bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes and prognostic factors of first-line combination of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) in TFE3-rearranged renal cell carcinoma.
Authors: Zhao Junjie , Tang Yanfeng , Hu Xu , Chen Junru , Liu Haoyang , Liu Haolin , Liang Jiayu , Zhang Xingming , Zhao Jinge , Shen Pengfei , Liu Zhenhua , Sun Guangxi , Zeng Hao
Published: January 2024

429

Background: Due to the rarity of TFE3-rearranged renal cell carcinoma ( TFE3-rRCC) and the poor understanding of its underlying mechanisms, the clinical treatment landscape in TFE3-rRCC is largely undefined. Hence, the optimal therapy for TFE3-rRCC remains to be determined. The diversity of fusion partners leads to the high heterogeneity of TFE3-rRCC, yet no studies have compared responses of patients with different fusion partners to systemic treatment. Methods: Data were collected retrospectively from our institution. Patients with metastatic TFE3-rRCC were eligible. Kaplan-Meier survival analysis and univariate and multivariate analysis were performed to compare survival outcomes. RNA-seq was performed to determine fusion partners and explore the transcriptomic features. Results: A total of 38 patients with metastatic TFE3-rRCC were enrolled in this study. The fusion partners were identified in 33 (87%) patients. Patients receiving first-line ICI plus TKI had longer PFS than those not receiving first-line ICI plus TKI (median PFS: 11.5 vs. 5.1 months, P=0.098). Subgroup analysis demonstrated that patients with ASPSCR1-TFE3 fusion significantly benefited from ICI plus TKI (PFS HR: 0.068, 95% CI: 0.008-0.609, P=0.016), whereas no improvement in PFS was observed in patients with other fusions. Univariate and multivariate cox regression analysis further demonstrated that besides IMDC risk score, ASPSCR1-TFE3 fusion could also serve as an independent prognostic factor for PFS in patients receiving first-line ICI plus TKI. Among patients receiving ICI plus TKI, those with ASPSCR1-TFE3 fusion had longer PFS than those with other fusions (median PFS: not reached vs. 6.5 months, P=0.01). Transcriptomic data revealed that ASPSCR1-TFE3 fusion rearranged RCC harbored higher angiogenesis activity. Additionally, decreased infiltration of immunosuppressive M2-phenotype macrophages and Tregs was observed in tumors with ASPSCR1-TFE3 fusion. Conclusions: Metastatic TFE3-rearranged RCC patients with ASPSCR1-TFE3 fusion could benefit from ICI plus TKI. Higher angiogenesis activity and decreased infiltration of immunosuppressive cells were observed in tumors with ASPSCR1-TFE3 fusions, which may explain the clinical outcome.
Neutrophil extracellular traps in relation to efficacy of systemic therapy for metastatic renal cell carcinoma.
Authors: Xie Rui-Yang , Shang Bing-Qing , Shi Hongzhe , Bi Xin-Gang , Song Yan , Qu Wang , Bai Hongsong , Wu Jie , Cui Honglei , Du Gan , Guo Lei , Zheng Shan , Ying Jianming , Li Changling , Ma Jianhui , Zhou Ai-Ping , Zhang Shudong , Shou Jianzhong
Published: January 2024

441

Background: The efficacy of systemic therapy regimens, such as immune checkpoint inhibitors and tyrosine kinase inhibitors (IO-TKI) and targeted therapy, for metastatic clear cell renal cell carcinoma (ccRCC) remains unpredictable due to the lack of effective biomarkers. This study investigates the predictive value of neutrophil extracellular traps (NETs) in determining the efficacy of metastatic ccRCC. Methods: In this retrospective study, patients with metastatic ccRCC who received targeted drugs and IO-TKI were included. Immunofluorescence staining was utilized to quantify the levels of tissue NETs through cell counts of H3Cit(+) and MPO(+) cells. The correlation between NETs and clinicopathological features was analyzed, and the predictive value of NETs for drug efficacy and prognosis was assessed using Cox proportional hazard analysis. Results: A total of 183 patients with metastatic ccRCC were enrolled, including 150 patients who received TKIs and 33 patients who received IO-TKI. H3Cit and MPO were predominantly expressed in the nucleus and cytoplasm, respectively. The levels of NETs in tumor tissue were significantly higher than in para-tumor tissue (p<0.001). Increased levels of NETs in tumor tissue were associated with tumor N stage (p=0.02) and neutrophil-to-lymphocyte ratio (NLR) (p=0.02). In terms of predicting drug efficacy, a correlation between NETs levels and progression-free survival (PFS) was observed in the TKI with metachronous metastasis group (HR 1.73 [95% CI 1.02-2.91], log-rank p=0.037), while no correlation was observed in the targeted agent with synchronous metastasis group and IO-TKI group. Regarding overall survival (OS), activated NETs levels were associated with poor OS (HR 1.87 [95% CI 1.24-2.81], log-rank p=0.003). Cox analysis revealed that IMDC score (HR 1.462 [95% CI 1.030-2.075], p=0.033) and tumor tissue NETs level (HR 1.733 [95% CI 1.165-2.579], p=0.007) were independent prognostic risk factors for OS in patients with metastatic ccRCC. Conclusions: The active NETs level in tumor tissue can serve as a predictor of drug efficacy in patients with metastatic ccRCC who received targeted agents with metachronous metastasis. However, no significant correlation was observed in the IO-TKI group, and further investigation is required. Elevated levels of NETs in tumor tissue were also associated with poor prognosis in OS prediction.
Multi-omic characterization of acquired resistance to immune checkpoint inhibitors in patients with metastatic renal cell carcinoma.
Authors: Saad Eddy , Labaki Chris , Miron Benjamin , Park Jihye , Bakouny Ziad , Nassar Amin , Saliby Renee Maria , Semaan Karl , Eid Marc , Meli Kevin , Nabil Laimon Yasmin , Geynisman Daniel M. , Kokate Rutika , Braun David A. , Signoretti Sabina , McGregor Bradley Alexander , Plimack Elizabeth R. , Choueiri Toni K. , Van Allen Eliezer Mendel , Zibelman Matthew R.
Published: January 2024

459

Background: While immune checkpoint inhibitors (ICI) have improved outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC), acquired resistance (ARX) is commonly encountered. We aimed to characterize the genomic and transcriptomic correlates underlying ARX in ICI-treated mRCC patients. Methods: We identified pts with mRCC at Dana-Farber Cancer Institute and Fox Chase Cancer Center, treated with ICI-based regimens who had an initial response to therapy followed by disease progression. Tissue samples from the primary tumors or metastases were collected before ICI treatment and after ARX from a treatment-emergent escape lesion. Whole exome sequencing (WES) and bulk RNA-sequencing (RNA-seq) were performed. Somatic mutations were called using the Cancer Genome Analysis pipeline. Differential gene expression analysis (DGE) was run using DESeq2, followed by gene set enrichment analysis (GSEA). Immune cell fractions were estimated using CIBERSORTx. Cell fraction and tertiary lymphoid structures (TLS) scores were compared between post and pre-ARX samples using the Wilcoxon test. Results: A total of 41 samples (n=23 pre-ARX and n=18 post-ARX) were collected from 14 unique patients. After quality control, WES and RNA-seq data were available for 27 samples (14 pre-ARX and 13 post-ARX) and 9 samples (3 pre-ARX and 6 post-ARX), respectively. No discernable enrichment of gene mutations was detected in the post-ARX setting compared to the pre-ARX. DGE identified 61 downregulated immunoglobulin genes in the post-ARX setting. GSEA revealed significant depletion of pathways associated with B-cell and T-cell function in post-ARX samples (all adjusted p<0.05). Similarly, a trend towards decreased naïve B cell and CD8+ T cell fractions was observed in the post-ARX setting (p=0.17 for both). Three previously reported TLS-associated expression signatures were depleted in the post-ARX samples compared to pre-ARX (p=0.015, p=0.065 and p=0.065, respectively). Immunohistochemistry assessment of 3 samples from one pt using ant-CD3 and CD20 antibodies confirmed the presence of TLS in the pre-ARX sample and their absence in two different post-ARX samples. Conclusions: In our cohort of pts with mRCC, no gene mutations were implicated as drivers of ARX. However, ARX was associated with downregulation of B-cell signaling and humoral mediated immunity, as well as absence of TLS. Ongoing efforts are in progress to include more samples.
Identification of a novel prognostic gene signature in a clear cell renal cell carcinoma (ccRCC) population using an integrated multi-study single-cell RNAseq dataset.
Authors: García-Esteve Samuel , Jiménez Natalia , Aversa Caterina , Ferrer-Mileo Laura , Garcia de Herreros Marta , Fernandez-Mañas Laia , González-Aguado Laura , Rubio-Pérez Carlota , Cobo-Diego Inés , Mazariegos Manuel , Prat Aleix , Mellado-González Begoña , Reig-Torras Òscar
Published: January 2024

465

Background: Clear cell renal cell carcinoma (ccRCC) is a highly heterogeneous disease with varying prognoses and treatment responses. Understanding the underlying molecular determinants of this diversity is key to tailoring effective treatment strategies for each patient (pt). Here, we leveraged single–cell RNA sequencing (scRNA–seq) data to assess intra–tumoral diversity and its impact on pt prognosis. Methods: scRNA–seq raw data from five published studies were processed with Seurat’s standard workflow and integrated to remove biases using Harmony. We then re–analyzed the malignant cell cluster, defined by CA9, NDUFA4L2, and IGFBP3 expression, at a higher resolution. The resulting tumor cell sub–clusters were subjected to differentially expressed gene (DEG) and gene ontology (GO) enrichment analyses. A signature based on all DEGs with a fold change > 1.25 was applied on TCGA–KIRC cohort using single–sample gene set enrichment analysis and then correlated with relapse–free survival (RFS) and overall survival (OS) by Kaplan–Meier and multivariate Cox analyses. Results: We integrated scRNA–seq data from 50 samples from 44 pt’s (40% T3–4, mean age 75, 10% females). A total of 288K cells were classified into 19 clusters. The tumor cluster was re–analyzed and three biologically distinct tumor cell sub–clusters (labeled MC1, MC2, and MC3) were identified, each with unique molecular markers. GO analysis showed enrichment in genes associated with iron sequestration, oxidative phosphorylation, and apoptotic signaling, respectively. In the KIRC cohort, a 23–DEG signature from MC2 strongly correlated with RFS (HR 0.49; 95% CI 0.35−0.67 p < 0.001; 5-RFS: 74% vs. 54%) and OS (HR 0.44; 95% CI 0.33−0.60 p < 0.001; 5-OS: 75% vs. 51%) and was independent of other clinical variables in the multivariate analysis (Table 1). Moreover, this signature identified a subset of T1–T2 tumors (47.8%) with low risk of relapse (HR 0.38; 95% CI 0.19−0.78, p = 0.008; 5-RFS: 92% vs. 80%) and longer OS (HR 0.35; 95% CI 0.20−0.62 p < 0.001; 5-RFS: 90% vs. 68%). Conclusions: We have identified three distinct tumor cell sub–populations in an integrated scRNA–seq database, each characterized by unique transcriptomic profiles. A gene expression signature based on the MC2 sub–cluster was prognostic in the TCGA dataset and may help in identifying patients with a higher risk of relapse and candidates to adjuvant therapy.[Table: see text]
The distribution of mutations across tumor size in ccRCC and their prognostic importance in small masses.
Authors: Monda Steven , Gulati Shuchi , May Allison , Dall'era Marc
Published: January 2024

479

Background: Substantial efforts have been made to delineate mutational pathways to progression in ccRCC and the prognostic importance of key mutations, yet the distribution of these mutations across tumor size remains unknown. We hypothesized that VHL and PBRM, as more truncal mutations, would be roughly equally prevalent across tumor sizes, while mutations associated with aggressive disease - SETD2, BAP1, and CDKN2a copy-number loss - would be predominantly observed in larger tumors. We further hypothesized that SETD2, BAP1, and CDKN2a copy-number loss mutations, when present in smaller (≤7 cm) ccRCC tumors, would portend worse prognosis. Methods: We assessed a combined cohort of 333 ccRCC tumors from TCGA-KIRC and TRACERx Renal for the distribution of mutations across tumor size. Logistic regression was used to model the presence of each mutation against tumor size. We assessed a subset of 194 tumors ≤7cm for associations of key mutations with clinical outcomes while controlling for size. In small masses, logistic regression was used to model the presence of metastatic disease and invasive disease, and Cox proportional hazards was used to model overall survival, against SETD2, BAP1, CDKN2a copy-number loss, and tumor size. Results: On logistic regression an increase in one centimeter of tumor size was associated with SETD2, BAP1, and CDKN2a loss at odds ratios of 1.16, 1.11, 1.19 (p<0.05); whereas no significant association was observed between tumor size and both VHL and PBRM1 (p=0.18, p=0.65). Among 194 tumors ≤7 cm, SETD2 and CDKN2a loss were associated with metastatic disease at odds ratios of 3.86 and 3.84 (p<0.05); CDKN2a loss was associated with worse overall survival at hazard ratio 2.19 (p<0.05), all while controlling for tumor size. Conclusions: SETD2 mutations, BAP1 mutations, and CDKN2a copy-number loss are rare in small ccRCC and are increasingly common in larger tumors, whereas VHL and PBRM1 are fairly evenly distributed across tumor sizes. In tumors≤7 cm, SETD2 mutation and CDKN2a loss were associated with metastatic disease and CDKN2a loss was associated with worse overall survival. SETD2 mutations and CDKN2a loss may help risk stratify ccRCC in biopsied and resected tumors. [Table: see text]
Genomic profiling in bladder cancer across a spectrum of measured socioeconomic inequality: A retrospective review utilizing next generation sequencing.
Authors: Barker Kenneth , Ruzdija Denis , Bertolo Aaron , Paster Irasema Concepcion , Guillen-Rodriguez Jose , Estrada-Mendizabal Ricardo J. , Chipollini Juan , Recio-Boiles Alejandro
Published: January 2024

545

Background: Socioeconomic inequality (SI) is a known risk factor for worse prognosis in bladder cancer. The mechanism behind this is likely due to a complex interplay between many factors including access to care, diet and exercise disparities, and frequency of tobacco/alcohol use. There remains a scarcity of studies looking at the impact of socioeconomic inequality on tumor biology in bladder cancer, yet genomic profiling to look for biomarkers with therapeutic targetability is becoming increasingly common through testing modalities such as next-generation sequencing (NGS). This study aimed to further understanding of the effect of SI on the genomic alterations with therapeutic implications seen in bladder cancer. Methods: This was a retrospective analysis of 108 patients (75 male and 33 female) ranging from 18-92 years old with bladder cancer presenting to the University of Arizona Cancer Center from 2016-2023. Of these 108 patients, 97 had NGS data available. Each actionable pathogenic mutation, tissue mutational burden (TMB), and combined positive score (CPS) for PDL1 expression was recorded for each patient. TMB score of >10 and/or CPS of >10 were considered as actionable mutations for immunotherapy. The Area Deprivation Index was used to measure SI levels of each patient’s neighborhood based on a national scale from 1-100 with 100 being most disadvantaged and 1 being the least. These patients were then split into three tertiles: 1-33, 34-67, and 68-100 to compare the frequency of genomic alternations using chi-squared for contingency tables and kruskal-wallis rank test for multiple samples. Results: Of the 97 patients with NGS, 18 were in tertile 1, 47 in tertile 2, and 34 in tertile 3. TMB-High>10 was significantly different between tertiles with the following frequencies of TMB >10: tertile 3 8/34 (23.5%), tertile 2 21/47 (44.6%), and tertile 1 10/18 (55.5%), (p=<0.05). The mean mutational burden in tertile 1, 2, and 3 was 11.3, 10.17, and 8.22 respectively (p=0.147). There was no correlation of SI with the selected frequent mutations KDM, ARID1A, TERT, TP53, PIK3CA, TP53, and TERT (p>0.05). Conclusions: Higher TMB in bladder cancer has been associated with a more favorable prognosis and predictive response to immunotherapy. Our results show patients from neighborhoods of higher SI have a significantly lower frequency of TMB score >10, and this could offer partial explanation for the worse prognosis seen with higher SI levels. Our relatively small sample size limits the power of our study. Further investigation through larger scale studies of the genomic alterations seen between SI levels have important implications in understanding both why and how to better address the worse outcomes seen in bladder cancers in patients with greater SI levels.
The association between social vulnerability and clinical trials awareness and participation: A HINTS-SEER analysis.
Authors: Sekar Rishi , Herrel Lindsey A. , Stensland Kristian
Published: January 2024

546

Background: Clinical trials are integral to science and can ensure access to standard of care treatments, providing benefits to individual participants and society. Unfortunately, fewer than 5% of eligible cancer patients participate in clinical trials, and large facets of the population remain starkly underrepresented, excluding them from these benefits and potentially compromising the generalizability of biomedical knowledge. Adverse social determinants of health (SDOH), or social vulnerability, may affect awareness and the decision to participate in a clinical trial, especially in underrepresented or historically excluded populations. In this study, we evaluate the association between population-level SDOH and clinical trials awareness and participation. Methods: We performed a cross-sectional analysis of the 2021 Health Information National Trends – Surveillance, Epidemiology, and End Results (HINTS-SEER), a nationally representative survey of 1,234 cancer survivors. The primary outcomes of interest included awareness of clinical trials “as a possible treatment option for your cancer” and “participation in a clinical trial for treatment of your cancer”. The primary exposure was the Centers for Disease Control and Prevention Social Vulnerability Index (CDC SVI), which was linked to each survey respondent by ZIP code of residence. Survey weighted multivariable logistic regression analyses were performed to evaluate the association between SVI quintile and clinical trial awareness and participation, adjusting for age, sex, race/ethnicity, and education level. Results: This survey weighted analysis represents a population of over 400,000 patients. Only 15.1% of patients were aware of clinical trials, with the most socially vulnerable patients having lower rates of awareness compared to the least socially vulnerable patients (8.5% vs. 17.9%). Similarly, only 7.7% of patients participated in a clinical trial, with the most socially vulnerable patients having lower rates of participation compared to the least socially vulnerable patients (3.0% vs. 10.1%). On multivariable analysis, the most socially vulnerable patients had significantly lower odds of clinical trials awareness (OR 0.43, CI 0.20 – 0.94) and clinical trials participation (OR 0.15, CI 0.03 – 0.73) compared to the least socially vulnerable patients, adjusting for age, sex, race/ethnicity, and education level. Conclusions: In this analysis of HINTS-SEER, a contemporary and novel survey of cancer survivors, rates of clinical trial awareness and participation remain concerningly low. Notably, adverse SDOH has a strong influence, with the most vulnerable patients being far less likely to be aware of or participate in a clinical trial. With the goal of achieving equitable cancer care, identifying and alleviating barriers to clinical trial participation, especially those rooted in SDOH, is critical.
Role of geriatric assessment and oncological multidimensional prognostic index (Onco-MPI) in a real-world cohort of elderly patients with advanced urothelial carcinoma.
Authors: Bimbatti Davide , Cavasin Nicolò , Bergo Eleonora , De Toni Chiara , Lai Eleonora , Erbetta Elisa , Jubran Salim , Pierantoni Francesco , Ruffini Camilla , Brunello Antonella , Basso Umberto , Maruzzo Marco
Published: January 2024

563

Background: At least 75% of bladder cancer (BC) are diagnosed in adults aged ≥65 years, with a median of 72 years. Older adults have poor outcomes but are also an heterogeneous population in which the functional status often does not reflect the chronological age. ASCO and SIOG recommend the use of geriatric assessment (GA) to guide management of these patients (pts) but very few data are present to date. Methods: We investigated the role of GA and an oncological version of MPI in pts ≥70 years old affected by advanced/metastatic urothelial carcinoma. Data were retrieved from a prospectively maintained database from 2010 to 2022. Comprehensive GA (CGA) is a multidimensional tool used to classify pts as fit, vulnerable and frail according to Balducci’s criteria. Onco-MPI was calculated by a validated algorithm derived from different GA domains and tumour characteristics. We also collected characteristics of pts, tumors and treatment regimens. Correlation between GA and treatments used and oncological outcomes were analysed. Results: Complete data and follow up were available for 181 patients. Pts characteristics are reported in Table 1. According to Onco-MPI all the pts but 7 were at high risk. The mFU was 46.2 months, while mOS was 8.2 months. Balducci’s CGA and Bellmunt groups had a concordance of 58%, p<0.01. Strong correlations between these scores and type of treatment received were found (pts fit or 0 score received more often a platinum-based treatment without reduction dose while frail or 2-3 score received more often treatment with a reduced dose or no treatment at all, p<0.01). The two scores have a strong prognostic value (18.5 vs 10.8 vs 3.8 months, p<0.01; 21.9 vs 8.5 vs 4.1 months, p<0.01, respectively for CGA and Bellmunt subgroups). At univariate analysis also timing of mets, number of sites, type of treatment and dose were good prognostic variables. All these variables retained their prognostic value at a multivariate analysis incorporating each of the two scores separately. Conclusions: CGA has a great prognostic value in older adults with metastatic urothelial cancer. This tool could help in decision making and patients stratification but validation in prospective cohort is needed. Onco-MPI could also be useful but new cut offs must be set in this specific population.[Table: see text]
Real-world survival of men with metastatic castration-sensitive prostate cancer (mCSPC) initiated on apalutamide (APA) or enzalutamide (ENZ) in an oncology database: ROME Study.
Authors: Bilen Mehmet Asim , Du Shawn , Khilfeh Ibrahim , Rossi Carmine , Korsiak Jill , Rahman Alvi , Lefebvre Patrick , Pilon Dominic , Shore Neal D.
Published: January 2024

57

Background: Androgen receptor signaling inhibitors (ARSIs), including APA and ENZ, have demonstrated progression-free and overall survival benefits for men with mCSPC in the clinical trial setting, but data evaluating real-world treatment effectiveness remains limited. The aim of this study was to describe real-world survival among men with mCSPC who initiated APA or ENZ in the United States (US). Methods: In this retrospective longitudinal cohort study, clinical data from the Flatiron Metastatic Prostate Cancer (PC) Core Registry Electronic DataMart (1/1/2013–05/31/2023) were used. Patients with chart-confirmed metastasis and without castration resistance were classified into two treatment cohorts based on earliest initiation of APA or ENZ on/after 12/16/2019 (index date). Patients had ≥12 months of clinical data pre-index and were followed from the index date until the earliest of 24 months post-index, end of clinical activity, or end of data availability. Patients’ date of death was obtained from electronic medical records, Social Security Death Index, or other confirmed sources. Using an intention-to-treat approach, Kaplan-Meier analysis was used to describe the proportion of patients surviving by 24 months post-index. An unadjusted Cox proportional hazards model was used to describe crude differences in survival rates between patients initiating APA and ENZ. Results: There were 234 APA (mean age: 73.2 years; 59.8% White, 13.7% Black) and 527 ENZ (mean age: 73.9 years; 55.2% White, 13.1% Black) patients included in this study (Table). APA median time on-treatment was 10.9 months over a median observation period of 13.3 months, while ENZ median time on-treatment was 11.1 months over a median 14.8 months observation period. By 24 months, a higher proportion of patients in the APA cohort survived than in the ENZ cohort (85.4% vs 73.9%; unadjusted hazard ratio=0.59, 95% confidence interval: 0.39, 0.95; p=0.030; Table). Conclusions: In this real-world analysis of patients with mCSPC, more patients treated with APA survived by 24 months following treatment initiation as compared to treatment with ENZ. While the current study reports unadjusted analyses, future studies adjusting for potential confounding variables should be conducted to confirm these findings in order to inform clinicians on treatment selection for patients with mCSPC. [Table: see text]
Analysis of real-world survival for patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) or abiraterone acetate (ABI) in an oncology database: ROMA study.
Authors: Bilen Mehmet Asim , Khilfeh Ibrahim , Rossi Carmine , Du Shawn , Korsiak Jill , Rahman Alvi , Lefebvre Patrick , Pilon Dominic , Shore Neal D.
Published: January 2024

58

Background: Androgen receptor signaling inhibitors (ARSI), including APA and ABI plus prednisone, are approved for the treatment of mCSPC. However, studies evaluating survival for these agents in clinical trials or the real-world have not been investigated. This study describes real-world survival among men with mCSPC who initiated APA or ABI in the United States (US). Methods: Data from the Flatiron Metastatic Prostate Cancer (PC) Core Registry Electronic DataMart (1/1/2013–05/31/2023) was used to identify ARSI-naïve patients with chart-confirmed metastasis and without evidence of castration resistance at ARSI initiation. Patients were classified into two treatment cohorts based on the start date for APA or ABI (index date) on/after 9/17/2019. Patients had ≥12 months of clinical data pre-index and were followed from the index date until the earliest of 24 months post-index, end of clinical activity, or end of data availability. Patients’ date of death was obtained by integrating data from electronic medical records, the Social Security Death Index, and or other confirmed sources. Using an intention-to-treat approach, Kaplan-Meier analysis was used to describe the proportion of patients surviving by 24 months post-index. An unadjusted Cox proportional hazards model was used to describe crude differences in survival rates between patients initiating APA and ABI. Results: This study included 242 APA (mean age: 73.0 years; 60.3% White, 13.6% Black) and 607 ABI (mean age: 73.1 years; 57.3% White, 16.8% Black) patients. APA median time on-treatment was 11.4 months over a median observation period of 14.3 months. ABI median time on-treatment was 10.8 months over a median observation of 14.0 months. By 24 months, 85.7% of the APA cohort and 75.9% of the ABI cohort were living (unadjusted hazard ratio=0.60, 95% confidence interval: 0.38, 0.96; p=0.033; Table). Conclusions: In this study, we observed that more ARSI-naïve patients with mCSPC survived by 24 months after initiating APA than those who initiated ABI. While the current study presents unadjusted comparisons, additional causal analyses controlling for confounding variables should be conducted to confirm these initial findings. [Table: see text]
Avelumab first-line maintenance (1LM) for advanced urothelial carcinoma (aUC): Long-term patient-reported outcomes (PROs) in the phase 3 JAVELIN Bladder 100 trial.
Authors: Grivas Petros , Aragon-Ching Jeanny B. , Bellmunt Joaquim , Loriot Yohann , Sridhar Srikala S. , SU Po-Jung , Park Se Hoon , Yamamoto Yoshiaki , Jacob Natalia , Hoffman Jason , Kearney Mairead , Schlichting Michael , Powles Thomas
Published: January 2024

581

Background: In the JAVELIN Bladder 100 trial, avelumab 1LM + best supportive care (BSC) significantly prolonged overall survival vs BSC alone in patients (pts) with aUC that had not progressed with 1L platinum-based induction chemotherapy, and health-related quality of life was maintained. We report long-term and exploratory PRO analyses in the overall avelumab + BSC arm (any treatment duration) and in the subgroup with ≥12 months of avelumab treatment. Methods: In JAVELIN Bladder 100 (NCT02603432), PROs were a secondary endpoint assessed at baseline, on day 1 of each 4-week cycle, at end of treatment/withdrawal, and up to 90 days post treatment. PRO instruments used were National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Bladder Symptom Index-18 (FBlSI-18) and EuroQol 5 Dimensions 5 Levels (EQ-5D-5L). Descriptive and mixed-effect model analyses were conducted. Data were not evaluated in the BSC alone arm because few pts remained on study treatment at later time points. Results: At data cutoff (Jun 4, 2021), median follow-up in the avelumab arm (n=350) was 38.0 months (≥2 years in all pts), and median duration of treatment was 5.8 months. In pts treated for ≥12 months (n=118 [33.7%]), baseline characteristics were similar to those in the overall avelumab + BSC arm, except for a higher proportion with ECOG performance status of 0 (70.3% vs 60.9%) and lower proportion with visceral metastases (47.5% vs 54.6%). In both populations, completion rates for both PRO instruments among evaluable pts were >80% at all time points during treatment. On average, PRO scores remained stable throughout treatment, and no clinically relevant changes from baseline were reported (Table). Among pts treated for ≥12 months, ≈75% of evaluable pts reported no change or a decrease in being bothered by treatment side effects throughout 24 months of treatment. Conclusions: Prolonged avelumab 1LM treatment (≥12 months) was associated with stable PROs, indicating preservation in quality of life. The results further support the use of avelumab 1LM until progression or unacceptable toxicity as standard of care with level 1 evidence in pts with aUC who are progression-free after platinum-based chemotherapy. Clinical trial information: NCT02603432 . [Table: see text]
Real-world (rw) treatment patterns, sequencing, and outcomes in patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC) receiving avelumab first-line maintenance (1LM) in the US.
Authors: Moon Helen H. , Kearney Mairead , Mahmoudpour Seyed Hamidreza , Ike Chiemeka , Morris Valerie A. , Rava Andrew , Kim Sonia , Sun Haiyan , Boyd Marley , Gomez Rey Gabriel
Published: January 2024

605

Background: Avelumab 1LM is recommended in international guidelines for pts with la/mUC and disease control after 1L platinum-based chemotherapy (PBC). This study describes the treatment landscape after FDA approval of avelumab in June 2020 by examining pt characteristics, treatment patterns and sequencing, and rw outcomes in pts treated with avelumab 1LM. Methods: This noninterventional retrospective study identified pts with la/mUC who received avelumab 1LM in the US using data from Flatiron Health’s electronic health record database. Pts aged ≥18 y with ≥2 visits on/after Jan 1, 2011, diagnosed with la/mUC from Jan 1, 2019 - Dec 31, 2022, treated with 1L PBC followed by avelumab 1LM on/after Jul 1, 2020, ≤90 d after 1L PBC discontinuation, and with no disease progression ≤14 wk after 1L PBC were included. Treatment patterns in 1LM, second line (2L), and third line (3L) were assessed. Clinical outcomes, including rw progression-free survival (rwPFS), rw overall survival (rwOS), time to treatment discontinuation (TTD), and time to next treatment (TTNT) from 1LM or 2L initiation, were assessed using Kaplan-Meier methods. Results: 214 avelumab 1LM-treated pts met eligibility criteria. Median age was 70 y; most pts were male (77%), White (66%), and had an ECOG of 0-1 (77%). Median follow-up from 1LM was 8.7 mo. Of 96 (45%) pts who received 2L treatment post avelumab 1LM, enfortumab vedotin (EV) monotherapy (55%) was most common, followed by carboplatin-based therapy (11%). Of 40 (42%) pts who received 3L treatment, EV monotherapy was most common (25%), followed by sacituzumab govitecan (20%). Median PFS and OS from start of avelumab 1LM was 5.1 (95% CI 4.1-7.0) and 23.8 (95% CI 18.2-NE) mo. Median TTNT from avelumab 1LM initiation was 7.0 (95% CI 5.6-8.6) mo. Of pts who received 2L EV, median rwPFS and rwOS from 2L initiation were 4.9 (95% CI 3.9-8.8) and 11.2 (95% CI 6.8-NE) mo. Further rw outcomes are presented in the Table. Conclusions: Clinical outcomes in this study are aligned with those of the JAVELIN Bladder 100 trial (NCT02603432), further supporting avelumab 1LM as a standard of care. With each additional line of therapy, substantial treatment attrition and less favorable clinical outcomes were observed. This study provides insights into the sequencing of treatments and management of pts with la/mUC after disease progression with avelumab 1LM in this rapidly evolving therapeutic landscape. The use of more effective upfront therapies may decrease the attrition rates. [Table: see text]
Efficacy and safety of disitamab vedotin combined with toripalimab as neoadjuvant treatment in patients with HER2 positive locally advanced muscle-invasive urothelial bladder cancer.
Authors: Li Chenglong , Zhu Jiefu , Yu Weimin
Published: January 2024

631

Background: For HER2 positive muscle-invasive bladder cancer (MIBC), the efficacy of cisplatin-based NAC is unsatisfied, and adverse reactions are inevitable or even intolerable. Disitamab vedotin is an antibody-drug conjugate composed of an anti-HER2 antibody disitamab and MMAE payload. Multiple clinical studies have confirmed that promising activity in HER2-positive locally advanced or mUC patients。This study aims to evaluate the safety and efficacy of disitamab vedotin, and toripalimab as a novel neoadjuvant treatment combination in patients with HER2 positive locally advanced MIBC. Methods: In this Study, Platinum intolerance and pathological andimaging diagnosed cT2-4bN0M0 MIBC patients with HER2 positive (HER2 IHC2+ or HER2 IHC3+) received 3 cycles toripalimab (200mg, iv, D1, Q2W) combined with disitamab vedotin (2mg/kg, iv, D1, Q2W). The primary endpoint was pCR, and the secondary endpoints included PFS, OS, and safety. Results: From July 2023 to Sep 2023, 12 patients were enrolled. The median age was 68 (55-82) years . By the data cut off in August 2023, the primary end point pCR was 80% (8/10). Median follow-up time was 4.2 (2.2-8.45) month. The median overall survival (OS) was not reached，ORR was100%. In terms of safety, the treatment-related adverse events (TRAEs) of any grade occurred in ten patients (83.3%), and the most common TRAEs were nausea (58.3%), followed by alopecia (33.3%), diarrhea (16.7%) and Cardiac tachycardia (8.3%). most of which are grade 1-2. Grade 3 TRAE is Cardiac tachycardia and occurred in one patient. No grade 4 and 5 TRAEs were observed. Conclusions: From July 2023 to Sep 2023, 12 patients were enrolled. The median age was 68 (55-82) years . By the data cut off in August 2023, the primary end point pCR was 80% (8/10). Median follow-up time was 4.2 (2.2-8.45) month. The median overall survival (OS) was not reached, ORR was100%. In terms of safety, the treatment-related adverse events (TRAEs) of any grade occurred in ten patients (83.3%), and the most common TRAEs were nausea (58.3%), followed by alopecia (33.3%), diarrhea (16.7%) and Cardiac tachycardia (8.3%). most of which are grade 1-2. Grade 3 TRAE is cardiac tachycardia and occurred in one patient. No grade 4 and 5 TRAEs were observed.
Real-world economic burden of patients with metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Kaye Deborah , Khilfeh Ibrahim , Muser Erik , Morrison Laura , Urosevic Ana , Kinkead Frederic , Lefebvre Patrick , Pilon Dominic , George Daniel J.
Published: January 2024

64

Background: In patients with prostate cancer (PC), progression to a metastatic disease stage is associated with substantial decline in prognosis as well as incremental economic burden. There is limited real-world evidence combining clinical data and payer claims to evaluate economic outcomes of patients with mCSPC. This study described healthcare costs of patients with mCSPC before and after the initiation of advanced therapy. Methods: Linked data from the Flatiron Metastatic PC Core Registry and all-payer claims data from Komodo Health Solutions were evaluated (Jan 2016 to Dec 2021). Patients in Flatiron who initiated advanced therapy for mCSPC (index date) in 2017 or later and had a corresponding pharmacy or medical claim in Komodo, following evidence of metastasis in the absence of castration resistance were included. Advanced therapies considered were androgen-receptor signaling inhibitors, chemotherapies, estrogens, immunotherapies, poly ADP-ribose polymerase inhibitors, and radiopharmaceuticals. Patients were excluded if they initiated a clinical trial drug as their index regimen or had <12 months of health insurance eligibility pre-index. All-cause and PC-related total costs (medical and pharmacy) per-patient-per-month (PPPM) were described from a payer’s perspective in the 12-month pre- and post-index period using 2022 US dollars. The post-index period was censored at evidence of castration resistance. Flatiron Health, Inc. did not participate in data analyses. Results: In total, 418 patients with mCSPC were identified (mean age 68 years, 56% white, 53% commercially insured, and 37% on Medicare). Pre-index androgen deprivation therapy was observed in 74% of patients. Pre-index, mean all-cause costs were $2,334 PPPM and PC-related costs were $964 PPPM with $90 PPPM attributable to PC-related pharmacy costs (Table). Post-index, patients averaged 14.5 months of follow-up, in which mean all-cause costs were $8,829 PPPM with PC-related costs of $7,232 PPPM, an increase of >7 times compared to pre-mCSPC therapy initiation. Conclusions: This real-world study demonstrated that costs associated with disease progression in PC are significant and lead to a need for more innovative therapies and medical management in this patient population. Approaches that effectively slow disease progression at earlier stages of PC disease may result in better overall outcomes and lower overall costs associated with progression to metastatic disease. [Table: see text]
Survival Outcomes of APA as a Starting treatment: Impact in real-world patients with mCSPC (OASIS).
Authors: Maughan Benjamin L. , Mundle Suneel , Nematian-Samani Mehregan , Wang Xiayi , Du Shawn , Liu Yanfang , Karsh Lawrence Ivan
Published: January 2024

65

Background: Over the last decade,androgen receptor signaling inhibitors (ARSIs; apalutamide [APA], enzalutamide [ENZ], abiraterone acetate + prednisone [AAP]) in combination with androgen-deprivation therapy (ADT) have emerged as more effective life-prolonging treatment options for mCSPC. We examined the impact of ARSI starting therapy in mCSPC on long-term clinical outcomes in real-world clinical practice in the US. Methods: This retrospective, observational cohort study evaluated clinical outcomes in adult patients with mCSPC using the ConcertAI RWD 360 prostate cancer dataset. All patients with newly diagnosed mCSPC from 1 Jan 2018 to 30 Sept 2022 were enrolled and followed up until 31 Mar 2023. Among other outcomes, PSA50 and PSA90 (PSA response defined as a ≥50% and ≥90% decline from baseline, respectively) and undetectable PSA (PSA ≤0.2 ng/mL) were assessed using the Kaplan-Meier method. Relative risks of onset of castration resistance (CR) and death were estimated using multivariate Cox proportional hazard models adjusted for potential confounding factors (age, comorbidities, BMI, baseline PSA). Results: 165 patients with mCSPC started on APA + ADT, 643 started on ENZ + ADT, 1064 on AAP +ADT, 293 on docetaxel (DTX) + ADT, and 543 on ADT alone (Table). A higher proportion of patients initiating APA achieved PSA50, PSA90, or undetectable PSA compared with other treatments. CR-free survival was significantly longer in patients first treated with an ARSI + ADT than those treated with DTX + ADT or ADT alone. Reduced risk of developing CR was observed in patients starting with APA + ADT compared with ADT alone (adjusted hazard ratio [aHR] 0.36, 95% CI 0.19, 0.67; p=0.0016). OS was longer in patients started on ARSIs compared to ADT alone. Patients starting with APA + ADT were observed to have a lower risk of death compared with ENZ + ADT (aHR 0.48, 95% CI 0.23, 0.99; p<0.05) or AAP + ADT (aHR 0.43, 95% CI 0.21, 0.90; p<0.05). Conclusions: ADT alone continues to be used widely despite the availability of newer and more effective life prolonging therapies. Use of APA + ADT as starting treatment for mCSPC demonstrated significantly better clinical outcomes than other ARSIs, DXT + ADT, or ADT alone in real-world clinical practice in the US. [Table: see text]
Mutational signature and prognosis in adenocarcinoma of bladder.
Authors: Yang Guoliang
Published: January 2024

655

Background: Adenocarcinoma of bladder is a rare urinary bladder carcinoma with limited therapy options due to lack of molecular characterization. Here we aim to reveal mutational and transcriptomic landscapes of adenocarcinoma of bladder and their relationship with prognosis. Methods: Between February 2015 and June 2021, a total of 23 patients with adenocarcinoma of bladder were included. These included 16 patients with primary bladder adenocarcinomas and 7 patients with urachal adenocarcinoma. Whole exome sequencing, whole genome sequencing, bulk RNA-Seq and single-cell RNA-Seq were conducted for the specimens. Correlation analysis, survival analysis and t tests were also performed. Results: Prevalent T>A substitutions were observed among somatic mutations, and major tri-nucleotide contexts included 5′-CTC-3′and 5′-CTG-3′. This pattern was mainly contributed by COSMIC Signature 22 related to chemical carcinogen exposure (probably aristolochic acid), which has not been reported in bladder adenocarcinoma. Moreover, genes with copy number changes also enriched KEGG term “chemical carcinogenesis”. Transcriptomic analysis implied high immune infiltration and luminal-like feature in majority of samples. Interestingly, a small fraction of samples with APOBEC-derived mutational signature exhibited higher risk of disease progression compared with samples with only chemical carcinogen-related signature, confirming molecular and prognosis heterogeneity in bladder adenocarcinoma. Conclusions: This study presents mutational and transcriptomic landscapes of bladder adenocarcinoma, and chemical carcinogen-related mutational signature indicates good prognosis in adenocarcinoma of bladder.
Activity of antibody-drug conjugates (ADCs) with radiation in preclinical bladder cancer models.
Authors: D'Andrea Vincent , Zhou Yuzhen , P Shanmugam Surish , Chroneos Rea , Stelter Isabella , Hanlon Timothy , Bekele Raie , Anderson William , Carvalho Filipe L.F. , Bellmunt Joaquim , Mouw Kent William
Published: January 2024

664

Background: Antibody-drug conjugates (ADCs) are a novel class of therapeutics that combine a tumor cell targeting antibody with a cytotoxic payload. Two ADCs are currently approved in the US for treatment of advanced bladder cancer: enfortumab vedotin (EV) and sacituzumab govitecan (SG). Radiation therapy (RT) plays a central role in trimodality therapy (TMT), a curative treatment approach for muscle-invasive bladder cancer (MIBC). However, the biological activity of ADCs combined with RT in preclinical MIBC models has not been reported. Methods: We use a molecularly annotated panel of human MIBC preclinical models to test the impact of RT on expression of ADC targets and define the combined activity of EV and SG with RT. We also test the in vivo activity of combining ADCs with image-guided, fractionated RT in bladder cancer flank xenograft mouse models. Results: Radiation has variable impact on expression levels of nectin-4 and trop-2, the targets of EV and SG, respectively, as determined by immunoblot, immunofluorescence microscopy, and immunohistochemistry (IHC). Whereas modest dose-dependent increases in nectin-4 and/or trop-2 levels were observed in some models, no significant changes were observed in other models. Importantly, RT did not lead to a significant decrease in nectin-4 or trop-2 expression in any of the models. EV and SG showed additive or synergistic cell killing when combined with RT across preclinical models in vitro. Combining EV or SG with fractionated RT in vivo was well-tolerated, showed improved tumor control, and prolonged survival in bladder cancer flank xenograft mouse models compared to either ADC or RT alone. Conclusions: ADCs demonstrate combination activity with RT across a panel of molecularly diverse bladder cancer preclinical models. These studies provide preclinical data supporting clinical trials to investigate the safety and efficacy of combining ADCs with RT as a bladder-preserving therapy for MIBC.
Outcomes with sacituzumab govitecan (SG) in patients (pts) with advanced urothelial carcinoma (aUC) and variant histologies (VH): Analysis of the UNITE study.
Authors: Nizam Amanda , Jindal Tanya , Jiang Cindy Y. , Alhalabi Omar , Davidsohn Matthew P. , Bakaloudi Dimitra Rafailia , Talukder Rafee , Nguyen Charles B , Oh Eugene , Taylor Amy K , Bilen Mehmet Asim , Basu Arnab , Kilari Deepak , Emamekhoo Hamid , Gupta Shilpa , Grivas Petros , Bellmunt Joaquim , Campbell Matthew T , Alva Ajjai Shivaram , Koshkin Vadim S
Published: January 2024

667

Background: SG is approved in pts with aUC refractory to platinum-based chemotherapy (PBT) and checkpoint inhibitor therapy (CPI). Data on SG outcomes in pts with subtype/variant histologies (VH) are limited. We examined SG-treated pts in the UNITE study and hypothesized that outcomes would be similar between pts with pure urothelial histology (pUC) and any VH component. Methods: UNITE is a multi-site retrospective study of pts with aUC treated (Tx) with targeted agents, such as enfortumab vedotin (EV) and SG. Pts who received SG monotherapy were included in this analysis. Observed response rate (ORR) was assessed by investigators at each site for evaluable pts with scans after ≥ 1 SG cycle using χ2 and logistic regression. Progression-free and overall survival (PFS, OS) from SG start were assessed using KM method and Cox proportional hazards model. Results: Among 633 total pts in UNITE, 116 received SG monotherapy at 11 US sites. Median age was 70; 79 (68%) male; 97 (84%) Caucasian; 86 (74%) ECOG PS 0/1; 84 (72%) lower tract tumor; 90 (78%) visceral or bone mets; 48 (41%) Bellmunt score ≥2; 72 pts (62%) had pUC and 44 (38%) VH, including 33 (28%) with UC predominant (<50% VH) and 11 (9%) with variant predominant (≥50% VH). For prior therapy, 109 pts (94%) received >2 prior lines; 75 (65%) PBT; 102 (88%) CPI; 109 (94%) EV. Median time from metastatic diagnosis to SG start was 18.6 months (mo) (0.9-84.5). Median follow up from SG start was 10.6 mo (8.5-15.4). Median time on SG was 1.6 mo (0.2-14.7). ORR to SG was 24% (20/84); median PFS and OS from SG start were 3.7 mo (95% CI 3.0-4.6) and 6.7 mo (95% CI 5.3-10.8). VH (n ≥1) included: squamous (SQH) (19, 16%), micropapillary (9, 8%), plasmacytoid (8, 7%), adenocarcinoma (3, 3%), neuroendocrine (NE) (2, 2%). In evaluable pts with VH, ORRs: squamous (3/14), micropapillary (1/4), plasmacytoid (0/6), adenocarcinoma (2/3), NE (1/2). No significant differences were observed in outcomes between pUC and any VH or pUC and SQH (Table). Conclusions: Pts with aUC treated with SG appear to have similar clinical outcomes between pUC and any VH. Responses to SG are observed across different VH. Limitations include low power, tumor heterogeneity, lack of central pathology/scan review, selection and confounding biases. These hypothesis-generating findings suggest activity of SG post-PBT, CPI, and EV in pts with VH, but should be validated in larger cohorts with adequate sample size of specific VH and longer follow up. [Table: see text]