512 Background: Non-clear cell renal cell carcinoma (nccRCC) includes several molecularly distinct subtypes of renal carcinoma. Due to their rarity, nccRCC subtypes have been understudied, and treatment options are often adapted from clear cell RCC therapies. Trials investigating immune checkpoint inhibitors (ICIs) have demonstrated promising efficacy and survival benefits in certain nccRCC histologies. This report aims to present our experience with nccRCC, focusing on patient characteristics, treatment choices, and survival outcomes in the era of ICIs. Methods: A retrospective analysis was conducted on adult patients with metastatic RCC treated at the Emory Winship Cancer Institute between 2018 and 2024. nccRCC histologies were identified and confirmed through pathology reports. An objective response is defined as a complete or partial response by RECIST v1.1. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method with SAS 9.4 software to calculate survival probabilities. Results: We identified 69 patients with various nccRCC histologies, with papillary RCC (pRCC) being the most common (36.2%), followed by unclassified RCC (24.6%). The median age was 63 years. 59.4 of the patients were male, and 75.4% of the patients had an ECOG PS of 0 or 1. 53.6% of the patients were White, while 40.6% were African American or Black. Nephrectomy was performed in 44 patients (63.8%). The median follow-up time was 24 months. ICI-based treatments were used as the first-line option in 52% of patients, with 88% of unclassified RCC patients receiving ICI-based regimens as first-line. The mOS was longest in patients with chromophobe RCC at 21 months (4, NA), followed by patients with unclassified RCC at 19 months (6, NA). Among pRCC patients, there was no significant difference in mOS between African American or Black patients (12 months) and White patients (10.5 months; p=0.61). mOS was similar across ICI monotherapy, dual ICI therapy, and ICI+TKI combinations. 12-month survival rates were 50%, 57%, and 33% (p=0.21), and objective response rates (ORR) were 11%, 14%, and 11% for ICI monotherapy, dual ICI, and ICI+TKI combinations, respectively. Conclusions: Our study highlights the heterogeneity of non-clear cell RCC subtypes. The rare nature of nccRCC and the small patient cohort in our study limited its statistical power, emphasizing the importance of larger studies and expanded clinical trials to better understand and optimize treatment strategies for this understudied group of renal carcinomas. Histology n White African American or Black 12 Months OS Rate 12 Months PFS Rate ORR Papillary 25 12 12 46% (25, 64) 44% (7, 78) 12% Unclassified 17 10 6 63% (35, 81) 43% (10, 73) 35% Translocation 9 4 3 67% (21, 91) 36% (17, 56) 0% Collecting Duct 7 4 3 43% (10, 73) 0% (NA) 14% Chromophobe 6 6 - 67% (20, 90) 34% (12, 58) 0%

603 Background: Multiple studies on various cancer types have investigated concomitant statin, aspirin, and metformin use with immune checkpoint inhibitors. While some found improved OS and PFS, others reported no significant effect. In RCC, a retrospective study linked statins with improved OS and PFS. We aimed to evaluate the impact of statin, aspirin, and metformin use on survival in RCC patients treated with ICIs. Methods: A retrospective analysis was conducted on adult patients with advanced RCC treated with ICIs at Emory Winship Cancer Institute between 2018 and 2024. Concomitant medication use was assessed via chart review during active ICI treatment. Clinical benefit (CB) is determined by stable disease, partial response, and complete response. The multivariate analysis model for statin was built by controlling the age, gender, race, smoking status, IMDC risk group, ECOG PS, clear cell histology, prior treatments, and liver metastases. Variables were subject to backward elimination at the significant level of p < 0.2. Results: Data from 400 patients were analyzed, with a median follow-up of 43.0 months (95% CI: 36.6-51.4). Of 400 patients, 138 (34.5%) were treated with ICI monotherapy, 131 (32.8%) treated with dual ICI combination, and 114 (28.5%) were treated with ICI and TKI combinations. 85 (21.3%) of the patients were African American or Black, 284 (71%) of them were White, and 239 (59.8%) were treated with ICIs as first-line. Statin use was more common among patients without prior treatment, without liver metastasis, older individuals, and those with a BMI ≥24.9. In univariate analysis, statin use showed potential associations with longer OS (HR 0.82; 95% CI 0.62-1.07 p=0.144), longer PFS (HR 0.81; 95% CI 0.64-1.02 p=0.071), and a higher likelihood of receiving CB (OR 1.85; 95% CI 1.17-2.92 p=0.008). However, multivariate analysis did not confirm significant differences in survival or CB. Survival outcomes are summarized in the table. Conclusions: Our analysis found no significant impact of concomitant statin, aspirin, or metformin use on RCC patient outcomes treated with ICIs. Further advancements in our understanding of tumor biology and checkpoint inhibitors might explain how concomitant medication affects treatment outcomes. Our study is limited by its retrospective design, and future prospective trials are necessary to provide definitive evidence. Univariate analysis of survival outcomes and clinical benefit. Overall Survival Progression-free survival Clinical Benefit HR (95% CI) p-value HR (95% CI) p-value OR (95% CI) p-value Statin Y n=170 0.82 (0.62-1.07) 0.144 0.81 (0.64-1.02) 0.071 1.85 (1.17-2.92) 0.008 Statin N n=230 - - - - - - Aspirin Y n=138 0.93 (0.70-1.24) 0.623 0.84 (0.66-1.07) 0.159 1.49 (0.93-2.40) 0.100 Aspirin N n=262 - - - - - - Metformin Y n=49 1.04 (0.68-1.57) 0.860 0.80 (0.55-1.15) 0.231 1.37 (0.68-2.78) 0.379 Metformin N n=351 - - - - -

Background: Immune checkpoint inhibitors (ICIs) have become the mainstay treatment of metastatic kidney cancer, demonstrating enhanced outcomes and durable responses in select patient subgroups. However, identifying reliable prognostic biomarkers for treatment outcomes remains challenging. Objectives: This study aimed to assess the correlation between baseline inflammatory markers and overall survival (OS), progression-free survival (PFS), and clinical benefit (CB) in metastatic kidney cancer patients receiving ICIs. CB was defined as patients achieving stable disease, partial response, or complete response. Design: Retrospective, single-center study. Methods: A retrospective analysis was conducted on 401 adult patients with advanced kidney cancer treated with ICIs at Emory Winship Cancer Institute between 2018 and 2023. Modified Glasgow Prognostic Score (mGPS), neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR), platelet-to-lymphocyte (PLR), and neutrophil-to-eosinophil ratios (NER) were collected from baseline blood samples. Results: Among 401 patients (median age, 66; 71% male; 21% Black/African American), median follow-up was 43.0 months (95% CI, 36.6–51.4). Patients with mGPS scores of 0 had longer OS than those with a score of 1 (hazard ratio (HR), 0.38; 95% CI, 0.23–0.62; p < 0.001) and 2 (HR, 0.37; 95% CI, 0.20–0.67; p = 0.001), and longer PFS compared to patients with mGPS scores of 1 (HR, 0.66; 95% CI, 0.44–0.98; p = 0.039) and 2 (HR, 0.44; 95% CI, 0.29–0.67; p < 0.001). Low baseline NLR was associated with longer PFS (HR, 0.73; 95% CI, 0.54–0.97; p = 0.032). Low baseline MLR correlated with improved OS (HR, 0.60; 95% CI, 0.44–0.83; p = 0.002) and PFS (HR, 0.73; 95% CI, 0.55–0.97; p = 0.031). Similarly, low baseline PLR was associated with higher CB likelihood (odds ratio (OR), 2.20; 95% CI, 1.31–3.69; p = 0.003), and low baseline NER was linked to improved OS (HR, 0.63; 95% CI, 0.46–0.87; p = 0.004), PFS (HR, 0.67; 95% CI, 0.51–0.88; p = 0.003), and higher CB (OR, 2.04; 95% CI, 1.20–3.46; p = 0.008). Conclusion: Lower levels of systemic inflammatory markers are associated with more favorable clinical outcomes with ICI treatment. Prospective studies are needed for further validation.

e16527 Background: Recent data have reported CD8 T cell infiltration into the intratumoral environment has been associated with favorable clinical outcomes in those patients who had tumor resection months/years prior to metastatic diagnosis and systemic therapy. We hypothesize that mRCC patients studied at our institution will display similar improved overall survival (OS) and progression free survival (PFS) in those with higher CD8 T cell infiltration. Methods: We conducted a retrospective analysis of patients with mRCC treated at Winship Cancer Institute between 1/1/2018 and 8/31/23. Overall survival (OS) and progression-free survival (PFS) were defined as months from treatment initiation to death or clinical/radiographic progression, respectively. The correlation between CD8 T cell infiltration and OS/PFS was studied in 39 patients diagnosed with metastatic RCC under systemic therapy. We used immunofluorescence (IF) imaging and flow cytometry to investigate how intratumoral T cells in patients’ tumors (resected months/years prior to receiving checkpoint therapy) predicted patient outcomes after immunotherapy. CD8 T cell infiltration was calculated as a proportion of T cells relative to other mononuclear cells within the tumor microenvironment. The groups were divided into high expressors of CD8 T cells (>0.79% CD8 T cell infiltration) or low expressors of CD8 T cells (< 0.79% CD 8 T cell infiltration). Univariate (UVA) analysis was carried out for OS and PFS using Cox proportional hazard model. Results: A total of 39 eligible patients were included with a median follow up of 60 months. Median age was 64 years (range = 38-77), 62% were male, 38% were female, and 80% had clear cell histology. 36% received checkpoint inhibitor (CPI) monotherapy, 28% received combination CPI, and 26% received CPI in combination with tyrosine kinase inhibitor (TKI). 4% received other therapies. Patients with higher CD8 T cell infiltration had improved OS and PFS outcomes on Kaplan Meier analysis (>0.79% T cell infiltration - OS at 60 months 35.2% [95% CI 14.7-56.6%], PFS at 60 months 25.6% [95% CI 9.7-45.1%]; <0.79% T cell infiltration - OS at 60 months 11.8% [95% CI 2.0-31.2%], PFS at 60 months 5.9% [95% CI 0.4-23.5%]. For those patients with CD8 T cell infiltration <0.79%, the hazard ratio for OS was 2.42 (1.21-4.85; 95% confidence interval; P-value 0.012). For those patients with CD8 T cell infiltration <0.79%, the hazard ratio for PFS was 2.22 (1.07-4.63; 95% confidence interval; P-value 0.033). Conclusions: This work furthers our understanding of the tumor environment in those patients who previously received surgical resection but progressed to metastatic disease. CD8 T cells in tumor environment are an important predictor of objective clinical response to CPI therapy. Further work needs to be done in larger, prospective trials to confirm these findings.

PURPOSE Patients with no evidence of disease (NED) after metastasectomy for renal cell carcinoma are at high risk of recurrence. Pazopanib is an inhibitor of vascular endothelial growth factor receptor and other kinases that improves progression-free survival in patients with metastatic RCC (mRCC). We conducted a randomized, double-blind, placebo-controlled multicenter study to test whether pazopanib would improve disease-free survival (DFS) in patients with mRCC rendered NED after metastasectomy. PATIENTS AND METHODS Patients with NED after metastasectomy were randomly assigned 1:1 to receive pazopanib 800 mg once daily versus placebo for 52 weeks. The study was designed to observe an improvement in DFS from 25% to 45% with pazopanib at 3 years, corresponding to 42% reduction in the DFS event rate. RESULTS From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events (92% information). The study did not meet its primary end point. An updated analysis at 60.5-month median follow-up from random assignment (95% CI, 59.3 to 71.0) showed that the 3-year DFS was 27.4% (95% CI, 17.9 to 41.7) for pazopanib and 21.9% (95% CI, 13.3 to 36.2) for placebo. Hazard ratio (HR) for DFS was 0.90 ([95% CI, 0.60 to 1.34]; Pone-sided = .29) in favor of pazopanib. Three-year overall survival (OS) was 81.9% (95% CI, 72.7 to 92.2) for pazopanib and 91.4% (95% CI, 84.4 to 98.9) for placebo. The HR for OS was 2.55 (95% CI, 1.23 to 5.27) in favor of placebo ( Ptwo-sided = .012). Health-related quality-of-life measures deteriorated in the pazopanib group during the treatment period. CONCLUSION Pazopanib did not improve DFS as the primary end point compared with blinded placebo in patients with mRCC with NED after metastasectomy. In addition, there was a concerning trend favoring placebo in OS.

e16535 Background: Recent data have reported on obesity as a probable protective factor in metastatic RCC (mRCC). Current knowledge and expanding data suggests a higher BMI (overweight and obese patients) have better survival outcomes. We hypothesize that mRCC patients studied at our institution, Emory’s Winship Cancer Institute, will display similar clinical outcome trends. Methods: We conducted a retrospective analysis of patients with mRCC treated at Winship Cancer Institute between 1/1/2018 and 8/31/23. Overall survival (OS) and progression-free survival (PFS) were defined as months from treatment initiation to death or clinical/radiographic progression, respectively. The correlation between BMI and OS/PFS was studied in 399 patients diagnosed with metastatic RCC under systemic therapy. The groups were divided into overweight and obesity (BMI > 25 kg/m2) and underweight or normal (BMI < 25 kg/m2). Univariate (UVA) and multivariate (MVA) analyses were carried out for OS and PFS using Cox proportional hazard model. Results: A total of 401 eligible patients were included with a median follow up of 60 months. Median age was 66 years (range = 18-95), 71% were male, 29% were female, and 81% had clear cell histology. 36% received checkpoint inhibitor (CPI) monotherapy, 28% received combination CPI, and 26% received CPI in combination with tyrosine kinase inhibitor (TKI). 4% received other therapies. Lower BMI (<25) at initiation of systemic therapy was significantly associated with worse OS and PFS (table). Conclusions: Lower BMI at baseline and during therapy was associated with worse clinical outcomes. This helps validate the association between obesity and improved survival, a potential "obesity paradox." Results should be validated in a larger, prospective study to further understand the complex relationship between BMI, lipid metabolism, and clinical outcomes in mRCC. [Table: see text]

4556 Background: Immune Checkpoint Inhibitors (ICIs) have been the mainstay treatment for advanced renal cell carcinoma (aRCC). However, irAEs are still a challenge in clinical practice. We tested irAEs with inflammatory biomarkers and their association with clinical outcomes. Methods: A retrospective analysis was conducted on adult patients with aRCC treated with ICIs at Emory Winship Cancer Institute between 2018 and 2023. irAEs determined by the primary oncologist and reported by CTCAE v5.0. Univariate and multivariate analyses were conducted to determine the association between race, gender, OS, PFS, clinical benefit (CB, stable disease, partial response, complete response), modified Glasgow Prognostic Score (mGPS), neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR), neutrophil to eosinophil ratio (NER), and any grade irAE. MVA was built by controlling gender, race, smoking status, and prior treatment. Results: We analyzed 401 patients; 191 (47.6%) patients experienced any grade irAEs, with 41 (21.5%) of those classified as grade 3 or higher. Of 401 patients, 139 (34.6%) were treated with PD-1 inhibitor (PD-1i) monotherapy, 131 (32.6%) with PD-1i and CTLA-4 inhibitor combination, 108 (26.9%) with PD-1i and tyrosine kinase inhibitor combination. The median follow-up time was 43.0 months (36.5-51.3). On univariate analysis, the incidence of irAEs was higher in females than males (Odds ratio (OR),1.66 (1.08-2.57), p=0.021), White patients had a higher incidence of irAEs compared to African American patients (OR 2.20 (1.32-3.66), p=0.009). On multivariate analysis, low mGPS was correlated with a higher risk of irAEs (OR for mGPS of 0-1-2 was 6.03 (2.07-17.62), 3.75 (1.31-10.70), and reference respectively; p=0.004). irAEs were correlated with greater CB (OR 2.56 (1.53-4.29); p <.001), longer OS (HR 0.55 (0.37-0.82); p=0.003), and longer PFS (HR 0.51 (0.37-0.71); p <.001). Conclusions: Female patients, White patients, and patients with low inflammatory biomarkers may have a higher likelihood of experiencing irAEs. Patients who experienced irAEs may have better outcomes. Future prospective trials are needed for further evidence. [Table: see text]

e16539 Background: Race has been regarded to be associated with clinical outcome of aRCC patients undergoing therapy with ICIs, but larger data is still limited. Here, we evaluated race and clinical outcome in aRCC patients treated with ICI. Methods: A retrospective analysis was conducted on adult patients with aRCC treated with ICIs at Emory Winship Cancer Institute between 1/1/2018 and 8/31/23. Overall survival (OS) and progression-free survival (PFS) was calculated from the date of treatment initiation to death and progression, respectively. Progression was determined by RECIST v1.1 or clinical progression. Clinical benefit (CB), including stable disease, partial response, and complete response, was determined by RECIST v.1.1. Univariate (UVA) and multivariate (MVA) analyses were conducted for CB, OS, and PFS in patients to assess the association with race. Results: There was a total of 401 patients, consisted of 71.1% White patients, 21.2% African American patients, and 7.7% patients with other racial profiles. Median age was 66 (range = 18-95). Treatment plan involved 139 (34.6%) patients for single ICI therapy, 131 (32.6%) patients for ICI/ICI therapy, 108 (26.9%) patients for ICI/TKI (tyrosine kinase inhibitor) therapy, 6 (1.5%) patients for ICI/ICI/TKI therapy, and 17 (4.23%) patients for therapy with ICI plus an experimental drug. Race was significantly associated with the CB, OS, and PFS of the patients in the UVA. African American patients demonstrated worse clinical outcomes with hazard ratios (HR) significantly less than 1 for both OS and PFS and odds ratios (OR) significantly greater than 1 for CB. According to the Kaplan-Meier plots, the median OS for African American and White patients were 17.1 and 34.8 months, respectively. Similarly, median PFS for African American, White, and patients of other races were 3.6, 7.7, and 13.9, respectively. MVA also suggested greater clinical benefit for patients of White and other racial backgrounds when compared to African American patients. Conclusions: The significant difference in clinical outcomes between the racial profile of patients suggest that African American patients may have worse clinical outcomes in treatment involving ICIs. A more in-depth analysis of race’s association with clinical outcomes can be conducted to assist with treatment plan decisions in the future. [Table: see text]

Introduction: The lymphoma microenvironment contributes to clinical treatment outcome. Previously, we showed that enrichment in M1 macrophages was associated with improved clinical outcome in patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; Yan et al., 2020). In the POLARIX study (NCT03274492), polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) demonstrated prolonged progression-free survival (PFS) versus R-CHOP in patients with previously untreated DLBCL (Tilly et al., 2022). Here, we investigate the relationship between the lymphoma microenvironment at baseline and clinical outcomes in patients treated with Pola-R-CHP or R-CHOP in POLARIX. Methods: Global gene expression patterns of baseline tumor biopsies from patients treated with Pola-R-CHP or R-CHOP in POLARIX were generated by RNA-seq. Immune and stromal cell tumor content was estimated using the xCell and QuanTIseq algorithms. Association of the infiltration scores with PFS was evaluated. Hazard ratios (HR) were adjusted for International Prognostic Index score (2 vs. 3–5), age (≤60 vs. >60 years), and cell of origin (activated B cell, germinal center B cell, unclassified, unknown). Results: Gene expression data were generated from 665 patients in POLARIX (Pola-R-CHP, n = 331; R-CHOP, n = 334). M1 macrophage infiltration levels were comparable between treatment arms. Quantity of M1 macrophage infiltration was the primary immune-related positive prognostic factor for PFS in patients treated with R-CHOP. High levels (above median) of M1 macrophages were associated with improved PFS when quantified by either QuanTIseq (HR 0.60, 95% confidence interval [CI]: 0.41–0.88) or xCell (HR 0.57, 95% CI: 0.39–0.84). In contrast, M1 macrophage infiltration did not impact clinical activity of the Pola-R-CHP regimen when quantified by either QuanTIseq (HR 0.90, 95% CI: 0.58–1.38) or xCell (HR 0.95, 95% CI: 0.62–1.46); the treatment benefit in patients with lymphomas with low M1 macrophage levels was similar to that of patients with high M1 macrophage levels (Figure). Enrichment in various immune infiltrates was linked to either improved or poor survival outcomes in the R-CHOP arm; however, PFS appeared to be largely independent of immune infiltration in the Pola-R-CHP arm. The research was funded by: The POLARIX study (NCT03274492) was sponsored by F. Hoffmann-La Roche Ltd and Genentech, Inc. Third-party editorial assistance, under the direction of the authors, was provided by Anna Nagy, BSc, of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann-La Roche Ltd. Keywords: aggressive B-cell non-Hodgkin lymphoma, targeting the tumor microenvironment Conflicts of interests pertinent to the abstract F. Morschhauser Consultant or advisory role: F. Hoffmann-La Roche Ltd/Genentech, Inc., Gilead Sciences, Celgene, Bristol-Myers Squibb, AbbVie, Epizyme, Servier, AstraZeneca, Novartis, Genmab Honoraria: F. Hoffmann-La Roche Ltd/Genentech, Inc., Chugai, Eisai Other remuneration: F. Hoffmann-La Roche Ltd/Genentech, Inc. (Expert Testimony) K. Hatzi Employment or leadership position: Genentech, Inc. Stock ownership: F. Hoffmann-La Roche Ltd G. Lenz Consultant or advisory role: F. Hoffmann-La Roche Ltd, Gilead Sciences, Janssen, Bristol-Myers Squibb, Novartis, AbbVie, Incyte, Genmab, Constellation, ADC Therapeutics, Karyopharm, Miltenyi, PentixaPharm, Sobi, Immagene, Genase, Hexal/Sandoz, Eli Lilly Research funding: Janssen, Bayer, AstraZeneca, MorphoSys Educational grants: AbbVie, Janssen, F. Hoffmann-La Roche Ltd Other remuneration: F. Hoffmann-La Roche Ltd, Gilead Sciences, Novartis, Takeda, Bristol-Myers Squibb, AbbVie, Incyte, ADC Therapeutics, Sobi, Hexal/Sandoz (Speaker's Bureau); F. Hoffmann-La Roche Ltd (Expert Testimony) A. F. Herrera Consultant or advisory role: Bristol-Myers Squibb, Seattle Genetics, Merck, Genentech, Inc./F. Hoffmann-La Roche Ltd, AstraZeneca/MedImmune, Karyopharm Therapeutics, ADC Therapeutics, Takeda, Regeneron, Genmab, Tubulis GmbH, Pfizer, Adicet Bio, Caribou Biosciences, AbbVie Research funding: Bristol-Myers Squibb, Merck, Genentech, Inc./F. Hoffmann-La Roche Ltd, Kite (a Gilead company), AstraZeneca, Seattle Genetics, Gilead Sciences, ADC Therapeutics Educational grants: Bristol-Myers Squibb C. R. Flowers Consultant or advisory role: Bayer, Gilead Sciences, Spectrum Pharmaceuticals, AbbVie, Celgene, Denovo Biopharma, BeiGene, Karyopharm Therapeutics, Pharmacyclics, Janssen, Genentech, Inc./F. Hoffmann-La Roche Ltd, Epizyme, Genmab, Seattle Genetics, Foresight Diagnostics, Bristol-Myers Squibb/Celgene, Curio Science, AstraZeneca, MorphoSys Stock ownership: Foresight Diagnostics, npower Research funding: Acerta Pharma, Janssen Oncology, Gilead Sciences, Celgene, TG Therapeutics, Genentech, Inc./F. Hoffmann-La Roche Ltd, Pharmacyclics, AbbVie, Millennium, Alimera Sciences, Xencor, 4D Pharma, Adaptimmune, Amgen, Bayer, Cellectis, EMD Serono, Guardant Health, Iovance Biotherapeutics, Kite/Gilead Sciences, MorphoSys, Nektar, Novartis, Pfizer, Sanofi, Takeda, Ziopharm Oncology M. Trněný Consultant or advisory role: Takeda, Bristol-Myers Squibb, Incyte, AbbVie, Amgen, F. Hoffmann-La Roche Ltd, Gilead Sciences, Janssen, MorphoSys, Novartis Honoraria: Janssen, Gilead Sciences, Takeda, Bristol-Myers Squibb, Amgen, AbbVie, F. Hoffmann-La Roche Ltd, MorphoSys, Novartis Educational grants: Gilead Sciences, Takeda, Bristol-Myers Squibb, F. Hoffmann-La Roche Ltd, Janssen, AbbVie J. M. Burke Consultant or advisory role: Adaptive Biotechnologies, AstraZeneca, BeiGene, Epizyme, Kura, Kymera, Morphosys, Nurix, F. Hoffmann-La Roche Ltd/Genentech, Inc., Seattle Genetics, TG Therapeutics, Verastem, X4 Pharmaceuticals Research funding: Novartis Other remuneration: Bristol-Myers Squibb, Seattle Genetics (Speaker’s Bureau) J. Hou Consultant or advisory role: AstraZeneca, AbbVie Research funding: AstraZeneca P. B. Staber Consultant or advisory role: F. Hoffmann-La Roche Ltd, AbbVie, Gilead Sciences, Janssen, AstraZeneca, Takeda, MSD, Bristol-Myers Squibb, Incyte, BeiGene, Eli Lilly Honoraria: F. Hoffmann-La Roche Ltd, AbbVie, Gilead Sciences, Janssen, AstraZeneca, Takeda, MSD, Bristol-Myers Squibb, Incyte, BeiGene, Eli Lilly Research funding: F. Hoffmann-La Roche Ltd Educational grants: F. Hoffmann-La Roche Ltd, AbbVie E. A. Hawkes Consultant or advisory role: Bristol-Meyers Squibb, F. Hoffmann-La Roche Ltd, Gilead Sciences, Antengene, Link, Novartis, BeiGene, MSD Research funding: AstraZeneca, Merck, Bristol-Myers Squibb, F. Hoffmann-La Roche Ltd Educational grants: AstraZeneca Other remuneration: Regeneron, Janssen, Merck, AstraZeneca, F. Hoffmann-La Roche Ltd K. Izutsu Consultant or advisory role: Genmab, BeigGene, Kyowa Kirin, Ono Pharmaceutical, Mitsubishi Tanabe Pharma, Eisai, Zenyaku Kogyo Honoraria: Bristol-Myers Squibb, AstraZeneca, Eisai, Zenyaku Kogyo, Kyowa Kirin, Takeda, Chugai, Novartis, MSD, SymBio, Nihon Shinyaku, AbbVie, Ono Pharmaceutical, Pfizer, Genmab, Eli Lilly, Meiji Seika Pharma, Daiichi Sankyo Research funding: MSD, AstraZeneca, AbbVie, Eisai, Incyte, Novartis, Pfizer, Janssen, Yakult, Kyowa Kirin, Ono Pharmaceutical, Daiichi Sankyo, Chugai, BeiGene, Genmab, LOXO Oncology, Otsuka, Regeneron S. Le Gouill Employment or leadership position: F. Hoffmann-La Roche Ltd D. Belada Consultant or advisory role: F. Hoffmann-La Roche Ltd Research funding: F. Hoffmann-La Roche Ltd Educational grants: F. Hoffmann-La Roche Ltd A. Tucci Consultant or advisory role: Janssen, Gentili, Sanofi Honoraria: Takeda, Kiowa Kyrin, MSD, Incyte M. Yan Employment or leadership position: Hoffmann-La Roche Ltd Stock ownership: Hoffmann-La Roche Ltd W. Harris Employment or leadership position: Genentech, Inc. Stock ownership: F. Hoffmann-La Roche Ltd J. Hirata Employment or leadership position: Genentech, Inc. Stock ownership: F. Hoffmann-La Roche Ltd C. Lee Employment or leadership position: F. Hoffmann-La Roche Ltd Stock ownership: F. Hoffmann-La Roche Ltd Y. Jiang Employment or leadership position: F. Hoffmann-La Roche Ltd/Genentech, Inc. Stock ownership: F. Hoffmann-La Roche Ltd/Genentech, Inc. F. Jardin Consultant or advisory role: F. Hoffmann-La Roche Ltd Honoraria: F. Hoffmann-La Roche Ltd, Celgene, Janssen, AbbVie, Genentech, Inc. Educational grants: F. Hoffmann-La Roche Ltd

Paramedics are key to the provision of emergency care in the community. Those living with dementia use paramedic services at a high rate, due to a range of issues related to comorbid conditions and other acute events which mean care cannot continue in the home. There is a paucity of literature related to care provided in such instances. Anecdotally, a perception exists that providing care to this group of people is challenging for paramedics in situations where high level assessment and emergency care are paramount. Paramedics in one Australian state were sought to participate in an exploratory study to enhance understanding of how they currently worked with people who lived in the community and had dementia. Sixteen participants were recruited to the study, and they worked in a number of areas, including urban and rural. Experience was broad, ranging from one to 36 years in the paramedic role. Inductive thematic analysis of interviews revealed key themes that framed the paramedic role and permeated interactions, assessment and decision-making. Paramedics participating in this study recognised people living with dementia who had high level impacts of the condition, suggesting those with less visible symptoms may remain hidden. With the projected increase of people diagnosed with dementia it is imperative that paramedics are aware of, and integrate dementia knowledge, skills and confidence into their practice. Deeper exploration of the area that includes volunteer ambulance personnel and further inquiry of the role of paramedics in relation to those living with dementia is needed. A focus on education and professional development to equip paramedics to work with people living with dementia is recommended. The findings suggest that greater work in this area is required.

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.

Renal Cell Carcinoma (RCC), is the 9th most common cancer in the United States. The major classifications of RCC include clear cell (ccRCC), papillary (pRCC) and chromophobe (chRCC). Treatment for the localized disease includes resection or ablation with curative intent, or surveillance if these procedures are not feasible. Unfortunately, about one-third of patients will present with metastatic disease at the time of diagnosis and there are currently no reliable biomarkers to guide clinical decision-making. There is growing evidence that epigenetics plays a role in kidney cancer tumorigenesis and aggressiveness and new strategies for biomarker development are emerging. For example, DNA methylation patterns may be useful in distinguishing different types of RCCs and for distinguishing malignant kidney neoplasms from benign tumors. Epigenetic changes in RCC have also been associated with poorer response to treatment and have the potential to be novel drug targets in the treatment of mRCC. Here we discuss the epigenetics of RCC and the corresponding clinical implications.

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.

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 onehalf (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.

671 Background: The full dose of cabo is 60 mg, but some pts are treated with a reduced dose with the clinical anticipation of adverse events (AEs). We compared AEs and CO in mRCC pts treated with full versus reduced dose cabo. Methods: We performed a retrospective analysis of 65 mRCC pts treated with cabo at Winship Cancer Institute from 2016-2018. CO were measured by overall survival (OS), progression-free survival (PFS), and objective response (OR). OS and PFS were measured from first dose of cabo to date of death and clinical or radiographic progression, respectively. OR was defined as partial response (PR) or complete response (CR) per RECISTv1.1. AEs were collected from clinic notes. Univariate analysis (UVA) of association between AEs and CO was performed using logistic regression model. Results: Most pts were males (68%) and the median age was 63 years. Most (79%) had clear cell RCC (ccRCC) and the majority were IMDC intermediate (59%) or poor (39%) risk. Most pts (68%) received 60 mg and 48% of these pts underwent a dose reduction for AEs. Nearly all pts (95%) who started on a reduced dose experienced AEs, compared to 66% for pts treated with 60 mg. OR rate was similar for pts on 60 mg (18%) and pts on a reduced dose (19%). The median survival was comparable in pts treated with 60 mg and pts treated with a reduced dose (10.9 vs. 8.8 months, p=0.92 for OS and 5.6 vs. 5.1 months, p=0.23 for PFS) per Kaplan Meier estimation. AEs, particularly gastrointestinal (GI) AEs, were associated with significantly lower chance of OR (Table). Conclusions: CO may be comparable in mRCC pts treated with full versus reduced dose of cabo, but a reduced dose of cabo may not be associated with decreased AEs. GI side effects may be a poor prognostic factor in mRCC pts treated with cabo. Larger studies are warranted to validate these findings. [Table: see text]

563 Background: The mGPS, a clinical tool that incorporates albumin and C-reactive protein, has proven useful in the prognostication of multiple cancers. Several CPI agents have been approved for the treatment of mUCC but a prognostic biomarker is needed. We investigated the impact of mGPS on survival outcomes in mUCC patients receiving CPI. Methods: We retrospectively reviewed mUCC patients treated with CPI (PD-1 or PD-L1 inhibitors) at Winship Cancer Institute from 2015 to 2018. Overall survival (OS) and progression-free survival (PFS) were measured from the start date of CPI until death or clinical/radiographic progression, respectively. mGPS was defined as a summary score with one point given for CRP > 10 mg/L and/or albumin < 3.5 g/dL. Univariate (UVA) and multivariate (MVA) analyses were carried out using Cox proportional hazard model for OS and PFS. Results: A total of 53 patients were included with a median follow up 27.1 months. The median age was 70 years with 84.9% male and 20.8% black. Baseline mGPS was 0 in 43.4%, 1 in 28.3% and 2 in 28.3%. The correlation between mGPS and other inflammatory biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR) and platelet-to-lymphocyte ratio (PLR), was high with Pearson correlation coefficients ≥ 0.48 (p ≤ 0.0003). Increased mGPS at the time of CPI initiation was associated with poorer OS and PFS (Table). Conclusions: The mGPS may be a useful prognostic tool in mUCC patients when treatment with CPI is under consideration. These results warrant a larger study for validation.[Table: see text]

INTRODUCTION:Frailty rates are increasing with population ageing. In paramedicine, Clinical Practice Guidelines (CPGs) are essential documents that support decision making, yet little evidence exists regarding the support CPGs provide paramedics in the care of frail and older adults.AIM:To investigate how CPGs support paramedics' care of frail and older adults.METHODS:CPGs from nine Australasian paramedic services were collected in 2019. Content analysis was used to explore two hundred and thirty-seven individual CPGs for decision support information regarding frail and older adults.RESULTS:Evidence-based content relating to older adults was sparse compared to paediatric content. Two overarching decision support domains were identified, patient assessment and management. Inconsistent age descriptors were widespread, particularly in pharmacological guidelines. Five service providers' CPGs contained validated assessment instruments for use with older adults.CONCLUSION:Decision support documentation regarding frail and older adults varies across Australasian paramedic services. Frailty and older adult specific CPGs, and validated assessment instruments suitable to the paramedicine environment could improve paramedic decision making and minimise patient risk. A collaborative approach encompassing service providers and educational institutions is crucial to develop consistent, evidence-based CPGs relevant to older adults.

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.

Background The 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. Methods We 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 albumin<3.5 g/dL, resulting in possible scores of 0, 1 and 2. If only albumin was low with a normal CRP, no points were awarded. Univariate analysis (UVA) and multivariate analysis (MVA) were carried out using Cox proportional hazard model. Outcomes were also assessed by Kaplan-Meier analysis. Results 156 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, p<0.001) and PFS (HR 1.90, 95% CI 1.20 to 3.01, p=0.006) relative to a score of 0; this disparity in outcome based on baseline mGPS persisted in MVA. The respective median OS of patients with baseline mGPS of 0, 1 and 2 was 44.5 (95% CI 27.3 to not evaluable), 15.3 (95% CI 11.0 to 24.2) and 10 (95% CI 4.6 to 17.5) months (p<0.0001). The median PFS of these three cohorts was 6.7 (95% CI 3.6 to 13.1), 4.2 (95% CI 2.9 to 6.2) and 2.6 (95% CI 2.0 to 5.6), respectively (p=0.0216). The discrimination power of baseline mGPS to predict survival outcomes was comparable to the IMDC risk score based on Uno's c-statistic (OS: 0.6312 vs 0.6102, PFS: 0.5752 vs 0.5533). Conclusion The 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.

BACKGROUND:Several immune checkpoint inhibitors (ICIs) are approved for the treatment of advanced urothelial carcinoma (UC). There are limited biomarkers for ICI-treated patients with UC. We investigated the association between body composition and clinical outcomes in ICI-treated UC patients.MATERIALS AND METHODS:We conducted a retrospective analysis of 70 ICI-treated patients with advanced UC at Winship Cancer Institute from 2015 to 2020. Baseline computed tomography images within 2 months of ICI initiation were collected at mid-L3 and muscle and fat compartments (subcutaneous, intermuscular, and visceral) were segmented using SliceOMatic v5.0 (TomoVision, Magog, Canada). A prognostic body composition risk score (high: 0-1, intermediate: 2-3, or low-risk: 4) was created based on the β coefficient from the multivariate Cox model (MVA) following best-subset variable selection. Our body composition risk score was skeletal muscle index (SMI) + 2 × attenuated skeletal muscle (SM) mean + visceral fat index (VFI). Concordance statistics (C-statistics) were used to quantify the discriminatory magnitude of the predictive model.RESULTS:Most patients (70%) were men and the majority received ICIs in the second- (46%) or third-line (21%) setting. High-risk patients had significantly shorter overall survival (OS; hazard ratio [HR], 6.72; p < .001), progression-free survival (HR, 5.82; p < .001), and lower chance of clinical benefit (odds ratio [OR], 0.02; p = .003) compared with the low-risk group in MVA. The C-statistics for our body composition risk group and myosteatosis analyses were higher than body mass index for all clinical outcomes.CONCLUSION:Body composition variables such as SMI, SM mean, and VFI may be prognostic and predictive of clinical outcomes in ICI-treated patients with UC. Larger, prospective studies are warranted to validate this hypothesis-generating data.IMPLICATIONS FOR PRACTICE:This study developed a prognostic body composition risk scoring system using radiographic biomarkers for patients with bladder cancer treated with immunotherapy. The study found that the high-risk patients had significantly worse clinical outcomes. Notably, the study's model was better at predicting outcomes than body mass index. Importantly, these results suggest that radiographic measures of body composition should be considered for inclusion in updated prognostic models for patients with urothelial carcinoma treated with immunotherapy. These findings are useful for practicing oncologists in the academic or community setting, particularly given that baseline imaging is routine for patients starting on treatment with immunotherapy.