PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal influenza vaccine.

Anti-programmed death-1 (anti-PD-1) immunotherapy reinvigorates CD8 T cell responses in patients with cancer but PD-1 is also expressed by other immune cells, including follicular helper CD4 T cells (Tfh) which are involved in germinal centre responses. Little is known, however, about the effects of anti-PD-1 immunotherapy on noncancer immune responses in humans. To investigate this question, we examined the impact of anti-PD-1 immunotherapy on the Tfh-B cell axis responding to unrelated viral antigens. Following influenza vaccination, a subset of adults receiving anti-PD-1 had more robust circulating Tfh responses than adults not receiving immunotherapy. PD-1 pathway blockade resulted in transcriptional signatures of increased cellular proliferation in circulating Tfh and responding B cells compared with controls. These latter observations suggest an underlying change in the Tfh-B cell and germinal centre axis in a subset of immunotherapy patients. Together, these results demonstrate dynamic effects of anti-PD-1 therapy on influenza vaccine responses and highlight analytical vaccination as an approach that may reveal underlying immune predisposition to adverse events.

Genomic ancestry in kidney cancer: Correlations with clinical and molecular features.

INTRODUCTION: Genetic ancestry (GA) refers to population hereditary patterns that contribute to phenotypic differences seen among race/ethnicity groups, and differences among GA groups may highlight unique biological determinants that add to our understanding of health care disparities. METHODS: A retrospective review of patients with renal cell carcinoma (RCC) was performed and correlated GA with clinicopathologic, somatic, and germline molecular data. All patients underwent next-generation sequencing of normal and tumor DNA using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, and contribution of African (AFR), East Asian (EAS), European (EUR), Native American, and South Asian (SAS) ancestry was inferred through supervised ADMIXTURE. Molecular data was compared across GA groups by Fisher exact test and Kruskal-Wallis test. RESULTS: In 953 patients with RCC, the GA distribution was: EUR (78%), AFR (4.9%), EAS (2.5%), SAS (2%), Native American (0.2%), and Admixed (12.2%). GA distribution varied by tumor histology and international metastatic RCC database consortium disease risk status (intermediate-poor: EUR 58%, AFR 88%, EAS 74%, and SAS 73%). Pathogenic/likely pathogenic germline variants in cancer-predisposition genes varied (16% EUR, 23% AFR, 8% EAS, and 0% SAS), and most occurred in CHEK2 in EUR (3.1%) and FH in AFR (15.4%). In patients with clear cell RCC, somatic alteration incidence varied with significant enrichment in BAP1 alterations (EUR 17%, AFR 50%, SAS 29%; p = .01). Comparing AFR and EUR groups within The Cancer Genome Atlas, significant differences were identified in angiogenesis and inflammatory pathways. CONCLUSION: Differences in clinical and molecular data by GA highlight population-specific variations in patients with RCC. Exploration of both genetic and nongenetic variables remains critical to optimize efforts to overcome health-related disparities.

Prognostic Factors for Survival in Patients Undergoing Surveillance After Cytoreductive Nephrectomy.

PURPOSE: The clinical course of patients being placed on surveillance in a cohort of systemic therapy-naïve patients who undergo cytoreductive nephrectomy is not well documented. Thus, we evaluated the clinical course of patients placed on surveillance following cytoreductive nephrectomy and identified predictors of survival. MATERIALS AND METHODS: In this large single-institution study, we retrospectively analyzed metastatic renal cell carcinoma patients who underwent cytoreductive nephrectomy followed by surveillance. Predictors of survival were evaluated using the Kaplan-Meier method with a log-rank test. Patients were risk stratified based on IMDC (International mRCC Database Consortium) and number of metastatic sites (Rini score), with IMDC score ≤1 and ≤2 metastatic organ sites considered favorable risk. Primary end point was systemic therapy-free survival. Secondary end points included intervention-free survival, cancer-specific survival, and overall survival. RESULTS: Median systemic therapy-free survival was 23.6 months (95% CI: 15.1-40.6), intervention-free survival was 11.8 months (95% CI: 8.0-18.4), cancer-specific survival was 54.2 months (95% CI: 46.2-71.4), and overall survival 52.4 months (95% CI: 40.3-66.8). Favorable-risk patients compared to unfavorable-risk patients had longer systemic therapy-free survival (50.6 vs 11.1 months, P < .01), survival (25.2 vs 7.3, P < .01), and cancer-specific survival (71.4 vs 46.2 months, P = .02). CONCLUSIONS: Using risk stratification based on IMDC and number of metastatic sites, surveillance in favorable-risk patients can be utilized for a period without the initiation of systemic therapy. This approach can delay patients' exposure to the side effects of systemic therapy.

Relationship between insurance status and interhospital transfers among cancer patients in the United States.

BACKGROUND: The relationship between insurance status and interhospital transfers has not been adequately researched among cancer patients. Hence this study aimed for understanding this relationship using a nationally representative database. METHODS: A retrospective analysis was conducted using National Inpatient Sample (NIS) data collected during 2010-2016 and included all cancer hospitalization between 18 and 64 years of age. Interhospital transfers were compared based on insurance status (Medicare, Medicaid, private, and uninsured). Weighted multivariable logistic regressions were used to calculate the odds of interhospital transfers based on insurance status, after adjusting for many covariates. RESULTS: There were 3,580,908 weighted cancer hospitalizations, of which 72,353 (2.02%) had interhospital transfers. Uninsured patients had significantly higher rates of interhospital transfers, compared to those with Medicare (P = 0.005) and private insurance (P < 0.001). Privately insured patients had significantly lower rates of interhospital transfers, compared to those with Medicare (P < 0.001) and Medicaid (P < 0.001). Logistic regression analyses showed that the odds of having interhospital transfers were significantly higher among uninsured (adjusted odds ratio [aOR], 1.57, 95% CI: 1.45-1.69), Medicare (aOR, 1.38, 95% CI: 1.32-1.45) and Medicaid (aOR, 1.23, 95% CI: 1.16-1.30) patients when compared to those with private insurance coverages. CONCLUSION: Among cancer patients, uninsured and Medicare and Medicaid beneficiaries were more likely to experience interhospital transfers. In addition to medical reasons, factors such as affordability and socioeconomic status are influencing interhospital transfer decisions, indicating existing healthcare disparities. Further studies should focus on identifying the causal associations between factors explored in this study as well as additional unexplored factors.

Evolving biological associations of upfront cytoreductive nephrectomy in metastatic renal cell carcinoma.

BACKGROUND: Systemic responses to cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) are variable and difficult to anticipate. The authors aimed to determine the association of CN with modifiable International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors and oncological outcomes. METHODS: Consecutive patients with mRCC referred for potential CN (2009-2019) were reviewed. The primary outcome was overall survival (OS); variables of interest included undergoing CN and the baseline number of modifiable IMDC risk factors (anemia, hypercalcemia, neutrophilia, thrombocytosis, and reduced performance status). For operative cases, the authors evaluated the effects of IMDC risk factor dynamics, measured 6 weeks and 6 months after CN, on OS and postoperative treatment disposition. RESULTS: Of 245 treatment-naive patients with mRCC referred for CN, 177 (72%) proceeded to surgery. The CN cases had fewer modifiable IMDC risk factors (P = .003), including none in 71 of 177 patients (40.1%); fewer metastases (P = .011); and higher proportions of clear cell histology (P = .012). In a multivariable analysis, surgical selection, number of IMDC risk factors, metastatic focality, and histology were associated with OS. Total risk factors changed for 53.8% and 57.2% of the patients from the preoperative period to 6 weeks and 6 months after CN, respectively. Adjusted for preoperative IMDC risk scores, an increase in IMDC risk factors at 6 weeks and 6 months was associated with adverse OS (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.13-2.19; P = .007; HR, 2.52; 95% CI, 1.74-3.65; P < .001). CONCLUSIONS: IMDC risk factors are dynamic clinical variables that can improve after upfront CN in select patients, and this suggests a systemic benefit of cytoreduction, which may confer clinically meaningful prognostic implications.

Combined haploidentical and cord blood transplantation for refractory severe aplastic anaemia and hypoplastic myelodysplastic syndrome.

Umbilical cord blood (UCB) transplantation is a potentially curative treatment for patients with refractory severe aplastic anaemia (SAA), but has historically been associated with delayed engraftment and high graft failure and mortality rates. We conducted a prospective phase 2 trial to assess outcome of an allogeneic transplant regimen that co-infused a single UCB unit with CD34+ -selected cells from a haploidentical relative. Among 29 SAA patients [including 10 evolved to myelodysplastic syndrome (MDS)] who underwent the haplo cord transplantation (median age 20 years), 97% had neutrophil recovery (median 10 days), and 93% had platelet recovery (median 32 days). Early myeloid engraftment was from the haplo donor and was gradually replaced by durable engraftment from UCB in most patients. The cumulative incidences of grade II-IV acute and chronic graft-versus-host disease (GVHD) were 21% and 41%, respectively. With a median follow-up of 7·5 years, overall survival was 83% and GVHD/relapse-free survival was 69%. Patient- and transplant-related factors had no impact on engraftment and survival although transplants with haplo-versus-cord killer-cell immunoglobulin-like receptor (KIR) ligand incompatibility had delayed cord engraftment. Our study shows haplo cord transplantation is associated with excellent engraftment and long-term outcome, providing an alternative option for patients with refractory SAA and hypoplastic MDS who lack human leucocyte antigen (HLA)-matched donors.

Prognosis of Incidental Brain Metastases in Patients With Advanced Renal Cell Carcinoma.

BACKGROUND: Metastatic renal cell carcinoma (mRCC) management guidelines recommend brain imaging if clinically indicated and the rate of occult central nervous system (CNS) metastasis is not well-defined. Early detection could have major therapeutic implications, because timely interventions may limit morbidity and mortality. PATIENTS AND METHODS: A retrospective review was performed to characterize patients with mRCC incidentally diagnosed with asymptomatic brain metastases during screening for clinical trial participation at Gustave Roussy and Memorial Sloan Kettering Cancer Center. Descriptive statistics and time-to-event methods were used to evaluate the cohort. RESULTS: Across 68 clinical trials conducted between 2001 and 2019 with a median 14.1-month follow-up, 72 of 1,689 patients (4.3%) with mRCC harbored occult brain metastases. The International Metastatic RCC Database Consortium (IMDC) risk status was favorable (26%), intermediate (61%), and poor (13%), and 86% of patients had ≥2 extracranial sites of disease, including lung metastases in 92% of patients. CNS involvement was multifocal in 38.5% of patients, and the largest brain metastasis was >1 cm in diameter in 40% of the cohort. Localized brain-directed therapy was pursued in 93% of patients, predominantly radiotherapy. Median overall survival was 10.3 months (range, 7.0-17.9 months), and the 1-year overall survival probability was 48% (95% CI, 37%-62%). IMDC risk and number or size of lesions did not correlate with survival (log-rank, P=.3, P=.25, and P=.067, respectively). CONCLUSIONS: This large multi-institutional mRCC cohort study identified occult brain metastasis in a notable proportion of patients (4.3%) and highlights that the risk of asymptomatic CNS involvement extends to those with favorable risk features per IMDC risk assessment. These data provide rationale for brain screening in patients with advanced RCC.

A qualitative framework of non-selection factors for cytoreductive nephrectomy.

PURPOSE: Cytoreductive nephrectomy (CN) benefits a subset of patients with metastatic renal cell carcinoma (mRCC), however proper patient selection remains complex and controversial. We aim to characterize urologists' reasons for not undertaking a CN at a quaternary cancer center. METHODS: Consecutive patients with mRCC referred to MSKCC urologists for consideration of CN between 2009 and 2019 were included. Baseline clinicopathologic characteristics were used to compare patients selected or rejected for CN. The reasons cited for not operating and the alternative management strategies recommended were extrapolated. Using an iterative thematic analysis, a framework of reasons for rejecting CN was designed. Kaplan-Meier estimates tested for associations between the reasons for not undertaking a CN and overall survival (OS). RESULTS: Of 297 patients with biopsy-proven mRCC, 217 (73%) underwent CN and 80 (27%) did not. Median follow-up of patients alive at data cut-off was 27.3 months. Non-operative patients were older (p = 0.014), had more sites of metastases (p = 0.008), harbored non-clear cell histology (p = 0.014) and reduced performance status (p < 0.001). The framework comprised seven distinct themes for recommending non-operative management: two patient-fitness considerations and five oncological considerations. These considerations were associated with OS; four of the oncological factors conferred a median OS of less than 12 months (p < 0.001). CONCLUSION: We developed a framework of criteria by which patients were deemed unsuitable candidates for CN. These new insights provide a novel perspective on surgical selection, could potentially be applicable to other malignancies and possibly have prognostic implications.

Immune checkpoint blockade in renal cell carcinoma.

Immune checkpoint blockade (ICB) is the foundation of current first-line therapies in patients with metastatic renal cell carcinoma (mRCC) with the potential for eliciting long-lasting remissions. With the expanding arsenal of ICB-based therapies, biomarkers of response are urgently needed to guide optimal therapeutic selection. We review the data behind ICB therapy in RCC, emerging biomarkers of response, and the evolving role of surgery in patients with mRCC.

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.

Unbiased Pathogen Detection and Host Gene Profiling for Conjunctivitis.

PURPOSE: The etiology of conjunctivitis is often misdiagnosed. An ideal diagnostic test would identify all possible infectious causes. In this study, we apply unbiased metagenomic RNA deep sequencing (MDS) to identify pathogens causing conjunctivitis. DESIGN: Molecular study of prospectively collected conjunctival swabs from patients with presumed infectious conjunctivitis. PARTICIPANTS: Patients with presumed acute infectious conjunctivitis. METHODS: Conjunctival swabs were collected from patients presenting with acute conjunctivitis. Swabs were processed for MDS. Pathogens were identified using a rapid computational pipeline to analyze the nonhost sequences obtained from MDS. Differential gene expression analysis was performed to evaluate for host transcriptome signatures for infectious types. Clinical samples were deidentified, and laboratory personnel handling the samples and interpreting the data were masked. MAIN OUTCOME MEASURES: Pathogens and differential transcripts identified by MDS. RESULTS: Metagenomic RNA deep sequencing detected pathogens in 86% (12/14) of the patients tested. Swabs from 10 of 14 patients were positive for human adenovirus (HAdV) while swabs from 2 of 14 patients were positive for Vittaforma corneae (a parasitic fungal species of the microsporidia group). Samples positive for HAdV by RNA-seq were independently verified in a CLIA-certified laboratory. Pathogen-directed polymerase chain reaction confirmed the presence of V. corneae genome in the samples positive by RNA-seq. Local host transcriptome analysis identified 12 differentially expressed genes that provided distinct expression signatures for patients infected with HAdV compared with V. corneae. CONCLUSIONS: Metagenomic RNA deep sequencing can reliably detect and quantify common and rare pathogens causing conjunctivitis, and identify strains. The unbiased nature of metagenomic RNA deep sequencing allowed an expanded scope of pathogen detection, including fungal species not commonly associated with acute conjunctivitis. In addition, the identification of infection type-specific local host transcriptome signatures may allow for pathogen detection even when the pathogen load is too low for direct identification.

Surgical Outcomes and Genomic Insights of Nonclear Cell Renal Cell Carcinoma with Synchronous and Metachronous Nodal Disease.

INTRODUCTION: Oncological outcomes in patients with nonclear cell renal cell carcinoma (non-ccRCC) treated with surgery for locoregional nodal disease (ND) remain incompletely characterized. The objective was to investigate the characteristics and outcomes of non-ccRCC patients treated with lymph node dissection (LND) and salvage-LND (S-LND). METHODS: A total of 1627 patients underwent nephrectomy for nonmetastatic non-ccRCC at Memorial Sloan Kettering Cancer Center between 2007 and 2023. Histology was grouped as papillary, chromophobe, unclassified, and rare subtypes. Retrospective evaluation identified 2.5% (n = 40) of patients with nodal disease at time of nephrectomy (synchronous-ND) and 1.1% (n = 18) with metachronous nodal disease limited to the retroperitoneum (metachronous-ND). Patients' demographics and tumor characteristics were recorded and evaluated by univariate and multivariate cox regression models. Recurrence-free survival (RFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Patients who underwent tumor DNA sequencing during their clinical course were considered for genomic analysis. RESULTS: OS trended toward longer in metachronous-ND (51 vs 105 months; P = .2), though 23% of patients with synchronous-ND were recurrence-free at 45 months median follow-up. In multivariate analysis, rare histologies were associated with decreased OS (P = .030) and metachronous-ND with improved OS (P = .036). RFS and OS after S-LND was 15 and 96 months, respectively. Late onset of metachronous-ND/recurrence was associated with improved OS (P = .008). Genetic alterations in SETD2, TP53, B2M, and FGFR3 were exclusively seen in synchronous-ND, and tumor mutation burden (TMB) was also higher in patients with synchronous-ND (P = .016). CONCLUSIONS: Patients with metachronous-ND tend to have prolonged OS compared to synchronous-ND, but a substantial portion of patients with synchronous-ND still enter a durable disease-free state following LND. S-LND can likewise provide long-term survival, particularly in patients with longer time to metachronous nodal recurrence. Synchronous-ND was associated with SETD2, TP53, and NF2 alteration as well as higher TMB.

Surgical outcomes of cytoreductive nephrectomy in patients receiving systemic immunotherapy for advanced renal cell carcinoma.

PURPOSE: The use of systemic immune checkpoint blockade before surgery is increasing in patients with metastatic renal cell carcinoma, however, the safety and feasibility of performing consolidative cytoreductive nephrectomy after the administration of systemic therapy are not well described. PATIENTS AND METHODS: A retrospective review of patients undergoing nephrectomy was performed using our prospectively maintained institutional database. Patients who received preoperative systemic immunotherapy were identified, and the risk of postoperative complications were compared to those who underwent surgery without upfront systemic treatment. Perioperative characteristics and surgical complications within 90 days following surgery were recorded. RESULTS: Overall, we identified 220 patients who underwent cytoreductive nephrectomy from April 2015 to December 2022, of which 46 patients (21%) received systemic therapy before undergoing surgery. Unadjusted rates of surgical complications included 20% (n = 35) in patients who did not receive upfront systemic therapy and 20% (n = 9) in those who received upfront systemic immunotherapy. In our propensity score analysis, there was no statistically significant association between receipt of upfront immunotherapy and 90-day surgical complications [odds ratio (OR): 1.82, 95% confidence interval (CI): 0.59-5.14; P = 0.3]. This model, however, demonstrated an association between receipt of upfront immunotherapy and an increased odds of requiring a blood transfusion [OR: 4.53, 95% CI: 1.83-11.7; P = 0.001]. CONCLUSION: In our cohort, there was no significant difference in surgical complications among patients who received systemic therapy before surgery compared to those who did not receive upfront systemic therapy. Cytoreductive nephrectomy is safe and with low rates of complications following the use of systemic therapy.

Cabozantinib Plus Nivolumab in Patients with Non-Clear Cell Renal Cell Carcinoma: Updated Results from a Phase 2 Trial.

Treatment options are limited for patients with non-clear cell renal cell carcinoma (nccRCC). Patients with nccRCC experienced a favorable objective response rate (ORR) in a phase 2 trial of cabozantinib plus nivolumab. We now report updated efficacy and safety results at median follow-up of 34 mo for patients with papillary, unclassified, or translocation-associated RCC. Cabozantinib and nivolumab were administered at standard doses to patients with metastatic nccRCC that had progressed on zero or one line of systemic therapy. The primary endpoint was the ORR according to Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events. Forty patients were treated. At median follow-up of 34 mo for survivors, the ORR was 48% (95% confidence interval [CI] 31.5-63.9%). Median PFS was 13 mo (95% CI 7-16); the 12-mo and 24-mo PFS rates were 51% (95% CI 34-65%) and 23% (95% CI 11-37%), respectively. Median OS was 28 mo (95% CI 23-43); the 18-mo and 36-mo OS rates were 70% (95% CI 53-82%) and 44% (95% CI 28-60%), respectively. No new safety signals were seen with cabozantinib and nivolumab. This extended follow-up analysis demonstrates promising efficacy, and highlights the potential for sustained responses with cabozantinib plus nivolumab in patients with metastatic nccRCC. PATIENT SUMMARY: We evaluated outcomes for patients with metastatic kidney cancer of the non-clear cell (NCC) type who were treated with cabozantinib + nivolumab. We found that 48% of the patients responded to the treatment, and there were no unexpected side effects. Among patients who responded to the treatment, the response lasted for a median of 17 months. We conclude that cabozantinib + nivolumab is a safe and effective treatment for NCC kidney cancer.

Progression-free Survival After Second Line of Therapy for Metastatic Clear Cell Renal Cell Carcinoma in Patients Treated with First-line Immunotherapy Combinations.

Immunotherapy (IO)-based combinations used to treat metastatic clear cell renal cell carcinoma (ccRCC) include dual immune checkpoint inhibition with ipilimumab and nivolumab (IO/IO) and several combinations of vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitors (TKIs) with an immune checkpoint inhibitor (TKI/IO). IO/IO and TKI/IO approaches have not been compared directly, and it is unknown whether patients who do not respond to first-line IO/IO can salvage long-term survival by receiving a second-line TKI. Progression-free survival after second-line therapy (PFS-2) evaluates the ability to be salvaged by second-line therapy. We retrospectively evaluated 173 patients treated with first-line IO/IO or TKI/IO for metastatic ccRCC at Memorial Sloan Kettering Cancer Center and report PFS-2, overall survival, and response to second line of therapy (ORR2nd) for groups defined by first-line category. Although ORR2nd was significantly higher with IO/IO than with TKI/IO (47% vs 13%, p < 0.001), there was no significant difference in median PFS-2 for TKI/IO versus IO/IO (44 vs 23 mo, log-rank p = 0.1) or restricted mean survival time (RMST) for PFS-2 when adjusted for propensity score (33 vs 30 mo; difference 2.6 mo [95% confidence interval {CI}: -2.6, 7.9]; p = 0.3). There was also no significant difference in RMST for overall survival when adjusted for propensity score (38 vs 37 mo; group difference 1.0 mo [95% CI: -3.4, 5.5]; p = 0.7). These findings do not support a change in current utilization practices for IO/IO and TKI/IO treatment strategies for ccRCC. PATIENT SUMMARY: In cases of metastatic clear cell renal cell carcinoma, no significant difference was observed in progression-free survival after second line of therapy between patients receiving ipilimumab plus nivolumab and those receiving a combination of a tyrosine kinase inhibitor and an immune checkpoint inhibitor.

A Phase 2 Trial of Talazoparib and Avelumab in Genomically Defined Metastatic Kidney Cancer.

BACKGROUND: Although different kidney cancers represent a heterogeneous group of malignancies, multiple subtypes including Von Hippel-Lindau (VHL)-altered clear cell renal cell carcinoma (ccRCC), fumarate hydratase (FH)- and succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC), and renal medullary carcinoma (RMC) are affected by genomic instability. Synthetic lethality with poly ADP-ribose polymerase inhibitors (PARPis) has been suggested in preclinical models of these subtypes, and paired PARPis with immune checkpoint blockade (ICB) may achieve additive and/or synergistic effects in patients with previously treated advanced kidney cancers. OBJECTIVE: To evaluate combined PARPi + ICB in treatment-refractory metastatic kidney cancer. DESIGN, SETTING, AND PARTICIPANTS: We conducted a single-center, investigator-initiated phase 2 trial in two genomically selected advanced kidney cancer cohorts: (1) VHL-altered RCC with at least one prior ICB agent and one vascular endothelial growth factor (VEGF) inhibitor, and (2) FH- or SDH-deficient RCC with at least one prior ICB agent or VEGF inhibitor and RMC with at least one prior line of chemotherapy. INTERVENTION: Patients received talazoparib 1 mg daily plus avelumab 800 mg intravenously every 14 d in 28-d cycles. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was objective response rate (ORR) by Immune Response Evaluation Criteria in Solid Tumors at 4 mo, and the secondary endpoints included progression-free survival (PFS), overall survival, and safety. RESULTS AND LIMITATIONS: Cohort 1 consisted of ten patients with VHL-altered ccRCC. All patients had previously received ICB. The ORR was 0/9 patients; one patient was not evaluable due to missed doses. In this cohort, seven patients achieved stable disease (SD) as the best response. The median PFS was 3.5 mo (95% confidence interval [CI] 1.0, 3.9 mo). Cohort 2 consisted of eight patients; four had FH-deficient RCC, one had SDH-deficient RCC, and three had RMC. In this cohort, six patients had previously received ICB. The ORR was 0/8 patients; two patients achieved SD as the best response and the median PFS was 1.2 mo (95% CI 0.4, 2.9 mo). The most common treatment-related adverse events of all grades were fatigue (61%), anemia (28%), nausea (22%), and headache (22%). There were seven grade 3-4 and no grade 5 events. CONCLUSIONS: The first clinical study of combination PARPi and ICB therapy in advanced kidney cancer did not show clinical benefit in multiple genomically defined metastatic RCC cohorts or RMC. PATIENT SUMMARY: We conducted a study to look at the effect of two medications, talazoparib and avelumab, in patients with metastatic kidney cancer who had disease progression on standard treatment. Talazoparib blocks the normal activity of molecules called poly ADP-ribose polymerase, which then prevents tumor cells from repairing themselves and growing, while avelumab helps the immune system recognize and kill cancer cells. We found that the combination of these agents was safe but not effective in specific types of kidney cancer.

Cytoreductive Nephrectomy for Patients with Metastatic Sarcomatoid and/or Rhabdoid Renal Cell Carcinoma Treated with Immune Checkpoint Therapy.

BACKGROUND: Renal cell carcinoma (RCC) with sarcomatoid and/or rhabdoid (S/R) dedifferentiation is a highly aggressive tumor with a poor prognosis. Immune checkpoint therapy (ICT) has shown significant treatment efficacy in this subtype. There remains uncertainly regarding the role of cytoreductive nephrectomy (CN) for patients with metastatic RCC (mRCC) with S/R who received ICT. OBJECTIVE: Here, we report the outcomes with ICT for patients with mRCC and S/R dedifferentiation by CN status. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review was conducted of 157 patients with sarcomatoid, rhabdoid, or sarcomatoid plus rhabdoid dedifferentiation who received an ICT-based regimen at two cancer centers. INTERVENTION: CN performed at any time point; nephrectomy with curative intent was excluded. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: ICT treatment duration (TD) and overall survival (OS) from ICT initiation were recorded. To address the immortal time bias, a time-dependent Cox regression model was generated that accounted for confounders identified by a directed acyclic graph as well as a time-dependent nephrectomy variable. RESULTS AND LIMITATIONS: A total of 118 patients underwent CN, and of them, 89 underwent upfront CN. The results did not contradict the supposition that CN does not improve ICT TD (hazard ratio [HR] 0.98, 95% confidence interval [CI] 0.65-1.47, p = 0.94) or OS from ICT initiation (HR 0.79, 95% CI 0.47-1.33, p = 0.37). In patients who underwent upfront CN compared with those who did not undergo CN, there was no association with ICT duration or OS (HR 0.61, 95% CI 0.35-1.06, p = 0.08). A detailed clinical summary of 49 patients with mRCC and rhabdoid dedifferentiation is provided. CONCLUSIONS: In this multi-institutional cohort of mRCC with S/R dedifferentiation treated with ICT, CN was not significantly associated with improved TD or superior OS when accounting for the lead time bias. There appears to be a subset of patients who derive meaningful benefit from CN, so improved tools for stratification prior to CN are needed to optimize outcomes. PATIENT SUMMARY: Immunotherapy has improved outcomes for patients with metastatic renal cell carcinoma (mRCC) who have sarcomatoid and/or rhabdoid (S/R) dedifferentiation, which is an aggressive and uncommon feature; yet, the utility of a nephrectomy in this setting is unclear. We found that nephrectomy did not significantly improve survival or time on immunotherapy for these patients with mRCC and S/R dedifferentiation; yet, there may be a subset of patients who benefit from this surgical approach.

Immunometabolic coevolution defines unique microenvironmental niches in ccRCC.

Tumor cell phenotypes and anti-tumor immune responses are shaped by local metabolite availability, but intratumoral metabolite heterogeneity (IMH) and its phenotypic consequences remain poorly understood. To study IMH, we profiled tumor/normal regions from clear cell renal cell carcinoma (ccRCC) patients. A common pattern of IMH transcended all patients, characterized by correlated fluctuations in the abundance of metabolites and processes associated with ferroptosis. Analysis of intratumoral metabolite-RNA covariation revealed that the immune composition of the microenvironment, especially the abundance of myeloid cells, drove intratumoral metabolite variation. Motivated by the strength of RNA-metabolite covariation and the clinical significance of RNA biomarkers in ccRCC, we inferred metabolomic profiles from the RNA sequencing data of ccRCC patients enrolled in 7 clinical trials, and we ultimately identifyied metabolite biomarkers associated with response to anti-angiogenic agents. Local metabolic phenotypes, therefore, emerge in tandem with the immune microenvironment, influence ongoing tumor evolution, and are associated with therapeutic sensitivity.

Molecular Characterization of the Tumor Microenvironment in Renal Medullary Carcinoma.

Renal medullary carcinoma (RMC) is a highly aggressive disease associated with sickle hemoglobinopathies and universal loss of the tumor suppressor gene SMARCB1. RMC has a relatively low rate of incidence compared with other renal cell carcinomas (RCCs) that has hitherto made molecular profiling difficult. To probe this rare disease in detail we performed an in-depth characterization of the RMC tumor microenvironment using a combination of genomic, metabolic and single-cell RNA-sequencing experiments on tissue from a representative untreated RMC patient, complemented by retrospective analyses of archival tissue and existing published data. Our study of the tumor identifies a heterogenous population of malignant cell states originating from the thick ascending limb of the Loop of Henle within the renal medulla. Transformed RMC cells displayed the hallmarks of increased resistance to cell death by ferroptosis and proteotoxic stress driven by MYC-induced proliferative signals. Specifically, genomic characterization of RMC tumors provides substantiating evidence for the recently proposed dependence of SMARCB1-difficient cancers on proteostasis modulated by an intact CDKN2A-p53 pathway. We also provide evidence that increased cystine-mTORC-GPX4 signaling plays a role in protecting transformed RMC cells against ferroptosis. We further propose that RMC has an immune landscape comparable to that of untreated RCCs, including heterogenous expression of the immune ligand CD70 within a sub-population of tumor cells. The latter could provide an immune-modulatory role that serves as a viable candidate for therapeutic targeting.