bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: Nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma.
Authors: Powles Thomas , Choueiri Toni K. , Burotto Mauricio , Escudier Bernard , Bourlon Maria Teresa , Shah Amishi Yogesh , Suárez Cristina , Hamzaj Alketa , Porta Camillo , Hocking Christopher , Kessler Elizabeth R , Gurney Howard , Tomita Yoshihiko , Bedke Jens , Zhang Joshua , Simsek Burcin , Scheffold Christian , Apolo Andrea B. , Motzer Robert J. 
Published: February 2022

350 Background: First-line nivolumab plus cabozantinib (N+C) demonstrated superiority over sunitinib (SUN) in the primary disclosure of the phase 3 CheckMate 9ER trial (NCT03141177; 10.6 months minimum follow-up; Choueiri TK et al. N Engl J Med 2021) in patients (pts) with advanced renal cell carcinoma (aRCC). Here, we report the preplanned final overall survival (OS) analysis with updated efficacy and safety in intent-to-treat (ITT) pts, and an exploratory assessment of target lesions by organ site after extended follow-up. Methods: Pts with aRCC (clear cell component) were randomized to N 240 mg every 2 weeks + C 40 mg once daily vs SUN 50 mg once daily (4 weeks of 6-week cycles). The primary endpoint was RECIST v1.1–defined progression-free survival (PFS) by blinded independent central review (BICR) in ITT pts; secondary endpoints included OS, objective response rate (ORR) by BICR, and safety. The preplanned final OS analysis was set to occur after observing 254 events. Maximal reduction of target lung, lymph node, kidney, and liver lesions were evaluated per BICR via post hoc exploratory analyses. Results: After 25.4 months minimum follow-up (median, 32.9 months) for OS in ITT pts, a total of 271 OS events occurred, and N+C continued to demonstrate OS improvement vs SUN (N = 323 vs 328; median 37.7 vs 34.3 months; HR 0.70 [95% CI 0.55–0.90]). PFS (median 16.6 vs 8.3 months; HR 0.56 [95% CI 0.46–0.68]) and ORR (55.7% [95% CI 50.1–61.2] vs 28.4% [95% CI 23.5–33.6]) benefits were maintained with N+C vs SUN, and 12.4% (N+C) vs 5.2% (SUN) of pts had a complete response. Median duration of response was 23.1 months with N+C vs 15.1 months with SUN. A higher percentage of pts experienced any reduction and ≥30% reduction from baseline with N+C vs SUN in target lesions at all organ sites assessed (Table). Among all treated pts, 97.2% (N+C; N = 320) vs 93.1% (SUN; N = 320) had a treatment-related adverse event (TRAE) of any grade (65.0% vs 54.1% had a grade ≥ 3 TRAE). Conclusions: N+C continued to provide survival improvement vs SUN among ITT pts in the final OS analysis, additionally PFS and ORR benefits with N+C were sustained with minimum 2-year follow-up. A higher proportion of pts experienced tumor shrinkage benefit with N+C vs SUN across all 4 organ sites assessed. No new safety signals emerged with extended follow-up in either arm. These results highlight N+C as a first-line treatment for pts with aRCC. Clinical trial information: NCT03141177. [Table: see text]
Association between on-treatment eosinophil dynamics and outcomes in metastatic renal cell carcinoma patients treated with ipilimumab/nivolumab.
Authors: Chen Yu-Wei , Tucker Matthew D , Yasin Hesham , Ancell Kristin Kathleen , Davis Nancy B. , Haake Scott Mattox , Kaiser Elizabeth , McAlister Renee , Rathmell Wendy Kimryn , Schaffer Kerry , Wallace Deborah , Beckermann Katy , Rini Brian I. 
Published: February 2022

364 Background: Baseline neutrophil to eosinophil ratio (NER) has been associated with response to immunotherapy in metastatic renal cell carcinoma (mRCC). The association of on-treatment changes in NER and absolute eosinophil count (AEC) during induction with ipilimumab/nivolumab and relation to clinical outcomes are reported. Methods: Patients with mRCC treated with ipilimumab/nivolumab at Vanderbilt-Ingram Cancer Center were identified. Contal and O’Quigley’s method was used to determine the optimal cutpoint associated with improved progression free survival (PFS) and overall survival (OS). Multivariable Cox proportional hazard function was used to assess the association between clinical outcomes and on treatment (week 3/6/9/12) maximum AEC and lowest NER, separately. Results: 63 patients were identified: 81% clear cell histology and 79% male; 24% IMDC favorable risk, 52% intermediate risk, and 24% poor risk. When maximum AEC was coded as a continuous variable, every increase of 100 AEC was associated with improved PFS (HR: 0.89, p-value: 0.017) and OS (HR: 0.87, p-value: 0.053). When the on treatment maximum AEC was dichotomized at the optimal cutpoint of 380 cells/µL, patients with maximum AEC ≥ 380 cells/µL had longer PFS (mPFS: 11.5 months vs 2.7 months, p-value: 0.001) and OS (mOS: 29.6 months vs 16.8 months, p-value: 0.08). When on treatment lowest NER was dichotomized at the optimal cutpoint of 13.2, patients with lowest NER <13.2 had improved PFS (mPFS: 12.5 months vs 2.7 months, p-value:<0.001) and OS (mOS: non-reached vs 16.5 months, p-value: 0.003). After baseline characteristic adjustment (Table), higher on treatment AEC was associated with improved PFS (HR: 0.38, p-value: 0.004), and lower on treatment NER was associated with improved PFS (HR:0.34, p-value:0.002) and OS (HR: 0.38, p-value: 0.036). Conclusions: Higher AEC and low NER while on treatment are associated with improved clinical outcomes in ipilimumab/nivolumab-treated patients with mRCC. Prospective study is warranted to validate these biomarkers.[Table: see text]
Single cell phenotyping of PDL1 and HLA1 on circulating tumor cells (CTC) in clear cell renal cell carcinoma (ccRCC) on systemic treatment with immunotherapy (IO) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKI).
Authors: Emamekhoo Hamid , Mannino Matthew C , Bootsma Matthew L , Bade Rory M. , Wells Meghan , Schehr Jennifer L. , Choueiri Toni K. , McKay Rana R. , Zhao Shuang , Lang Joshua Michael 
Published: February 2022

381 Background: Single agent or combination regimens using different IO and TKI agents have dramatically improved survival of patients (pt) with advanced ccRCC. Nevertheless, selecting optimal combination and sequencing of treatments remains challenging given the current absence of predictive biomarkers. Considering substantial disease heterogeneity and tumor clonal evolution, CTCs could provide a more comprehensive and longitudinal assessment of disease and response to treatment when compared to single site biopsy. In this study we explore changes in CTC characteristics in correlation with pt’s response (Resp) to treatment and progression (PD). Methods: 152 blood sample time points from 44 ccRCC pts (mean=3.5 sample/pt, range= 1-9) were included. An automated microfluidic platform using exclusion-based sample technology was employed for high sensitivity enrichment of RCC CTCs using EpCAM and CAIX antibodies. High-specificity CTC identification was achieved with positive staining for pCK or CAXII, and negative staining for CD45, CD34 and CD66b. Single cell phenotyping of PDL1 and HLA1 expression on each CTC was quantified with automated image analysis algorithms followed by manual visual QA of the putative CTCs. Cellular-level expression of PDL1 and HLA1 were compared within treatment-response groupings, using Wilcoxon rank-sum tests (Table). Results: Pts were 70% male, 93% Caucasian, 51% de novo metastatic, 98% received systemic treatment. CTC samples were collected at baseline (12) or while on treatment with IO (71), TKI (55), or IO/TKI (14). Across treatments, the number of CTCs increased from Resp to PD but this trend was not statistically significant. PDL1 expression was higher at PD compared to Resp on IO and IO/TKI but not significantly different on TKI. HLA1 expression was higher at PD compared to Resp on IO and TKI but not significantly different on IO/TKI. Average CTC PD-L1 expression was higher at Resp to IO compared to baseline. Conclusions: Single cell phenotyping of PDL1 and HLA1 were done at Resp compared to PD time points on IO and/or TKI to identify potential mechanisms of resistance. Further evaluation of these preliminary results in prospective trials is ongoing to advance new predictive biomarkers for ccRCC.[Table: see text]
Transcriptomic signatures can aid in post-operative risk stratification of clear cell renal cell carcinoma.
Authors: Shuch Brian M. , Davicioni Elai , Patel Neal , Proudfoot James , Liu Yang , Hakansson Alexander K. , Muraki Peter 
Published: February 2022

383 Background: The ability to risk stratify patient’s post-nephrectomy is critical to select candidates for surveillance and adjuvant therapy. Whether transcriptomic information adds value to current prognostic information is unclear. Methods: Data from confirmed clear cell renal cell carcinoma (ccRCC) used in the TCGA Pan-RCC analysis was downloaded from cBioportal and GDC bioportal. Clinicopathologic variables were used to calculate the integrated staging system, SSIGN (stage, size, grade, and necrosis). The 16 gene recurrence score (RS) signature was generated as described in Rini 2015 using the TCGA data with log TPM normalization. The RS was stratified into high and low risk groups by median. SSIGN was divided into low (0-1) intermediate (2-4) and high ( > = 5) risk groups. RS and SSIGN prognostic significance were evaluated using disease recurrence as an end point, censoring by death. Results: SSIGN and recurrence scores (RS) were calculated for 369 (71.2%) of 518 available TCGA subjects with non-metastatic clear cell renal carcinoma. On multivariable analysis, the RS (continuous variable) was independently associated with disease-free status (HR 1.18 [95%CI (1.02-1.37)], p = 0.031) for each 10 point increase in RS) after adjusting for SSIGN. Categorizing SSIGN into low, intermediate and high-risk groups showed 3.9%, 18.5% and 39.8% 3-year recurrence rates. Stratifying SSIGN risk groups by RS scores we found an RS to further risk stratify the SSIGN intermediate risk group (HR 1.60 [95%CI 1.21-2.12], p < 0.001]). The AUC for at 3 years for SSIGN in the intermediate risk group was 0.68, for RS was 0.74 and the combination was 0.78 (with boot-strapping for optimism adjustment). At 3 years, patients with SSIGN intermediate risk disease (n = 135) with low RS had 3-year recurrence rate of 7.1% compared to 31.0% for those with high RS scores. Conclusions: Transcriptomic recurrence scores can risk stratify intermediate SSIGN clinical risk patients. Patients with intermediate risk disease but a high RS score had poorer outcomes similar to clinically high risk patients. Transcriptomic signatures may add value to existing clinicopathologic variables in ccRCC and clinical implementation is warranted.
CD70 is a promising CAR-T cell target in patients with advanced renal cell carcinoma.
Authors: Ye Huihui , Huang Rong Rong , Shuch Brian M. , Chen Zhengshan , Said Jonathan W. , Pantuck Allan J. , Panowski Siler 
Published: February 2022

384 Background: Renal cell carcinoma (RCC) comprises a heterogeneous group of tumors of different histological subtypes. Each subtype is characterized by distinct immunohistochemical and molecular features and different biology. Currently, patients with advanced RCC have poor disease outcomes despite recent breakthroughs in immunotherapy. Chimeric antigen receptor (CAR)-T cell therapy has produced remarkably effective and durable clinical responses in hematological malignancies. However, there have been very limited success of CAR-T cell therapy in solid tumors. CD70 and its signaling partner CD27 are cell surface molecules that have emerged as novel targets for immune modulation approach. CD70 is also a promising target for CAR-T cell therapy, as it is overexpressed on multiple types of solid tumors including RCC and not expressed in most normal tissue. Studies have shown clear cell RCC (CCRCC) commonly expresses CD70. To date, no studies has evaluated CD70 expression in metastatic RCC in comparison with primary RCC. Methods: Four Tissue Microarrays (TMAs) were constructed using 395 tumors from 374 patients with RCC, 4 to 8 cores per tumor. There were 359 primary tumors, 36 metastatic tumors, and 344 matched normal. The primary RCC included 309 CCRCC including 11 with sarcomatoid differentiation, 38 papillary RCC (pRCC) including 1 with sarcomatoid differentiation, 8 chromophobe RCC (ChRCC), and 4 collecting duct RCC (CDC). The metastatic RCC were composed of 31 CCRCC including 3 with sarcomatoid differentiation and 5 PRCC. CD70 expression was evaluated using immunohistochemistry (IHC) and Definiens image analysis. CD70 expression was measured using the percentage of CD70-positive tumor cells. A CD70-positive tumor was defined as CD70 immunopercentage ≥ cutoff value in at least one core. Results: CD70 staining was detected in tumor cells in primary and metastatic RCC, with minimal staining in normal renal parenchyma. When the positive cutoff was defined as ≥1% of tumor cells demonstrating CD70 staining, the positive rate in CCRCC, pRCC, ChRCC, CDC, and SarRCC was 98%, 32%, 0%, 11%, and 46%, respectively. When the positive cutoff was defined as ≥ 25% of tumor cells stained positive for CD70, the positive rate in CCRCC, pRCC, ChRCC, CDC, and SarRCC was 41%, 10%, 0%, 0%, and 23%, respectively. Finally, when the positive cutoff was defined as ≥50%, the positive rate in CCRCC, pRCC, ChRCC, CDC, and SarRCC was 22%, 2%, 0%, 0%, and 8%, respectively. Metastatic RCC showed a higher % of tumor cells expressing CD70 compared to primary RCC for patients with CCRCC (mean 15% vs 9%) or SarRCC (12% vs 9%). Conclusions: Clear cell and sarcomatoid RCC are the RCC subtypes that demonstrate the highest CD70 expression. CD70 expression is further increased in metastatic lesions compared to the primary tumors. Anti-CD70 CAR-T cell therapy may benefit a significant fraction of patients with advanced CCRCC and sarcomatoid RCC.
Molecular residual disease (MRD) detection with a tissue comprehensive genomic profiling (CGP)-informed personalized monitoring assay: An exploratory analysis of the IMvigor-010 observation arm.
Authors: Young Amanda , Nimeiri Halla , Madison Russell , Fine Alexander D. , Zollinger Daniel , Gjoerup Ole , Aushev Vasily N. , Wu Hsin-Ta , Aleshin Alexey , Davarpanah Nicole N. , Assaf Zoe , Mariathasan Sanjeev , Oxnard Geoffrey R. , Renkonen Elise , Powles Thomas , Hegde Priti 
Published: February 2022

448 Background: There is compelling rationale that detection of MRD following curative therapy may identify patients at high risk of relapse requiring intensified adjuvant therapy. Combining MRD detection with CGP creates an opportunity to offer MRD-guided treatment with precision cancer therapeutics. Here we analyze the observation arm of the IMvigor-010 study to understand the genomics of resected early stage bladder cancer and to validate CGP-informed personalized MRD detection in circulating tumor DNA (ctDNA). Methods: Using the resected tumor, tissue CGP was performed retrospectively with a 300+ gene assay, followed by MRD detection using FoundationOne Tracker (F1T). Briefly, coding, synonymous, and non-coding variants were selected from tumor tissue sequencing using an optimized algorithm that filters out non-tumor derived variants (germline, clonal hematopoiesis derived, sequencing artifacts). Tumor-informed personalized multiplex PCR-next generation sequencing (Natera) assay was designed and used to detect and quantify variant allelic frequency (VAF) in ctDNA from 182 patients. ctDNA levels were reported in mean tumor molecules per mL of plasma. F1T, a tissue-informed personalized monitoring assay, was performed on plasma samples collected at an MRD timepoint a median of 11 weeks post-surgery. Results: At the MRD timepoint, ctDNA was detected in 66/182 (36%). Focusing on the 66 ctDNA-positive patients, 58 had relapsed (88% PPV) at time of analysis. Median disease-free survival (DFS) from randomization was 3 months in ctDNA-positive vs not reached in ctDNA-negative population (HR = 5.7, 95% CI: 3.8-8.6, p <.0001). Median overall survival (OS) was 13 months in ctDNA-positive vs not reached in ctDNA-negative (HR = 5.7, 95% CI: 3.4-9.7, p <.0001). Potentially actionable CGP findings included FGFR2/3 short variants (SVs) and fusions (13%), ERBB2 SVs and amplifications (13%), PIK3CA SVs (20%), CDKN2A SVs and losses (41%) and tumor mutational burden (TMB) ≥10 mutations/Mb (35%). Conclusions: Tissue CGP-informed personalized MRD detection can detect low levels of residual ctDNA in patients with resected early stage bladder cancer, identifying a population with inferior DFS and OS. This technologic approach, synergizing regulatory-grade actionable CGP with ctDNA-based MRD detection, creates new opportunities for precision adjuvant therapy across a range of high-risk cancer types. Clinical trial information: NCT02450331.
Real-world evidence from a single U.K. cancer center for atezolizumab in second-line setting in advanced urothelial cancer: Moving beyond clinical trials.
Authors: Hussain Syed A. , Qureshi Muneeb , Tahir Bilal , Rehan Ahmed , Catto James W.F. 
Published: February 2022

461 Background: Atezolizumab is approved for use in advanced urothelial cancer in second line setting after platinum based chemotherapy. We conducted a retrospective study to evaluate clinical outcomes in patients treated in a single UK cancer centre with Atezolizumab for advanced urothelial cancer. Methods: Data was collected from electronic records for patients treated with Atezolizumab for advanced urothelial cancer patients between January 2019 to June 2021. Patients with histologically proven advanced urothelial cancer, PS 0-1, GFR > 30 ml/min by Cockcroft-Gault formula, who had progressed after platinum based chemotherapy were eligible. Maximum duration of treatment allowed was 24 months as per National Cancer Drugs Fund criteria. Initially 3 weekly cycles using Atezolizumab at a dose of 1200 mg was used, patients received 4 weekly dose once 1680 mg dose was available. Kaplan Meier survival estimates were used to calculate progression free survival and overall survival. Results: 32 patients received Atezolizumab between Jan 2019 to June 2021. The mean age was 70.6 years (range 44-88). 10 patients had ECOG PS 0, 22 patients had PS 1. Male 19, Female 13. At the time of analysis, 9 out of 32 patients were alive, 2 patients had completed 24 months of treatment and had no evidence of disease progression. Total 297 cycles of Atezolizumab were delivered (190 cycles were delivered at 3 weekly intervals, while 107 were delivered 4 weekly). The median progression free survival was 24.290 weeks (95% CI: 23.202-25.378), and the median overall survival was 40.860 weeks (95% CI: 19.788-61.932). 10 patients (31.2%) were alive at 12 months, 8 patients (25%) were alive at 18 months. The number of patients with toxicity of grade ≥3 were 4.There were no treatment related deaths. Conclusions: Atezolizumab is effective and well tolerated in patients with advanced urothelial cancer in second line setting. Durable responses were noted with 25% of patients alive at 18 months.
Contemporary analysis of cystectomy complications.
Authors: Chua Kevin Joseph , Patel Hiren V. , Srivastava Arnav , Doppalapudi Sai Krishnaraya , Lichtbroun Benjamin , Elsamra Sammy , Singer Eric A. , Jang Thomas L , Ghodoussipour Saum 
Published: February 2022

473 Background: Radical cystectomy (RC) is a curative treatment for patients with invasive bladder cancer, but carries significant morbidity. Modern improvements in perioperative care have decreased length of stay (LOS) without effect on complication or readmission rates. Herein, we examine contemporary changes in complication rates of RC. Methods: The National Surgical Quality Improvement Program (NSQIP) database was queried for RC performed from 2006-2018 for nondisseminated bladder cancer identified by CPT, ICD-9 and 10 codes. Demographics and outcomes were studied across time periods: 2006-2011, 2012-2014 and 2015-2018. 30 day complications were classified as minor (urinary tract infection (UTI), superficial incisional surgical site infection (SSI), pneumonia, blood transfusion) or major (readmission, reoperation, sepsis/septic shock, deep vein thrombosis (DVT), stroke, reintubation, renal failure, myocardial infarction, pulmonary embolus (PE), dehiscence, cardiac arrest, deep incisional SSI, organ/space SSI, death). Results: We identified 11,351 RC performed during the study period. Baseline characteristics were similar across the different time periods. Mean length of stay (10.5, 9.8 and 8.6 days, respectively, p<0.001) decreased over time while readmission (20.0, 21.3, and 21.0%, respectively) and mortality rates were stable (2.7, 1.7, 2.0%, respectively). There was a significant decrease in overall minor complications over time, including superficial SSIs and transfusions (Table). The rate of major complications decreased over time, though not statistically significantly. Deep SSIs and PEs significantly decreased, while sepsis rates remained stable and high over time (Table). Rates of UTI was stable over time (10.1%, 8.8%, 8.3%, respectively, p=0.11). Conclusions: An analysis of the contemporary era shows continued decrease in LOS after RC and a decrease in overall complications. This may reflect beneficial effects of changes in perioperative bladder cancer management such as increased use of neoadjuvant chemotherapy, enhanced recovery after surgery protocols and laparoscopic/robotic techniques. Further efforts to improve care must target infectious complications and readmissions.[Table: see text]
Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): Long-term follow-up results from the JAVELIN Bladder 100 trial.
Authors: Powles Thomas , Park Se Hoon , Voog Eric , Caserta Claudia , Pérez-Valderrama Begoña , Gurney Howard , Loriot Yohann , Sridhar Srikala S. , Tsuchiya Norihiko , Sternberg Cora N. , Bellmunt Joaquim , Aragon-Ching Jeanny B. , Petrylak Daniel P. , Blake-Haskins Andy , Laliberte Robert J , Wang Jing , Costa Nuno Matos , Grivas Petros 
Published: February 2022

487 Background: The phase 3 JAVELIN Bladder 100 trial (NCT02603432) showed significantly longer overall survival (OS) with avelumab + best supportive care (BSC) vs BSC alone in patients (pts) with advanced UC that had not progressed with 1L platinum-containing chemotherapy. Avelumab 1L maintenance is now considered standard of care in treatment guidelines. We report trial data with ≥2-years follow-up in all pts (additional 19 months from the initial analysis). Methods: Pts with unresectable locally advanced or metastatic UC without disease progression with 4-6 cycles of 1L gemcitabine + cisplatin or carboplatin were randomized 1:1 to receive avelumab + BSC or BSC alone. The primary endpoint was OS, assessed from randomization in all pts and in pts with PD-L1+ tumors (Ventana SP263 assay). Secondary endpoints included progression-free survival (PFS) and safety. Results: 700 pts were randomized (350 per arm); 358 (51.1%) had PD-L1+ tumors. With extended follow-up (median, ≥38 months in both arms for all pts; data cutoff, June 4, 2021), OS remained significantly longer in the avelumab + BSC vs BSC alone arm in all randomized pts and in pts with PD-L1+ tumors (Table). An OS benefit was observed across prespecified subgroups. PFS (by investigator) was longer with avelumab + BSC vs BSC alone in all randomized pts and in pts with PD-L1+ tumors (Table). In the avelumab + BSC and BSC alone arms, respectively, 185 (52.9%) vs 252 (72.0%) pts received a subsequent anticancer drug therapy, including a PD-(L)1 inhibitor in 40 (11.4%) vs 186 (53.1%) pts. Long-term safety was consistent with previous avelumab monotherapy studies, with no new safety signals. Conclusions: Long-term follow-up from the JAVELIN Bladder 100 trial continues to show prolonged OS with avelumab + BSC vs BSC alone. These results further support the standard-of-care role for avelumab as 1L maintenance in pts with advanced UC that has not progressed with 1L platinum-containing chemotherapy. Clinical trial information: NCT02603432. [Table: see text]