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There is a paucity of data on the safety of cabozantinib use in combination with radiotherapy.To report the practice patterns, safety, and efficacy of cabozantinib with radiotherapy in metastatic renal cell carcinoma (mRCC).An international multicenter retrospective study was conducted. Patients with mRCC treated with cabozantinib at any line of therapy and who received radiotherapy between 30 d prior to the start date of cabozantinib and 30 d following discontinuation of cabozantinib, from 2014 to 2020, were included. Concurrent use was defined as the use of cabozantinib on radiotherapy treatment days during any course of radiotherapy.The primary outcomes of interest were the rate of grade ≥3 adverse events (AEs) occurring within 90 d of receipt of radiotherapy. Secondary outcomes included hospitalization rate and patterns of cabozantinib and radiotherapy use. Baseline characteristics and AEs were presented descriptively.A total of 127 consecutive patients were included. Most patients had clear cell histology (88%), had International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk disease (57%), and had received at least one prior line of therapy (93%). Of 127 patients, 67 (53%) received concurrent cabozantinib with radiotherapy, while the remaining held cabozantinib on radiotherapy days. Overall, grade 3-4 AEs occurred in 6.3% (n = 8/127) of patients. No grade 5 events were observed. In patients treated with conventional palliative radiotherapy (n = 88), the rate of grade 3-4 AEs in those who had concurrent versus those who had nonconcurrent cabozantinib was 6.3% (n = 3/48) versus 5.0% (n = 2/40). No patient was hospitalized due to radiotherapy-related toxicity. In patients treated with stereotactic ablative body radiotherapy (SABR; n = 50), the rate of grade 3-4 AEs in those who had concurrent versus those who had nonconcurrent cabozantinib was 3.6% (n = 1/28) versus 9.1% (n = 2/22). One patient in the nonconcurrent group was hospitalized due to muscle weakness suspected to be related to associated vasogenic edema 19 d after SABR for multiple brain metastases.In this real-world study of patients with mRCC treated with cabozantinib, 53% of patients received radiotherapy concurrently, with few grade 3-4 AEs reported within 90 d of receiving radiotherapy. The use of radiotherapy and cabozantinib requires a risk-benefit assessment of patient and disease characteristics to optimize therapy regimens.Our study reports the real-world experience of using radiotherapy in patients receiving cabozantinib for metastatic kidney cancer. Over half of the patients continued taking cabozantinib while receiving radiotherapy, and few patients developed serious side effects. The combined use of radiotherapy and cabozantinib requires a careful risk-benefit assessment to achieve optimal treatment outcomes.

Summary Background Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness. Methods In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. Findings Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57–76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53–2·21), male sex (1·63, 1·07–2·48), smoking status (former smoker vs never smoked: 1·60, 1·03–2·47), number of comorbidities (two vs none: 4·50, 1·33–15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11–7·18), active cancer (progressing vs remission: 5·20, 2·77–9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79–4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07–0·84) or the US-Midwest (0·50, 0·28–0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. Interpretation Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments. Funding American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

Translocation renal cell carcinoma (tRCC) is an aggressive and 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 tRCC patients identified across multiple 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 many targeted therapies. Consistently, we find that outcomes for tRCC patients treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKI) are worse than those treated with immune checkpoint inhibition (ICI). Multiparametric immunofluorescence confirmed the presence of CD8 + tumor-infiltrating T cells compatible with a clinical benefit from ICI and revealed an exhaustion immunophenotype distinct from clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses.

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.

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., Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.

When the COVID-19 pandemic began, formal frameworks to collect data about affected patients were lacking. The COVID-19 and Cancer Consortium (CCC19) was formed to collect granular data on patients with cancer and COVID-19 at scale and as rapidly as possible. CCC19 has grown from five initial institutions to 125 institutions with >400 collaborators. More than 5,000 cases with complete baseline data have been accrued. Future directions include increased electronic health record integration for direct data ingestion, expansion to additional domestic and international sites, more intentional patient involvement, and granular analyses of still-unanswered questions related to cancer subtypes and treatments.

BackgroundCD73–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.MethodsPatients 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 CD73negative(CS=0), CD73lowor CD73high(< 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 highNT5E,ENTPD1andADORA2Agene expression groups. Gene expression signatures for infiltrating immune cells, angiogenesis, myeloid inflammation, and effector T-cell response were compared betweenNT5E,ENTPD1andADORA2Aexpression groups.ResultsAmong 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 CD73hightumor expression had significantly worse 5-year DFS (42%) and 10-year OS (22%) compared with those in the CD73negativegroup (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, highNT5Eexpression was associated with significantly worse 5-year OS (p=0.008).NT5EandENTPD1expression correlated with higher regulatory T cell (Treg) signature, whileADORA2Aexpression was associated with increased Treg and angiogenesis signatures.ConclusionsHigh 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.

Summary Immune checkpoint blockade (ICB) results in durable disease control in a subset of patients with advanced renal cell carcinoma (RCC), but mechanisms driving resistance are poorly understood. We characterize the single-cell transcriptomes of cancer and immune cells from metastatic RCC patients before or after ICB exposure. In responders, subsets of cytotoxic T cells express higher levels of co-inhibitory receptors and effector molecules. Macrophages from treated biopsies shift toward pro-inflammatory states in response to an interferon-rich microenvironment but also upregulate immunosuppressive markers. In cancer cells, we identify bifurcation into two subpopulations differing in angiogenic signaling and upregulation of immunosuppressive programs after ICB. Expression signatures for cancer cell subpopulations and immune evasion are associated with PBRM1 mutation and survival in primary and ICB-treated advanced RCC. Our findings demonstrate that ICB remodels the RCC microenvironment and modifies the interplay between cancer and immune cell populations critical for understanding response and resistance to ICB., Graphical abstract, Highlights • Distinct CD8+ T cell phenotypes are enriched after immune checkpoint blockade (ICB) • Immune checkpoint ligands are upregulated in macrophages and tumor cells after ICB • Two cancer cell subpopulations are conserved across heterogeneous RCC tumors • Cancer cell programs drive distinct immune interactions and predict patient outcomes, Bi et al. dissect the cancer cell and immune microenvironmental transcriptional programs in immune checkpoint blockade-exposed metastatic renal cell carcinoma, revealing immune subpopulation reprogramming and interactions with distinct cancer cell populations in the context of clinical resistance.

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 tumors1–3, 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 shed light on the molecular drivers of aggressivity and responsiveness to immune checkpoint inhibitors of S/R RCC tumors.

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-TKI) are worse than those treated with immune checkpoint inhibition (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.

Improving early cancer detection has the potential to substantially reduce cancer-related mortality. Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) is a highly sensitive assay capable of detecting early-stage tumors. We report accurate classification of patients across all stages of renal cell carcinoma (RCC) in plasma (area under the receiver operating characteristic (AUROC) curve of 0.99) and demonstrate the validity of this assay to identify patients with RCC using urine cell-free DNA (cfDNA; AUROC of 0.86).

The tumor immune microenvironment plays a critical role in cancer progression and response to immunotherapy in clear cell renal cell carcinoma (ccRCC), yet the composition and phenotypic states of immune cells in this tumor are incompletely characterized. We performed single-cell RNA and T cell receptor sequencing (scRNA-seq/scTCR-seq) on 164,722 individual cells from tumor and adjacent non-tumor tissue in patients with ccRCC across disease stages – early, locally advanced, and advanced/metastatic. Terminally exhausted CD8(+) T cells were enriched in metastatic disease and were restricted in TCR diversity. Within the myeloid compartment, pro-inflammatory macrophages were decreased, and suppressive M2-like macrophages were increased in advanced disease. Terminally exhausted CD8(+) T cells and M2-like macrophages co-occurred in advanced disease and expressed ligands and receptors that support T cell dysfunction and M2-like polarization. This immune dysfunction circuit is associated with a worse prognosis in external cohorts and identifies potentially targetable immune inhibitory pathways in ccRCC.

Introduction: Patients with thoracic malignancies are susceptible to severe outcomes from coronavirus disease 2019 (COVID-19). The aim of this study was to evaluate the disruption to care of patients with thoracic malignancies during the COVID-19 pandemic. Methods: The COVID-19 and Cancer Outcomes Study (CCOS) is a multicenter prospective cohort study comprised of adult patients with a current or past history of hematological malignancy or invasive solid tumor who had an outpatient medical oncology visit on the index week between March 2 and March 6, 2020 at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York, NY (MSSM) or the Dana-Farber Cancer Institute in Boston, MA (DFCI). An electronic data capture platform was used to collect patient-, cancer-, and treatment-related variables during the three months prior to the index week (the baseline period) and the following three months (the pandemic period). Two-by-three contingency tables with Fisher’s exact tests were computed. All tests were two-tailed and considered statistically significant for p Citation Format: Sheena Bhalla, Ziad Bakouny, Andrew L. Schmidt, John A. Steinharter, Douglas A. Tremblay, Mark M. Awad, Alaina J. Kessler, Robert I. Haddad, Michelle Evans, Fiona Busser, Michael Wotman, Catherine R. Curran, Brittney S. Zimmerman, Gabrielle Bouchard, Tomi Jun, Pier V. Nuzzo, Qian Qin, Laure Hirsch, Jonathan Feld, Kaitlin M Kelleher, Danielle Seidman, Hsin-Hui Huang, Chris Labaki, Heather M. Anderson-Keightly, Sarah Abou Alaiwi, Talia D. Rosenbloom, Penina S. Stewart, Matthew D. Galsky, Toni K. Choueiri, Deborah B. Doroshow. Disruption to care of patients with thoracic malignancies: A COVID-19 and cancer outcomes study [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr S06-02.

Background: The COVID-19 pandemic has rapidly altered cancer care However, the ways in which it has done so and the associated impact at the individual and societal levels remains poorly defined Methods: CCOS is a multicenter prospective cohort study designed to define the impact of the pandemic on cancer care delivery and outcomes The CCOS cohort comprised consecutive outpatients with cancer seen at two US cancer centers from March 2 to March 6, 2020 (index visit) Data was collected at baseline, retrospectively from the preceding 3 months, and prospectively at 3-month follow up Per patient changes in numbers of visits were compared using Wilcoxon signed rank tests Correlates of increases in telehealth visits and decreases in in-person visits were evaluated using multivariable logistic regression models Adjusted Odds ratios [aOR] and 95% confidence intervals (CI) were reported Results: Of 2365 included patients, 1219 (51 6%) had a decrease in in-person visit frequency during the pandemic period relative to the preceding 3 months Conversely, 760 (32 2%) had an increased frequency of telehealth visits (decrease in in-person and increase in telehealth visits;both p

4582 Background: CD73 or ecto-5'-nucleotidase mediates the de-phosphorylation of adenosine monophosphate to adenosine which promotes immunosuppression in the tumor microenvironment. Its prognostic significance in localized RCC has not been well characterized. Methods: We assessed CD73 protein expression using immunohistochemistry (Cell Signaling Technology, D7F9A, 1:25) on tissue microarrays (TMAs) containing tumor tissue from patients with pT1-4,N0-1, M0 RCC who underwent nephrectomy.CD73 expression was quantified using a combined score (CS: intensity x percentage of cells staining positive). CD73 positivity was defined as any CD73 expression on tumor cells (CS > 0). Patients were categorized into CD73 negative (CS = 0), low ( < median CS) and high (≥ median CS) groups. Clinical data was collected retrospectively.Baseline patient characteristics were compared between CD73 negative and positive (high + low) groups using the Cochran-Armitage trend test. Multivariable Cox regression evaluated associations of CD73 expression with disease-free and overall survival (DFS, OS) after adjusting for other baseline prognostic variables. Results: Of the 112 patients included, clear cell was the most common histology (70%) followed by chromophobe (12.5%), and papillary (12%) RCC. CD73 expression (CS > 0) was noted in 22% (n = 25) of tumors and was associated with more advanced stage (T3-4/N+: 37.5% vs. 25%; p = 0.02) and a trend towards higher nuclear grade (≥3: 48% vs. 35%; p = 0.07). Median follow-up from nephrectomy was 9.7 yrs. In multivariable analysis adjusting for nuclear grade ( < 3 vs. ≥3) and stage (T1-2, N0 vs. T3-4/N+), tumors with high CD73 expression had significantly worse DFS and OS (Table). Conclusions: CD73 expression was found in 22% of RCC patients and was associated with adverse pathologic features and poor prognosis independent of tumor stage and histologic grade. Our results provide strong rationale for further investigation of the CD73/adenosine pathway as a therapeutic target in RCC. [Table: see text]

4514 Background: S/R mRCC are poorly characterized rapidly progressing tumors associated with poor prognosis. Although conventional therapies are less effective for these tumors, emerging data suggests that ICIs may be especially effective. Our aim was to characterize the genomic alterations (GA) in S/R mRCC tumors and evaluate their response to ICIs. Methods: We retrospectively compared the activity of first-line ICIs to non-ICI-based therapies for S/R mRCC patients (pts) treated at DFCI and analyzed sequencing data from an NGS panel (275-447 genes) on a subset of these patients (matched by histology to non-S/R mRCC). For S/R mRCC pts treated with ICI vs non-ICI therapies, overall survival (OS) and time to treatment failure (TTF) were compared by Cox regression and objective response rate (ORR) by logistic regression. GA frequencies were compared by Fisher’s test and tumor mutational burden (TMB) by Mann Whitney U between S/R and non-S/R mRCC. Results were considered statistically significant if p < 0.05 or q < 0.10. Results: 125 S/R mRCC pts were included (88 S, 23 R, 14 S&R) among which 103 were clear cell and 48 had sequencing data. GA in BAP1 were significantly more frequent in S/R vs non-S/R (25% vs 4.3%; q = 0.096) while other GA had similar frequencies and TMB (median [IQR]) was similar (7.2 [5.2-8.4] vs 6.8 [5.3-9.1] mut/Mb; p = 0.98). Median follow-up was 35.4 (95% CI = 24.9 – 46.0) months (m). On multivariable analysis, S/R mRCC pts treated with ICI had significantly better clinical outcomes (Table). Conclusions: Pts with S/R mRCC have a higher frequency of BAP1 GA and better outcomes on ICIs compared to non-ICI-based therapies. Future studies should determine the molecular mechanisms underlying the improved response to ICIs in S/R mRCC. [Table: see text]