Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study.

BACKGROUND: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. METHODS: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. FINDINGS: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. INTERPRETATION: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. FUNDING: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.

High-Grade, Nonsarcomatoid Chromophobe Renal Cell Carcinoma: A Series of 22 Cases With Novel Molecular Features on a Subset.

Chromophobe renal cell carcinoma (ChRCC) is the third most common subtype of renal cell carcinoma and typically exhibits indolent behavior, though a rare subset can exhibit high-grade morphologic features and is associated with a poor prognosis. Although there are limited data on the molecular characteristics of metastatic and sarcomatoid ChRCC, the molecular features of high-grade, nonsarcomatoid ChRCC remain unexplored. Herein, we characterize 22 cases of ChRCC with high-grade, nonsarcomatoid components. High-grade ChRCC frequently demonstrated advanced stage at diagnosis (64% ≥pT3a or N1), with regions of extrarenal extension, nodal metastases, and vascular invasion consisting solely of high-grade ChRCC morphologically. We performed spatially guided panel-based DNA sequencing on 11 cases comparing high-grade and low-grade regions (n = 22 samples). We identified recurring somatic alterations emblematic of ChRCC, including deletions of chromosomes 1, 2, 6, 10, 13, 17, and 21 in 91% (10/11) of cases and recurring mutations in TP53 (81.8%, n = 9/11) and PTEN (36.4%, n = 4/11). Notably, although PTEN and TP53 alterations were found in both high-grade and low-grade regions, private mutations were identified in 3 cases, indicating convergent evolution. Finally, we identified recurring RB1 mutations in 27% (n = 3) of high-grade regions leading to selective protein loss by immunohistochemistry not observed in adjacent low-grade regions. This finding was confirmed in The Cancer Genome Atlas cohort where 2 of 66 cases contained RB1 mutations and demonstrated unequivocal high-grade, nonsarcomatoid morphology. We also detected multiple chromosomal gains confined to the high-grade regions, consistent with imbalanced chromosome duplication. These findings broaden our understanding of the molecular pathogenesis of ChRCC and suggest that subclonal RB1 mutations can drive the evolution to high-grade, nonsarcomatoid ChRCC.

NCCN Guidelines® Insights: Kidney Cancer, Version 2.2024.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on the systemic therapy options for patients with advanced RCC and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Kidney Cancer.

Beyond the knife: strategic patient selection for cytoreductive nephrectomy.

PURPOSE OF REVIEW: To evaluate the current role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) within the context of evolving treatment paradigms, focusing on implications for patient selection. RECENT FINDINGS: Two randomized trials failed to show significant benefits from CN for intermediate and poor-risk patients undergoing targeted therapy. Despite this, subgroup analysis and retrospective data suggest potential benefits for a subset of good and intermediate-risk patients. Although currently used risk stratification tools guide CN eligibility, they have limitations, including, subjectivity, perioperative variability, and missing validation. Deferred CN may benefit patients responding to systemic treatment, whereas other patients may benefit from upfront CN. Emerging data supports the value of CN with immune checkpoint inhibitors (ICI) in selected patients, emphasizing the need for ongoing trials in the ICI era. SUMMARY: The role and timing of CN in mRCC have evolved across therapeutic eras. Although awaiting prospective evidence in the current era of ICI, CN still has a role in the therapeutic approach for a subset of patients. The decision to recommend CN must be personalized and involve multidisciplinary discussions considering both patient- and tumor-related factors.

Molecular differences in renal cell carcinoma between males and females.

PURPOSE: The disparity in renal cell carcinoma (RCC) risk and treatment outcome between males and females is well documented, but the underlying molecular mechanisms remain poorly elucidated. METHODS: We performed a narrative review synthesizing contemporary evidence on sex-specific molecular differences in healthy kidney tissue and RCC. RESULTS: In healthy kidney tissue, gene expression differs significantly between males and females, including autosomal and sex-chromosome-linked genes. The differences are most prominent for sex-chromosome-linked genes and attributable to Escape from X chromosome-linked inactivation and Y chromosome loss. The frequency distribution of RCC histologies varies between the sexes, particularly for papillary, chromophobe, and translocation RCC. In clear-cell and papillary RCC, sex-specific gene expressions are pronounced, and some of these genes are amenable to pharmacotherapy. However, for many, the impact on tumorigenesis remains poorly understood. In clear-cell RCC, molecular subtypes and gene expression pathways have distinct sex-specific trends, which also apply to the expression of genes implicated in tumor progression. CONCLUSION: Current evidence suggests meaningful genomic differences between male and female RCC, highlighting the need for sex-specific RCC research and personalized sex-specific treatment approaches.

Self-reported quality of life as a predictor of mortality in renal cell carcinoma.

BACKGROUND: This study evaluated the utility of self-reported quality of life (QOL) metrics in predicting mortality among all-comers with renal cell carcinoma (RCC) and externally tested the findings in a registry of patients with small renal masses. METHODS: The Surveillance, Epidemiology, and End Results-Medicare Health Outcomes Survey (SEER-MHOS) captured QOL metrics composed of mental component summary (MCS) and physical component summary (PCS) scores. Regression models assessed associations of MCS and PCS with all-cause, RCC-specific, and non-RCC-specific mortality. Harrell's concordance statistic (the C-index) and the Akaike information criterion (AIC) determined predictive accuracy and parsimony, respectively. Findings were tested in the prospective Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry. RESULTS: In SEER-MHOS, 1494 patients had a median age of 73.4 years and a median follow-up time of 5.6 years. Each additional MCS and PCS point reduced the hazard of all-cause mortality by 1.3% (95% CI, 0.981-0.993; P < .001) and 2.3% (95% CI, 0.971-0.984; P < .001), respectively. Models with QOL metrics demonstrated higher predictive accuracy (C-index, 72.3% vs 70.1%) and parsimony (AIC, 9376.5 vs 9454.5) than models without QOL metrics. QOL metrics exerted a greater effect on non-RCC-specific mortality than RCC-specific mortality. External testing in the DISSRM registry confirmed these findings with similar results for all-cause mortality. CONCLUSIONS: Models with self-reported QOL metrics predicted all-cause mortality in patients with RCC with higher accuracy and parsimony than those without QOL metrics. Physical health was a stronger predictor of mortality than mental health. The findings support the incorporation of QOL metrics into prognostic models and patient counseling for RCC.

Kidney Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Kidney Cancer focus on the screening, diagnosis, staging, treatment, and management of renal cell carcinoma (RCC). Patients with relapsed or stage IV RCC typically undergo surgery and/or receive systemic therapy. Tumor histology and risk stratification of patients is important in therapy selection. The NCCN Guidelines for Kidney Cancer stratify treatment recommendations by histology; recommendations for first-line treatment of ccRCC are also stratified by risk group. To further guide management of advanced RCC, the NCCN Kidney Cancer Panel has categorized all systemic kidney cancer therapy regimens as "Preferred," "Other Recommended Regimens," or "Useful in Certain Circumstances." This categorization provides guidance on treatment selection by considering the efficacy, safety, evidence, and other factors that play a role in treatment selection. These factors include pre-existing comorbidities, nature of the disease, and in some cases consideration of access to agents. This article summarizes surgical and systemic therapy recommendations for patients with relapsed or stage IV RCC.

Transcriptomic signatures related to the obesity paradox in patients with clear cell renal cell carcinoma: a cohort study.

BACKGROUND: Obesity is associated with an increased risk of developing clear cell renal cell carcinoma (RCC) but, paradoxically, obesity is also associated with improved oncological outcomes in this cancer. Because the biological mechanisms underlying this paradoxical association are poorly understood, we aimed to identify transcriptomic differences in primary tumour and peritumoral adipose tissue between obese patients and those at a normal weight. METHODS: In this cohort study, we assessed data from five independent clinical cohorts of patients with clear cell RCC aged 18 years and older. Overweight patients were excluded from each cohort for our analysis. We assessed patients from the COMPARZ phase 3 clinical trial, a cohort from the Cancer Genome Atlas (TCGA), and a Memorial Sloan Kettering (MSK) observational immunotherapy cohort for their inclusion into our study. We assessed overall survival in obese patients (those with a body-mass index [BMI] ≥30 kg/m2) and in patients with a normal weight (BMI 18·5-24·9 kg/m2, as per WHO's BMI categories), defined as the time from treatment initiation (in the COMPARZ and MSK immunotherapy cohorts) or surgery (in the TCGA cohort) to the date of any-cause death or of censoring on the day of the last follow-up. We also evaluated and validated transcriptomic differences in the primary tumours of obese patients compared with those of a normal weight. We compared gene-expression differences in peritumoral adipose tissue and tumour tissue in an additional, prospectively collected cohort of patients with non-metastatic clear cell RCC (the MSK peritumoral adipose tissue cohort). We analysed differences in gene expression between obese patients and those at a normal weight in the COMPARZ, TCGA, and peritumoral adipose tissue cohorts. We also assessed the tumour immune microenvironment in a prospective cohort of patients who had nephrectomy for localised RCC at MSK. FINDINGS: Of the 453 patients in the COMPARZ trial, 375 (83%) patients had available microarray data, pretreatment BMI measurements, and overall survival data for analyses, and we excluded 119 (26%) overweight patients, leaving a final cohort of 256 (68%) patients from this study for our analyses. From 332 patients in the TCGA cohort, we evaluated clinical and demographic data from 152 (46%) patients with advanced (ie, stages III and IV) clear cell RCC treated by nephrectomy; after exclusion of 59 (39%) overweight patients, our final cohort consisted of 93 (61%) patients. After exclusion of 74 (36%) overweight patients from the initial MSK immunotherapy study population of 203 participants, our final cohort for overall survival analysis comprised 129 (64%) participants. We found that overall survival was longer in obese patients than in those with normal weight in the TCGA cohort, after adjustment for stage or grade (adjusted HR 0·41, 95% CI 0·22-0·75), and in the COMPARZ clinical trial after adjustment for International Metastatic RCC Database (IMDC) risk score (0·68, 0·48-0·96). In the MSK immunotherapy cohort, the inverse association of BMI with mortality (HR 0·54, 95% CI 0·31-0·95) was not significant after adjustment for IMDC risk score (adjusted HR 0·72, 95% CI 0·40-1·30). Tumours of obese patients showed higher angiogenic scores on gene-set enrichment analysis-derived hallmark gene set angiogenesis signatures than did those of patients at a normal weight, but the degree of immune cell infiltration did not differ by BMI. We found increased peritumoral adipose tissue inflammation in obese patients relative to those at a normal weight, especially in peritumoral fat near the tumour. INTERPRETATION: We found aspects of the tumour microenvironment that vary by BMI in the tumour and peritumoral adipose tissue, which might contribute to the apparent survival advantage in obese patients with clear cell RCC compared with patients at a normal weight. The complex interplay between the clear cell RCC tumour and peritumoral adipose tissue microenvironment might have clinical relevance and warrants further investigation. FUNDING: Ruth L Kirschstein Research Service Award, American Society of Clinical Oncology Young Investigator Award, MSK's Ludwig Center, Weiss Family Kidney Research Fund, Novartis, The Sidney Kimmel Center for Prostate and Urologic Cancers, and the National Institutes of Health (National Cancer Institute) Cancer Center Support Grant.

Everolimus plus bevacizumab is an effective first-line treatment for patients with advanced papillary variant renal cell carcinoma: Final results from a phase II trial.

BACKGROUND: We previously reported on a phase 2 study of everolimus plus bevacizumab across various nonclear cell renal cell carcinoma (nccRCC) histologies and observed encouraging activity among patients with papillary RCC (pRCC) and unclassified RCC (uRCC) with a major papillary component. We subsequently expanded the study to enroll additional patients with pRCC variants. METHODS: Everolimus plus bevacizumab was administered at standard doses until disease progression or intolerance to therapy. The primary endpoint was the 6-month progression-free survival (PFS) rate; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Correlative analyses included next-generation sequencing (NGS) from tumor and germline across >341 genes of interest. RESULTS: In addition to 19 patients with pRCC variants in the original cohort, 20 patients with similar features were enrolled on the expansion cohort (uRCC with papillary features [n = 24], pRCC [n = 14], and translocation-associated RCC with papillary features [n = 1]). Among 37 evaluable patients, the 6-month PFS rate was 78%, the median PFS was 13.7 months (95% CI, 10.8-16.4 months), and the ORR was 35%. With a median follow-up of 17.6 months, the median OS was 33.9 months (95% CI, 23.3-71.9). Tolerance was consistent with prior reports for everolimus plus bevacizumab. NGS results (n = 33) identified responses in patients with a wide spectrum of genomic alterations, including ARID1A, FH, and MET mutations. CONCLUSION: The expansion cohort results confirm robust activity of everolimus plus bevacizumab in metastatic pRCC variants, supporting this regimen as a standard option for this patient population.

Systemic therapy for advanced clear cell renal cell carcinoma after discontinuation of immune-oncology and VEGF targeted therapy combinations.

BACKGROUND: Several phase 3 studies reported positive results for combinations of Immune-Oncology (IO) and Vascular Endothelial Growth Factor (VEGF) targeted therapies in patients with metastatic clear cell Renal Cell Carcinoma (ccRCC). However, there are limited data on outcomes to systemic therapy after IO-VEGF combinations. METHODS: A retrospective analysis was performed on patients with metastatic ccRCC treated at the Memorial Sloan Kettering Cancer Center and Cleveland Clinic who initiated systemic therapy post IO-VEGF including combinations with VEGF receptor (VEGFR) tyrosine kinase inhibitors (IO-TKI) and combinations with the anti-VEGF monoclonal antibody bevacizumab (IO-Bev). The study objectives were to evaluate the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) on systemic therapy post IO-VEGF. RECIST v1.1 criteria were used to determine radiological responses and progression. Survival estimates were evaluated with the Kaplan-Meier methods and the log-rank test from the start of systemic therapy post IO-VEGF to the event of interest. RESULTS: A total of fifty-nine patients were treated post discontinuation of IO-VEGF regimens which included IO-Bev (n = 35; 59%) and IO-TKI (n = 24; 41%). Fifty-eight patients (98%) received IO-VEGF regimens as part of a clinical trial. Subsequent therapies included cabozantinib (n = 22; 37%), axitinib (n = 18; 31%), pazopanib (n = 4; 7%), lenvatinib and everolimus (n = 4; 7%), mTOR inhibitor monotherapy (n = 3; 5%), axitinib and dalantercept (n = 2; 3%), sunitinib (n = 1; 2%), sorafenib (n = 1; 2%), and treatment with agents on unreported clinical trials (n = 4; 7%). Patients treated on unreported clinical trials were excluded from the efficacy analysis. Post IO-VEGF, the ORR was 25% and median PFS was 12.0 months (95% CI, 8.2-24.5). Median OS was 24.5 months (95% CI, 12-NE) and 12 months OS rate was 63.3% (95% CI, 48.6-74.9). We observed no differences post IO-VEGF OS when comparing IO- TKI vs IO-Bev (Log-rank p = 0.73). CONCLUSIONS: Post IO-VEGF, most patients received VEGFR-TKIs. In this setting, VEGFR-TKIs demonstrated clinical activity and remain a viable option for salvage therapy after progression on IO-VEGF.

Prognostic significance of pT3a staging subclassifications in renal cell carcinoma: Not all pT3a are equal.

OBJECTIVE: To examine the prognostic significance of perinephric fat, renal sinus fat, and renal vein invasion in patients with pT3a renal cell carcinoma (RCC) by histologic type. METHODS: A population-based retrospective cohort study of patients with pT3aN0M0 RCC was performed using Surveillance, Epidemiology, and End Results (SEER) data for the years 2010 through 2019. Cox proportional hazards models were used to examine the relationship between pT3a subclassification groups and cancer-specific survival (CSS) by histological subtype (clear cell, papillary, chromophobe, and other). RESULTS: The cohort consisted of 10,170 patients with pT3a RCC, including 8,446 (83.0%) with clear cell RCC and 1,724 (17.0%) with nonclear cell RCC (nccRCC). Median follow up was 36 months. Differences in CSS by pT3a subclassification groups were observed in all histological subtypes but were most pronounced in nccRCC, specifically papillary RCC. Compared to perinephric fat (PF) invasion only, renal vein (RV) invasion (HR = 4.9, 95%CI: 2.5-9.3, P < 0.01), renal sinus fat invasion (HR = 3.0, 95%CI: 1.4-6.2), RV and PF invasion (HR = 7.5, 95%CI: 3.5-16.0), and combination of all three characteristics (HR = 4.4, 95%CI: 1.2-15.5) were associated with worse CSS in patients with papillary RCC. CONCLUSION: We examined the prognostic role of pT3a staging subclassifications in RCC by histologic subtype and observed survival differences, particularly in papillary RCC. Our findings highlight the need to refine pT3a staging criteria to help guide individualized, multimodal treatment strategies for locally advanced RCC.

Survival outcomes and molecular drivers of testicular cancer in hispanic men.

OBJECTIVE: To examine survival outcomes and molecular drivers in testis cancer among Hispanic men using a large national sample and molecular database. METHODS: We reviewed the SEER registry for testicular cancer from 2000 to 2020. Cox proportional hazards models were used to examine the relationship between race/ethnicity and cancer-specific survival (CSS) by tumor type (seminoma vs. nonseminomatous germ cell tumors [NSGCT]). All models were adjusted for demographic, socioeconomic, and treatment variables. We accessed somatic mutations for testicular cancers through AACR Project GENIE v13.1 and compared mutational frequencies by ethnicity. RESULTS: Our cohort consisted of 43,709 patients (23.3% Hispanic) with median follow-up 106 months (interquartile range: 45-172). Compared to Non-Hispanic Whites (NWH), Hispanics presented at a younger age but with more advanced disease. Hispanics experienced worse CSS for NSGCT (HR 1.7, 95% CI: 1.5-2.0, P < 0.01) but not seminoma. Somatic mutation data was available for 699 patients. KIT and KRAS mutations occurred in 24.2% and 16.9% of seminoma patients (n = 178), respectively. TP53 and KRAS mutations occurred in 12.1% and 7.9% of NSGCT patients (n = 521), respectively. No differences in mutational frequencies were observed between ethnic groups. There was significant heterogeneity in primary ancestral group for Hispanic patients with available data (n = 53); 14 (26.4%) patients had primary Native American ancestry and 30 (56.6%) had primary European ancestry. CONCLUSIONS: Cancer-specific survival is worse for Hispanic men with non-seminoma of the testicle. Somatic mutation analysis suggests no differences by ethnicity, though genetic ancestry is heterogeneous among patients identifying as Hispanic.

Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma.

Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephrectomy for high-risk, non-metastatic clear cell renal cell carcinoma (ccRCC). We conducted a prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from that cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response. We found that nivolumab durably induces a pro-inflammatory state within the primary tumor, and baseline immune infiltration within the primary tumor correlates with nivolumab responsiveness. Nivolumab increases CTLA-4 expression in the primary tumor, and subsequent nephrectomy increases circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. These findings form the basis to consider neoadjuvant immune checkpoint inhibition (ICI) for high-risk ccRCC while the tumor remains in situ and provide the rationale for perioperative strategies of novel ICI combinations.

First-in-human Phase I Trial of TPST-1120, an Inhibitor of PPARα, as Monotherapy or in Combination with Nivolumab, in Patients with Advanced Solid Tumors.

PURPOSE: TPST-1120 is a first-in-class oral inhibitor of peroxisome proliferator-activated receptor α (PPARα), a fatty acid ligand-activated transcription factor that regulates genes involved in fatty acid oxidation, angiogenesis, and inflammation, and is a novel target for cancer therapy. TPST-1120 displayed antitumor activity in xenograft models and synergistic tumor reduction in syngeneic tumor models when combined with anti-PD-1 agents. EXPERIMENTAL DESIGN: This phase I, open-label, dose-escalation study (NCT03829436) evaluated TPST-1120 as monotherapy in patients with advanced solid tumors and in combination with nivolumab in patients with renal cell carcinoma (RCC), cholangiocarcinoma (CCA), or hepatocellular carcinoma. Objectives included evaluation of safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity (RECIST v1.1). RESULTS: A total of 39 patients enrolled with 38 treated (20 monotherapy, 18 combination; median 3 prior lines of therapy). The most common treatment-related adverse events (TRAE) were grade 1-2 nausea, fatigue, and diarrhea. No grade 4-5 TRAEs or dose-limiting toxicities were reported. In the monotherapy group, 53% (10/19) of evaluable patients had a best objective response of stable disease. In the combination group, 3 patients had partial responses, for an objective response rate of 20% (3/15) across all doses and 30% (3/10) at TPST-1120 ≥400 mg twice daily. Responses occurred in 2 patients with RCC, both of whom had previously progressed on anti-PD-1 therapy, and 1 patient with late-line CCA. CONCLUSIONS: TPST-1120 was well tolerated as monotherapy and in combination with nivolumab and the combination showed preliminary evidence of clinical activity in PD-1 inhibitor refractory and immune compromised cancers. SIGNIFICANCE: TPST-1120 is a first-in-class oral inhibitor of PPARα, whose roles in metabolic and immune regulation are implicated in tumor proliferation/survival and inhibition of anticancer immunity. This first-in-human study of TPST-1120 alone and in combination with nivolumab supports proof-of-concept of PPARα inhibition as a target of therapeutic intervention in solid tumors.

Kidney Cancer Updates from the 2023 American Society of Clinical Oncology Annual Meeting in Chicago.

This report highlights key research from the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, with a focus on clear cell renal cell carcinoma (ccRCC) and non-clear cell RCC (nccRCC) across clinical trials and translational studies. Essential updates in the metastatic ccRCC clinical space encompass results from the CONTACT-03 study, which evaluated an immunotherapy containing regimen for patients who progressed on an initial immunotherapy containing regimen, alongside updated results from the KEYNOTE-426 and CLEAR trials. In the metastatic nccRCC domain, we review clinical trials of combination immunotherapies and tyrosine kinase inhibitors (TKIs). Additionally, we highlight exciting early-phase studies exploring novel targets in RCC and engineered T-cell methodologies. Finally, we summarize notable efforts in translational research, emphasizing biomarker investigations to determine predictors of immunotherapy response, the application of molecular classifiers in RCC, and the relationship between the microbiome and RCC. There were many important RCC related abstracts presented at this year's ASCO conference, attesting to the continued momentum of research in the field. All conference materials, including abstracts and presentations, can be accessed online through the conference website.

Robotic-assisted cytoreductive partial nephrectomy for metastatic sarcomatoid renal cell carcinoma following dramatic response to combination immunotherapy in a young female.

Novel immune checkpoint inhibitors (ICI) have yielded remarkable response rates in metastatic renal cell carcinoma (RCC), including sarcomatoid RCC (sRCC). Here, we show the feasibility and efficacy of robotic-assisted cytoreductive partial nephrectomy (cPN) following a remarkable response to combination ICI for metastatic sRCC in a young female. A female in her late 40s presented with poor-risk, metastatic sRCC emanating from a 6.5 cm left renal mass including pulmonary involvement, retroperitoneal lymphadenopathy, and a scalp metastasis. She received 4 cycles of combination ipilimumab and nivolumab followed by maintenance nivolumab with a remarkable and durable response. Given the apparent downstaging of her primary tumor, a robotic cPN was pursued for residual ypT1aNoRo sRCC and found to be both feasible and safe with exceptional perioperative outcomes. She has since done well clinically and oncologically. Our unique case of metastatic sRCC in a young female highlights several aspects pertinent to the contemporary management of metastatic RCC including the role for cytoreductive nephrectomy in selected patients, the safety and feasibility of a nephron-sparing and minimally-invasive approach to cytoreduction after downstaging with ICI, and remarkable sensitivity of sRCC-a classically aggressive entity-to ICI.

Vascular Expression of Prostate-specific Membrane Antigen (PSMA) in MiTF Family Translocation Renal Cell Carcinoma and Related Neoplasms.

Multiple studies have demonstrated prostate-specific membrane antigen (PSMA) expression in the neo-vasculature of non-prostate tumors including clear cell renal cell carcinoma (ccRCC). However, PSMA expression in rare renal tumors including MiTF family translocation renal cell carcinoma has not been previously characterized. We examined PSMA expression by immunohistochemistry in a series of MiTF family translocation renal cell carcinomas as well as in several genetically related tumors including alveolar soft part sarcoma and PEComas with TFE3 rearrangements. PSMA expression was also studied in several cases of ccRCC and papillary RCC. Overall, PSMA immunohistochemistry was performed in 61 samples from 58 patients. Vascular PSMA expression was seen with the highest frequency in ccRCC [88% (14/16)] (38% focal, 50% diffuse). Translocation RCC (tRCC) demonstrated the second highest frequency of PSMA expression [71% (22/28)] (57% focal, 14% diffuse), followed by alveolar soft part sarcoma [50% (4/8)] (38% focal, 12% diffuse). No PSMA expression was seen in PEComas with TFE3 rearrangement (0/3) or papillary RCC (0/6). PSMA expression was only present in tumor-associated neo-vasculature. A patient with oligometastatic tRCC underwent 68 Ga-PSMA-11 PET imaging which detected multiple putative metastatic lesions not detected on conventional computed tomography imaging performed 2 weeks prior, supporting the potential utility of PSMA imaging in tRCC. These findings have potential implications for the utility of PSMA guided diagnostic and therapeutic agents in both common and uncommon renal cell carcinoma subtypes as well as genetically related mesenchymal neoplasms.

Socioeconomic determinants of racial disparities in survival outcomes among patients with renal cell carcinoma.

PURPOSE: Racially driven outcomes in cancer are challenging to study. Studies evaluating the impact of race in renal cell carcinoma (RCC) outcomes are inconsistent and unable to disentangle socioeconomic disparities from inherent biological differences. We therefore seek to investigate socioeconomic determinants of racial disparities with respect to overall survival (OS) when comparing Black and White patients with RCC. METHODS: We queried the National Cancer Database (NCDB) for patients diagnosed with RCC between 2004 and 2017 with complete clinicodemographic data. Patients were examined across various stages (all, cT1aN0M0, and cM1) and subtypes (all, clear cell, or papillary). We performed Cox proportional hazards regression with adjustment for socioeconomic and disease factors. RESULTS: There were 386,589 patients with RCC, of whom 46,507 (12.0%) were Black. Black patients were generally younger, had more comorbid conditions, less likely to be insured, in a lower income quartile, had lower rates of high school completion, were more likely to have papillary RCC histology, and more likely to be diagnosed at a lower stage of RCC than their white counterparts. By stage, Black patients demonstrated a 16% (any stage), 22.5% (small renal mass [SRM]), and 15% (metastatic) higher risk of mortality than White patients. Survival differences were also evident in histology-specific subanalyses. Socioeconomic factors played a larger role in predicting OS among patients with SRMs than in patients with metastasis. CONCLUSIONS: Black patients with RCC demonstrate worse survival outcomes compared to White patients across all stages. Socioeconomic disparities between races play a significant role in influencing survival in RCC.

Combinatorial biomarker for predicting outcomes to anti-PD-1 therapy in patients with metastatic clear cell renal cell carcinoma.

With a rapidly developing immunotherapeutic landscape for patients with metastatic clear cell renal cell carcinoma, biomarkers of efficacy are highly desirable to guide treatment strategy. Hematoxylin and eosin (H&E)-stained slides are inexpensive and widely available in pathology laboratories, including in resource-poor settings. Here, H&E scoring of tumor-infiltrating immune cells (TILplus) in pre-treatment tumor specimens using light microscopy is associated with improved overall survival (OS) in three independent cohorts of patients receiving immune checkpoint blockade. Necrosis score alone does not associate with OS; however, necrosis modifies the predictive effect of TILplus, a finding that has broad translational relevance for tissue-based biomarker development. PBRM1 mutational status is combined with H&E scores to further refine outcome predictions (OS, p = 0.007, and objective response, p = 0.04). These findings bring H&E assessment to the fore for biomarker development in future prospective, randomized trials, and emerging multi-omics classifiers.

Kidney Cancer Research Highlights from ASCO 2022 Annual Meeting.

The 2022 American Society of Clinical Oncology (ASCO) annual meeting was held June 3-7, 2022, in Chicago, Illinois. This hybrid meeting gathered international cancer experts across multidisciplinary specialties and was held both virtually and in-person. Here, we highlight key kidney cancer research updates presented at the meeting. Slides from the meeting's presentations are available on the ASCO meeting library website.