The Evolving Landscape of Biomarkers for Immune Checkpoint Blockade in Genitourinary Cancers.

In the past decade, immune checkpoint inhibitors (ICI) have been approved for treatment of genitourinary malignancies and have revolutionized the treatment landscape of these tumors. However, despite the remarkable success of these therapies in some GU malignancies, many patients' tumors do not respond to these therapies, and others may experience significant side effects, such as immune-related adverse events (iRAEs). Accordingly, biomarkers and improved prognostic tools are critically needed to help predict which patients will respond to ICI, predict and mitigate risk of developing immune-related adverse events, and inform personalized choice of therapy for each patient. Ongoing clinical and preclinical studies continue to provide an increasingly robust understanding of the mechanisms of the response to immunotherapy, which continue to inform biomarker development and validation. Herein, we provide a comprehensive review of biomarkers of the response to immunotherapy in GU tumors and their role in selection of therapy and disease monitoring.

Understanding and overcoming resistance to immunotherapy in genitourinary cancers.

The introduction of novel immunotherapies has significantly transformed the treatment landscape of genitourinary (GU) cancers, even becoming the standard of care in some settings. One such type of immunotherapy, immune checkpoint inhibitors (ICIs) like nivolumab, ipilimumab, pembrolizumab, and atezolizumab play a pivotal role by disturbing signaling pathways that limit the immune system's ability to fight tumor cells. Despite the profound impact of these treatments, not all tumors are responsive. Recent research efforts have been focused on understanding how cancer cells manage to evade the immune response and identifying the possible mechanisms behind resistance to immunotherapy. In response, ICIs are being combined with other treatments to reduce resistance and attack cancer cells through multiple cellular pathways. Additionally, novel, targeted strategies are currently being investigated to develop innovative methods of overcoming resistance and treatment failure. This article presents a comprehensive overview of the mechanisms of immunotherapy resistance in GU cancers as currently described in the literature. It explores studies that have identified genetic markers, cytokines, and proteins that may predict resistance or response to immunotherapy. Additionally, we review current efforts to overcome this resistance, which include combination ICIs and sequential therapies, novel insights into the host immune profile, and new targeted therapies. Various approaches that combine immunotherapy with chemotherapy, targeted therapy, vaccines, and radiation have been studied in an effort to more effectively overcome resistance to immunotherapy. While each of these combination therapies has shown some efficacy in clinical trials, a deeper understanding of the immune system's role underscores the potential of novel targeted therapies as a particularly promising area of current research. Currently, several targeted agents are in development, along with the identification of key immune mediators involved in immunotherapy resistance. Further research is necessary to identify predictors of response.

Immunotherapy has transformed the treatment landscape for many cancer types, including genitourinary malignancies such as renal and bladder cancers.However, not all patients or tumor types, such as prostate cancer, respond to this type of treatment.Understanding the mechanisms of immunotherapy resistance is critical for developing strategies to overcome these challenges.Primary resistance, which is present at the onset of treatment, can bedue to genetic abnormalities or immune system dysregulation. These factors alter the interactions between host cells and cancer cells.Adaptive resistance develops during therapy due to dynamic changes in the levels of growth factors, cytokines, and the tumor microenvironment (TME).Acquired resistance mainly occurs at the genetic and translational levels, involving the downregulation of critical human leukocyte antigen (HLA) molecules and interference with mutational repair.Future therapies may focus on detailed genetic profiling of patients to guide treatment selection and on the use of immune profile monitoring to assist in assessing responsiveness, alongside developing novel targeted therapies and ICIs.Further research is needed to identify predictors of response to ICIs.

Adrenocortical Carcinomas: Molecular Pathogenesis, Treatment Options, and Emerging Immunotherapy and Targeted Therapy Approaches.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy in the advanced setting with poor prognosis. This narrative review provides an overview of the epidemiology of ACC and its molecular pathogenesis with a summary of the main involved signaling pathways. We then provide an update on the clinical presentation, diagnosis, and current management strategies of both localized and metastatic disease from a multidisciplinary perspective. We highlight the debate around the use of mitotane in the adjuvant setting and review the use of combination chemotherapy with etoposide, doxorubicin, and cisplatin. The review also focuses on emerging data providing hope for the use of immune checkpoint inhibitors and targeted therapies in ACC with a summary of ongoing trials.

Established and emerging biomarkers of immunotherapy in renal cell carcinoma.

Immunotherapies, such as immune checkpoint inhibitors, have heralded impressive progress for patient care in renal cell carcinoma (RCC). Despite this success, some patients' disease fails to respond, and other patients experience significant side effects. Thus, development of biomarkers is needed to ensure that patients can be selected to maximize benefit from immunotherapies. Improving clinicians' ability to predict which patients will respond to immunotherapy and which are most at risk of adverse events - namely through clinical biomarkers - is indispensable for patient safety and therapeutic efficacy. Accordingly, an evolving suite of therapeutic biomarkers continues to be investigated. This review discusses biomarkers for immunotherapy in RCC, highlighting current practices and emerging innovations, aiming to contribute to improved outcomes for patients with RCC.

Renal cell carcinoma (RCC) is a type of kidney cancer. Treatments that target the body's immune system, called immunotherapies, are generally effective in RCC, but not all patients' cancer will respond (shrink or disappear) after receiving this treatment. Because of this, signals, called biomarkers, are needed to signal which patients' cancer will respond and which patients may experience unwanted side effects after treatment. This article highlights biomarkers that have been or are being studied for understanding immunotherapy in RCC.

A plain language summary exploring a new treatment combination for untreated locally advanced or metastatic urothelial cancer: enfortumab vedotin plus pembrolizumab.

WHAT IS THIS SUMMARY ABOUT?: This summary provides the results of a study of two treatments for cancer, enfortumab vedotin and pembrolizumab, that were studied together against locally advanced or metastatic urothelial cancer (la/mUC), a cancer that occurs most commonly in the bladder. WHAT WERE THE RESULTS?: In the 45 patients studied, around 16% did have serious side effects, but most side effects were manageable. Twenty-four percent of patients, however, stopped the study treatment because of their side effects. Within about 2 months of starting treatment, most patients' (73%) tumors were smaller and stayed smaller, on average, for more than 2 years. WHAT DO THE RESULTS MEAN?: The combination of enfortumab vedotin plus pembrolizumab is a new treatment option for patients with locally advanced or metastatic urothelial cancer when they cannot receive the typical treatment, cisplatin. Advanced or metastatic urothelial cancer is a type of cancer where the cancer has already spread outside of the bladder or urinary tract.

Case Report: Exceptional response to nivolumab plus cabozantinib in a patient with extrarenal clear cell renal cell carcinoma.

Extrarenal clear cell renal cell carcinoma (eccRCC) is a rare type of RCC that arises in areas other than the kidney. Given its rarity, consensus guidelines for optimal treatment of eccRCC have not been established, and the literature is lacking any reports of patient response to systemic therapy and any reports of administration of immunotherapy to patients with ecRCC. Here, we present the case of a patient in their 60s with eccRCC arising in the spleen. The patient underwent splenic resection and then received systemic therapy, due to disease recurrence, with a combination of immunotherapy (IO) and tyrosine kinase inhibitor targeted therapy (VEGF-TKI). The patient had an excellent and durable response to this therapeutic regimen with minimal adverse effects, completing 2 years of therapy of nivolumab and cabozantinib. At the time of this report, the disease remains stable. This case demonstrates that combination therapy with IO+VEGF-TKI represents a reasonable and well-tolerated treatment option with activity in eccRCC and reveals interesting correlative data, including nests of stem-like CD8+T-cell infiltration in tumor tissue, which provide important biological context to this patient's exceptional therapeutic response.

Comprehensive genomic profiling of penile squamous cell carcinoma and the impact of human papillomavirus status on immune-checkpoint inhibitor-related biomarkers.

BACKGROUND: Advanced penile squamous cell carcinoma (pSCC) is a rare and aggressive malignancy with limited success of immune-checkpoint inhibitors (ICIs). Approximately half of pSCC cases are associated with human papillomavirus (HPV) infection. METHODS: Evaluation was done retrospectively of the landscape of somatic alterations and ICI-related biomarkers in pSCC by using the Caris Life Sciences data set with the aim to establish signatures for HPV-dependent oncogenesis. The pSCC tumors were analyzed by using next-generation sequencing (NGS) of DNA and RNA. Programmed death ligand 1 (PD-L1) expression was evaluated by immunohistochemistry (IHC). Microsatellite instability (MSI) was tested by fragment analysis, IHC (SP142; ≥1%), and NGS. Tumor mutational burden (TMB)-high was defined as ≥10 mutations/Mb. HPV16/18 status was determined by using whole-exome sequencing (WES) when available. Significance was adjusted for multiple comparisons (q value < .05). RESULTS: NGS of the overall cohort (N = 108) revealed TP53 (46%), CDKN2A (26%), and PIK3CA (25%) to be the most common mutations. Overall, 51% of tumors were PD-L1+, 10.7% had high TMB, and 1.1% had mismatch repair-deficient (dMMR)/MSI-high status. Twenty-nine patients had their HPV status made available by WES (HPV16/18+, n = 13; HPV16/18-, n = 16). KMT2C mutations (33% vs. 0%) and FGF3 amplifications (30.8% vs. 0%) were specific to HPV16/18+ tumors, whereas CDKN2A mutations (0% vs. 37.5%) were exclusive to HPV16/18- tumors. TMB-high was exclusively found in the HPV16/18+ group (30.8%). The two groups had comparable PD-L1 and dMMR/MSI-H status. CONCLUSIONS: In a large and comprehensive NGS-based evaluation of somatic alterations in pSCC, HPV16/18+ versus HPV16/18- pSCCs were molecularly distinct tumors. Our finding that TMB-high is exclusive to HPV16/18+ tumors requires confirmation in larger data sets. PLAIN LANGUAGE SUMMARY: Penile squamous cell carcinoma (pSCC) is a rare and aggressive malignancy in the advanced setting, with poor prognosis and little success with immune-checkpoint inhibitors (ICIs) in an unselected patient approach. Human papillomavirus (HPV) infection is a known risk factor for pSCC; its impact on genomic tumor profiling is less defined. Using next-generation sequencing, we explored the genetic landscape and ICI-related biomarkers of pSCC and HPV-driven oncogenic molecular signatures. Our results indicate that HPV-positive and HPV-negative pSCCs are molecularly distinct tumors. Increased tumor mutational burden is associated with HPV-positive tumors, and could serve as a biomarker for predicting therapeutic response to ICI-based therapies. Our results support the growing literature indicating that HPV status in pSCC can be used to guide patient stratification in ICI-based clinical trials.

Immune-Related Adverse Events and Clinical Outcomes in Advanced Urothelial Cancer Patients Treated With Immune Checkpoint Inhibitors.

BACKGROUND: In advanced urothelial cancers (UC), immune checkpoint inhibitors (ICI) show promise as a durable therapy. Immune-related adverse events (irAEs), a side effect of ICIs, may serve as an indicator of beneficial response. We investigated the relationship between irAEs and clinical outcomes in patients with advanced UC who received ICI. MATERIALS AND METHODS: In this retrospective study, we investigated 70 patients with advanced UC treated with ICIs at Winship Cancer Institute from 2015 to 2020. Data on patients were collected through chart review. Cox's proportional hazard model and logistic regression were applied to estimate the association with overall survival (OS), progression-free survival (PFS), and clinical benefit (CB). The possible lead-time bias was handled in extended Cox regression models. RESULTS: The median age of the cohort was 68. Over one-third (35%) of patients experienced an irAE, with skin being the most frequent organ involved (12.9%). Patients that experienced at least one irAE had significantly enhanced OS (HR: 0.38, 95% CI, 0.18-0.79, P = .009), PFS (HR: 0.27, 95% CI, 0.14-0.53, P < .001), and CB (OR: 4.20, 95% CI, 1.35-13.06, P = .013). Patients who experienced dermatologic irAEs also had significantly greater OS, PFS, and CB. CONCLUSION: Of patients with advanced UC that had undergone ICI therapy, those who had irAEs, especially dermatologic irAEs, had significantly greater OS, PFS, and CB. These results may suggest that irAE's may serve as an important marker of durable response to ICI therapy in urothelial cancer. The findings of this study need to be validated with larger cohort studies in the future.

Immune Checkpoint Therapy Combinations in Adult Advanced MiT Family Translocation Renal Cell Carcinomas.

BACKGROUND: There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC). METHODS: This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods. RESULTS: There were 29 patients identified with median age of 38 (21-70) years, and F:M ratio 0.9:1. FISH revealed TFE3 and TFEB translocations in 22 and 7 patients, respectively. Dual ICT and ICT + VEGF TT were used in 18 and 11 patients, respectively. Seventeen (59%) patients received ICT combinations as first-line therapy. ORR was 1/18 (5.5%) for dual ICT and 4/11 (36%) for ICT + VEGF TT. At a median follow-up of 12.9 months, median PFS was 2.8 and 5.4 months in the dual ICT and ICT + VEGF TT groups, respectively. Median OS from metastatic disease was 17.8 and 30.7 months in the dual ICT and ICT + VEGF TT groups, respectively. CONCLUSION: In this retrospective study of advanced tRCC, limited response and survival were seen after frontline dual ICT combination therapy, while ICT + VEGF TT therapy offered some efficacy. Due to the heterogeneity of tRCC, insights into the biological underpinnings are necessary to develop more effective therapies.

Baseline Neutrophil-to-Eosinophil Ratio Is Associated with Outcomes in Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Biomarkers have the potential to guide treatment selection and clinical care in metastatic renal cell carcinoma (mRCC) in an expanding treatment landscape. We report baseline neutrophil-to-eosinophil ratios (NER) in patients with mRCC treated with immune checkpoint inhibitors (CPIs) and their association with clinical outcomes. METHODS: We conducted a retrospective review of patients with mRCC treated with CPIs at Winship Cancer Institute from 2015 to 2020 in the United States of America (USA). Demographics, disease characteristics, and laboratory data, including complete blood counts (CBC) were described at the initiation of CPIs. Clinical outcomes were measured as overall survival (OS), progression-free survival (PFS), and clinical benefit (CB) associated with baseline lab values. RESULTS: A total of 184 patients were included with a median follow-up time of 25.4 months. Patients with baseline NER were categorized into high or low subgroups; high group was defined as NER >49.2 and low group was defined as NER <49.2 with 25% of patients in the high NER group. Univariate analyses (UVA) and multivariable analyses (MVA) identified decreased overall survival (OS) associated with elevated NER. In MVA, patients with a high baseline NER group had a hazard ratio (HR) of 1.68 (95%CI, 1.01-2.82, P = .048) for OS; however, there was no significant difference between groups for PFS. Clinical benefit was seen in 47.3% of patients with low baseline NER and 40% with high NER. CONCLUSIONS: We conclude that elevated baseline NER may be associated with worse clinical outcomes in mRCC. Although results require further validation, NER is a feasible biomarker in patients with CPI-treated mRCC.

CD8+ T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor.

Improvements in tumor immunotherapies depend on better understanding of the anti-tumor T cell response. By studying human tumor-draining lymph nodes (TDLNs), we found that activated CD8+ T cells in TDLNs shared functional, transcriptional, and epigenetic traits with TCF1+ stem-like cells in the tumor. The phenotype and TCR overlap suggested that these TDLN cells were precursors to tumor-resident stem-like CD8+ T cells. Murine tumor models revealed that tumor-specific CD8+ T cells were activated in TDLNs but lacked an effector phenotype. These stem-like cells migrated into the tumor, where additional co-stimulation from antigen-presenting cells drove effector differentiation. This model of CD8+ T cell activation in response to cancer is different from that of canonical CD8+ T cell activation to acute viruses, and it proposes two stages of tumor-specific CD8+ T cell activation: initial activation in TDLNs and subsequent effector program acquisition within the tumor after additional co-stimulation.

Prognostic Value of Sarcopenia and Albumin in the Surgical Management of Localized Renal Cell Carcinoma.

INTRODUCTION: A universally accepted model for preoperative surgical risk stratification in localized RCC patients undergoing nephrectomy is currently lacking. Both the evaluation of body composition and nutritional status has demonstrated prognostic value for patients with cancer. This study aims to investigate the potential associations between sarcopenia and hypoalbuminemia and survival outcomes in patients with localized kidney cancer treated with partial or radical nephrectomy. MATERIALS AND METHODS: We retrospectively analyzed 473 patients with localized RCC managed with radical and partial nephrectomy. Skeletal muscle index (SMI) was measured from preoperative CT and MRI. Sarcopenic criteria were created using BMI- and sex-stratified thresholds. Relationships between sarcopenia and hypoalbuminemia (Albumin <3.5 g/dL) with overall (OS), recurrence-free (RFS), and cancer-specific survival (CSS) were determined using multivariable and Kaplan-Meier analysis. RESULTS: Of the 473 patients, 42.5% were sarcopenic and 24.5% had hypoalbuminemia. Sarcopenia was significantly associated with shorter OS (HR=1.51, 95% CI 1.07-2.13), however, was nonsignificant in the RFS (HR = 1.33, 95% CI 0.88-2.03) and CSS (HR=1.66, 95% CI 0.96-2.87) models. Hypoalbuminemia predicted shorter OS (HR=1.76, 95% CI 1.22-2.55), RFS (HR=1.86, 95% CI 1.19-2.89), and CSS (HR=1.82, 95% CI 1.03-3.22). Patients were then stratified into low, medium, and high-risk groups based on the severity of sarcopenia and hypoalbuminemia. Risk groups demonstrated an increasing association with shorter OS (all p<0.05). Reduced RFS was observed in the medium risk-hypoalbuminemia (HR=2.18, 95% CI 1.16-4.09) and high-risk groups (HR=2.42, 95% CI 1.34-4.39). Shorter CSS was observed in the medium risk-hypoalbuminemia (HR=2.31, 95% CI 1.00-5.30) and high-risk groups (HR=2.98, 95% CI 1.34-6.61). CONCLUSION: Localized RCC patients with combined preoperative sarcopenia and hypoalbuminemia displayed a two to a three-fold reduction in OS, RFS, and CSS after nephrectomy. These data have implications for guiding prognostication and treatment election in localized RCC patients undergoing extirpative surgery.

Challenges and opportunities in the management of non-urothelial bladder cancers.

Urothelial carcinoma accounts for approximately 90% of all bladder cancer diagnoses. Localized, muscle-invasive disease is often managed with a multidisciplinary approach including either neoadjuvant chemotherapy (NAC) followed by radical cystectomy or concurrent chemoradiation, whereas multiple immunotherapies and novel antibody drug conjugates have recently joined platinum-based chemotherapy as standard of care therapy for metastatic disease. However, the clinical trials leading to these standards often require majority if not complete urothelial histology for eligibility. As many as one quarter of patients diagnosed with bladder cancer will have either divergent differentiation of their urothelial carcinoma or an alternate epithelial tumor such as squamous cell carcinoma, adenocarcinoma, or small cell carcinoma; even more rare are non-epithelial tumors such as sarcoma. The rarity of these diseases and their general exclusion from treatment within prospective clinical trials has created a challenging situation where treatment plans are often derived from case series or extrapolated from other disease types and outcomes are poor compared to pure urothelial carcinoma. In this review, we summarize the existing data on the diagnosis and treatment of epithelial, non-urothelial bladder cancers including adenocarcinoma, squamous cell carcinoma, and small cell carcinoma in their localized and advances stages. We will also review the current clinical trial landscape investigating novel approaches to these diseases.

Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer.

PURPOSE: Cisplatin-based combination chemotherapy remains the standard of care for locally advanced or metastatic urothelial cancer (la/mUC); however, toxicity is substantial, responses are rarely durable, and many patients with la/mUC are ineligible. Each enfortumab vedotin and pembrolizumab have shown a survival benefit versus chemotherapy in UC, are not restricted by cisplatin eligibility, and warrant investigation as a first-line (1L) combination therapy in patients ineligible for cisplatin. METHODS: In this ongoing phase Ib/II, multicenter, open-label study, 1L cisplatin-ineligible patients with la/mUC received enfortumab vedotin 1.25 mg/kg once daily on days 1 and 8 and pembrolizumab 200 mg (day 1) intravenously once daily in 3-week cycles. The primary end point was safety. Key secondary end points included confirmed objective response rate, duration of response (DOR), and overall survival (OS). RESULTS: Forty-five patients received enfortumab vedotin plus pembrolizumab. The most common treatment-related adverse events (TRAEs) were peripheral sensory neuropathy (55.6%), fatigue (51.1%), and alopecia (48.9%). Twenty-nine patients (64.4%) had grade 3 or higher TRAEs; the most common were increased lipase (17.8%), maculopapular rash (11.1%), and fatigue (11.1%). One death (2.2%) was classified as a TRAE. The confirmed objective response rate after a median of nine cycles was 73.3% with a complete response rate of 15.6%. The median DOR and median OS were 25.6 months and 26.1 months, respectively. CONCLUSION: Enfortumab vedotin plus pembrolizumab showed a manageable safety profile. Most patients experienced tumor shrinkage. The median DOR and median OS exceeding 2 years in a cisplatin-ineligible patient population make this a promising combination currently under investigation in a phase III study (ClinicalTrials.gov identifier: NCT04223856).

Prognostic Evaluation of Metastatic Castration Resistant Prostate Cancer and Neuroendocrine Prostate Cancer with [68Ga]Ga DOTATATE PET-CT.

Objectives: Prostate cancer is well known to express high levels of somatostatin receptors and preliminary data suggests that PET imaging with the somatostatin analog, [68Ga]Ga-DOTATATE, may allow for whole body staging of patients with metastatic castration resistant prostate cancer (mCRPC) and neuroendocrine prostate cancer (NePC). This study explores the utility of [68Ga]Ga-DOTATATE PET-CT to identify metastatic deposits in men with mCRPC and NePC and prognosticate disease progression. Methods: [68Ga]Ga-DOTATATE PET-CT was performed in 17 patients with mCRPC and of those, 2/17 had NePC. A semiquantitative analysis with standardized uptake values (SUV) (e.g., SUVmax, SUVmean) was performed for each metastatic lesion and reference background tissues. [68Ga]Ga-DOTATATE uptake in metastatic deposits was further classified as: mild (less than liver), moderate (up to liver average), or marked (greater than liver). Serial prostate-specific antigen measurements and patient survival were followed up to 3 years after PET imaging to assess response to standard of care treatment. Results: All patients had at least one metastatic lesion with identifiable [68Ga]Ga-DOTATATE uptake. Marked [68Ga]Ga-DOTATATE uptake was found in 7/17 patients, including both NePC patients, and all were non-responders to systemic therapy and died within the follow up period, with a mean time to death of 8.1 months. Three patients had mild [68Ga]Ga-DOTATATE uptake, and all were responders to systemic therapy and were alive 36 months after [68Ga]Ga-DOTATATE imaging. Conclusions: [68Ga]Ga-DOTATATE is able to identify mCRPC and NePC metastatic deposits, and lesions with [68Ga]Ga-DOTATATE uptake > liver may portend poor outcomes in patients with mCRPC.

Durable complete response for oligometastatic renal cell carcinoma with immune checkpoint inhibition and cytoreductive nephrectomy in a Jehovah's witness: A case report.

The role of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma is a subject of debate. We report a durable complete response in a 62-year-old man Jehovah's Witness with metastatic clear cell renal cell carcinoma who received two cycles of nivolumab/ipilimumab followed by radical nephrectomy and metastasectomy of known pulmonary disease site, both without a clinical need for perioperative blood transfusions. The patient continues to be without evidence of disease and without additional need for systemic therapy over a year after his radical nephrectomy. The case highlights that cytoreductive nephrectomy continues to play a role in the era of immune checkpoint inhibitors.

Data regarding covariates significantly associated with sarcopenia and varying albumin statuses in patients with renal cell carcinoma.

Poor functional, nutritional, and muscle status is a significant negative predictor for surgical and survival outcomes in patients with cancer, including renal cell carcinoma. This dataset displays results from preoperative muscle composition analysis and albumin levels in a large cohort (n = 473) of patients undergoing surgery for renal cell carcinoma. Data was obtained from retrospective review of prospectively maintained databases and retrospective image analysis. The optimal cut-point for skeletal muscle index (sarcopenia) was determined by a receiver operatic characteristic analysis to optimally stratify cohort, adjusting for BMI and sex. A threshold value of 3.5 g/dL was used to categorize normal versus low serum albumin. Patients were stratified into low risk (non-sarcopenic and normal albumin), medium risk (non-sarcopenic and low albumin, or sarcopenic and normal albumin), and high risk (sarcopenic and low albumin) groups. This data could potentially be used in future studies to determine other relationships between nutrition and musculature in renal cell carcinoma patients.

Combination Immune Checkpoint Blockade Regimens for Previously Untreated Metastatic Renal Cell Carcinoma: The Winship Cancer Institute of Emory University Experience.

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.