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Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is common and disabling among cancer survivors. Little is known about the association of CIPN with other measures of the nervous system's integrity, such as executive dysfunction. We compared measures of executive function in older chemotherapy-treated cancer survivors with and without CIPN., Materials and Methods: This cross-sectional study enrolled 50 chemotherapy-treated cancer survivors (65.6 ± 11.5 years, 88% female) post-chemotherapy treatment who were previously referred for outpatient rehabilitation at the request of the cancer survivor or a medical provider. Twenty-two participants (44%) had CIPN defined by patient-reported distal paresthesia or numbness, which began with chemotherapy and continued to the time of cognitive testing. Measures of executive function included Trails-B, Stroop, and rapid reaction accuracy (RRA) and were evaluated between cancer survivors with and without CIPN using t-tests. Multivariable models were then used to determine whether CIPN was an independent determinant of the measures of executive function (Trails-B, Stroop Incongruent, and RRA). Models were adjusted for age, sex, history of anxiety, and benzodiazepine use due to their known associations with CIPN and executive function., Results: Cancer survivors with CIPN (CIPN+) had reduced executive function compared to survivors without CIPN (CIPN-) on Trails-B (CIPN+: 84.9 s ± 44.1 s, CIPN-: 59.1 s ± 22.5 s, p = 0.01), Stroop (CIPN+: 100.6 s ± 38.2 s, CIPN-: 82.1 s ± 17.3 s, p = 0.03), and RRA (CIPN+: 60.3% ± 12.9%, CIPN-: 70.6% ± 15.7%, p = 0.01). There were no differences in cancer stage severity or functional status by patient report or sit-to-stand function. The association between CIPN and reduced executive function was found in multivariable models after adjusting for age, sex, anxiety, and benzodiazepine use for Trails-B (ß:17.9, p = 0.046), Stroop (ß:16.9, p = 0.02), and RRA (ß:-0.072, p = 0.03)., Discussion: In this population, CIPN is associated with reduced executive function in older cancer survivors treated with chemotherapy. Future research is required to further understand this preliminary association, the causality, and the potential risk factors., Competing Interests: Declaration of Competing Interest MKH reports receiving consulting fees from Argenx, Alexion, UCB Pharma, Janssen, and Immunovant; honoraria from Medscape, Springer Health, AANEM, Medlink Neurology, and Continuum Lifelong Learning in Neurology; grants from University of Vermont Medical Center and Myasthenia Gravis Foundation of America; and leadership roles in the Neuromuscular Study Group and AANEM Neuromuscular Fellowship Committee. NK reports funding from the National Cancer Institute; receiving consulting fees from the Eisana Corporation; and receiving honoraria from AANEM. JKR reports funding from the Newman Family Foundation; payment for expert testimony; sharing a patent for the ReacStick with colleagues James Ashton-Miller, James T. Eckner, and Hogene Kim., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Competing Interests: Declaration of Competing Interest BLM, KM, JM, NK, JAS, HC, MKH, RR, SGB, MR, CR, JKR, NK report no conflicts of interest with the current manuscript. NK reports receiving consulting fees from Eisana Corporation as a medical consultant and honoraria for lectures from AANEM. MKH reports receiving consulting fees from Argenx, Alexion, UCB Pharma, Janssen, and Immunovant and honoraria from Medscape, Springer Health, AANEM, Medlink Neurology, and Continuum Lifelong Learning in Neurology.

Introduction: Balance decrements and increased fall risk in older cancer survivors have been attributed to chemotherapy-induced peripheral neuropathy (CIPN). Cognition is also affected by chemotherapy and may be an additional contributing factor to poor balance through changes in executive functioning. We examined the association of executive function with balance and falls in older cancer survivors who had been treated with chemotherapy., Materials and Methods: Fifty cancer survivors (aged 65.6 ± 11.5 years; 88% female) who were all treated with chemotherapy were included in this cross-sectional study at a tertiary medical center. Executive function was measured by Trails-B, Stroop, and rapid reaction accuracy, a measure emphasizing rapid inhibitory function. Balance was measured by five sit-to-stand time (5STS), repetitions of sit-to-stand in thirty seconds (STS30), and unipedal stance time (UST), which was the primary balance outcome measure. Self-reported falls in the past year were also recorded and was a secondary outcome. Bivariate analyses were conducted between executive function measures and balance variables. Multivariable models were constructed for UST and falls outcomes and included covariates of age and chemotherapy induced peripheral neuropathy status., Results: Pearson correlations demonstrated significant relationships between two executive function measures (rapid reaction accuracy, Trails-B) and all the balance measures assessed (UST, STS30, and 5STS). Rapid reaction accuracy correlations were stronger than Trails-B. The Stroop measure correlated solely with UST. In multivariable models, rapid reaction accuracy was associated with better UST (standardized regression coefficient: 64.1, p < 0.01), decreased any fall (odds ratio = 0.000901, p = 0.04), and decreased recurrent falls (odds ratio = 0.0000044, p = 0.01). The interaction of CIPN with the inhibitory measures in the prediction of balance was not significant., Discussion: Measures of executive function were associated with balance, but among the executive function tests, rapid reaction accuracy had the strongest correlations to balance and was independently associated with falls. The findings suggest that executive function should be considered when assessing fall risk and developing interventions intended to reduce fall risk in older chemotherapy-treated cancer survivors., Competing Interests: Declaration of Competing Interest BLM, KM, JM, NK, JAS, HC, MKH, RR, MR, CR, JKR, NK report no conflicts of interest with the current manuscript., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Renal cell carcinoma (RCC) of variant histology comprises approximately 20% of kidney cancer diagnoses, yet the optimal therapy for these patients and the factors that impact immunotherapy response remain largely unknown. To better understand the determinants of immunotherapy response in this population, we characterized blood- and tissue-based immune markers for patients with variant histology RCC, or any RCC histology with sarcomatoid differentiation, enrolled in a phase II clinical trial of atezolizumab and bevacizumab. Baseline circulating (plasma) inflammatory cytokines were highly correlated with one another, forming an "inflammatory module" that was increased in International Metastatic RCC Database Consortium poor-risk patients and was associated with worse progression-free survival (PFS; P = 0.028). At baseline, an elevated circulating vascular endothelial growth factor A (VEGF-A) level was associated with a lack of response (P = 0.03) and worse PFS (P = 0.021). However, a larger increase in on-treatment levels of circulating VEGF-A was associated with clinical benefit (P = 0.01) and improved overall survival (P = 0.0058). Among peripheral immune cell populations, an on-treatment decrease in circulating PD-L1+ T cells was associated with improved outcomes, with a reduction in CD4+PD-L1+ [HR, 0.62; 95% confidence interval (CI), 0.49-0.91; P = 0.016] and CD8+PD-L1+ T cells (HR, 0.59; 95% CI, 0.39-0.87; P = 0.009) correlated with improved PFS. Within the tumor itself, a higher percentage of terminally exhausted (PD-1+ and either TIM-3+ or LAG-3+) CD8+ T cells was associated with worse PFS (P = 0.028). Overall, these findings support the value of tumor and blood-based immune assessments in determining therapeutic benefit for patients with RCC receiving atezolizumab plus bevacizumab and provide a foundation for future biomarker studies for patients with variant histology RCC receiving immunotherapy-based combinations., (©2023 American Association for Cancer Research.)

Background: The role of upfront cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) in the era of immune checkpoint inhibitors is unclear., Objective: To evaluate the relationship between upfront CN and clinical outcomes in the setting of mRCC treated with immune checkpoint inhibitors or targeted therapy., Design, Setting, and Participants: Using the International Metastatic RCC Database Consortium, we retrospectively identified patients diagnosed with de novo mRCC treated with immune checkpoint inhibitors or targeted therapy., Outcome Measurements and Statistical Analysis: Overall survival (OS) was compared between the two groups using the Kaplan-Meier method and multivariable Cox regressions adjusting for known prognostic factors., Results and Limitations: We identified a total of 4639 eligible patients with mRCC. Among the 4202 patients treated with targeted therapy and 437 patients treated with immune checkpoint inhibitors, 2326 (55%) and 234 (54%) patients received upfront CN prior to treatment start. In multivariable analyses, CN was associated with significantly better OS in both the immune checkpoint inhibitor-treated (hazard ratio [HR]: 0.61; 95% confidence interval [CI], 0.41-0.90, p = 0.013) and the targeted therapy treatment (HR: 0.72; 95% CI, 0.67-0.78, p < 0.001) group. There was no difference in OS benefit of CN between the immune checkpoint inhibitor and targeted therapy treatment groups (interaction p = 0.6). Limitations include selection of patients from large academic centers and the retrospective nature of the study., Conclusions: Upfront CN is associated with a significant OS benefit in selected patients treated by either immune checkpoint inhibitors or targeted therapy, and still has a role in selected patients in the era of immune checkpoint inhibitors., Patient Summary: Before effective systemic therapies were available for metastatic kidney cancer, surgical removal of the primary (kidney) tumor was the mainstay of treatment. The role of removing the primary tumor has recently been called into question given that more effective systemic therapies have become available. In this study, we find that removal of the primary kidney tumor still has a benefit for selected patients treated with highly effective modern systemic therapies, including targeted therapies and immune checkpoint inhibitors., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: COVID-19 disproportionately impacted patients with cancer as a result of direct infection, and delays in diagnosis and therapy. Oncological clinical trials are resource-intensive endeavors that could be particularly susceptible to disruption by the pandemic, but few studies have evaluated the impact of the pandemic on clinical trial conduct., Patients and Methods: This prospective, multicenter study assesses the impact of the pandemic on therapeutic clinical trials at two large academic centers in the Northeastern United States between December 2019 and June 2021. The primary objective was to assess the enrollment on, accrual to, and activation of oncology therapeutic clinical trials during the pandemic using an institution-wide cohort of (i) new patient accruals to oncological trials, (ii) a manually curated cohort of patients with cancer, and (ii) a dataset of new trial activations., Results: The institution-wide cohort included 4756 new patients enrolled to clinical trials from December 2019 to June 2021. A major decrease in the numbers of new patient accruals (-46%) was seen early in the pandemic, followed by a progressive recovery and return to higher-than-normal levels (+2.6%). A similar pattern (from -23.6% to +30.4%) was observed among 467 newly activated trials from June 2019 to June 2021. A more pronounced decline in new accruals was seen among academically sponsored trials (versus industry sponsored trials) (P < 0.05). In the manually curated cohort, which included 2361 patients with cancer, non-white patients tended to be more likely taken off trial in the early pandemic period (adjusted odds ratio: 2.60; 95% confidence interval 1.00-6.63), and substantial pandemic-related deviations were recorded., Conclusions: Substantial disruptions in clinical trial activities were observed early during the pandemic, with a gradual recovery during ensuing time periods, both from an enrollment and an activation standpoint. The observed decline was more prominent among academically sponsored trials, and racial disparities were seen among people taken off trial., Competing Interests: Disclosure The authors report the following conflicts of interest: ZB non-financial support, Bristol Myers Squibb (BMS); research support, Genentech/imCore. Honoraria from UpToDate. CL research support, Genentech/imCore. AS educational travel support, Pfizer and Astellas. MMA research support, BMS Lilly, AstraZeneca, and Genentech; consulting/advisory role, BMS, Lilly, AstraZeneca, Genentech, Merck, Achilles, and Abbvie. RH consulting/advisory role, BMS, Merck, Pfizer, Genetech, AstraZeneca, and GSK; research grant/funding, Merck, BMS, Pfizer, Genentech, GSK, and AstraZeneca. ST institutional research funding from AstraZeneca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, Exelixis, BMS, Eisai, Nanostring, Cyclacel, Odonate, and Seattle Genetics; has served as an advisor/consultant to AstraZeneca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, BMS, Eisai, Nanostring, Puma, Sanofi, Celldex, Paxman, Puma, Silverback Therapeutics, G1 Therapeutics, AbbVie, Athenex, OncoPep, Outcomes4Me, Kyowa Kirin Pharmaceuticals, Daiichi-Sankyo, and Samsung Bioepsis Inc. MDG reports: Stock, Rappta Therapeutics; consulting/advisory role, BioMotiv, Janssen, Dendreon, Merck, GlaxoSmithKline, Lilly, Astellas, Genentech, BMS, Novartis, Pfizer, EMD Serono, AstraZeneca, Seattle Genetics, Incyte, Alleron Therapeutics, Dracen, Inovio Pharmaceuticals, Numab, Dragonfly Therapeutics; institutional research funding, Janssen, Dendreon, Novartis, Bristol-Myers Squibb, Merck, AstraZeneca, Genentech/Roche. TKC research support, AstraZeneca, Alexion, Bayer, BMS/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, Takeda; honoraria, AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc. (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), Research to Practice, L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology, Heron Therapeutics, Lilly Oncology; consulting or advisory role, AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, Pionyr, Tempest, Lilly Ventures; Stocks: Pionyr, Osel, and Tempest; leadership role, Director of Genitourinary Oncology Division at Dana-Farber and past President of Medical Staff at Dana-Farber, member of NCCN Kidney panel and the GU Steering Committee, past chairman of the Kidney Cancer Association Medical and Scientific Steering Committee, KidneyCan Advisory board, Kidney cancer Research Summit co-chair (2019-); patents, royalties or other intellectual properties related to checkpoint inhibitors biomarkers and ctDNA (no royalties made as to date); travel, accommodations, expenses, in relation to consulting, advisory roles, or honoraria; medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies (ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, Oxford PharmaGenesis, and others). TKC’s institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. TKC has mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. DD Consulting/Advisory role, Mirati, Ipsen, Boehringer Ingelheim, Atheneum Partners, Boston Healthcare Associates, Dedham Group, Guidepoint Global Advisors; travel expenses, Ipsen. All other authors have declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Purpose: Neuroendocrine prostate cancer (NEPC) is a resistance phenotype that emerges in men with metastatic castration-resistant prostate adenocarcinoma (CR-PRAD) and has important clinical implications, but is challenging to detect in practice. Herein, we report a novel tissue-informed epigenetic approach to noninvasively detect NEPC., Experimental Design: We first performed methylated immunoprecipitation and high-throughput sequencing (MeDIP-seq) on a training set of tumors, identified differentially methylated regions between NEPC and CR-PRAD, and built a model to predict the presence of NEPC (termed NEPC Risk Score). We then performed MeDIP-seq on cell-free DNA (cfDNA) from two independent cohorts of men with NEPC or CR-PRAD and assessed the accuracy of the model to predict the presence NEPC., Results: The test cohort comprised cfDNA samples from 48 men, 9 with NEPC and 39 with CR-PRAD. NEPC Risk Scores were significantly higher in men with NEPC than CR-PRAD (P = 4.3 × 10-7) and discriminated between NEPC and CR-PRAD with high accuracy (AUROC 0.96). The optimal NEPC Risk Score cutoff demonstrated 100% sensitivity and 90% specificity for detecting NEPC. The independent, multi-institutional validation cohort included cfDNA from 53 men, including 12 with NEPC and 41 with CR-PRAD. NEPC Risk Scores were significantly higher in men with NEPC than CR-PRAD (P = 7.5×10-12) and perfectly discriminated NEPC from CR-PRAD (AUROC 1.0). Applying the predefined NEPC Risk Score cutoff to the validation cohort resulted in 100% sensitivity and 95% specificity for detecting NEPC., Conclusions: Tissue-informed cfDNA methylation analysis is a promising approach for noninvasive detection of NEPC in men with advanced prostate cancer., (©2021 American Association for Cancer Research.)

Translocation renal cell carcinoma (tRCC) is a poorly characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 patients with tRCC identified across genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to targeted therapies. Consistently, we find that outcomes for patients with tRCC treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKIs) are worse than those treated with immune checkpoint inhibitors (ICI). Using multiparametric immunofluorescence, we find that the tumors are infiltrated with CD8 + T cells, though the T cells harbor an exhaustion immunophenotype distinct from that of clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses., Competing Interests: Declaration of interests Z.B.: research funding from Bristol-Myers Squibb & Genentech/imCORE; honoraria from UpToDate. X.G.: advisory board for Exelixis, Bayer and Guardant Health. D.A.B.: non-financial support from Bristol Myers Squibb, honoraria from LM Education/Exchange Services, advisory board fees from Exelixis and Aveo, and consulting/personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, and Insight Strategy outside of the submitted work. N.I.V.: advisory board to Sanofi/Genzyme, Oncocyte, and Lilly. M.S.H.: consultant, Janssen Pharmaceuticals and UpToDate. R.H.: research funding from Novartis. B.A.M.: consultant for Bayer, Astellas, AstraZeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, Dendreon, Bristol Myers Squibb, Calithera, and EMD Serono; research funding to the institution from Bristol Myers Squibb, Calithera, Exelixis, and Seattle Genetics. A.S.F.: consultant, Olympus America, Inc.; honoraria, Roche, Janssen; advisory board, Vessi Medical. C.J.W.: equity holder of BioNTech, Inc; research funding from Pharmacyclics. D.F.M.: honoraria from BMS, Pfizer, Merck, Alkermes, Inc., EMD Serono, Eli Lilly and Company, Iovance, Eisai, Inc., Werewolf Therapeutics, and Calithera Biosciences; research support from BMS, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, and Alkermes, Inc. D.Y.C.H.: consultancies and research funding from Pfizer, Novartis, BMS, Merck, Eisai, Ipsen, and Exelixis. S.S.: grants from Exelixis, grants from Bristol-Myers Squibb, personal fees from Merck, grants and personal fees from AstraZeneca, personal fees from CRISPR Therapeutics, personal fees from NCI, and personal fees from AACR; a patent for Biogenex with royalties paid. E.M.V.A.: advisory/consulting, Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Janssen, Manifold Bio, Monte Rosa; research support, Novartis, BMS; equity, Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa; patents, institutional patents filed on chromatin mutations and immunotherapy response and methods for clinical interpretation. T.K.C.: research (institutional and personal), Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb/ER Squibb and Sons, LLC, Calithera, Cerulean, Corvus, Eisai, Exelixis, F. Hoffmann-La Roche, Foundation Medicine, Inc., Genentech, GlaxoSmithKline, Ipsen, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Roche, Roche Products Limited, Sanofi/Aventis, Takeda, and Tracon; consulting/honoraria or advisory role, Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb/ER Squibb and Sons, LLC, Cerulean, Corvus, Eisai, EMD Serono, Exelixis, Foundation Medicine, Inc., Genentech, GlaxoSmithKline, Heron Therapeutics, Infinity Pharma, Ipsen, Jansen Oncology, IQVIA, Lilly, Merck, NCCN, Novartis, Nuscan, Peloton, Pfizer, Pionyr, Prometheus Labs, Roche, Sanofi/Aventis, Surface Oncology, Tempest, and Up-to-Date; CME-related events (e.g., OncLIve, PVI, MJH Life Sciences); NCI GU Steering Committee; stock ownership, Pionyr and Tempest; patents filed, royalties, or other intellectual properties, related to biomarkers of immune checkpoint blockers and ctDNA; travel, accommodations, expenses, medical writing in relation to consulting, advisory roles, or honoraria; no speaker’s bureau. S.R.V.: consulting, MPM Capital and Vida Ventures; spouse is an employee of and holds equity in Kojin Therapeutics. All other authors report no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Patients with lung cancer (LC) are susceptible to severe outcomes from COVID-19. This study evaluated disruption to care of patients with LC during the COVID-19 pandemic., Methods: The COVID-19 and Cancer Outcomes Study (CCOS) is a prospective cohort study comprised of patients with a current or past history of hematological or solid malignancies with outpatient visits between March 2 and March 6, 2020, at two academic cancer centers in the Northeastern United States (US). Data was collected for the three months prior to the index week (baseline period) and the following three months (pandemic period)., Results: 313 of 2365 patients had LC, 1578 had other solid tumors, and 474 had hematological malignancies. Patients with LC were not at increased risk of COVID-19 diagnosis compared to patients with other solid or hematological malignancies. When comparing data from the pandemic period to the baseline period, patients with LC were more likely to have a decrease in in-person visits compared to patients with other solid tumors (aOR 1.94; 95% CI, 1.46-2.58), but without an increase in telehealth visits (aOR 1.13; 95% CI 0.85-1.50). Patients with LC were more likely to experience pandemic-related treatment delays than patients with other solid tumors (aOR 1.80; 95% CI 1.13-2.80) and were more likely to experience imaging/diagnostic procedure delays than patients with other solid tumors (aOR 2.59; 95% CI, 1.46-4.47) and hematological malignancies (aOR 2.01; 95% CI, 1.02-3.93). Among patients on systemic therapy, patients with LC were also at increased risk for decreased in-person visits and increased treatment delays compared to those with other solid tumors., Discussion: Patients with LC experienced increased cancer care disruption compared to patients with other malignancies during the early phase of the COVID-19 pandemic. Focused efforts to ensure continuity of care for this patient population are warranted., (Copyright © 2021. Published by Elsevier B.V.)

Although therapeutic options for patients with advanced renal cell carcinoma (RCC) have increased in the past decade, no biomarkers are yet available for patient stratification or evaluation of therapy resistance. Given the dynamic and heterogeneous nature of clear cell RCC (ccRCC), tumor biopsies provide limited clinical utility, but liquid biopsies could overcome these limitations. Prior liquid biopsy approaches have lacked clinically relevant detection rates for patients with ccRCC. This study employed ccRCC-specific markers, CAIX and CAXII, to identify circulating tumor cells (CTC) from patients with metastatic ccRCC. Distinct subtypes of ccRCC CTCs were evaluated for PD-L1 and HLA-I expression and correlated with patient response to therapy. CTC enumeration and expression of PD-L1 and HLA-I correlated with disease progression and treatment response, respectively. Longitudinal evaluation of a subset of patients demonstrated potential for CTC enumeration to serve as a pharmacodynamic biomarker. Further evaluation of phenotypic heterogeneity among CTCs is needed to better understand the clinical utility of this new biomarker., (© 2021 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.

Background: CD73-adenosine signaling in the tumor microenvironment is immunosuppressive and may be associated with aggressive renal cell carcinoma (RCC). We investigated the prognostic significance of CD73 protein expression in RCC leveraging nephrectomy samples. We also performed a complementary analysis using The Cancer Genome Atlas (TCGA) dataset to evaluate the correlation of CD73 (ecto-5'-nucleotidase ( NT5E ), CD39 (ectonucleoside triphosphate diphosphohydrolase 1 ( ENTPD1 )) and A2 adenosine receptor (A2AR; ADORA2A ) transcript levels with markers of angiogenesis and antitumor immune response., Methods: Patients with RCC with available archived nephrectomy samples were eligible for inclusion. Tumor CD73 protein expression was assessed by immunohistochemistry and quantified using a combined score (CS: % positive cells×intensity). Samples were categorized as CD73 negative (CS=0), CD73 low or CD73 high (< and ≥median CS, respectively). Multivariable Cox regression analysis compared disease-free survival (DFS) and overall survival (OS) between CD73 expression groups. In the TCGA dataset, samples were categorized as low, intermediate and high NT5E , ENTPD1 and ADORA2A gene expression groups. Gene expression signatures for infiltrating immune cells, angiogenesis, myeloid inflammation, and effector T-cell response were compared between NT5E , ENTPD1 and ADORA2A expression groups., Results: Among the 138 patients eligible for inclusion, 'any' CD73 expression was observed in 30% of primary tumor samples. High CD73 expression was more frequent in patients with M1 RCC (29% vs 12% M0), grade 4 tumors (27% vs 13% grade 3 vs 15% grades 1 and 2), advanced T-stage (≥T3: 22% vs T2: 19% vs T1: 12%) and tumors with sarcomatoid histology (50% vs 12%). In the M0 cohort (n=107), patients with CD73 high tumor expression had significantly worse 5-year DFS (42%) and 10-year OS (22%) compared with those in the CD73 negative group (DFS: 75%, adjusted HR: 2.7, 95% CI 1.3 to 5.9, p=0.01; OS: 64%, adjusted HR: 2.6, 95% CI 1.2 to 5.8, p=0.02) independent of tumor stage and grade. In the TCGA analysis, high NT5E expression was associated with significantly worse 5-year OS (p=0.008). NT5E and ENTPD1 expression correlated with higher regulatory T cell (Treg) signature, while ADORA2A expression was associated with increased Treg and angiogenesis signatures., Conclusions: High CD73 expression portends significantly worse survival outcomes independent of stage and grade. Our findings provide compelling support for targeting the immunosuppressive and proangiogenic CD73-adenosine pathway in RCC., Competing Interests: Competing interests: AT: advisory role for Foundation Medicine, Pfizer; research funding to institution from EMD Serono, Bayer, Clovis Oncology, Aravive Inc, WindMIL therapeutics, Corvus Pharmaceuticals; EL, WX, AF, JAS, ESG, GB, JHF, CG, CM and LT: none; NM-C: support for research travel from Pfizer and Ipsen, and consulting fees from BMS and Bayer; XXW: research funding to institution from Bristol-Myers Squibb (BMS); MG: research funding from BMS and Merck; BAM: payment for consulting with Bayer, Astellas, Astra Zeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai and EMD Serono, and received research support to Dana Farber Cancer Institute (DFCI) from BMS, Calithera, Exelixis, Seattle Genetics. TKC: supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI. Research (institutional and personal): AstraZeneca, Alexion, Bayer, BMS/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc, Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, Takeda. Honoraria: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc, Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), Research to Practice, L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology, Heron Therapeutics, Lilly Oncology. Consulting or advisory Role: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, Pionyr, Tempest, Lilly Ventures. Stock ownership: Pionyr, Tempest. Other present or past leadership roles: Director of GU Oncology Division at Dana-Farber and past President of medical Staff at Dana-Farber), member of NCCN Kidney panel and the GU Steering Committee, past chairman of the Kidney Cancer Association Medical and Scientific Steering Committee), KidneyCan Advisory board, Kidney cancer Research Summit co-chair (2019-). Patents, royalties or other intellectual properties: related to biomarkers of immune checkpoint blockers. Travel, accommodations, expenses, in relation to consulting, advisory roles, or honoraria: Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies (ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, Oxford PharmaGenesis, and others).The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. CV provided upon request for scope of clinical practice and researchMentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. NA: consultancy to Astellas, Astra Zeneca, Bayer, Bristol Myers Squibb, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Janssen, Merck, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics. Research funding to my institution: Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Glaxo Smith Kline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. DFM: Honorarium for consultancy from BMS, Pfizer, Merck, Alkermes Inc, EMD Serono, Eli Lilly, Iovance and Eisai. Research support from BMS, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, Alkermes. SS: reports receiving commercial research grants from Bristol-Myers Squibb, AstraZeneca, Exelixis and Novartis; is a consultant/advisory board member for Merck, AstraZeneca, Bristol-Myers Squibb, CRISPR Therapeutics AG, AACR, and NCI; and receives royalties from Biogenex. LCH: Reports consulting fees from Genentech, Dendreon, Pfizer, Medivation/Astellas, Exelixis, Bayer, Kew Group, Corvus, Merck, Novartis, BMS, Michael J Hennessy Associates (Healthcare Communications Company and several brands such as OncLive and PER), Jounce, EMD Serrano, ASIM CME, and Ology Medical Education. Research funding from Bayer, Sotio, BMS, Merck, Takeda, Dendreon/Valient, Jannsen, Medivation/Astellas, Genentech, Pfizer, Endocyte (Novartis). Support for research travel from Bayer and Genentech. Currently employed by Surface Oncology., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Prior data have variably implicated the inactivation of the mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) complex with increased tumor sensitivity to immune checkpoint inhibitors (ICI). Herein, we examined the association between mSWI/SNF variants and clinical outcomes to ICIs. We correlated somatic loss-of-function (LOF) variants in a predefined set of mSWI/SNF genes ( ARID1A, ARID1B, SMARCA4, SMARCB1, PBRM1 , and ARID2 ) with clinical outcomes in patients with cancer treated with systemic ICIs. We identified 676 patients from Dana-Farber Cancer Institute (DFCI, Boston, MA) and 848 patients from a publicly available database from Memorial Sloan Kettering Cancer Center (MSKCC, New York, NY) who met the inclusion criteria. Multivariable analyses were conducted and adjusted for available baseline factors and tumor mutational burden. Median follow-up was 19.6 (17.6-22.0) months and 28.0 (25.0-29.0) months for the DFCI and MSKCC cohorts, respectively. Seven solid tumor subtypes were examined. In the DFCI cohort, LOF variants of mSWI/SNF did not predict improved overall survival (OS), time-to-treatment failure (TTF), or disease control rate. Only patients with renal cell carcinoma with mSWI/SNF LOF showed significantly improved OS and TTF with adjusted HRs (95% confidence interval) of 0.33 (0.16-0.7) and 0.49 (0.27-0.88), respectively, and this was mostly driven by PRBM1 In the MSKCC cohort, where only OS was captured, LOF mSWI/SNF did not correlate with improved outcomes across any tumor subtype. We did not find a consistent association between mSWI/SNF LOF variants and improved clinical outcomes to ICIs, suggesting that mSWI/SNF variants should not be considered as biomarkers of response to ICIs., (©2020 American Association for Cancer Research.)

Background: Cabozantinib is approved for the first and subsequent line treatment of metastatic clear-cell renal cell carcinoma (ccRCC) based on trials in which most patients were immune checkpoint blockade (ICB) naive. With an expanding role of ICB in earlier lines of therapy, we assessed activity of cabozantinib in patients with metastatic ccRCC after progressing on anti-PD-1/PD-L1-based ICBs., Methods: We retrospectively analysed the clinical outcomes of 86 patients from 2 academic centres who received cabozantinib after progression on ICB alone, ICB in combination with vascular endothelial growth factor inhibitors (VEGFis) or ICB in combination with other therapies. Overall response rate (ORR, investigator assessed), time to treatment failure (TTF), overall survival (OS) and toxicities leading to dose reductions or cessation were evaluated., Results: Eighty-six patients were included in the analysis; the median age was 63 years (range 33-84) and the median number of prior therapies was 2 (range 1-10). The type of prior ICB therapy was ICBs alone (64%), an ICB in combination with a VEGFi (29%) or ICBs in combination with other therapies (7%). At the time of cabozantinib treatment, 71% of patients were in the International Metastatic RCC Database Consortium good- or intermediate-risk groups. Approximately half of patients (52%) were started on cabozantinib at the full 60 mg daily dose. The ORR was 36% (95% confidence interval [CI] = 26-47%) with no complete response and 43% achieving stable disease; 21% had primary progressive disease. The median TTF was 6.5 months (95% CI = 5.3-8.5.). The median OS was 13.1 months (95% CI = 8.7-NR) with 55% (95% CI = 41-66%) OS rate at 12 months. Most common reasons for dose reductions were fatigue (27%), palmar-plantar erythrodysesthesia (16%) and diarrhoea (10%)., Conclusions: Cabozantinib is active in patients treated with prior ICB-based therapies, with no new safety signals. This study supports the use of cabozantinib after ICB-based therapies., Competing Interests: Conflict of interest statement B.A.M. is reports serving as a consultant for Bayer, Astellas, AstraZeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech and EMD Serono and reports receiving research support to Dana Farber Cancer Institute (DFCI) from Bristol Myers Squibb, Calithera, Exelixis andSeattle Genetics. A.-K.AL. reports serving as a consultant for AbbVie, Astellas, Bristol-Myers Squibb, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer, Roche and TerSera and reports receiving research grants (institution or personal) from Bristol-Myers Squibb, Novartis, Roche andIpsen. D.A.B. reports receiving non-financial support from Bristol-Myers Squibb and personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group and Insight Strategy, outside the submitted work. X.X.W. reports receiving research support to DFCI from Bristol Myers Squibb. L.C.H. reports serving as a consultant for Genentech, Dendreon, Pfizer, Medivation/Astellas, Exelixis, Bayer, Kew Group, Corvus, Merck, Novartis, Michael J Hennessy Associates (Healthcare Communications Company and several brands such as OncLive and PER), Jounce, EMD Serrano and Ology Medical Education; reports receiving research funding to the institution (DFCI) from Bayer, Sotio, Bristol-Myers Squib, Merck, Takeda, Dendreon/Valient, Jannsen, Medivation/Astellas, Genentech, Pfizer and Endocyte (Novartis) and reports receiving financial support for research travel from Bayer and Genentech. M.A.B. reports serving as a consultant for Exelixis, Seattle Genetics, EMD Serono, Nektar and Sanofi and receiving institutional research funding from Bayer, Bristol-Myers Squibb, Genentech/Roche, Xencor, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peleton and Pfizer. T.K.C. reports serving as a consultant for Analysis Group, AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Heron Therapeutics, Lilly, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology and receiving research support to DFCI from Analysis Group, AstraZeneca, Alexion, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Sanofi/Aventis andTakeda. All remaining authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

National and international consortia will play a key role in understanding the effects of the coronavirus disease 2019 (COVID-19) pandemic on cancer patients. The COVID-19 and Cancer Consortium (CCC19) aims to collect and analyze observational data at scale to inform clinical practice in real-time., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Antibiotic use alters commensal gut microbiota, which is a key regulator of immune homeostasis., Objective: To investigate the impact of antibiotic use on clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with systemic agents., Design, Setting, and Participants: We analyzed two cohorts: an institutional cohort (n=146) receiving programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-based immune checkpoint inhibitors (ICIs) and a trial-database cohort (n=4144) receiving interferon-α (n=510), mammalian target of rapamycin (mTOR) inhibitors (n=660), and vascular endothelial growth factor targeted therapies (VEGF-TT; n=2974) on phase II/III clinical trials., Outcomes Measurements and Statistical Analysis: The association of antibiotic use (defined as use from 8 wk before to 4 wk after the initiation of anticancer therapy) with progression-free survival (PFS) and overall survival (OS) was evaluated using Cox regression, adjusted for known prognostic factors including International Metastatic RCC Database Consortium risk factors., Results and Limitations: Most patients were male, had clear cell histology, and were at an intermediate risk. Overall, in the institutional cohort, objective response rate (ORR) was 30%, PFS was 7.2 mo, and 1-yr OS was 77%. Antibiotic users (n=31, 21%) had a lower ORR (12.9% vs 34.8%, p=0.026) and shorter PFS (adjusted hazard ratio [HR]=1.96, 95% confidence interval [CI] 1.20-3.20, p=0.007) than antibiotic nonusers. In the trial-database cohort, antibiotic use (n=709, 17%) adversely impacted OS in patients treated with interferon (HR=1.62, 95% CI 1.13-2.31, p=0.008) or with VEGF-TT and prior cytokines (HR=1.65, 95% CI 1.04-2.62, p=0.033), but not patients treated with mTOR inhibitors or VEGF-TT without prior cytokines. Limitations include retrospective design, and limited details regarding concomitant medications and antibiotic indication/duration., Conclusions: Antibiotic use appears to reduce the efficacy of immunotherapy-based regimens in mRCC. The modulation of gut microbiota may play an important role in optimizing outcomes of patients treated with ICIs., Patient Summary: We evaluated metastatic renal cell carcinoma patients and found that those who were treated with immunotherapy had worse outcomes if they also received antibiotics at the start of treatment. This study highlights the importance of judicious antibiotic use., (Copyright © 2019. Published by Elsevier B.V.)

Background: International Metastatic Renal Cell Carcinoma (mRCC) Database Consortium (IMDC) risk groups are important when considering therapeutic options for first-line treatment., Materials and Methods: Adult patients with clear cell mRCC initiating first-line sunitinib between 2010 and 2018 were included in this retrospective database study. Median time to treatment discontinuation (TTD) and overall survival (OS) were estimated using Kaplan-Meier analysis. Outcomes were stratified by IMDC risk groups and evaluated for those in the combined intermediate and poor risk group and separately for those in the intermediate risk group with one versus two risk factors., Results: Among 1,769 patients treated with first-line sunitinib, 318 (18%) had favorable, 1,031 (58%) had intermediate, and 420 (24%) had poor IMDC risk. Across the three risk groups, patients had similar age, gender, and sunitinib initiation year. Median TTD was 15.0, 8.5, and 4.2 months in the favorable, intermediate, and poor risk groups, respectively, and 7.1 months in the combined intermediate and poor risk group. Median OS was 52.1, 31.5, and 9.8 months in the favorable, intermediate, and poor risk groups, respectively, and 23.2 months in the combined intermediate and poor risk group. Median OS (35.1 vs. 21.9 months) and TTD (10.3 vs. 6.6 months) were significantly different between intermediate risk patients with one versus two risk factors., Conclusion: This real-world study found a median OS of 52 months for patients with favorable IMDC risk treated with first-line sunitinib, setting a new benchmark on clinical outcomes of clear cell mRCC. Analysis of intermediate risk group by one or two risk factors demonstrated distinct clinical outcomes., Implications for Practice: This analysis offers a contemporary benchmark for overall survival (median, 52.1 months; 95% confidence interval, 43.4-61.2) among patients with clear cell metastatic renal cell carcinoma who were treated with sunitinib as first-line therapy in a real-world setting and classified as favorable risk according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group classification. This study demonstrates that clinical outcomes differ between IMDC risk groups as well as within the intermediate risk group based on the number of risk factors, thus warranting further consideration of risk group when counseling patients about therapeutic options and designing clinical trials., (© AlphaMed Press 2020.)

Background: Immune checkpoint inhibitors (ICI) induce a range of immune-related adverse events (irAEs) with various degrees of severity. While clinical experience with ICI retreatment following clinically significant irAEs is growing, the safety and efficacy are not yet well characterized., Methods: This multicenter retrospective study identified patients with metastatic renal cell carcinoma treated with ICI who had >1 week therapy interruption for irAEs. Patients were classified into retreatment and discontinuation cohorts based on whether or not they resumed an ICI. Toxicity and clinical outcomes were assessed descriptively., Results: Of 499 patients treated with ICIs, 80 developed irAEs warranting treatment interruption; 36 (45%) of whom were restarted on an ICI and 44 (55%) who permanently discontinued. Median time to initial irAE was similar between the retreatment and discontinuation cohorts (2.8 vs 2.7 months, p=0.59). The type and grade of irAEs were balanced across the cohorts; however, fewer retreatment patients required corticosteroids (55.6% vs 84.1%, p=0.007) and hospitalizations (33.3% vs 65.9%, p=0.007) for irAE management compared with discontinuation patients. Median treatment holiday before reinitiation was 0.9 months (0.2-31.6). After retreatment, 50% (n=18/36) experienced subsequent irAEs (12 new, 6 recurrent) with 7 (19%) grade 3 events and 13 drug interruptions. Median time to irAE recurrence after retreatment was 2.8 months (range: 0.3-13.8). Retreatment resulted in 6 (23.1%) additional responses in 26 patients whose disease had not previously responded. From first ICI initiation, median time to next therapy was 14.2 months (95% CI 8.2 to 18.9) and 9.0 months (5.3 to 25.8), and 2-year overall survival was 76% (95%CI 55% to 88%) and 66% (48% to 79%) in the retreatment and discontinuation groups, respectively., Conclusions: Despite a considerable rate of irAE recurrence with retreatment after a prior clinically significant irAE, most irAEs were low grade and controllable. Prospective studies are warranted to confirm that retreatment enhances survival outcomes that justify the safety risks., Competing Interests: Competing interests: WX reports consulting role with Bayer. NM-C reports support for research travel from Pfizer and Ipsen, and consulting fees for BMS. BAM reports advisory roles for Astellas/Seattle Genetics, Astra Zeneca, Nektar, Exelixis, Pfizer and consultant roles for Astellas, Bayer, Genentech, Janssen and EMD Serono. DYCH reports consulting roles with BMS, Novartis, Pfizer, Ipsen and Exelixis. MAB has a consulting/advisory role with Exelixis, Seattle Genetics, EMD Serono, Nektar and Sanofi and receives institutional research funding from Bayer, Bristol-Myers Squibb, Genentech/Roche, Xencor, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peleton and Pfizer. TKC reports research (institutional and personal) funds from AstraZeneca, Alexion, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, Takedal Honoraria from AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), Research to Practice, L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology, Heron Therapeutics, Lilly; consulting or advisory Role for AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, Pionyr, Tempest; stock ownership in Pionyr, Tempest; no leadership or employment in for-profit companies; other present or past leadership roles: Director of GU Oncology Division at Dana-Farber and past President of medical Staff at Dana-Farber), member of NCCN Kidney panel and the GU Steering Committee, past chairman of the Kidney Cancer Association Medical and Scientific Steering Committee); patents, royalties or other intellectual properties: International Patent Application No. PCT/US2018/12209, entitled “PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response,” filed January 3, 2018, claiming priority to U.S. Provisional Patent Application No. 62/445,094, filed January 11, 2017 and International Patent Application No. PCT/US2018/058430, entitled “Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy,” filed October 31, 2018, claiming priority to U.S. Provisional Patent Application No. 62/581,175, filed November 3, 2017; travel, accommodations, expenses, in relation to consulting, advisory roles, or honoraria; medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies (ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, Oxford PharmaGenesis, and others).The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. CV provided upon request for scope of clinical practice and research. He reports mentoring several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. LCH reports consulting fees from Genentech, Dendreon, Pfizer, Medivation/Astellas, Exelixis, Bayer, Kew Group, Corvus, Merck, Novartis, Michael J Hennessy Associates (Healthcare Communications Company and several brands such as OncLive and PER), Jounce, EMD Serrano, Ology Medical Education; Research funding from Bayer, Sotio, Bristol-Myers Squib, Merck, Takeda, Dendreon/Valient, Jannsen, Medivation/Astellas, Genentech, Pfizer, Endocyte (Novartis), and support for research travel from Bayer and Genentech., (© 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.)

Purpose: In this multicenter phase II trial, we evaluated atezolizumab combined with bevacizumab in patients with advanced renal cell carcinoma (RCC) with variant histology or any RCC histology with ≥ 20% sarcomatoid differentiation., Patients and Methods: Eligible patients may have received previous systemic therapy, excluding prior bevacizumab or checkpoint inhibitors. Patients underwent a baseline biopsy and received atezolizumab 1,200 mg and bevacizumab 15 mg/kg intravenously every 3 weeks. The primary end point was overall response rate (ORR) by RECIST version 1.1. Additional end points were progression-free survival (PFS), toxicity, biomarkers of response as determined by programmed death-ligand 1 (PD-L1) status, and on-therapy quality-of-life (QOL) metrics using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 and the Brief Fatigue Inventory., Results: Sixty patients received at least 1 dose of either study agent; the majority (65%) were treatment naïve. The ORR for the overall population was 33% and 50% in patients with clear cell RCC with sarcomatoid differentiation and 26% in patients with variant histology RCC. Median PFS was 8.3 months (95% CI, 5.7 to 10.9 months). PD-L1 status was available for 36 patients; 15 (42%) had ≥ 1% expression on tumor cells. ORR in PD-L1-positive patients was 60% (n = 9) v 19% (n = 4) in PD-L1-negative patients. Eight patients (13%) developed treatment-related grade 3 toxicities. There were no treatment-related grade 4-5 toxicities. QOL was maintained throughout therapy., Conclusion: In this study, atezolizumab and bevacizumab demonstrated safety and resulted in objective responses in patients with variant histology RCC or RCC with ≥ 20% sarcomatoid differentiation. This regimen warrants additional exploration in patients with rare RCC, particularly those with PD-L1-positive tumors.

The current standard of care for treatment of metastatic renal cell carcinoma (mRCC) patients is PD-1/PD-L1 inhibitors until progression or toxicity. Here, we characterize the clinical outcomes for 19 mRCC patients who experienced an initial clinical response (any degree of tumor shrinkage), but after immune-related adverse events (irAE) discontinued all systemic therapy. Clinical baseline characteristics, outcomes, and survival data were collected. The primary endpoint was time to progression from the date of treatment cessation (TTP). Most patients had clear cell histology and received anti-PD-1/PD-L1 therapy as second-line or later treatment. Median time on PD-1/PD-L1 therapy was 5.5 months (range, 0.7-46.5) and median TTP was 18.4 months (95% CI, 4.7-54.3) per Kaplan-Meier estimation. The irAEs included arthropathies, ophthalmopathies, myositis, pneumonitis, and diarrhea. We demonstrate that 68.4% of patients ( n = 13) experienced durable clinical benefit off treatment (TTP of at least 6 months), with 36% ( n = 7) of patients remaining off subsequent treatment for over a year after their last dose of anti-PD-1/PD-L1. Three patients with tumor growth found in a follow-up visit, underwent subsequent surgical intervention, and remain off systemic treatment. Nine patients (47.4%) have ongoing irAEs. Our results show that patients who benefitted clinically from anti-PD-1/PD-L1 therapy can experience sustained beneficial responses, not needing further therapies after the initial discontinuation of treatment due to irAEs. Investigation of biomarkers indicating sustained benefit to checkpoint blockers are needed. Cancer Immunol Res; 6(4); 402-8. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: An elevated Neutrophil-to-lymphocyte ratio (NLR) is associated with worse outcomes in several malignancies. However, its role with contemporary immune checkpoint blockade (ICB) is unknown. We investigated the utility of NLR in metastatic renal cell carcinoma (mRCC) patients treated with PD-1/PD-L1 ICB., Methods: We examined NLR at baseline and 6 (±2) weeks later in 142 patients treated between 2009 and 2017 at Dana-Farber Cancer Institute (Boston, USA). Landmark analysis at 6 weeks was conducted to explore the prognostic value of relative NLR change on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Cox and logistic regression models allowed for adjustment of line of therapy, number of IMDC risk factors, histology and baseline NLR., Results: Median follow up was 16.6 months (range: 0.7-67.8). Median duration on therapy was 5.1 months (<1-61.4). IMDC risk groups were: 18% favorable, 60% intermediate, 23% poor-risk. Forty-four percent were on first-line ICB and 56% on 2nd line or more. Median NLR was 3.9 (1.3-42.4) at baseline and 4.1 (1.1-96.4) at week 6. Patients with a higher baseline NLR showed a trend toward lower ORR, shorter PFS, and shorter OS. Higher NLR at 6 weeks was a significantly stronger predictor of all three outcomes than baseline NLR. Relative NLR change by ≥25% from baseline to 6 weeks after ICB therapy was associated with reduced ORR and an independent prognostic factor for PFS (p < 0.001) and OS (p = 0.004), whereas a decrease in NLR by ≥25% was associated with improved outcomes., Conclusions: Early decline and NLR at 6 weeks are associated with significantly improved outcomes in mRCC patients treated with ICB. The prognostic value of the readily-available NLR warrants larger, prospective validation.

Background: Monoclonal antibodies targeting the PD-1/PD-L1 axis have gained increasing attention across many solid tumors and hematologic malignancies due to their efficacy and favorable toxicity profile. With more than 1 agent now FDA-approved in a wide variety of tumor types, and with others in clinical trials, it is becoming more common that patients present to clinic for potential treatment with a second PD-1/PD-L1 inhibitor., Case Presentation: In this report, we present two patients with renal cell carcinoma and one with melanoma who received PD-1/PD-L1 inhibitors. Upon progression on their first-line PD-1/PD-L1 inhibitors, these patients received a different PD-1 inhibitor (nivolumab in all cases) and all had progressive disease as their best response to the subsequent PD-1 inhibitor. The reported clinical information focuses on the course of the disease and the responses to all treatment regimens., Conclusions: Clinicians should refrain from using multiple PD-1/PD-L1 inhibitors sequentially outside of clinical trials until there is sufficient data to support this practice routinely. Prospective studies that allow prior treatment with PD-1/PD-L1 are needed to validate the efficacy and safety of these drugs in the second line or later setting. Furthermore, ongoing efforts that aim to identify mechanisms of resistance to immunotherapy will be informative and may ultimately assist physicians in select the optimal treatment following progression on PD-1/PD-L1 inhibitor.