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Purpose: Combination systemic therapies (CSTs) of immuno-oncologic (IO) and VEGF-inhibiting agents (VEGFi) have become the standard of care for management of metastatic clear cell renal cell carcinoma (m-ccRCC). However, treatment outcomes vary between patients, with no established biomarkers to determine optimal CST regimens (IO/IO or IO/VEGFi). Prostate Specific Membrane Antigen (PSMA), encoded by the FOLH1 gene, is a marker of tumor neovasculature in ccRCC, the downstream target of VEGFi. We evaluated the relation between FOLH1 expression and angiogenesis, as well as clinical outcomes, in 5 m-ccRCC ST trials., Materials and Methods: using Spearman's rank correlation (SPRC) test, we assessed the correlation between FOLH1 expression and gene expression signature (GES) scores corresponding to angiogenic and immunologic features of the tumor microenvironment (TME) of m-ccRCC in our trial cohorts. Using Cox proportional hazard regression (Cox-PHR), we assessed the association between FOLH1 expression level, summarized by within-study quantiles (qFOLH1), and progression-free and overall survival (PFS, OS)., Results: Increased FOLH1 expression was significantly associated with higher TME angiogenesis GES scores (SPRC +0.5, P < 0.001), but did not consistently correlate with immune feature GES scores. Meta-analysis of PFS in the sunitinib TKI arm of trial cohorts showed an overall positive association with qFOLH1 (HR = 0.89; 95% CI = 0.85-0.94, P < 0.0001). qFOLH1 was not significantly associated with OS in the sunitinib arms of the two trials with OS data (COMPARZ, HR 0.87, 95% CI 0.71-1.07, P = 0.17; and Checkmate-214, HR 0.89, 95% CI 0.67-1.17, P = 0.70)., Conclusions: PSMA-encoding FOLH1 gene expression correlates with neoangiogenesis and predicts PFS in m-ccRCC patients treated with sunitinib TKI, suggesting that PSMA PET could be explored as a noninvasive biomarker for guiding CST choice (IO/IO or IO/VEGFi) as well as prediction of treatment response to VEGFi in m-ccRCC patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Sari Khaleel reports financial support was provided by National Cancer Institute. Ritesh Kotecha reports financial support was provided by US Office of Congressionally Directed Medical Research Programs. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Immunotherapy (ICIs) remains a mainstay for treatment of advanced clear-cell renal cell carcinoma (ccRCC). Biomarker analyses have demonstrated that gene expression profiles are associated with regimen-specific outcomes. These transcriptomic analyses used mixed sample cohorts (primary and metastatic tumor specimens) and it is unknown whether the clinical relevance of transcriptomic signatures is impacted by tissue site. We evaluated data for 1132 patients with metastatic ccRCC treated with ICI in prior studies (IMmotion151 and CheckMate-009, -010, and -025). We identified significant and reproducible differences in gene expression by tissue site. We tested the association between previously described molecular tissue clusters (MTCs) by tissue site (MTC1-primary and MTC1-metastasis) and progression-free survival (PFS) and objective response to systemic therapy. In IMmotion151, MTC2-metastasis was significantly associated with better PFS on sunitinib (hazard ratio [HR] 3.39, 95% confidence interval [CI] 1.32-8.69; p = 0.01) in comparison to MTC2-primary (HR 0.95, 95% CI 0.65-1.38; p = 0.80; p interaction  = 0.02). Evaluation of known RNA signatures in the CheckMate trials revealed that JAVELIN-metastasis was associated with better PFS on ICI (HR 0.77, 95% CI 0.62-0.97; p = 0.03) in comparison to JAVELIN-primary (HR 1.04, 95% CI 0.91-1.19; p = 0.56; p interaction  = 0.02). These results indicate that tissue site may be a relevant confounder in biomarker analyses., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

Background: Molecular profiles of renal cell carcinoma (RCC) brain metastases (BMs) are not well characterized. Effective management with locoregional therapies, including stereotactic radiosurgery (SRS), is critical as systemic therapy advancements have improved overall survival (OS)., Objective: To identify clinicogenomic features of RCC BMs treated with SRS in a large patient cohort., Design, Setting, and Participants: A single-institution retrospective analysis was conducted of all RCC BM patients treated with SRS from January 1, 2010 to March 31, 2021., Intervention: SRS for RCC BMs., Outcome Measurements and Statistical Analysis: Next-generation sequencing was performed to identify gene alterations more prevalent in BM patients. Clinical factors and genes altered in ≥10% of samples were assessed per patient using Cox proportional hazards models and per individual BM using clustered competing risks regression with competing risk of death., Results and Limitations: Ninety-one RCC BM patients underwent SRS to 212 BMs, with a median follow-up of 38.8 mo for patients who survived. The median intracranial progression-free survival and OS were 7.8 (interquartile range [IQR] 5.7-11) and 21 (IQR 16-32) mo, respectively. Durable local control of 83% was achieved at 12 mo after SRS, and 59% of lesions initially meeting the radiographic criteria for progression at 3-mo evaluation would be considered to represent pseudoprogression at 6-mo evaluation. A comparison of genomic alterations at both the gene and the pathway level for BM+ patients compared with BM- patients revealed phosphoinositide 3-kinase (PI3K) pathway alterations to be more prevalent in BM+ patients (43% vs 16%, p = 0.001, q = 0.01), with the majority being PTEN alterations (17% vs 2.7%, p = 0.003, q = 0.041)., Conclusions: To our knowledge, this is the largest study investigating genomic profiles of RCC BMs and the only such study with annotated intracranial outcomes. SRS provides durable in-field local control of BMs. Recognizing post-SRS pseudoprogression is crucial to ensure appropriate management. The incidence of PI3K pathway alterations is more prevalent in BM+ patients than in BM- patients and warrants further investigation in a prospective setting., Patient Summary: We examined the outcomes of radiotherapy for the treatment of brain metastases in kidney cancer patients at a single large referral center. We found that radiation provides good control of brain tumors, and certain genetic mutations may be found more commonly in patients with brain metastasis., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2024. Published by Elsevier B.V.)

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., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

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., (© 2023 American Cancer Society.)

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., Competing Interests: Declaration of Competing Interest Maria Carlo has no conflicts of interest to disclose. Jonathan Coleman has no conflicts of interest to disclose. Lennert Eismann has no conflicts of interest to disclose. Darren Feldman reports research funding from Telix, BioNTech, Astellas, and Decibel Therapeutics; is a consultant for Telix and BioNTech; and reports royalties from UpToDate. Alvin Goh is a consultant for Medtronic. A. Ari Hakimi is on the Merck Advisory board. Sari Khaleel (KhaleelS@mskcc.org) has no conflicts of interest to disclose. Ritesh Kotecha reports advisory board consultation for Eisai; receives institutional research funding from Pfizer, Novartis, Takeda, and Allogene Therapeutics; and is supported in part by the Academy of Kidney Cancer Investigators of the CDMRP/DOD (KC200127). Chung-Han Lee reports honoraria from Ideology Health, Intellisphere, Research to Practice, American Institute of Continuing Medical Education, and Medscape; has a consulting or advisory role for Aveo, Cardinal Health, Eisai, Bristol Myers Squibb, Merck, Pfizer/EMD Serono, and Exelixis; and reports research funding from Eisai, Bristol Myers Squibb, Calithera Biosciences, Exelixis, Merck, and AstraZeneca. Richard Matulewicz has no conflicts of interest to disclose. Robert Motzer reports grants from Bristol Myers Squibb and Pfizer; grants and personal fees from Eisai, Exelixis, Merck, and Genentech/Roche; and personal fees from EMD Serono Research. Irina Ostrovnaya has no conflicts of interest to disclose. Stephen Reese has no conflicts of interest to disclose. Katiana Vazquez-Rivera has no conflicts of interest to disclose. Paul Russo has no conflicts of interest to disclose. Juan Arroyave Villada has no conflicts of interest to disclose. Martin Voss reports receiving commercial research grants from Bristol Myers Squibb, Pfizer, and Genentech/Roche; honoraria from Novartis and Bristol Myers Squibb; and travel/accommodation from AstraZeneca, Eisai, Novartis, and Takeda; and serving as a consultant/advisory board member for Alexion Pharmaceuticals, Aveo, Bayer, Calithera Biosciences, Corvus Pharmaceuticals, Exelixis, Eisai, Genentech, GlaxoSmithKline, Merck, Natera, Onquality Pharmaceuticals, Novartis, and Pfizer. Charlie White has no conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Early palliative/pre-emptive intervention improves clinical outcomes and quality of life for patients with metastatic cancer. A previous signal-seeking randomized controlled trial (RCT) demonstrated that early upfront radiotherapy to asymptomatic or minimally symptomatic high-risk osseous metastases led to reduction in skeletal-related events (SREs), a benefit driven primarily by subgroup of high-risk spine metastasis. The current RCT aims to determine whether early palliative/pre-emptive radiotherapy in patients with high-risk, asymptomatic or minimally symptomatic spine metastases will lead to fewer SREs within 1 year., Methods: This is a single-center, parallel-arm, in-progress RCT in adults (≥ 18 years) with ECOG performance status 0-2 and asymptomatic or minimally symptomatic (not requiring opioids) high-risk spine metastases from histologically confirmed solid tumor malignancies with > 5 sites of metastatic disease on cross-sectional imaging. High-risk spine metastases are defined by the following: (a) bulkiest disease sites ≥ 2 cm; (b) junctional disease (occiput to C2, C7-T1, T12-L2, L5-S1); (c) posterior element involvement; or (d) vertebral body compression deformity > 50%. Patients are randomized 1:1 to receive either standard-of-care systemic therapy (arm 1) or upfront, early radiotherapy to ≤ 5 high-risk spine lesions plus standard-of-care systemic therapy (arm 2), in the form of 20-30 Gy of radiation in 2-10 fractions. The primary endpoint is SRE, a composite outcome including spinal fracture, spinal cord compression, need for palliative radiotherapy, interventional procedures, or spinal surgery. Secondary endpoints include (1) surrogates of health care cost, including the number and duration of SRE-related hospitalizations; (2) overall survival; (3) pain-free survival; and (4) quality of life. Study instruments will be captured pre-treatment, at baseline, during treatment, and at 1, 3, 6, 12, and 24 months post-treatment. The trial aims to accrue 74 patients over 2 years to achieve > 80% power in detecting difference using two-sample proportion test with alpha < 0.05., Discussion: The results of this RCT will demonstrate the value, if any, of early radiotherapy for high-risk spine metastases. The trial has received IRB approval, funding, and prospective registration (NCT05534321) and has been open to accrual since August 19, 2022. If positive, the trial will expand the scope and utility of spine radiotherapy., Trial Registration: ClinicalTrials.Gov NCT05534321 . Registered September 9, 2022., Trial Status: Version 2.0 of the protocol (2021-KOT-002), revised last on September 2, 2022, was approved by the WCG institutional review board (Study Number 1337188, IRB tracking number 20223735). The trial was first posted on ClinicalTrials.Gov on September 9, 2022 (NCT05534321). Patient enrollment commenced on August 19, 2022, and is expected to be completed in 2 years, likely by August 2024., (© 2024. The Author(s).)

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., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of interests R.R.K. is a consultant and/or on the Advisory Board of Eisai and reports receiving institutional research funding from Pfizer, Takeda, Novartis, Xencor, and Allogene Therapeutics. Y.-B.C. is a consultant for Inspirna, Inc. M.H.V. is a consultant and/or on the Advisory Board of Eisai, Exelixis, Merck, Calithera, Aveo, Genentech, Oncorena, Affimed, MICU Rx Aravive, onQuality, Astra Zeneca, and Mertelsmann Foundation. M.H.V. has received research funding from Pfizer, BMS, and Genentech. C.-H.L. has received research funding from AstraZeneca, BMS, Calithera, Eisai, Eli Lilly, Exelixis, and Merck. C.-H.L. is a consultant for Aadi, Aveo, BMS, Exelixis, Eisai, Merck, Pfizer, EMD Serono, and Cardinal Health. C.-H.L. has received honoraria from AiCME, IDEOlogy Health, Intellisphere, Medscape, MJH, and Research to Practice. M.G. was an employee and a shareholder of Illumina Inc. during the preparation of this study. M.G. is currently an employee and a shareholder of Roche. R.J.M. is a consultant and/or on the Advisory Board of AstraZeneca, Aveo, Calithera Biosciences, Eisai, Exelixis, Genentech/Roche, Incyte, Pfizer, and Merck. R.J.M. has received research funding from Aveo, Bristol Myers Squibb, Eisai, Exelixis, Genentech/Roche, Novartis, Pfizer, and Merck. A.A.H. is on the Advisory Board of Merck. E.R. is a consultant for Xontogeny, LLC., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.

Introduction: Traditionally, brain metastases have been treated with stereotactic radiosurgery (SRS), whole-brain radiation (WBRT), and/or surgical resection. Non-small cell lung cancers (NSCLC), over half of which carry EGFR mutations, are the leading cause of brain metastases. EGFR-directed tyrosine kinase inhibitors (TKI) have shown promise in NSCLC; but their utility in NSCLC brain metastases (NSCLCBM) remains unclear. This work sought to investigate whether combining EGFR-TKI with WBRT and/or SRS improves overall survival (OS) in NSCLCBM., Methods: A retrospective review of NSCLCBM patients diagnosed during 2010-2019 at a tertiary-care US center was performed and reported following the 'strengthening the reporting of observational studies in epidemiology' (STROBE) guidelines. Data regarding socio-demographic and histopathological characteristics, molecular attributes, treatment strategies, and clinical outcomes were collected. Concurrent therapy was defined as the combination of EGFR-TKI and radiotherapy given within 28 days of each other., Results: A total of 239 patients with EGFR mutations were included. Of these, 32 patients had been treated with WBRT only, 51 patients received SRS only, 36 patients received SRS and WBRT only, 18 were given EGFR-TKI and SRS, and 29 were given EGFR-TKI and WBRT. Median OS for the WBRT-only group was 3.23 months, for SRS + WBRT it was 3.17 months, for EGFR-TKI + WBRT 15.50 months, for SRS only 21.73 months, and for EGFR-TKI + SRS 23.63 months. Multivariable analysis demonstrated significantly higher OS in the SRS-only group (HR = 0.38, 95% CI 0.17-0.84, p = 0.017) compared to the WBRT reference group. There were no significant differences in overall survival for the SRS + WBRT combination cohort (HR = 1.30, 95% CI = 0.60, 2.82, p = 0.50), EGFR-TKIs and WBRT combination cohort (HR = 0.93, 95% CI = 0.41, 2.08, p = 0.85), or the EGFR-TKI + SRS cohort (HR = 0.46, 95% CI = 0.20, 1.09, p = 0.07)., Conclusions: NSCLCBM patients treated with SRS had a significantly higher OS compared to patients treated with WBRT-only. While sample-size limitations and investigator-associated selection bias may limit the generalizability of these results, phase II/III clinicals trials are warranted to investigate synergistic efficacy of EGFR-TKI and SRS.

Gliomas, the most common type of malignant primary brain tumor, were conventionally classified through WHO Grades I-IV (now 1-4), with low-grade gliomas being entities belonging to Grades 1 or 2. While the focus of the WHO Classification for Central Nervous System (CNS) tumors had historically been on histopathological attributes, the recently released fifth edition of the classification (WHO CNS5) characterizes brain tumors, including gliomas, using an integration of histological and molecular features, including their epigenetic changes such as histone methylation, DNA methylation, and histone acetylation, which are increasingly being used for the classification of low-grade gliomas. This review describes the current understanding of the role of DNA methylation, demethylation, and histone modification in pathogenesis, clinical behavior, and outcomes of brain tumors, in particular of low-grade gliomas. The review also highlights potential diagnostic and/or therapeutic targets in associated cellular biomolecules, structures, and processes. Targeting of MGMT promoter methylation, TET-hTDG-BER pathway, association of G-CIMP with key gene mutations, PARP inhibition, IDH and 2-HG-associated processes, TERT mutation and ARL9-associated pathways, DNA Methyltransferase (DNMT) inhibition, Histone Deacetylase (HDAC) inhibition, BET inhibition, CpG site DNA methylation signatures, along with others, present exciting avenues for translational research. This review also summarizes the current clinical trial landscape associated with the therapeutic utility of epigenetics in low-grade gliomas. Much of the evidence currently remains restricted to preclinical studies, warranting further investigation to demonstrate true clinical utility.

Background: Intratumoral heterogeneity (ITH) is a hallmark of clear cell renal cell carcinoma (ccRCC) that reflects the trajectory of evolution and influences clinical prognosis. Here, we seek to elucidate how ITH and tumor evolution during immune checkpoint inhibitor (ICI) treatment can lead to therapy resistance., Methods: Here, we completed a single-arm pilot study to examine the safety and feasibility of neoadjuvant nivolumab in patients with localized RCC. Primary endpoints were safety and feasibility of neoadjuvant nivolumab. Then, we spatiotemporally profiled the genomic and immunophenotypic characteristics of 29 ccRCC patients, including pre- and post-therapy samples from 17 ICI-treated patients. Deep multi-regional whole-exome and transcriptome sequencing were performed on 29 patients at different time points before and after ICI therapy. T cell repertoire was also monitored from tissue and peripheral blood collected from a subset of patients to study T cell clonal expansion during ICI therapy., Results: Angiogenesis, lymphocytic infiltration, and myeloid infiltration varied significantly across regions of the same patient, potentially confounding their utility as biomarkers of ICI response. Elevated ITH associated with a constellation of both genomic features (HLA LOH, CDKN2A/B loss) and microenvironmental features, including elevated myeloid expression, reduced peripheral T cell receptor (TCR) diversity, and putative neoantigen depletion. Hypothesizing that ITH may itself play a role in shaping ICI response, we derived a transcriptomic signature associated with neoantigen depletion that strongly associated with response to ICI and targeted therapy treatment in several independent clinical trial cohorts., Conclusions: These results argue that genetic and immune heterogeneity jointly co-evolve and influence response to ICI in ccRCC. Our findings have implications for future biomarker development for ICI response across ccRCC and other solid tumors and highlight important features of tumor evolution under ICI treatment., Trial Registration: The study was registered on ClinicalTrial.gov (NCT02595918) on November 4, 2015., (© 2022. The Author(s).)

Brain metastases occur in almost one-third of adult patients with solid tumor malignancies and lead to considerable patient morbidity and mortality. The rising incidence of brain metastases has been ascribed to the development of better imaging and screening techniques and the formulation of better systemic therapies. Until recently, the multimodal management of brain metastases focused primarily on the utilization of neurosurgical techniques, with varying combinations of whole-brain radiation therapy and stereotactic radio-surgical procedures. Over the past 2 decades, in particular, the increment in knowledge pertaining to molecular genetics and the pathogenesis of brain metastases has led to significant developments in targeted therapies and immunotherapies. This review article highlights the recent updates in the management of brain metastases with an emphasis on novel systemic therapies., (© 2022. The Author(s).)

Background: Succinate dehydrogenase-deficient and fumarate hydratase-deficient renal cell carcinomas (SDHRCC and FHRCC) are rare kidney cancers driven by loss of TCA cycle enzymes., Objective: To define and compare the genomic and metabolomic hallmarks of SDHRCC and FHRCC., Design, Setting, and Participants: We analyzed SDHRCC and FHRCC tumors with either immunohistochemical evidence of loss of protein expression or genomically confirmed biallelic inactivation of SDHA/B/C/D/AF2 or FH., Outcome Measurements and Statistical Analysis: Somatic alterations were identified using clinical pipelines, with allele-specific copy number alterations (CNAs) identified using FACETS. Mass spectrometry-based metabolomic profiling was performed on available SDHRCC and FHRCC tumors., Results and Limitations: Tumors were analyzed for 42 patients (25 FHRCC, 17 SDHRCC). In the germline analysis, 16/17 SDHRCCs harbored a germline alteration in SDHB, whereas only 17/22 FHRCCs had pathogenic germline FH variants. SDHRCCs had a lower mutation burden (p = 0.02) and CNA burden (p = 0.0002) than FHRCCs. All SDHRCCs presented with deletion of chromosome 1p (overlapping SDHB), whereas FHRCCs demonstrated high but not ubiquitous loss of 1q (FH locus). Both SDHRCCs and FHRCCs exhibited significant idiopathic accumulation of the metabolite guanine. FHRCC tumors had elevated levels of urea cycle metabolites (argininosuccinate, citrulline, and fumarate), whereas SDHRCC tumors had elevation of numerous acylcarnitines. These characteristic metabolic changes allowed identification of a previously unrecognized SDH-deficient RCC., Conclusions: Despite sharing similar genetic etiology, SDHRCC and FHRCC represent distinct molecular entities with unique genetic and metabolic abnormalities., Patient Summary: Kidney cancers driven by loss of the gene encoding either the succinate dehydrogenase or fumarate hydratase enzyme are rare. We sought to define and compare the genetic and metabolic features of these cancer entities., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: 'Stable disease (SD)' as per RECIST is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs). This study aimed to characterize SD and identify the subset of patients with SD who are benefiting from treatment. Understanding SD would facilitate drug development and improve precision in correlative research., Patients and Methods: A systematic review was carried out to characterize SD in ICI trials. SD and objective response were compared to proliferation index using The Cancer Genome Atlas gene expression data. To identify a subgroup of SD with outcomes mirroring responders, we examined a discovery cohort of non-small-cell lung cancer (NSCLC). Serial cutpoints of two variables, % best overall response and progression-free survival (PFS), were tested to define a subgroup of patients with SD with similar survival as responders. Results were then tested in external validation cohorts., Results: Among trials of ICIs (59 studies, 14 280 patients), SD ranged from 16% to 42% in different tumor types and was associated with disease-specific proliferation index (ρ = -0.75, P = 0.03), a proxy of tumor kinetics, rather than relative response to ICIs. In a discovery cohort of NSCLC [1220 patients, 313 (26%) with SD to ICIs], PFS ranged widely in SD (0.2-49 months, median 4.9 months). The subset with PFS >6 months and no tumor growth mirrored partial response (PR) minor (overall survival hazard ratio 1.0) and was proposed as the definition of SD responder. This definition was confirmed in two validation cohorts from trials of NSCLC treated with durvalumab and found to apply in tumor types treated with immunotherapy in which depth and duration of benefit were correlated., Conclusions: RECIST-defined SD to immunotherapy is common, heterogeneous, and may largely reflect tumor growth rate rather than ICI response. In patients with NSCLC and SD to ICIs, PFS >6 months and no tumor growth may be considered 'SD responders'. This definition may improve the efficiency of and insight derivable from clinical and translational research., Competing Interests: Disclosure JL has received honoraria from Targeted Oncology and Physicians’ Education Resource. SW and QZ are former employees of AstraZeneca. MKC receives institutional research funding from Bristol-Myers Squibb; and has received personal fees from Merck, InCyte, Moderna, ImmunoCore, and AstraZeneca. ANS reports advisory board positions with Bristol-Myers Squibb, Immunocore, Novartis, and Castle Biosciences; and institutional research support from BMS, Immunocore, Xcovery, Polaris, Novartis, Pfizer, Checkmate Pharmaceuticals, and Foghorn Therapeutics. MAP reports consulting fees from Bristol-Myers Squibb, Merck, Array BioPharma, Novartis, Incyte, NewLink Genetics, Pfizer, and Aduro; honoraria from BMS and Merck; and institutional research support from Rgenix, Infinity, BMS, Merck, Array BioPharma, Novartis, and AstraZeneca. MHV reports receiving commercial research support from Bristol-Myers Squibb, Pfizer, and Genentech/Roche; honoraria from Novartis and Bristol-Myers Squibb; travel/accommodation from Astra Zeneca, Eisai, Novartis, and Takeda; and consultant/advisory board member for Aveo, Calithera Biosciences, Corvus Pharmaceuticals, Exelixis, Eisai, Merck, Onquality Pharmaceuticals, Novartis, and Pfizer. MSG has been a compensated consultant for Ultimate Opinions in Medicine LLC and MORE Health, Inc. AG and RR are employees of AstraZeneca. RR has a patent pending related to tumor mutation burden. MGK receives personal fees from AstraZeneca, Pfizer, Regeneron, and Daiichi-Sankyo; received honoraria for participation in educational programs from WebMD, OncLive, Physicians Education Resources, Prime Oncology, Intellisphere, Creative Educational Concepts, Peerview, i3 Health, Paradigm Medical Communications, AXIS, Carvive Systems, AstraZeneca, and Research to Practice; and received travel support from AstraZeneca, Pfizer, Regeneron, and Genentech; is an employee of Memorial Sloan Kettering. Memorial Sloan Kettering has received research funding from The National Cancer Institute (USA), The Lung Cancer Research Foundation, Genentech/Roche, and PUMA Biotechnology for research conducted by MGK. MSK has licensed testing for EGFR T790M to MolecularMD. MDH, as of November 2021, is an employee of AstraZeneca; has received personal fees from Achilles, Adagene, Adicet, Arcus, Blueprint Medicines, Bristol-Myers Squibb, DaVolterra, Eli Lilly, Genentech/Roche, Genzyme/Sanofi, Janssen, Immunai, Instil Bio, Mana Therapeutics, Merck, Mirati, Natera, Pact Pharma, Shattuck Labs, and Regeneron; has options from Factorial, Shattuck Labs, Immunai, and Arcus; and has a patent filed by Memorial Sloan Kettering related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. All other authors have declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

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., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: The clinical utility of cell-free DNA (cfDNA) as a biomarker for advanced clear cell renal cell carcinoma (ccRCC) remains unclear. We evaluated the validity of cfDNA-based genomic profiling in a large cohort of patients with ccRCC with matched next-generation sequencing (NGS) from primary tumor tissues., Materials and Methods: We performed paired NGS of tumor DNA and plasma cfDNA using the MSK-IMPACT platform in 110 patients with metastatic ccRCC. Tissues were profiled for variants and copy number alterations with germline comparison. Manual cross-genotyping between cfDNA and tumor tissue was performed. Deep sequencing with a higher sensitivity platform, MSK-ACCESS, was performed on a subset of cfDNA samples. Clinical data and radiographic tumor volumes were assessed to correlate cfDNA yield with treatment response and disease burden., Results: Tumor tissue MSK-IMPACT testing identified 582 genomic alterations (GAs) across the cohort. Using standard thresholds for de novo variant calling in cfDNA, only 24 GAs were found by MSK-IMPACT in cfDNA in 7 of 110 patients (6%). With manual cross-genotyping, 210 GAs were detectable below thresholds in 74 patients (67%). Intrapatient concordance with tumor tissue was limited, including VHL (31.6%), PBRM1 (24.1%), and TP53 (52.9%). cfDNA profiling did not identify 3p loss because of low tumor fractions. Tumor volume was associated with cfDNA allele frequency, and VHL concordance was superior for patients with greater disease burden., Conclusion: cfDNA-based NGS profiling yielded low detection rates in this metastatic ccRCC cohort. Concordance with tumor profiling was low, even for truncal mutations such as VHL , and some findings in peripheral blood may represent clonal hematopoiesis. Routine cfDNA panel testing is not supported, and its application in biomarker efforts must account for these limitations.

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., Competing Interests: RK reports advisory board consultation for Eisai, and reports receiving institutional research funding from Pfizer and Takeda. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tourigny, Zucker, Kim, Russo, Coleman, Lee, Carlo, Chen, Hakimi, Kotecha and Reznik.)

Purpose: Community-academic partnerships have the potential to improve access to clinical trials for under-represented minority patients who more often receive cancer treatment in community settings. In 2017, the Memorial Sloan Kettering (MSK) Cancer Center began opening investigator-initiated clinical trials in radiation oncology in targeted community-based partner sites with a high potential to improve diverse population accrual. This study evaluates the effectiveness of a set of implementation strategies for increasing overall community-based enrollment and the resulting proportional enrollment of Hispanic patients on trials on the basis of availability in community-based partner sites., Methods: An interrupted time series analysis evaluating implementation strategies was conducted from April 2018 to September 2021. Descriptive analysis ofHispanic enrollment on investigator-initiated randomized therapeutic radiation trials open at community-based sites was compared with those open only at themain academic center., Results: Overall, 84 patients were enrolled in clinical trials in the MSK Alliance, of which 48 (56%) identified as Hispanic. The quarterly patient enrollment pre- vs postimplementation increased from 1.39 (95% CI, -3.67 to 6.46) to 9.42 (95% CI, 2.05 to 16.78; P5 .017). In the investigator-initiated randomized therapeutic radiation trials open in the MSK Alliance, Hispanic representation was 11.5% and 35.9% in twometastatic trials and 14.2% in a proton versus photon trial. Inmatched trials open only at the main academic center, Hispanic representation was 5.6%, 6.0%, and 4.0%, respectively., Conclusion: A combination of practice-level and physician-level strategies implemented at community-based partner sites was associated with increased clinical trial enrollment, which translated to improved Hispanic representation. This supports the role Q:2 of strategic community-academic partnerships in addressing disparities in clinical trial enrollment., Competing Interests: Daniel R. GomezHonoraria: Varian Medical Systems, Merck, Bristol Myers Squibb, AstraZeneca, RefleXion Medical, Vindico Medical Education, US Oncology, GRAILConsulting or Advisory Role: Olympus Medical Systems, Medtronic, Johnson & Johnson/JanssenResearch Funding: Merck, Varian Medical Systems, AstraZeneca, Bristol Myers SquibbTravel, Accommodations, Expenses: Varian Medical Systems, AstraZeneca, Merck, Vindico Medical Education, US Oncology, Driver Inc Jonathan T. YangStock and Other Ownership Interests: Nanocan TherapeuticsConsulting or Advisory Role: Debiopharm Group, Galera Therapeutics, AstraZeneca, Nanocan TherapeuticsResearch Funding: AstraZeneca, Kazia Therapeutics, X-RAD Therapeutics Nancy Y. LeeConsulting or Advisory Role: Merck, Pfizer, Merck Serono, Sanofi, Mirati Therapeutics, Roche/GenentechResearch Funding: AstraZeneca, Pfizer (Inst) Andreas RimnerHonoraria: More HealthConsulting or Advisory Role: AstraZeneca, Merck, Boehringer IngelheimResearch Funding: Varian Medical Systems (Inst), Boehringer Ingelheim (Inst), Pfizer (Inst), AstraZeneca (Inst), Merck (Inst) Yoshiya YamadaEmployment: Memorial Sloan-Kettering Cancer CenterLeadership: Chordoma FoundationHonoraria: Varian Medical Systems, BrainLAB, Vision RTSpeakers' Bureau: BrainLAB, Vision RT, Varian Medical SystemsResearch Funding: Varian Medical SystemsTravel, Accommodations, Expenses: Philips HealthcareOther Relationship: University of Wollongong Michael J. ZelefskyHonoraria: AccurayConsulting or Advisory Role: Alpha Tau, Boston ScientificPatents, Royalties, Other Intellectual Property: Ferring provided partial funding for a clinical trial (Inst)Other Relationship: Editor in Chief for Brachytherapy Noah S. KalmanConsulting or Advisory Role: Naveris Rupesh R. KotechaHonoraria: Accuray, Novocure, Elekta, BrainLAB, Elsevier, ViewRay, PeerViewConsulting or Advisory Role: ViewRay, NovocureSpeakers' Bureau: NovocureResearch Funding: Medtronic (Inst), Blue Earth Diagnostics (Inst), Novocure (Inst), GT Medical Technologies (Inst), AstraZeneca (Inst), Exelixis (Inst), ViewRay (Inst), BrainLAB (Inst)Travel, Accommodations, Expenses: PeerView Minesh P. MehtaLeadership: OncoceuticsStock and Other Ownership Interests: ChimerixConsulting or Advisory Role: Karyopharm Therapeutics, Mevion Medical Systems, ZappRx, Sapience Therapeutics, XoftPatents, Royalties, Other Intellectual Property: WARF patent 14/934,27, Topical vasoconstrictor preparations and methods for protecting cells during cancer chemotherapy and radiotherapyUncompensated Relationships: Xcision Medical Systems, ViewRay Michael D. ChuongEmployment: Fertility and IVF Center of MiamiHonoraria: ViewRay, Sirtex MedicalConsulting or Advisory Role: ViewRay, Advanced Accelerator ApplicationsSpeakers' Bureau: ViewRay, Sirtex MedicalResearch Funding: AstraZeneca/MedImmune, ViewRayTravel, Accommodations, Expenses: ViewRay Andrew L. SalnerConsulting or Advisory Role: Best Doctors Inc Jamie S. OstroffPatents, Royalties, Other Intellectual Property: UptoDate David G. PfisterConsulting or Advisory Role: Boehringer Ingelheim, IncyteResearch Funding: Boehringer Ingelheim (Inst), AstraZeneca (Inst), Exelixis (Inst), Novartis (Inst), MedImmune (Inst), Merck (Inst), Genentech/Roche (Inst), Lilly (Inst), Bayer (Inst), Eisai (Inst), Regeneron (Inst), Atara Biotherapeutics (Inst), MeiraGTx (Inst), Hookipa Pharma (Inst) Fumiko ChinoThis author is a Consultant Editor for JCO Oncology Practice. Journal policy recused the author from having any role in the peer review of this manuscript. Jillian TsaiHonoraria: Varian Medical IncConsulting or Advisory Role: Varian Medical Systems Erin F. GillespieOther Relationship: eContourNo other potential conflicts of interest were reported.

Therapeutic combinations of VEGFR tyrosine kinase inhibitor plus immune checkpoint blockade now represent a standard in the first-line management of patients with advanced renal cell carcinoma. Tumor molecular profiling has shown notable heterogeneity when it comes to activation states of relevant pathways, and it is not clear that concurrent pursuit of two mechanisms of action is needed in all patients. Here, we applied an in silico drug model to simulate combination therapy by integrating previously reported findings from individual monotherapy studies. Clinical data was collected from prospective clinical trials of axitinib, cabozantinib, pembrolizumab and nivolumab. Efficacy of two-drug combination regimens (cabozantinib plus nivolumab, and axitinib plus pembrolizumab) was then modeled assuming independent effects of each partner. Reduction in target lesions, objective response rates (ORR), and progression-free survival (PFS) were projected based on previously reported activity of each agent, randomly pairing efficacy data from two source trials for individual patients and including only the superior effect of each pair in the model. In silico results were then contextualized to register phase III studies of these combinations with similar ORR, PFS, and best tumor response. As increasingly complex therapeutic strategies emerge, computational tools like this could help define benchmarks for trial designs and precision medicine efforts. Summary statement: In silico drug modeling provides meaningful insights into the effects of combination immunotherapy for patients with advanced kidney cancer., Competing Interests: Competing interests: RRK reports advisory board consultation for Eisai and reports receiving institutional research funding from Pfizer and Takeda. MHV reports receiving commercial research support from Bristol-Myers Squibb, Pfizer and Genentech/Roche; honoraria from Novartis and Bristol-Myers Squibb; travel/accommodation from Astra Zeneca, Eisai, Novartis and Takeda; consultant/advisory board member for Aveo, Calithera Biosciences, Corvus Pharmaceuticals, Exelixis, Eisai, Merck, Onquality Pharmaceuticals, Novartis and Pfizer. C-HL reports consulting fees from Amgen, Bristol Myers Squibb, Exelixis, Pfizer, Eisai, Merck and EMD Serono; honoraria from AiCME, Intellisphere, and Research to Practice; institutional research support from Bristol Myers Squibb, Calithera, Eisai, Eli Lilly, Exelixis, Merck, and Pfizer. The remaining authors have no competing interests to declare., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2021 American Cancer Society.)

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., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (© 2021 British Society for Haematology and John Wiley & Sons Ltd. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Purpose: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive form of RCC associated with hereditary leiomyomatosis and RCC syndrome. Evidence for systemic therapy efficacy is lacking., Experimental Design: We studied clinical and genomic characteristics of FH-RCC, including response [objective response rate (ORR)] to systemic therapies and next-generation sequencing (NGS). Patients with metastatic FH-RCC, defined by presence of pathogenic germline or somatic FH mutation plus IHC evidence of FH loss, were included., Results: A total of 28 of 32 included patients (median age 46; range, 20-74; M:F, 20:12) underwent germline testing; 23 (82%) harbored a pathogenic FH germline variant. Five (16%) were negative for germline FH mutations; all had biallelic somatic FH loss. Somatic NGS (31/32 patients) revealed co-occurring NF2 mutation most frequently ( n = 5). Compared with clear-cell RCC, FH-RCC had a lower mutation count (median 2 vs. 4; P < 0.001) but higher fraction of genome altered (18.7% vs. 10.3%; P = 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination ( n = 18, ORR 44%), VEGF monotherapy ( n = 15, ORR 20%), checkpoint inhibitor therapy ( n = 8, ORR 0%), and mTOR monotherapy ( n = 4, ORR 0%). No complete responses were seen. Median overall and progression-free survival were 21.9 months [95% confidence interval (CI): 14.3-33.8] and 8.7 months (95% CI: 4.8-12.3), respectively., Conclusions: Although most FH-RCC tumors are due to germline FH alterations, a significant portion result from biallelic somatic FH loss. Both somatic and germline FH-RCC have similar molecular characteristics, with NF2 mutations, low tumor mutational burden, and high fraction of genome altered. Although immunotherapy alone produced no objective responses, combination mTOR/VEGF therapy showed encouraging results., (©2021 American Association for Cancer Research.)

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., (© 2020 Wiley Periodicals LLC.)

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.

Purpose: Translocation renal cell carcinoma (tRCC) is a rare, aggressive renal cell carcinoma (RCC) subtype. There is currently limited understanding on the role of molecular alterations in the pathogenesis and progression of these tumors. We investigated the association between somatic alterations and clinical outcomes in two independent cohorts profiled using DNA sequencing., Experimental Design: Twenty-two tRCCs underwent targeted sequencing [Memorial Sloan Kettering Cancer Center (MSK)-IMPACT]; a subset was profiled using exome-sequencing and combined with exome data from The Cancer Genome Atlas (TCGA) for analysis. The prognostic value of specific somatic aberrations, tumor mutation burden (TMB), and fraction of copy-number-altered genome (FCNAg) was explored. In TCGA cases, neoantigen prediction and immune cell deconvolution were performed using RNA-sequencing and exome data. Overall survival estimates were computed using the Kaplan-Meier method; time-on-treatment was calculated for 14 MSK-IMPACT patients who underwent systemic therapy. Associations between molecular features and outcomes were evaluated using nonparametric testing., Results: Copy-number aberrant tRCCs were associated with poor overall survival ( P = 0.03). Pediatric patients had tumors with lower FCNAg ( P = 0.01). In one adult case with two chronologically distinct tumor samples sequenced, we confirmed that copy-number events occurred early during evolution. TERT promoter mutations were found exclusively in high-stage tumors. We found that tRCCs displayed distinct angiogenesis and PD-L1 gene expression profiles compared with other RCC subtypes., Conclusions: Tumors molecularly defined by increased copy-number variations were associated with aggressive disease in tRCC. A higher burden of genomic events in adults compared with pediatric cases likely reflects a more aggressive clinical course. The unique immunophenotypic characteristics of tRCC merit further exploration., (©2020 American Association for Cancer Research.)

Background: Loss-of-function alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may determine benefit from immune-oncology (I/O) agents as shown in colon cancer. However, biologic significance and relevance to I/O in metastatic clear cell RCC (ccRCC) are unknown., Methods: Genomic data and treatment outcomes were retrospectively collected for patients with metastatic ccRCC. Tumor and germline DNA were subject to targeted next generation sequencing across >400 genes of interest, including 34 DDR genes. Patients were dichotomized according to underlying DDR gene alteration into (1) deleterious DDR gene alterations present (Del DDR); (2) wild-type (WT) and variants of unknown significance (VUS) DDR gene alterations present (WT/VUS DDR). Association between DDR status and therapeutic benefit was investigated separately for I/O and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy., Results: Del DDR were detected in 43/229 patients (19%). The most frequently altered genes were CHEK2 and ATM . Clonality analysis was performed in 27 somatic DDR mutations and 17 were clonal (63%). For patients with I/O treatment, Del DDR status was associated with superior overall survival (log-rank p=0.049); after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium risks and extent of prior therapy, the HR for Del DDR was 0.41 (95% CI: 0.14-1.14; p=0.09). No association was seen with VEGF-TKI treatment (log-rank p=0.903)., Conclusion: Del DDR alterations are recurrent genomic events in patients with advanced RCC and were mostly clonal in this cohort. Loss-of-function events in these genes may affect outcome with I/O therapy in metastatic RCC, and these hypothesis-generating results deserve further study., Competing Interests: Competing interests: MIC reports consulting/advisory role for Pfizer. C-HL reports consulting/advisory role for Exelixis and Eisai. DRF reports research support from Novartis and Seattle Genetics. TAC reports research support from Bristol-Myers Squibb, AstraZeneca, Eisai, An2H and Illumina. TAC holds a patent for the use of TMB to predict immunotherapy response. This is licensed to PGDx and MSKCC and TAC are entitled to receive royalties. TAC is a cofounder of Gritstone Oncology and holds equity. RJM reports grants and personal fees from Pfizer, grants and personal fees from Eisai, personal fees from Exelixis, grants and personal fees from Novartis, grants from Bristol-Myers Squibb, grants and personal fees from Genentech/Roche, personal fees from Merck, personal fees from Incyte, grants from GlaxoSmithKline, outside the submitted work. MHV reports receiving commercial research grants from Bristol-Myers Squibb and Genentech/Roche. Honoraria from Novartis. Travel/accommodation from Eisai, Novartis and Takeda. Consultant/advisory board member for Alexion Pharmaceuticals, Bayer, Calithera Biosciences, Corvus Pharmaceuticals, Exelixis, Eisai, GlaxoSmithKline, Natera, Novartis and Pfizer., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Over the past decade, the treatment landscape for patients with metastatic renal cell carcinoma (RCC) has evolved dramatically. The therapeutic options available have expanded and now include immune-checkpoint inhibitors, novel targeted agents and combination strategies, and thus optimal patient selection and treatment sequencing are increasingly pertinent for optimizing clinical outcomes. A better understanding of the underlying biology of the tumour and its microenvironment continues to drive the inception of new diagnostic and therapeutic approaches. Furthermore, many biomarkers robustly associated with treatment and disease-specific outcomes have been identified, and their integration into clinical decision-making for patients with advanced-stage disease will soon become a reality. Herein, we review relevant aspects of the molecular biology of metastatic RCC, with an emphasis on predictive and prognostic biomarkers, and suggest tailored algorithms to individualize and guide treatment approaches for specific subgroups of patients.

Renal cell carcinoma stands out as one of the most immune-infiltrated tumors in pan-cancer comparisons. Features of the tumor microenvironment heavily affect disease biology and may affect responses to systemic therapy. With evolving frontline options in the metastatic setting, several immune checkpoint blockade regimens have emerged as efficacious, and there is growing interest in characterizing features of tumor biology that can reproducibly prognosticate patients and/or predict the likelihood of their deriving therapeutic benefit. Herein, we review pertinent characteristics of the tumor microenvironment with dedicated attention to candidate prognostic and predictive signatures as well as possible targets for future drug development. SIGNIFICANCE: Tumor microenvironment features broadly characterizing angiogenesis and inflammatory signatures have shown striking differences in response to immune checkpoint blockade and antiangiogenic agents. Integration of stromal and immune biomarkers may hence produce predictive and prognostic signatures to guide management with existing regimens as well as future drug development., (©2019 American Association for Cancer Research.)

Background: Immune checkpoint inhibitors (ICIs) are being increasingly utilised in the front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) vascular endothelial growth factor-receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy after 1L ICI therapy., Patients and Methods: This is a retrospective study of mccRCC patients treated with 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Patients were treated at MD Anderson Cancer Center or Memorial Sloan Kettering Cancer Center between December 2015 and February 2018. Objective response was assessed by blinded radiologists' review using Response Evaluation Criteria in Solid Tumours v1.1. Descriptive statistics and Kaplan-Meier method were used., Results: Seventy patients were included in the analysis. Median age at mccRCC diagnosis was 59 years; 8 patients (11%) had international metastatic database consortium favourable-risk disease, 48 (69%) had intermediate-risk disease and 14 (20%) had poor-risk disease. As 1L therapy, 12 patients (17%) received anti-programmed death ligand-1 (PD-(L)1) monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab and 25 (36%) received combination anti-PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib and cabozantinib. On 2L TKI therapy, one patient (1.5%) achieved a complete response, 27 patients (39.7%) a partial response and 36 patients (52.9%) stable disease. Median progression-free survival (mPFS) was 13.2 months (95% confidence interval: 10.1, NA). Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity., Conclusions: In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy after 1L ICI, we observed 2L antitumour activity and tolerance comparable to historical data for 1L TKI., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Importance: With the growing use of oral chemotherapy, there is an urgent need to develop safe and effective systems to administer and manage these agents. A comprehensive synthesis of literature on oral chemotherapy care delivery programs to which clinicians can look for best practices is lacking., Objective: To summarize the peer-reviewed and gray literature on interventions to improve oral chemotherapy care delivery toward describing best practices and identifying current gaps., Evidence Review: Using search terms pertaining to the concepts of oral chemotherapy, cancer, and interventions and outcomes, we performed a systematic review of PubMed, EMBASE, and CINAHL from January 1995 to May 24, 2016, to identify oral chemotherapy intervention programs. We searched the gray literature from January 1995 through February 2016 and contacted gray literature authors for further information. Four physician abstractors reviewed the titles, abstracts, and articles. Quality of the articles was assessed using SQUIRE2 guidelines. Interventions were evaluated in the categories of prescribing, preparation/dispensing, education, administration, monitoring, and storage/disposal. The population of interest included all ages and was limited to traditional cytotoxic and targeted anticancer oral agents., Findings: From 7984 abstracts identified in the peer-reviewed literature search, 16 full-text articles met inclusion criteria representing 3612 patients. Interventions focused on prescribing (n = 1), preparation/dispensing (n = 2), education (n = 11), administration (n = 5), monitoring (n = 14), and storage/disposal (n = 1). In the 10 articles with adherence as the primary outcome, 4 evaluation methods were used. Most improvements were seen in toxic effects/safety compared with adherence. Of the 7 interventions with statistically significant improvement in the primary outcome, 3 nursing phone calls to contact patients within the first few days after treatment initiation, 2 of them with standardized toxic effects management protocols. Interventions using technology to increase touch points between care teams and patients (including video directly observed therapy, automated voice response, and text messages) were not effective., Conclusions and Relevance: A framework for the oral chemotherapy management process with standardized outcome definitions is needed to ensure constructive research. Existing data suggest that a monitoring program should include personal contact with patients within the first weeks of treatment. Whether such contact can be enhanced by technology is uncertain.