bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world treatment outcomes of first-line axitinib plus pembrolizumab in patients with advanced renal cell carcinoma in the United States.
Authors: Zakharia Yousef , Thomaidou Despina , Li Benjamin , Siu Gordan , Levin Rebecca , Vlahiotis Anna , Zanotti Giovanni
Published: February 2022

314

Background: The combination of axitinib plus pembrolizumab (AXI+PEM) is a standard of care in the first-line (1L) treatment of patients with advanced clear cell renal cell carcinoma (RCC). This analysis describes the demographic and clinical characteristics, treatment and outcomes of patients receiving 1L AXI+PEM in a real-world setting. Methods: Medical record data were extracted from the Flatiron Health Database, which includes ̃280 cancer clinics across 800 sites in the US. Patients had confirmed Stage IV or metastatic RCC and initiated 1L AXI+PEM on or after 1/1/2018 to 3/31/2021. Tumor response is reported as best overall response to 1L therapy; real-world progression-free survival (rwPFS) and overall survival (rwOS) are reported as patients without a clinical event (rwPFS; progression/death; rwOS; death) at landmark time periods (3, 6, 9, and 12 months); denominators include censored patients. Other data are reported as medians (min, max) unless otherwise noted. Results: Three hundred and fifty-five patients received 1L AXI+PEM, with follow-up of 9.7 (0.1–24.3) months. Most patients were male (69.6%), and age was 68.0 (21.0–84.0) years. At diagnosis, 55.5% of patients had Stage IV RCC and 77.2% of patients had clear cell histology. IMDC Risk Score was favorable, intermediate, and poor in 27 (7.6%), 126 (35.5%), and 76 (24.4%) patients, respectively. At the time of analysis, 270 patients (76.1%) received only 1L therapy with AXI+PEM, while 85 patients (24.3%) received ≥1 subsequent line of treatment. VEGF-R inhibitors were the most commonly used second-line (2L) treatment (51 patients, 60.0%), with cabozantinib as the most frequently used VEGF-R inhibitor (40 patients, 47.1%). rwPFS at 3 months and 1 year was achieved by 248 patients (69.9%) and 77 patients (21.7%), respectively. rwOS ranged from 293 patients (82.5%) surviving at 3 months to 142 patients (40.0%) surviving at 1 year. Best overall response rate to 1L was 47.9% (complete or partial response observed in 170/355 patients). Conclusions: This study provides real-world evidence for the use and effectiveness of 1L AXI+PEM in patients with advanced RCC. AXI+PEM was used across all IMDC risk groups. While these initial finding support the use of AXI+PEM, additional follow-up is warranted to provide further understanding of the clinical outcomes and treatment patterns of patients with advanced RCC in the US receiving 1L AXI+PEM.
Real-world experience of axitinib as second-line treatment in metastatic renal cell carcinoma: Analysis of the Swedish population.
Authors: Strambi Angela , Jakobsson Maria , Nilsson Fredrik , Arpegard Johannes , Dalén Johan
Published: February 2022

315

Background: Axitinib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1-3, was approved in 2012 for the treatment of metastatic renal cell carcinoma (mRCC) after failure of prior treatment with sunitinib or a cytokine. Outside of randomized clinical trials, it is important to describe the clinical outcomes of more heterogeneous populations. This analysis aimed to describe time-to-treatment discontinuation (TTD) and overall survival (OS) for second-line (2L) axitinib in a real-world setting for a nationwide Swedish mRCC cohort. Methods: This retrospective analysis utilized the Swedish Health Data Registers, covering the entire Swedish population. Patients (aged ≥ 18 years) with mRCC had ≥ 1 filled prescription of axitinib in the 2L setting, after an anti-angiogenic targeted therapy, from marketing approval until December 2019. This analysis relied on data relating to dispensed pack size, strength and according to dosing as recommended by the product label. A grace period of 90 days was allowed between filled prescriptions including medication accumulated from overlapping prescriptions. Kaplan-Meier methods were used to describe TTD and OS. Results: In total, 110 patients received 2L axitinib. Patients were predominantly male (n = 84, 76.4%) with a mean (SD) age of 60.9 (9.6) years at diagnosis and 65.5 (9.9) years at 2L treatment initiation. Median (95% confidence interval [CI]) time to TTD was 5.2 (3.7, 6.1) months, with 6 (5.5%) patients still receiving treatment at the time of analysis. Median OS (95% CI) was 12.2 (7.7, 14.2) months; 25.5% (n = 28) of patient data remained censored at the time of analysis. Conclusions: OS in this analysis of a real-world Swedish population was generally consistent with that of the pivotal 2L axitinib clinical trial in patients with mRCC who previously received sunitinib (median [95% CI] 15.2 [12.8, 18.3] months; Motzer et al. Lancet Oncol 2013; 14: 552–62). TTD was consistent with the reported progression-free survival (median 6.5 months [95% CI] 5.7–7.9]). These results provide reassurance for the effectiveness of 2L axitinib in an unselected patient population in a real-world setting.
CABOSEQ: The efficacy of cabozantinib post up-front immuno-oncology combinations in patients with advanced renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Navani Vishal , Wells Connor , Boyne Devon J. , Cheung Winson Y. , Brenner Darren , McGregor Bradley Alexander , Labaki Chris , Schmidt Andrew Lachlan , McKay Rana R. , Pal Sumanta K. , Meza Luis A , Donskov Frede , Beuselinck Benoit , Ernst Matthew Scott , Otiato Maxwell , Ludwig Lisa , Powles Thomas , Szabados Bernadett , Choueiri Toni K. , Heng Daniel Yick Chin
Published: February 2022

318

Background: There are limited data to understand the activity of cabozantinib (CABO) as second line (2L) therapy post standard of care ipilimumab-nivolumab (IPI-NIVO) or immuno-oncology(IO)/vascular endothelial growth factor (VEGF) inhibitor combinations (IOVE). The activity of subsequent 3L approved therapies post CABO has not been established. Methods: Using the IMDC dataset, we examined all patients who received 2L CABO. We sought to identify the overall response rate (ORR), time to treatment failure (TTF) and overall survival (OS) of 2L CABO after IPI-NIVO, approved IOVE combinations and other 1L approaches. Additionally, we examined these outcomes for patients that received an approved 3L treatment post 2L CABO. Hazard ratios were adjusted for IMDC risk groups. Results: 346 patients were identified who had all received 2L CABO (78 post 1L IPI NIVO, 46 post 1L IOVE, 222 post 1L other). Of the entire cohort, 12.6%, 62.6% and 24.8% were IMDC favourable, intermediate and poor risk, respectively. 84% had clear cell histology, 18.5% had a sarcomatoid component and 38.3% had bone metastases at diagnosis. Outcomes for patients that received 2L CABO, stratified by 1L therapy are outlined in the table, followed by outcomes for patients that received subsequent 3L therapy post 2L CABO. After adjustment for IMDC criteria, the HR for 2L CABO OS and TTF for IOVE vs IPI-NIVO were 1.73 (95% CI 0.83-3.62 p = 0.14) and 1.62 (0.89-2.95 p = 0.11), respectively. Conclusions: There is clinically meaningful activity of CABO post IPI-NIVO, IOVE and other standard 1L approved therapies. Broadly, time to event endpoints and response rates are similar irrespective of 1L therapy. Approved systemic therapies post CABO, mainly single agent VEGF inhibitors also have activity, though as expected this is diminished compared to earlier lines of therapy. These are real world benchmarks with which to counsel our patients when using single agent CABO.[Table: see text]
Randomized phase II study to assess the efficacy and tolerability of sunitinib by dose administration regimen in anti-angiogenic naïve patients with metastatic renal cell carcinoma (mRCC): Final analysis of SURF study.
Authors: Thiery-Vuillemin Antoine , Gravis Gwenaelle , Schlürmann Friederike , Bompas Emmanuelle , Rolland Frederic , Gross-Goupil Marine , Vano Yann-Alexandre , Guillot Aline , Barthélémy Philippe , Joly Charlotte , Laramas Mathieu , Dourthe Louis-Marie , Maurina Tristan , Gauthier Hélène , Taillandy Kristell , Meurisse Aurelia , Vernerey Dewi , Albiges Laurence
Published: February 2022

344

Background: SUN is approved in mRCC setting at the dose of 50mg daily for 4 weeks followed by 2 weeks rest (4/2 schedule). The 4/2 schedule often requires dose modifications for toxicity. Current recommendation is to reduce the dose to 37.5mg per day. Alternative schedules (2 weeks of treatment followed by one-week rest (2/1 schedule) have shown promising results. SURF trial evaluated prospectively schedule 2/1 when toxicity occurs. Methods: SURF [NCT02689167] is a prospective, non-comparative randomized study. Patients (pts) with mRCC (clear cell) were included at SUN initiation. When a dose adjustment of SUN was required, patients were randomized between 4/2 schedule at 37.5mg daily and experimental 2/1 schedule at 50mg daily. Primary objective was to assess duration of SUN treatment among the 73 first evaluable pts. Overall 226 pts were enrolled with 133 randomized. All other analyses are shown for the 133 randomized patients. Results: Pts were 75.2% males, with a median age 63.7 years for 94% with a Karnofsky ≥ 80%. Of them, 54.9% had partial/total nephrectomy. IMDC risk score was favourable (45.1%), intermediate (46.6%) or poor (8.3%). Pts characteristics were well balanced between 2 arms. Metastatic sites were lungs (60.5%), bones (16.3%), lymph nodes (15.5%). At 6 months, 48 patients (65.8%) of the 2/1 schedule were still on treatment (above predefined threshold for positivity). Other data are listed on the table. No new safety signal was identified. Permanent SUN discontinuation due to toxicity was 22.2% in control arm vs 12.3% in experimental arm. Conclusions: SURF is the largest prospective randomised trial evaluating two different SUN schedules modifications in mRCC in case of toxicity. This positive trial confirms the role of adapting SUN to a 2/1 schedule rather than reducing SUN dose to the classical 4/2 schedule. Clinical trial information: NCT02689167. [Table: see text]
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]
VAX014 for instillation in subjects with nonmuscle-invasive bladder cancer.
Authors: Lerner Seth P. , Karsh Lawrence Ivan , O'Donnell Michael A. , Shore Neal D. , Lotan Yair , Tsuji Shingo , Giacalone Matthew
Published: February 2022

488

Background: VAX014 is a novel tumor targeted oncolytic agent for intravesical administration. It is comprised of recombinant bacterial minicells, that actively target a3b1 and a5b1 integrins expressed on NMIBC and deliver an active cytotoxic/oncolytic protein payload, perfringolysin O. VAX014 is being investigated for the intravesical treatment of NMIBC in an ongoing multi-center Phase 1 marker lesion trial in subjects with low grade Ta disease (NCT 03854721). Methods: Subjects with up to 5 pathologically confirmed TaG1 lesions ≥ 5mm but ≤ 15mm are eligible to receive six (6) weekly intravesical instillations of VAX014. Subjects with presence or history of high-grade bladder cancer are ineligible. Phase 1a will establish the MTD using a 3+3 design. After the DSMB establishes the RP2D, a Phase 1b expansion will use this dose to treat an additional 10 patients. Results: No serious adverse events or dose limiting toxicities have been recorded through two dose cohorts (3 + 3 design) and evidence of clinical response has been observed. Treatment related adverse events have been limited to Grade 1/2 hematuria, dysuria, and urgency. Preclinical studies indicate the pharmacodynamic activity of VAX014 following weekly intravesical administration to immune competent mice bearing bladder tumors is immune dependent and synergizes with systemic PD-L1 blockade to eliminate organ confined tumors and extravesical tumors. Surviving mice are capable of rejecting tumor rechallenge due to development of protective antitumor immunologic memory in response to therapy. Exploratory immunohistochemical target validation studies in bladder tumor biopsy specimens from subjects with more advanced stage tumors (T1-T3), indicate overexpression of VAX014’s target integrins, a3b1 and a5b1, in most samples tested. Conclusions: These clinical and preclinical data support the further development of VAX014 for the intravesical treatment of NMIBC and set a foundation for combination therapy with systemically administered immune checkpoint blockade in subjects with advanced disease. Clinical trial information: NCT03854721.
Analysis of disease-free survival in CheckMate 274 by PD-L1 combined positive score and tumor proportion score.
Authors: Galsky Matt D. , Bajorin Dean F. , Witjes J. Alfred , Gschwend Jürgen E. , Tomita Yoshihiko , Nasroulah Federico , Li Jun , Collette Sandra , Pérez-Valderrama Begoña , Grimm Marc-Oliver , Appleman Leonard Joseph , Gravis Gwenaelle , Necchi Andrea , Ye Dingwei , Stenner Frank , Wind-Rotolo Megan , Zhang Joshua , Unsal-Kacmaz Keziban
Published: February 2022

491

Background: CheckMate 274 demonstrated a significant improvement in disease-free survival (DFS) with nivolumab (NIVO) versus placebo (PBO) both in the intent-to-treat population (hazard ratio [HR], 0.70; 98.22% confidence interval [CI], 0.55–0.90; P < 0.001) and in patients (pts) with tumor programmed death ligand 1 (PD-L1) expression ≥ 1% assessed by the tumor proportion score (TPS) (HR, 0.55; 98.72% CI, 0.35–0.85; P < 0.001). An exploratory subgroup analysis showed a trend toward a DFS benefit with NIVO in pts with TPS < 1% (0.82; 95% CI, 0.63–1.06). To further characterize the relationship between PD-L1 expression and NIVO efficacy, we report an analysis of DFS based on PD-L1 expression in both tumor and immune cells using the combined positive score (CPS). Methods: CheckMate 274 is a phase 3, randomized, double-blind, multicenter trial of NIVO versus PBO in pts with high-risk muscle-invasive urothelial carcinoma after radical surgery. Pts were randomized 1:1 to NIVO 240 mg or PBO every 2 weeks intravenously for 1 year of adjuvant treatment. The primary endpoints of the study are DFS in the intent-to-treat population and in pts with TPS ≥ 1%. The Dako PD-L1 IHC 28-8 pharmDx assay was used to evaluate TPS. CPS was determined retrospectively from previously stained immunohistochemistry slides using the CPS algorithm. CPS was calculated as the number of both PD-L1 positive tumor and immune cells divided by the number of viable tumor cells in the evaluable tumor area, multiplied by 100; TPS was similarly calculated with the number of PD-L1 positive tumor cells as the numerator. This analysis only included pts with both quantifiable CPS and TPS. Results: Of the 629 pts with quantifiable TPS and CPS, 249 (40%) had TPS ≥ 1% (NIVO, n = 124; PBO, n = 125), 380 (60%) had TPS < 1% (NIVO, n = 191; PBO, n = 189), 557 (89%) had CPS ≥ 1 (NIVO, n = 281; PBO, n = 276), and 72 (11%) had CPS < 1 (NIVO, n = 34; PBO, n = 38). Within TPS < 1% pts, 81% (n = 309) had CPS ≥ 1. The number of pts and the DFS outcomes in pts with TPS ≥ 1% and CPS ≥ 1 are shown in the Table. In pts with TPS < 1% who also had CPS ≥ 1, median DFS (95% CI) was 19.2 (15.6–33.4) months with NIVO versus 10.1 (8.2–19.4) months with PBO. The HR for NIVO versus PBO in these pts was 0.73 (95% CI, 0.54–0.99). Conclusions: This exploratory analysis of PD-L1 expression by CPS showed a higher proportion of pts with CPS ≥ 1 than TPS ≥ 1%, and that most pts with TPS < 1% had CPS ≥ 1. In the CPS ≥ 1 subgroup, median DFS with NIVO was more than double that with placebo. These results support the conclusion that pts with TPS < 1% also benefit from adjuvant NIVO. Clinical trial information: NCT02632409. [Table: see text]
Defining innate immune training potential as a predictor of Bacillus Calmette-Guérin immunotherapy response in nonmuscle-invasive bladder cancer.
Authors: Jiang Song , Redelman-Sidi Gil , Pietzak Eugene J. , Bochner Bernard H. , Glickman Michael S
Published: February 2022

522

Background: Intravesical instillation of the live attenuated mycobacterium Bacillus Calmette-Guerin (BCG) remains the most effective therapy for the treatment of non-muscle invasive bladder cancer. The precise mechanism of BCG is thought to involve phagocytosis, induction of inflammation, activation of the innate immune apparatus, and an effective cell-mediated T cell response. An increasing body of evidence suggests that the innate immune system has characteristics that involve a heterologous memory of past insults through a process thought to involve epigenetic reprogramming, termed trained immunity. We seek to investigate the potential for innate immune training as a predictor of the anti-tumor effects of BCG. Methods: A prospective biospecimen collection was performed on venous blood from non-muscle invasive bladder cancer patients prior to receiving intravesical BCG therapy. To investigate the role of trained immunity in primary monocytes, cells were isolated from peripheral blood mononuclear cells (PBMC) by plate adhesion. 2-5 x 105 cells/well were assayed in 96-well format, cultured in RPMI 1640 supplemented with 10% Fetal Bovine Serum and 2mM L-glutamine and stimulated with 10:1 MOI BCG for 24 hours. Cells were then washed in media and allowed to rest 6 days. Media was changed on day 3 of rest. Subsequently, cells were stimulated with 25 ng/ml lipopolysaccharide (a TLR4 agonist) for 24 hours. Cell free supernatant was measured for TNF-alpha production by enzyme-linked immunosorbent assay. Results: In vitro training of primary monocytes induced an increase in proinflammatory cytokine production upon re-stimulation. This phenotype was dose dependent on stimulation with LPS, however, the relative change between trained and untrained cells was diminished at higher concentrations of agonist. In our in vitro training experiments, there was demonstrable interpatient variability seen pre-BCG exposure in a cohort of NMIBC patients. These results will be correlated with future long term BCG response in this prospective cohort. Conclusions: We present data on a trained innate immune phenotype on primary monocytes collected from patient samples. These data serve as proof of principle for the ability to induce a trained phenotype in vitro. These findings will be correlated with prospective clinical data on BCG responsiveness and recurrence free survival to allow us to garner further insight into the role of trained immunity in BCG immunotherapy. Such insight will have potential clinical impact on the development of biomarkers and clinical assays that could predict immune responsiveness to BCG a priori, as well as identify possible immunological adjuvants that could enhance the effect of intravesical BCG.
Actionable genomic landscapes from a real-world cohort of localized urothelial carcinoma patients.
Authors: Gerald Thomas , Margulis Vitaly , Meng Xiaosong , Cole Suzanne , Qin Qian , Call Greg , Mauer Elizabeth , Lotan Yair , Woldu Solomon L.
Published: February 2022

525

Background: Recent targeted therapies for advanced and metastatic urothelial cancer have generated enthusiasm, but the actionable genomic landscape of early-stage disease remains largely unknown. Here, we used real-world evidence to investigate differences between somatic and germline mutations in localized, early-stage urothelial cancers and advanced urothelial cancers. Methods: We retrospectively analyzed de-identified NGS data from 1,146 bladder cancer patients (stages I-IV) with formalin-fixed, paraffin-embedded tumor biopsies sequenced using the Tempus|xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage; whole-exome capture RNA-seq). For the subset of patients with tumor-normal match sequencing (n=758), additional incidental germline alterations in 46 different genes were assessed. Results: A total of 1,146 bladder cancer tumors were investigated: stage I-II (n=124), stage III (n=159), and stage IV (n=863)—summarized in Table. Tumor mutational burden (TMB) was calculated for 1,126 tumors, and TMB-high (TMB-H; ≥10 mutations per megabase) was similar across tumor stages. PD-L1 immunohistochemical staining was performed on 698 tumors, and no significant differences were observed. Microsatellite instability high (MSI-H) status was detected in only 2 (1.6%) stage I-II tumors and 8 (0.9%) stage IV tumors. Alterations—single nucleotide variants, insertions/deletions, and copy number variants—in FGFR2/3, homologous recombination repair genes (18 genes including BRCA1/2 and ATM), additional DNA repair gene mutations ( ERCC2, RB1, FANCC) and NTRK fusions were detected at similar frequencies across disease stages. In 758 patients with tumor/normal matched sequencing, we identified a low rate of incidental germline mutations in MUTYH (stage III, 1%; stage IV, 1.9%), BRCA2 (stages I-II, 1.2%; stage III, 1%; stage IV, 0.5%), BRIP1 (stages I-II, 1.2%), ATM (stage III, 1%; stage IV, 0.7%), MSH6 (stage III, 1%; stage IV, 0.2%), and TP53 (stage III, 1%; stage IV, 0.2%). Conclusions: Patients with bladder cancer have similar rates of potentially actionable mutations and genomic landscapes regardless of clinical disease stage. These findings provide a rationale for further investigating targeted therapies among early-stage bladder cancer patients.[Table: see text]
Expression of Nectin-4 and PD-L1 in bladder cancer with variant histology.
Authors: Case Katherine , Martini Dylan J. , Dababneh Melad , Nazha Bassel , Brown Jacqueline T , Joshi Shreyas S. , Narayan Vikram M. , Ogan Kenneth , Master Viraj A. , Carthon Bradley Curtis , Kucuk Omer , Harik Lara , Bilen Mehmet Asim
Published: February 2022

529

Background: Nectin-4, a cell adhesion molecule found in a frequently amplified region of the bladder cancer (BC) genome, has been recently used as target for the systemic treatment of locally advanced or metastatic BC. BC with variant histology (BCVH) is associated with poor clinical outcomes, and there is an unmet need for novel treatments in this population. Little is known about Nectin-4 expression and other targets. We investigated Nectin-4 and programmed death-ligand 1 (PD-L1) expression in BCVH. Methods: We performed a retrospective analysis of 117 patients with BCVH whose samples were collected at Winship Cancer Institute of Emory University from 2011-2021. Immunohistochemistry (IHC) was performed for Nectin-4 and PD-L1 expression on formalin-fixed, paraffin-embedded (FFPE) tissue. Nectin-4 staining was performed by Q2 Solutions using non-commercially available anti-Nectin-4 antibody (clone M22-312B41.1). Expression was measured using the H-score method (H-score = [% of strong positive tumor cells × 3] + [% of moderate positive tumor cells × 2] + [% of weak positive tumor cells × 1]). PD-L1 levels were assessed in tumor-infiltrating immune cells using DAKO 22C3 IHC to determine PD-L1 high, defined by a Combined Positive Score (CPS) of ≥10. Results: Median age was 70 years (mean=67.2, range 22-91), with 61.5% male, 54.7% white, and 32.5% black. Nearly all samples were taken from the bladder (95.7%), with 4.3% from sites of metastasis. The most common histologic variant was squamous cell carcinoma (26.5%), and the distribution of variants is summarized in table. Nectin-4 staining was successfully performed on 111 samples, and PD-L1 staining on 116. Nectin-4 expression was seen across different histological subtypes (mean H-score: 153.1, median [range]: 157 [0-300]), with highest expression in plasmacytoid and squamous, and lowest expression in small cell and sarcomatoid (Table). More than one-third (35.3%) were PD-L1 high, and greater in sarcomatoid and squamous cell histology (70.8% and 50% positivity, respectively). Only 5% of plasmacytoid samples were PD-L1 high. Conclusions: Although there is heterogeneity, our results showed expression of Nectin-4 and PD-L1 in this cohort of patients with BCVH. These findings highlight the therapeutic potential of antibody-drug conjugates against Nectin-4- and anti PD1/PD-L1-based therapy in this population. Additional analysis including clinical outcomes and genomic analyses are ongoing, and a prospective clinical trial is planned.[Table: see text]