

BACKGROUND Body mass index (BMI) is used to define obesity, but it is an imperfect measure of body composition. In the current study, the authors explored the association between types of fat and survival in patients treated with immunotherapy. METHODS A retrospective analysis of 90 patients who were treated with immunotherapy on phase 1 clinical trials at the Winship Cancer Institute in Atlanta, Georgia, from 2009 through 2017 was performed. Overall survival (OS) and progression-free survival (PFS) were used to measure clinical outcomes. Baseline BMI and radiographic images at the middle of the third lumbar vertebrae were obtained. Fat densities were calculated and converted to indices (subcutaneous fat index [SFI], intermuscular fat index [IFI], and visceral fat index [VFI]) after dividing by height in meters squared. Risk groups were created using recursive partitioning and the regression trees method for SFI and IFI, which were selected by stepwise variable selection among all fat-related variables. The Cox proportional hazards model and Kaplan-Meier method were used for the association with OS and PFS. RESULTS The majority of patients (59%) were male and diagnosed with melanoma (33%) or gastrointestinal cancers (22%). The median BMI was 27.4 kg/m2 , the median SFI was 62.78, the median IFI was 4.06, and the median VFI was 40.53. Low-risk patients (those with an SFI ≥73) had a significantly longer OS (hazard ratio, 0.20; 95% CI, 0.09-0.46 [P

Translocation-associated renal cell carcinoma (tRCC) is a rare, aggressive malignancy that primarily affects children and young adults. There is no clear consensus on the most effective treatment for tRCC and there are no biomarkers of response to treatments in these patients. We present a case of a 23 year-old female with metastatic tRCC to the lungs who was started on treatment with nivolumab and ipilimumab. She had a complete radiographic response to treatment and has been progression-free for over 18 months. Immunofluorescence imaging performed on the baseline primary tumor sample showed significant intratumoral immune infiltration. Importantly, these cells are present in niches characterized by TCF1+ CD8+ T cells. Histopathologic investigation showed the presence of lymphocytes in the fibrovascular septae and foci of lymphovascular invasion. Furthermore, lymphovascular invasion and intratumor niches with TCF1+ CD8+ T cells may predict a favorable response to treatment with nivolumab and ipilimumab. These findings have significant clinical relevance given that immune checkpoint inhibitors are approved for several malignancies and predictive biomarkers for response to treatment are lacking. Importantly, the identification of these TCF1+ CD8+ T cells may guide treatment for patients with tRCC, which is a rare malignancy without a consensus first-line treatment option.

Key Points Question Given the higher COVID-19–related mortality rate observed among men than among women, is androgen deprivation therapy associated with decreased rate of 30-day mortality from COVID-19 among patients with prostate cancer? Findings In this cohort study of 1106 patients, no statistically significant difference was found in the rates of all cause 30-day mortality following COVID-19 infection among men with prostate cancer receiving androgen deprivation therapy (15%) vs those not receiving androgen deprivation therapy (14%). Meaning The findings of this cohort study do not support an association between androgen deprivation therapy and 30-day mortality among patients with COVID-19 infection., Importance Androgen deprivation therapy (ADT) has been theorized to decrease the severity of SARS-CoV-2 infection in patients with prostate cancer owing to a potential decrease in the tissue-based expression of the SARS-CoV-2 coreceptor transmembrane protease, serine 2 (TMPRSS2). Objective To examine whether ADT is associated with a decreased rate of 30-day mortality from SARS-CoV-2 infection among patients with prostate cancer. Design, Setting, and Participants This cohort study analyzed patient data recorded in the COVID-19 and Cancer Consortium registry between March 17, 2020, and February 11, 2021. The consortium maintains a centralized multi-institution registry of patients with a current or past diagnosis of cancer who developed COVID-19. Data were collected and managed using REDCap software hosted at Vanderbilt University Medical Center in Nashville, Tennessee. Initially, 1228 patients aged 18 years or older with prostate cancer listed as their primary malignant neoplasm were included; 122 patients with a second malignant neoplasm, insufficient follow-up, or low-quality data were excluded. Propensity matching was performed using the nearest-neighbor method with a 1:3 ratio of treated units to control units, adjusted for age, body mass index, race and ethnicity, Eastern Cooperative Oncology Group performance status score, smoking status, comorbidities (cardiovascular, pulmonary, kidney disease, and diabetes), cancer status, baseline steroid use, COVID-19 treatment, and presence of metastatic disease. Exposures Androgen deprivation therapy use was defined as prior bilateral orchiectomy or pharmacologic ADT administered within the prior 3 months of presentation with COVID-19. Main Outcomes and Measures The primary outcome was the rate of all-cause 30-day mortality after COVID-19 diagnosis for patients receiving ADT compared with patients not receiving ADT after propensity matching. Results After exclusions, 1106 patients with prostate cancer (before propensity score matching: median age, 73 years [IQR, 65-79 years]; 561 (51%) self-identified as non-Hispanic White) were included for analysis. Of these patients, 477 were included for propensity score matching (169 who received ADT and 308 who did not receive ADT). After propensity matching, there was no significant difference in the primary end point of the rate of all-cause 30-day mortality (OR, 0.77; 95% CI, 0.42-1.42). Conclusions and Relevance Findings from this cohort study suggest that ADT use was not associated with decreased mortality from SARS-CoV-2 infection. However, large ongoing clinical trials will provide further evidence on the role of ADT or other androgen-targeted therapies in reducing COVID-19 infection severity., This cohort study using data from the COVID-19 and Cancer Consortium registry examines whether androgen deprivation therapy is associated with decreased rates of mortality within 30 days of COVID-19 diagnosis among patients with prostate cancer.

BackgroundTumor infiltrating T-cells have a prognostic benefit in many tumor types,1–8 and we recently sought to determine whether the level of T-cell infiltration into renal tumors predicts clinical outcomes. In our recent publication,9 we showed that patients with high of CD8 T-cell infiltration have improved progression free survival (PFS). Further, we found that this T-cell response is supported by TCF1+ stem-like CD8 T-cells, which reside within dense regions of closely clustered antigen presenting cells within the tumor. Interestingly, aggregations of immune cells have also been described in other tumor types and termed ‘tertiary lymphoid structures’ (TLS), which are typically defined as B-cell-dominant aggregates, containing high endothelial venules and reactive germinal centers.10–12 Together, these findings raise several important questions, which we explore here—(1) what additional cell types comprise these niches?9 and (2) how are these niches similar to or different from TLS?MethodsTumor tissue was collected from patients with renal tumors undergoing surgery at Emory University Hospital. Intraoperative tumor samples were analyzed by flow cytometry, RNA sequencing, immunofluorescence, and immunohistochemistry. Immunofluorescence data was analyzed using our custom quantitative analysis pipelines, which allows for delineation of cell type and location, cell-cell distance, and density of cellular aggregation.ResultsThe proportion of CD8 T-cells infiltration human renal tumors varied widely, consistent with our previous reports.9 TCF1+ stem-like CD8 T-cells were identifiable by both flow cytometry and immunofluorescence and resided in dense antigen presenting niches. Quantitative immunofluorescence revealed the location of aSMA+ fibroblasts within tumor tissue, in relation to antigen presenting niches, and in tumors with many infiltrating T-cells. Pathologist scored hematoxylin and eosin-stained slides were delineated TLS+ or TLS-. Quantitative immunofluorescence imaging analysis revealed the detailed composition of tumor infiltrating immune cell populations and the contrasting cellular organization in TLS as compared to in antigen presenting niches.ConclusionsAs we have shown CD8 T-cell infiltration to predict PFS in renal tumors and that antigen presenting niches containing stem-like cells maintain the anti-tumor T-cell response,9 it is critical to understand the additional cell types present in these niches and to understand how these niches relate to previously described phenomena of immune organization, such as TLS.10–12 This mechanistic understanding of the anti-tumor immune response represents an opportunity to inform development of enhanced prognostic tools and innovative therapeutic possibilities.ReferencesAzimi F, et al. Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol 2012;30(21):2678–83. Epub 2012/06/20. doi: 10.1200/jco.2011.37.8539. PubMed PMID: 22711850.Galon J, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313(5795):1960–4. Epub 2006/09/30. doi: 10.1126/science.1129139. PubMed PMID: 17008531.Mlecnik B, et al. Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability. Immunity 2016;44(3):698–711. Epub 2016/03/18. doi: 10.1016/j.immuni.2016.02.025. PubMed PMID: 26982367.Mlecnik B, et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol 2011;29(6):610–8. Epub 2011/01/20. doi: 10.1200/JCO.2010.30.5425. PubMed PMID: 21245428.Pagès F, et al. Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene 2009;29:1093. doi: 10.1038/onc.2009.416.Peranzoni E, et al. Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment. Proceedings of the National Academy of Sciences of the United States of America 2018;115(17):E4041–E50. Epub 2018/04/11. doi: 10.1073/pnas.1720948115. PubMed PMID: 29632196.Savas P, et al. Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat Med 2018;24(7):986–93. Epub 2018/06/27. doi: 10.1038/s41591-018-0078-7. PubMed PMID: 29942092.Tosolini M, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res 2011;71(4):1263–71. Epub 2011/02/10. doi: 10.1158/0008-5472.Can-10-2907. PubMed PMID: 21303976.Jansen CS, et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature 2019;576(7787):465–70. doi: 10.1038/s41586-019-1836-5.Dieu-Nosjean MC, et al. Tertiary lymphoid structures in cancer and beyond. Trends Immunol 2014;35(11):571–80. Epub 2014/12/03. doi: 10.1016/j.it.2014.09.006. PubMed PMID: 25443495.Goc J, et al. Characteristics of tertiary lymphoid structures in primary cancers. Oncoimmunology 2013;2(12):e26836. Epub 2014/02/06. doi: 10.4161/onci.26836. PubMed PMID: 24498556; PMCID: PMC3912008.Sautes-Fridman C, et al. Tertiary lymphoid structures in the era of cancer immunotherapy. Nature reviews Cancer 2019;19(6):307–25. Epub 2019/05/17. doi: 10.1038/s41568-019-0144-6. PubMed PMID: 31092904.Ethics ApprovalSamples are collected under an approved IRB protocol (The Urological Satellite Specimen Bank at Emory University, IRB00055316). All patients provided informed consent.ConsentSamples are collected under an approved IRB protocol (The Urological Satellite Specimen Bank at Emory University, IRB00055316). All patients provided informed consent.

Enfortumab vedotin (EV) is a novel antibody-drug conjugate approved for advanced urothelial cancer (aUC) refractory to prior therapy. In the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study, the authors looked at the experience with EV in patient subsets of interest for which activity had not been well defined in clinical trials.UNITE was a retrospective study of patients with aUC treated with recently approved agents. This initial analysis focused on patients treated with EV. Patient data were abstracted from chart reviews by investigators at each site. The observed response rate (ORR) was investigator-assessed for patients with at least 1 post-baseline scan or clear evidence of clinical progression. ORRs were compared across subsets of interest for patients treated with EV monotherapy.The initial UNITE analysis included 304 patients from 16 institutions; 260 of these patients were treated with EV monotherapy and included in the analyses. In the monotherapy cohort, the ORR was 52%, and it was40% in all reported subsets of interest, including patients with comorbidities previously excluded from clinical trials (baseline renal impairment, diabetes, and neuropathy) and patients with fibroblast growth factor receptor 3 (FGFR3) alterations. Progression-free survival and overall survival were 6.8 and 14.4 months, respectively. Patients with a pure urothelial histology had a higher ORR than patients with a variant histology component (58% vs 42%; P = .06).In a large retrospective cohort, responses to EV monotherapy were consistent with data previously reported in clinical trials and were also observed in various patient subsets, including patients with variant histology, patients with FGFR3 alterations, and patients previously excluded from clinical trials with an estimated glomerular filtration rate30 mL/min and significant comorbidities.Enfortumab vedotin, approved by the Food and Drug Administration in 2019, is an important new drug for the treatment of patients with advanced bladder cancer. This study looks at the effectiveness of enfortumab vedotin as it has been used at multiple centers since approval, and focuses on important patient populations previously excluded from clinical trials. These populations include patients with decreased kidney function, diabetes, and important mutations. Enfortumab vedotin is effective for treating these patients. Previously reported clinical trial data have been replicated in this real-world setting, and support the use of this drug in broader patient populations.

Immune-oncologic (IO) therapy has revolutionized the treatment and management of oncologic disease. Immunotherapy functions by enhancing the host immune-systems ability to endogenously clear malignant cells, however, this activation can also lead to immune-mediated damage to healthy native tissues. These side effects are known as immune-related adverse events or irAEs and can even present with phenotypes similar to autoimmune diseases. IrAEs are the major consequence of checkpoint inhibitors and can have a significant impact on a patient’s cancer treatment and long-term quality of life. The management of these irAEs follows a similar approach to autoimmune diseases. More specifically, the management is akin to that of autoimmune disease exacerbations. While there is an array of immune-suppressing agents that can be used, steroids, immunomodulators and IO discontinuation are cornerstones of irAE management. The exact approach and dosing are based on the severity and subtype of irAE presented. Within recent years, there has been a push to better prevent and manage irAEs when they arise. There has been an additional effort to increase the number of steroid-sparing agents available for irAE treatment given the consequences of long-term steroid therapy as well as patient contraindications to steroids. The goals of this review are to summarize irAE management, highlight significant advances made in recent years and emphasize the future directions that will optimize the use of IO therapy in oncology.

Simple Summary Genitourinary malignancies include cancers along the urinary tract and the male reproductive tract, encompassing the adrenal glands, kidneys, bladder, prostate, and testicles. Immunotherapy, which treats cancer by using the immune system to attack malignant cells, has historically been successful in treating some types of genitourinary cancers, especially of the bladder and kidney. In the past decade, a more precise method of immunotherapy, known as immune checkpoint inhibition, has gained popularity as it enhances the immune system’s ability to recognize and destroy tumor cells. Several immune checkpoint inhibitors have achieved success in patients with advanced genitourinary cancers. This review provides a brief overview of traditional immunotherapies, focuses on how immune checkpoint inhibitors have achieved success in patients with advanced cancers, and investigates the role for immunotherapy in genitourinary malignancies in the future. Abstract For decades, limited options existed to treat metastatic genitourinary cancers, including treatment options that could be classified as immunotherapy. Historically, immunotherapy centered on systemic cytokines for the treatment of metastatic kidney cancer, which had several adverse effects, as well as the Bacillus Calmette–Guérin vaccine for non-metastatic bladder cancer. Within the past decade, advances in immunotherapy have led to several approvals from the United States Food and Drug Administration, particularly in the field of immune checkpoint inhibition. Immune checkpoint inhibitors (ICIs) are now being used extensively to treat multiple solid tumors, including kidney and bladder cancers, and they are also being tested in many other cancers. Despite encouraging data from phase 2/3 clinical trials, less is known about biomarkers that may predict better response to ICIs. The effect of ICIs in genitourinary cancers is heterogeneous, with some tumor types having little clinical data available, or ICIs having limited activity in other tumors. In this review, we briefly discuss approved immunotherapy agents prior to the time of ICIs. Then, given the emergence of this class of agents, we summarize the several important ICIs and the clinical trials that led to their approval. Finally, we mention ongoing and future clinical trials.

Reliable and routine isolation of circulating tumor cells (CTCs) from peripheral blood would allow effective monitoring of the disease and guide the development of personalized treatments. Negative enrichment of CTCs by depleting normal blood cells ensures against a biased selection of a subpopulation and allows the assay to be applied on different tumor types. Here, we report an additively manufactured microfluidic device that can negatively enrich viable CTCs from clinically-relevant volumes of unmanipulated whole blood samples. Our device depletes nucleated blood cells based on their surface antigens and the smaller anucleated cells based on their size. Enriched CTCs are made available off the device in suspension making our technique compatible with standard immunocytochemical, molecular and functional assays. Our device could achieve a ~ 2.34-log depletion by capturing > 99.5% of white blood cells from 10 mL of whole blood while recovering > 90% of spiked tumor cells. Furthermore, we demonstrated the capability of the device to isolate CTCs from blood samples collected from patients (n = 15) with prostate and pancreatic cancers in a pilot study. A universal CTC assay that can differentiate tumor cells from normal blood cells with the specificity of clinically established membrane antigens yet require no label has the potential to enable routine blood-based tumor biopsies at the point-of-care.

BACKGROUND: Immunotherapy terminology is complex and can be difficult for patients to understand, threatening informed consent. The aims of this exploratory study are to determine whether patients understand immunotherapy terminology and if the provider defining the term improves patient understanding. METHODS: Conversations between oncology providers and patients discussing immunotherapy were observed(n=39), and technical terms used were noted. With consent, patients were interviewed post-conversation to assess their understanding of these terms(n=39). Comparisons of the terms were conducted using chi-square tests, Fisher’s exact tests, or ANOVA where appropriate. RESULTS: ‘Immunotherapy’ was the most difficult for participants to understand with 48.7% (19/39) correctly defining immunotherapy. ‘Immunotherapy agents’ was understood 53.8% (14/26) of the time. ‘Immune system’ was well understood (88.5%;23/26). Providers defined immunotherapy in 97.4% of conversations. There was no correlation between having immunotherapy defined in the conversation, and the likelihood of a correct definition (p=0.487). ‘Immune system’ was defined in 92.3% of conversations (n=26), and defining it in the conversation was correlated with increased patient understanding (p=0.009). CONCLUSION: Our results indicate that patients have difficulty understanding some immunotherapy terminology. Since patient understanding of key terminology is crucial for informed consent and patient care, it is essential to implement interventions to improve understanding.

Background The outcomes of metastatic hormone-sensitive prostate cancer (mHSPC) have significantly improved through treatment intensification, yet Black representation in those studies is suboptimal. Methods A multi-institutional, retrospective analysis of Black men with mHSPC was conducted, focusing on baseline demographics, treatment patterns, genomic profiles, clinical outcomes including prostate-specific antigen response, time to castrate-resistant prostate cancer (CRPC), and subsequent treatments. Results A total of 107 patients, median age 64 years, 62% with de novo metastases at diagnosis and 64% with high-volume disease, were included. Twenty-nine patients (27%) were treated with androgen deprivation therapy (ADT) with and without first generation anti-androgens, while 20%, 38% and 5% received chemotherapy, abiraterone, and enzalutamide, respectively. At time of data cut-off, 57 (54%) patients had developed CRPC, with a median time to CRPC of 25.4 months (95% CI 20.3-30.4). The median time to CRPC was 46.3 months (18.9-73.7) and 23.4 months (18.6-28.2) for patients who received ADT with or without first-generation anti-androgens and treatment intensification, respectively. The 2-year survival rate was 93.3%, and estimated median overall survival of was 74.9 months (95% CI, 68.7-81.0). Most patients (90%) underwent germline testing; the most frequent known alterations were found within the DNA repair group of genes. Somatic testing revealed pathogenic alterations of interest, notably TP53 (24%) and CDK12 (12%). Conclusion In our cohort, Black men with mHSPC presented with a high proportion of de novo metastases and high-volume disease. Treatment outcomes were very favorable with ADT-based regimens. The genomic landscape suggests different molecular profile relative to White patients with potential therapeutic implications.

BackgroundImmune checkpoint inhibitors (ICI) have revolutionized the treatment of metastatic renal cell carcinoma (mRCC). Biomarkers for mRCC patients treated with ICI are limited, and body composition is underutilized in mRCC. We investigated the association between body composition and clinical outcomes in ICI-treated mRCC patients.MethodsWe performed a retrospective analysis of 79 ICI-treated mRCC patients at Winship Cancer Institute from 2015-2020. Baseline CT images were collected at mid-L3 and segmented using SliceOMatic v5.0 (TomoVision). Density of skeletal muscle (SM), subcutaneous fat, inter-muscular fat, and visceral fat were measured and converted to indices by dividing by height(m)2 (SMI, SFI, IFI, and VFI, respectively). Total fat index (TFI) was defined as the sum of SFI, IFI, and VFI. Patients were characterized as high versus low for each variable at gender-specific optimal cuts using overall survival (OS) as the primary outcome. A prognostic risk score was created based on the beta coefficient from the multivariable Cox model after best subset variable selection. Body composition risk score was calculated as IFI + 2*SM mean + SFI and patients were classified as poor (0-1), intermediate (2), or favorable risk (3-4). Kaplan-Meier method and Log-rank test were used to estimate OS and PFS and compare the risk groups. Concordance statistics (C-statistics) were used to measure the discriminatory magnitude of the model.ResultsMost patients were male (73%) and most received ICI as first (35%) or second-line (51%) therapy. The body composition poor-risk patients had significantly shorter OS (HR: 6.37, pConclusionsRisk stratification using the body composition variables IFI, SM mean, SFI, and TFI may be prognostic and predictive of clinical outcomes in mRCC patients treated with ICI. Larger, prospective studies are warranted to validate this hypothesis-generating data.

BackgroundThe modified Glasgow Prognostic Score (mGPS) is a composite biomarker that uses albumin and C reactive protein (CRP). There are multiple immune checkpoint inhibitor (ICI)-based combinations approved for metastatic renal cell carcinoma (mRCC). We investigated the ability of mGPS to predict outcomes in patients with mRCC receiving ICI.MethodsWe retrospectively reviewed patients with mRCC treated with ICI as monotherapy or in combination at Winship Cancer Institute between 2015 and 2020. Overall survival (OS) and progression-free survival (PFS) were measured from the start date of ICI until death or clinical/radiographical progression, respectively. The baseline mGPS was defined as a summary score based on pre-ICI values with one point given for CRP>10 mg/L and/or albuminResults156 patients were included with a median follow-up 24.2 months. The median age was 64 years and 78% had clear cell histology. Baseline mGPS was 0 in 36%, 1 in 40% and 2 in 24% of patients. In UVA, a baseline mGPS of 2 was associated with shorter OS (HR 4.29, 95% CI 2.24 to 8.24, pConclusionThe mGPS is prognostic in this cohort of patients with mRCC treated with ICI as monotherapy or in combination. These results warrant external and prospective validation.

BackgroundImmune-checkpoint-inhibitors (ICIs) have become the cornerstone of metastatic renal-cell-carcinoma (mRCC) therapy. However, data are limited regarding clinical outcomes by race. In this study, we compared the real-world outcomes between African American (AA) and Caucasian mRCC patients treated with ICIs.MethodsWe performed a retrospective study of 198 patients with mRCC who received ICI at the Emory Winship Cancer Institute from 2015-2020. Clinical outcomes were measured by overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) defined as a complete or partial response maintained for at least 6 months per response evaluation criteria in solid tumors version 1.1. Univariate and multivariable analyses were carried out for OS and PFS by Cox proportional-hazard model and ORR by logistical-regression model. Descriptive statistics compared rates of immune-related adverse events (irAEs) and non-clear-cell-RCC (nccRCC) histology were assessed using Chi-square test.ResultsOur cohort was comprised of 38 AA and 160 Caucasian patients. Most were diagnosed with clear-cell-RCC (ccRCC) (78%) and more than half received (57%) PD-1/PD-L1 monotherapy. Most patients were intermediate or poor-risk groups (83%). Comparing to Caucasians, our AA cohort contained more females and nccRCC cases. Kaplan-Meier method showed AAs had no statistically different median OS (17 vs 25 months, p=0.368) and PFS (3.1 vs 4.4 months, p=0.068) relative to Caucasian patients. On multivariable analysis, AA patients had significantly shorter PFS (HR=1.52, 95% CI: 1.01-2.3, p=0.045), similar ORR (OR=1.04, 95% CI: 0.42-2.57, p=0.936) and comparable OS (HR=1.09, 95% CI: 0.61-1.95, p=0.778) relative to Caucasians.ConclusionsOur real-world analysis of ICI-treated mRCC patients showed that AAs experienced shorter PFS but similar OS relative to Caucasians. This similarity in survival outcomes is reassuring for the use of ICI amongst real-world patient populations, however, the difference in treatment response is poorly represented in early outcomes data from clinical trials. Thus, the literature requires larger prospective studies to validate these findings.

Background Immune checkpoint inhibitors (ICIs) are an important treatment for metastatic renal cell carcinoma (mRCC). These agents may cause immune-related adverse events (irAEs), and the relationship between irAEs and outcomes is poorly understood. We investigated the association between irAEs and clinical outcomes in patients with mRCC treated with ICIs. Methods We performed a retrospective study of 200 patients with mRCC treated with ICIs at Winship Cancer Institute from 2015 to 2020. Data on irAEs were collected from clinic notes and laboratory values and grades were determined using Common Terminology Criteria in Adverse Events version 5.0. The association with overall survival (OS) and progression-free survival (PFS) was modeled by Cox proportional hazards model. Logistic regression models were used to define odds ratios (ORs) for clinical benefit (CB). Landmark analysis and extended Cox models were used to mitigate lead-time bias by treating irAEs as a time-varying covariate. Results Most patients (71.0%) were male, and one-third of patients (33.0%) experienced at least one irAE, most commonly involving the endocrine glands (13.0%), gastrointestinal tract (10.5%), or skin (10.0%). Patients who experienced irAEs had significantly longer OS (hazard ratio [HR], 0.52; p = .013), higher chance of CB (OR, 2.10; p = .023) and showed a trend toward longer PFS (HR, 0.71; p = .065) in multivariate analysis. Patients who had endocrine irAEs, particularly thyroid irAEs, had significantly longer OS and PFS and higher chance of CB. In a 14-week landmark analysis, irAEs were significantly associated with prolonged OS (p = .045). Patients who experienced irAEs had significantly longer median OS (44.5 vs. 18.2 months, p = .005) and PFS (7.5 vs. 3.6 months, p = .003) without landmark compared with patients who did not. Conclusion We found that patients with mRCC treated with ICIs who experienced irAEs, particularly thyroid irAEs, had significantly improved clinical outcomes compared with patients who did not have irAEs. This suggests that irAEs may be effective clinical biomarkers in patients with mRCC treated with ICIs. Future prospective studies are warranted to validate these findings. Implications for Practice This study found that early onset immune-related adverse events (irAEs) are associated with significantly improved clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICIs). In this site-specific irAE analysis, endocrine irAEs, particularly thyroid irAEs, were significantly associated with improved clinical outcomes. These results have implications for practicing medical oncologists given the increasing use of ICIs for the treatment of mRCC. Importantly, these results suggest that early irAEs and thyroid irAEs at any time on treatment with ICIs may be clinical biomarkers of clinical outcomes in patients with mRCC treated with ICIs.

Body composition is associated with risk of disease progression and treatment complications in a variety of conditions. Therefore, quantification of skeletal muscle mass and adipose tissues on Computed Tomography (CT) and/or Magnetic Resonance Imaging (MRI) may inform surgery risk evaluation and disease prognosis. This article describes two quantification methods originally described by Mourtzakis et al. and Avrutin et al.: tissue segmentation and linear measurement of skeletal muscle. Patients' cross-sectional image at the midpoint of the third lumbar vertebra was obtained for both measurements. For segmentation, the images were imported into Slice-O-Matic and colored for skeletal muscle, intramuscular adipose tissue, visceral adipose tissue, and subcutaneous adipose tissue. Then, surface areas of each tissue type were calculated using the tag surface area function. For linear measurements, the height and width of bilateral psoas and paraspinal muscles at the level of the third lumbar vertebra are measured and the calculation using these four values yield the estimated skeletal muscle mass. Segmentation analysis provides quantitative, comprehensive information about the patients' body composition, which can then be correlated with disease progression. However, the process is more time-consuming and requires specialized training. Linear measurements are an efficient and clinic-friendly tool for quick preoperative evaluation. However, linear measurements do not provide information on adipose tissue composition. Nonetheless, these methods have wide applications in a variety of diseases to predict surgical outcomes, risk of disease progression and inform treatment options for patients.

Background Among patients with advanced renal cell carcinoma (RCC), those with sarcomatoid histology (sRCC) have the poorest prognosis. This analysis assessed the efficacy of avelumab plus axitinib versus sunitinib in patients with treatment-naive advanced sRCC. Methods The randomized, open-label, multicenter, phase III JAVELIN Renal 101 trial (NCT02684006) enrolled patients with treatment-naive advanced RCC. Patients were randomized 1 : 1 to receive either avelumab plus axitinib or sunitinib following standard doses and schedules. Assessments in this post hoc analysis of patients with sRCC included efficacy (including progression-free survival) and biomarker analyses. Results A total of 108 patients had sarcomatoid histology and were included in this post hoc analysis; 47 patients in the avelumab plus axitinib arm and 61 in the sunitinib arm. Patients in the avelumab plus axitinib arm had improved progression-free survival [stratified hazard ratio, 0.57 (95% confidence interval, 0.325-1.003)] and a higher objective response rate (46.8% versus 21.3%; complete response in 4.3% versus 0%) versus those in the sunitinib arm. Correlative gene expression analyses of patients with sRCC showed enrichment of gene pathway scores for cancer-associated fibroblasts and regulatory T cells, CD274 and CD8A expression, and tumors with The Cancer Genome Atlas m3 classification. Conclusions In this subgroup analysis of JAVELIN Renal 101, patients with sRCC in the avelumab plus axitinib arm had improved efficacy outcomes versus those in the sunitinib arm. Correlative analyses provide insight into this subtype of RCC and suggest that avelumab plus axitinib may increase the chance of overcoming the aggressive features of sRCC., Highlights • Patients with sarcomatoid renal cell carcinoma had improved progression-free survival with avelumab + axitinib versus sunitinib. • The objective response rate was 46.8% for patients in the avelumab + axitinib arm versus 21.3% for those in the sunitinib arm. • Correlative analyses showed enrichment for cancer-associated fibroblasts and regulatory T cells, and CD274 and CD8A expression. • Our findings suggest that avelumab + axitinib may improve the chance of overcoming the aggressive features of this subtype.

Summary Background Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma. Methods We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment. Findings Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19–36) of 112 patients. At a median follow-up of 11 months (IQR 6–18), median time to treatment failure was 6·7 months (95% CI 5·5–8·6), median progression-free survival was 7·0 months (5·7–9·0), and median overall survival was 12·0 months (9·2–17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhoea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status. Interpretation While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options. Funding None.

Background Because cell-free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy. Methods Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer-associated genes. Clinical factors, therapy information, failure-free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated. Results Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta-1 (CTNNB1), and AT-rich interactive domain-containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure-free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes. Conclusions ctDNA frequently was detected in this large cohort of "real-world" patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients.

PURPOSE: Radical cystectomy currently remains the standard of care for muscle-invasive bladder cancer (MIBC). However, surgery can be associated with considerable morbidity and mortality, including the removal of the bladder. An alternative strategy is to preserve the bladder through concurrent chemo-radiation following a maximal trans-urethral resection of the tumor. National protocols using a bladder preservation approach have demonstrated disease-specific outcomes comparable to radical cystectomy in selected patients, but these results have not been replicated in previously reported population-based series. Here, we describe an outcomes analysis of patients with MIBC treated with either radical surgery or bladder-preserving chemo-radiation (BPCRT) for those patients meeting BPCRT criterion using the National Cancer Database (NCDB). METHODS AND MATERIALS: Using the NCDB, patients with AJCC clinical T2-3, N0, M0 urothelial carcinoma diagnosed between 2004–2013 were included for analysis. Only patients treated with definitive intent with either radical cystectomy or concurrent chemotherapy and radiation after a maximal transurethral tumor resection were included. Propensity-score matching was employed. RESULTS: Among 8,454 eligible patients, 7,276 (86%) underwent radical cystectomy, and 1,178 (14%) underwent BPCRT. Patients undergoing BPCRT were significantly older (median age 77 vs 68, p

Isolation and analysis of circulating tumor cells (CTCs) from blood samples present exciting opportunities for basic cancer research and personalized treatment of the disease. While microchip-based negative CTC enrichment offers both sensitive microfluidic cell screening and unbiased selection, conventional microchips are inherently limited by their capacity to deplete a large number of normal blood cells. In this paper, we use 3D printing to create a monolithic device that combines immunoaffinity-based microfluidic cell capture and a commercial membrane filter for negative enrichment of CTCs directly from whole blood. In our device, stacked layers of chemically-functionalized microfluidic channels capture millions of white blood cells (WBCs) in parallel without getting saturated and the leuko-depleted blood is post-filtered with a 3 μm-pore size membrane filter to eliminate anucleated blood cells. This hybrid negative enrichment approach facilitated direct extraction of viable CTCs off the chip on a membrane filter for downstream analysis. Immunofluorescence imaging of enriched cells showed ∼90% tumor cell recovery rate from simulated samples spiked with prostate, breast or ovarian cancer cells. We also demonstrated the feasibility of our approach for processing clinical samples by isolating prostate cancer CTCs directly from a 10 mL whole blood sample.

Background: Novel anti-PSMA (prostate-specific membrane antigen) targeted therapies have exhibited encouraging antitumor activity in prostate cancer and most non-prostate solid tumors express PSMA in tumor neovasculature. ARX517 is an antibody drug conjugate composed of a fully humanized anti-PSMA monoclonal antibody linked to pAF-AS269, a potent microtubule inhibitor. Upon binding to PSMA on the surface of cancer cells, ARX517 is internalized and pAF-AS269 is released following lysosomal metabolism. Methods: This Phase 1, dose-escalation and dose-expansion study is evaluating the safety, pharmacokinetics, and preliminary anti-tumor activity of ARX517 in adults with prostate cancer or other solid tumors whose disease is resistant or refractory to standard therapies. Patients must have metastatic castration-resistant prostate cancer refractory to standard therapies, including abiraterone, darolutamide, apalutamide or enzalutamide and progression by Prostate Cancer Working Group criteria. Non-prostate advanced solid tumors must be pathologically confirmed, metastatic, or unresectable solid tumors that have disease progression despite at least 1 prior standard of care systemic treatment and have no satisfactory treatment alternatives. All patients must have adequate organ function and any brain metastasis must demonstrate radiographic stability. Exploratory pharmacodynamic assessment includes PSMA-PET/CT imaging, which is optional for low dose cohorts but required starting at 1.4 mg/kg dose. Dose-escalation will consist of ascending dose levels of ARX517 administered as a single agent and will use a i3+3 design. The number of subjects in the dose-expansion will be based on the number of doses to be expanded for further evaluation of safety, PK, and clinical activity. Through dose levels one and two, no dose limiting toxicities have been observed. Ascending dose levels of ARX517 as a single agent will be administered until the recommended Phase 2 dose or maximum tolerated dose is determined. Status: ARX517-2011 began recruiting patients in July 2021 and as of January 2022 has completed enrollment in the 3rd cohort of dose-escalation. Citation Format: Russell K. Pachynski, Luke Nordquist, Michael T. Schweizer, John Shen, Nabil Adra, Mehmet A. Bilen, Zachery R. Reichert, Rahul Aggarwal, Bilal A. Siddiqui, Matt Li, Dong Xu, Richard Huhn, Darryl Z. L'Heureux, Jinchun Yan, Ying Buechler, Sulan Yao, John Simitzi, Wenge Shi, Shawn Zhang, Scott T. Tagawa. A phase 1 dose-escalation and dose-expansion study to evaluate the safety, pharmacokinetics, and anti- tumor activity of ARX517 in subjects with advanced solid tumors resistant or refractory to standard therapies (APEX-01 trial, NCT04662580) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT211.

Immune checkpoint inhibitors (ICI) are now the bedrock for the treatment of metastatic renal cell carcinoma (RCC). Clear cell RCC (ccRCC) represents the most common subtype of this malignancy. Herein, we explore the therapeutic landscape of ccRCC by discussing the standard of care whose backbone consists of immune checkpoint inhibitors (ICI) and vascular endothelial growth factor inhibitors (VEGF). For ccRCC, pembrolizumab-axitinib, pembrolizumab-lenvatinib, and avelumab-axitinib or nivolumab-cabozantinib are now FDA-approved frontline options for all risk groups while nivolumab-ipilimumab is reserved for intermediate- and poor-risk groups. Monotherapy with pembrolizumab or nivolumab is a potential option for patients who are unable to take VEGFR-tyrosine kinase inhibitors. While outcomes have improved with the adoption of ICI therapies, many patients develop therapy-resistant disease, creating an unmet need for further investigation. The efficacy of novel therapies as well as novel combinations in the post-ICI era is unclear. This review summarizes the most significant clinical trials involving dual ICI/ICI and ICI/VEGFR therapies, in addition to other selected combination therapies that are likely to inform management in the near future.

5082 Background: Immunotherapy has limited efficacy in castration-resistant prostate cancer. Androgen deprivation therapy (ADT) has significant immunomodulatory effects and initially induces a complex immune infiltrate before castration-resistance develops. However, ADT also recruits immunosuppressive myeloid cells to the tumor microenvironment by increasing interleukin-8 (IL-8). We conducted a phase Ib/II clinical trial of immunotherapy plus ADT in men with recurrent castration-sensitive prostate cancer (CSPC). We hypothesized that anti-PD-1 (nivolumab) +/- anti-IL-8 (BMS-986253) given at the time of castration could induce anti-tumor immune responses and decrease disease progression. Methods: MAGIC-8 was a multicenter, phase Ib/II study evaluating nivolumab +/- BMS-986253 combined with a short course of degarelix acetate in patients with recurrent CSPC and rapid PSA doubling time (≤ 12 mos). In the Phase Ib portion, patients were treated with nivolumab (480mg Q4W) for 8 wks followed by nivolumab plus degarelix for an additional 16 wks. In the phase II portion, patients were randomized 1:2 to nivolumab + degarelix (Arm A) versus nivolumab + BMS-986253 (2400mg Q2W) + degarelix (Arm B). The primary endpoints were PSA recurrence at 10 mos following randomization and safety. Key secondary endpoints included biochemical recurrence-free survival (bPFS), time to recovery of testosterone (> 150ng/dl), and bPFS after recovery of testosterone. Results: Between October 16, 2019 and March 9, 2021, 59 patients were enrolled. The first 15 patients were treated on Arm A followed by 1:2 randomization to Arm A (N = 15) versus Arm B (N = 29). Median follow up was 11.6 mos at the data cutoff (1/24/22). Patients treated on Arm A had a significantly lower rate of PSA relapse (17.39%) at 10 mos compared to historical controls (p = < 0.001), including a subgroup of patients (6.67%) with recovery of testosterone and no PSA relapse at > 2 years of follow up. Median time-to-recovery of testosterone was 12.7 mos, median bPFS was 14.0 mos and median bPFS after recovery of testosterone was 5.5 mos. In Arm B, there was no difference in PSA relapse at 10 mos (35%, p = 0.09), median time-to-recovery of testosterone, median bPFS and median bPFS after recovery of testosterone compared to historical controls. Treatment in both arms was well tolerated with a lower rate of grade 3-4 treatment-related adverse events in Arm B compared to Arm A (3.5% vs 12.9%). Conclusions: A short course of ADT plus nivolumab may decrease the rate of PSA relapse and lead to durable long-term responses after recovery of testosterone in a subset of patients. These data support further evaluation of combining nivolumab with ADT in CSPC. Although the addition of BMS-986253 did not improve rate of PSA relapse, we observed significantly less toxicity with the addition of IL-8 inhibition. Clinical trial information: NCT03689699.

e18591 Background: Racial and ethnic minority populations are consistently under-represented in oncology clinical trials despite comprising a disproportionate share of cancer burden. Due in part to difficulties associated with participation, phase 1 trials pose a unique challenge and opportunity for minority inclusion. Here we examine the sociodemographics of phase 1 clinical trial patients at an NCI-designated Comprehensive Cancer Center compared to all patients treated at the center, patients with new cancer diagnoses in metropolitan Atlanta, and the state of Georgia (GA). Methods: Patients enrolled on phase 1 trials at the Winship Cancer Institute (WCI) from 2015-2020, identified from a data warehouse, were compared to new patient registrations at WCI from 2015-2019. Patients with cancer in metro Atlanta and GA were identified from the Surveillance, Epidemiology, and End Results (SEER) Program: Nov 2018 Submission. Covariates for the phase 1 and institutional cohort included sex, race, ECOG PS, insurance, and age at consent. Covariates for SEER patients included sex, race, and age at diagnosis. Summary statistics are reported for categorical variables using frequencies and percentages, and for continuous variables using mean, median, standard deviation, and range. One-sample proportion tests were utilized to compare observed demographic proportions on phase 1 trials with proportions calculated from new patient registrations at WCI and from SEER case data. Results: From 2015-2020, 2325 patients (43.4% F, 56.6% M) signed consent for phase 1 trials. Grouped race distribution was 70.3% White, 26.2% Black, 3.5% Other. Insurance distribution was 42.9% private, 48% government, 9.1% uninsured/other. Mean age at consent was 61.7 years (MD 63, ran 19-92). Of new patient registrations at WCI in 2015 ( N= 12358) (49.7% F, 50.3% M), grouped race distribution was 64.0% W, 28.2% B, 8% O. Atlanta 2015 SEER patients ( N= 31101) (50.3%F, 49.7%M) showed grouped race distribution 58.4% W, 37.2% B, 4.3% O. Mean age at diagnosis was 62.9. GA 2015 SEER patients ( N= 99487) (48.6%F, 51.4%M) showed grouped race distribution 71.2% W, 26.7% B, 2.1% O. Mean age at diagnosis was 64.2. The race and sex distribution of phase 1 patients was significantly different than proportions calculated from new patient registrations at WCI and SEER data from patients in Atlanta ( p< 0.001). Sex distribution was significantly different than GA SEER patients. Conclusions: Phase 1 patients were significantly more likely to be white and male, compared with patients treated at the cancer center, as well as patients with cancer in Atlanta. Race distribution was not significantly different from patients with cancer in GA. Our intent is to characterize existing disparities in order to increase representation of patients from racial and ethnic minority backgrounds in phase 1 clinical trials.

4545 Background: Despite recent advances in the treatment of clear cell RCC, there is a paucity of data to guide management of nccRCC due to the heterogeneity and rarity of these tumors. The clinical activity of combination therapies (including IO-IO, IO-VEGF, VEGF-mTOR) in subtypes of advanced nccRCC is unknown. Methods: In this multicenter retrospective analysis, we evaluated the efficacy of combination systemic therapies in patients with nccRCC. Eligible patients included those with nccRCC as determined by local genitourinary pathology review and receipt of one of three combination regimens during any line treatment (IO-IO, IO-VEGF, mTOR-VEGF). The primary endpoint was objective response rate (ORR) assessed by investigator review. Secondary endpoints were progression- free survival (PFS), disease control rate (DCR), and overall survival (OS). Results: Among 128 included patients, median age was 57 years; 66% were male and 65% white. Histologies included papillary (37%), unclassified (33%), chromophobe (16%), translocation (9%), and other (5 %). Among all patients, 69% had prior nephrectomy; 80% were IMDC intermediate/poor risk; 20% had sarcomatoid and/or rhabdoid differentiation, 27% and 29% had liver and bone metastasis respectively and 63% received combination treatment as first line. Comparison of outcomes based on treatment regimen, line of treatment and subtype is shown in the table. Median PFS and OS were longer with IO/IO and IO/VEGF compared to VEGF/ mTOR at 8.5, 9.5 and 3.7 months and 24.4, 18.2 and 15.4 months respectively. Conclusions: Antitumor activity was observed with novel combinations in nccRCC in both frontline and later line setting. Optimal management of nccRCC remains an unmet need and prospective data is warranted to guide treatment selection for this population. [Table: see text]

TPS4604 Background: Papillary RCC accounts for 10-15% of kidney cancers and is the second most common subtype of RCC after clear cell RCC. HLRCC is a familial cancer syndrome characterized by a propensity for developing papillary kidney cancer. HLRCC-associated renal tumors are known to be clinically aggressive, with a paucity of treatment options. The combination of bevacizumab and erlotinib has shown promising activity in patients with HLRCC-associated RCC and sporadic pRCC (Srinivasan et al, ASCO 2020). We hypothesize that the addition of a PDL-1 inhibitor might provide synergistic clinical activity against these tumors. Methods: This is an ETCTN-sponsored, open-label, multicenter, phase 2 study evaluating bevacizumab, erlotinib and atezolizumab in adult and pediatric patients with advanced 1) HLRCC-associated RCC or 2) sporadic pRCC. Eligible patients will have cytologically or histologically confirmed advanced HLRCC- associated or sporadic pRCC, age ≥12 years, ECOG PS ≤2, no more than two prior regimens targeting the VEGF pathway, no prior treatment with PD-1 or PD-L1 inhibitors and adequate organ and marrow function. Patients with HLRCC-associated RCC or sporadic pRCC will be enrolled into parallel, independent cohorts. Initially, 12 adult patients with advanced HLRCC-associated RCC or sporadic pRCC will be enrolled into the safety run-in portion of the trial. If ≤ 3 dose-limiting toxicities are observed, enrollment will proceed into both cohorts and pediatric patients will be allowed to enroll. A Simon two-stage phase 2 minimax design will be used to determine accrual to each cohort. In the first stage, 12 evaluable patients will be enrolled into cohort 1) HLRCC-associated RCC or cohort 2) sporadic pRCC. If 0 of 12 patients have a CR, then no further patients will be enrolled in that cohort. If 1 or more of the first 12 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 21 evaluable patients (adult or pediatric) have been enrolled into each cohort for a total of 42 patients. Adult patients will receive a fixed dose of bevacizumab (15 mg/kg IV every 21 days) plus atezolizumab (1,200 mg IV every 21 days) and erlotinib (150 mg PO daily). Pediatric patients will receive bevacizumab (15 mg/kg IV every 21 days) plus atezolizumab 15 mg/kg (max 1,200 mg IV every 21 days) and erlotinib 85 mg/m2 (max 150 mg PO daily). The primary endpoint is to assess the complete response rate according to RECIST 1.1 in patients with advanced 1) HLRCC-associated RCC and 2) sporadic pRCC. Secondary endpoints include safety and tolerability, objective response rate, disease control rate, progression-free survival and overall survival. Key exploratory endpoints include evaluation of immunologic modulation associated with this regimen. The study has just opened to accrual. Clinical trial information: NCT04981509.

5013 Background: Black men have been underrepresented in large-scale molecular prostate cancer (PC) surveys, despite having higher PC incidence and mortality. Since molecular profiling to guide the use of targeted agents is increasingly important in mCRPC, we compared precision medicine data and utilization in a cohort of black and white men with mCRPC. Methods: The PROMISE precision medicine database is an academic collaboration to compile clinical and genomic data from men with PC. All patients have had germline and/or somatic genetic testing performed. Eligibility criteria for this analysis included a diagnosis of mCRPC with available race and biomarker data. The primary outcome was the proportion of non-Hispanic black (NHB) and non-Hispanic white (NHW) men with actionable molecular data, defined as the presence of mismatch repair deficiency (MMRd/MSI-H), homologous recombination repair deficiency (HRRd), tumor mutational burden (TMB) ≥ 10 mut/MB, or AR-V7. Secondary outcomes included the proportion of NHB and NHW men with other alterations, the type and timing of genomic testing performed, and the use of targeted therapy. Results: A total of 962 mCRPC patients (21.2% NHB; 78.8% NHW) met inclusion criteria of 1619 in the overall database. Median age (NHB/NHW) was 61/63; 77.5/68.8% had Gleason 8-10; 52.5/56.7% presented with de novo metastatic disease (33.8/29.9% LN, 36.2/32.2% bone and 8.3/6.1% viscera). The median time from diagnosis to first molecular result was 56.3 mo for NHB v 58.7 mo for NHW (p = 0.45). Use of blood-based molecular testing was more common in NHB men (48.7% v 36.4%, p < 0.001). Overall, 32.8% of NHB men harbored actionable molecular data compared to 30.3% of NHW men (Table). MMRd/MSI-H was more common in NHB men (9.1 v 4.9%, p = 0.04). Other than PTEN (12.7/23.8% NHB/NHW, p = 0.0001), no significant differences were seen in the 15 most frequently mutated genes, including TP53, AR, CDK12, RB1, and PIK3CA. Tumor suppressor co-mutations (PTEN/TP53/RB1) were found in 13.1% of NHB and 18.0% NHW (p = 0.13). Delivery of targeted therapy was reported in 19.6% of NHB and 23.7% of NHW men (p = 0.25) after a median of 2 CRPC lines. Median OS from development of mCRPC was 41.5 mo (95% CI, 34.7-51.3) and 44.7 mo (95% CI, 41.1-51.5) for NHB and NHW men, respectively (p = 0.14). Conclusions: In a real-world mCRPC molecular profiling cohort, we found similar overall rates of actionable molecular alterations in NHB and NHW men, but higher rates of MMRd/MSI-H and lower frequency of PTEN alterations in NHB men. We did not find differences in delivery of targeted therapy. [Table: see text]

e18595 Background: Multidisciplinary tumor boards (TBs) are a key component of high-quality oncology care. Access is variable, particularly outside the academic setting, and limited access likely disproportionately impacts underserved patient populations and may contribute to healthcare disparities. Virtual tumor boards (VTBs) may provide a solution. Methods: Objectives of this endeavor are to test the feasibility of conducting VTBs and assess their perceived benefit and educational value. Expert US faculty formed VTB panels via an online platform to discuss complex cases submitted by clinicians. Each panel included a moderator and a radiologist, as well as a medical, radiation and surgical oncologist. After the panel discussion, written recommendations and video recordings (de-identified) were shared with submitters. Recordings were available online to viewers with embedded questions to assess learning. Submitters were surveyed as to their perceived benefit of the discussion. Viewers were surveyed to assess the educational value. Results: From 07/2020-12/2021, 323 cases (97 breast, 109 thoracic, 49 gastrointestinal, 37 genitourinary, 31 hematologic) were submitted by 48 clinicians to 38 VTBs. Submitters were surveyed with a 73% response rate; 100% reported they were likely to submit a future case for discussion and that they believe the VTB will improve care for patients. Viewers (n = 39) were surveyed with a 72% response rate and included trainees and APPs working in medical, radiation, and surgical oncology as well as radiology. All viewers endorsed that the videos were a good educational resource, and that they would use them in the future. Both embedded questions were answered 74% of the time (315/425); answers post-viewing changed 43% of the time (137/315). Conclusions: VTBs are feasible and lead to a high degree of satisfaction among case submitters. In this cohort, users reported that their patient management changed based on the discussion. Of those who discussed the case at their own TB, most felt that the VTB expanded upon prior recommendations. A large proportion of users stated that their case was not discussed at an internal TB, suggesting the VTB may address an unmet need. Those who watched the videos found them to be a good resource and would use them in the future. Data from larger cohorts will be key in understanding the full impact of this endeavor, particularly in helping to address healthcare disparities.[Table: see text]