bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cabozantinib plus pembrolizumab as first-line therapy for cisplatin-ineligible advanced urothelial carcinoma (PemCab).
Authors: Jain Rohit K. , Swami Umang , Bilen Mehmet Asim , Boucher Kenneth M. , Brown Jacqueline T , Chahoud Jad , Gupta Sumati , Agarwal Neeraj , Sonpavde Guru P. , Maughan Benjamin L. 
Published: January 2024

539 Background: Pembrolizumab (pem) was initially approved in the first line setting for cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients (pts) with high PD-L1 expression and platinum ineligible pts regardless of PD-L1 status; this later changed to only platinum ineligible pts. There is a high disease progression (PD) rate with pem monotherapy. Cabozantinib (cabo) is a multiple receptor tyrosine kinase inhibitor targeting MET and VEGFR2 approved in multiple other malignancies as monotherapy or in combination with PD-1 inhibition. We hypothesized that combination of pem and cabo therapy will be safe and efficacious in patients with treatment naïve mUC. Methods: This is a phase II, open label, multi-center, single arm trial evaluating the tolerability and activity of pem 200 mg every 3 weeks and cabo 40 mg daily as first-line treatment for patients with mUC. Key inclusion criteria were histologically proven locally advanced or mUC, ECOG-PS 0-2, cisplatin-ineligible (including patient refusal of cisplatin), treatment naïve, and no prior PD-1/L1 therapy. The primary endpoint was objective response rate (ORR). Key secondary endpoints included progression-free survival (PFS) and overall survival (OS). There was a lead-in safety cohort of 6 pts. We hypothesized that combination therapy would improve ORR to > 32%. With 35 evaluable subjects, the lower bound of the 95% confidence interval would extend no more than 26% from the observed proportion. With ≥17 objective responses, the confidence interval excludes 32%. Results: Between December 26, 2018, and April 19, 2023, 36 pts were enrolled of which 35 were evaluable for response with the median follow up of 14.4 months (95% CI 12.2 – 16.2). The median age was 72.5y [range, 47-82]; ECOG PS 0-1 in 89% pts. Responses were observed in 15 pts (ORR= 42.8%) including complete responses in 5 pts (14.3%). Stable disease was seen in 10 pts (28.6%). The disease control rate was 68.5% (25/35). Median PFS was 7.7 months (95% CI 4.2 – 11.2). Fifty-two percent of pts developed any grade treatment-related adverse events (TRAE) attributable to either cabozantinib or pembrolizumab. The most common grade 1/2 TRAE were diarrhea, anorexia, dysgeusia, weight loss, and nausea. Forty-four percent pts developed grade 3/4 TRAEs most common being hypertension, hypophosphatemia, alanine transaminase elevation, diarrhea, and fatigue. Conclusions: This novel phase II trial of pem + cabo demonstrated a manageable toxicity profile and promising efficacy as first-line therapy in mUC including patient’s ineligible for cisplatin. Further investigation with a focus on predictive biomarkers is ongoing. Clinical trial information: NCT03534804 .
Development of a novel RNA-based immune checkpoint inhibitor response signature (ICI-PRS) that avoids standard-of-care (SOC) prognostic signal for use in patients with urothelial cancer (UC).
Authors: Shepherd Jonathan , Mayhew Gregory , Guo John , Beebe Kirk , Eisner Joel Robert , Milburn Michael Vance 
Published: January 2024

549 Background: Immune checkpoint inhibition (ICI) shows great promise, including approval of pembrolizumab, nivolumab and avelumab in urothelial cancer (UC). However, the overall percentage of UC patients with clinical benefit is relatively small, despite biomarker use to select patients (e.g., PD-1 expression and TMB). Recently, several accelerated approvals (atezolizumab and durvalumab) were subsequently withdrawn following failure to show improved survival compared to standard of care (SOC) treatment in Phase 3 +/- biomarker use. To address the need for better ICI biomarkers, we developed an RNA-based predictive response signature (ICI-PRS) with the primary objective of being prognostic for ICI-treated patients, but not for SOC treatment. Methods: A survival-based model trained on 2/3 of the combined IMVigor210 dataset (n=298 locally advanced or metastatic UC patients treated with atezolizumab) and TCGA BLCA cohort (n=405 patients treated with non-ICI SOC) identified genes associated with survival across these data sets (prognostic agnostic to therapy) and genes distinctly associated with survival with ICI treatment (candidate ICI-predictive). Candidate ICI-predictive genes were developed into a model that was applied to the remaining IMVigor210 and TCGA BLCA samples, UC-GENOME urothelial carcinoma samples, and an ICI-treated melanoma dataset (Gide et al, 2019 : DOI: 10.1016/j.ccell.2019.01.003). Associations with tumor mutation burden (TMB) were examined. Expanded models incorporating this signature with additional immune markers were also investigated. Results: The ICI-PRS shows consistent associations with overall survival (OS) dependent on ICI treatment status. A higher hazard ratio (HR) was found for cohorts with ICI-therapy [HR (95% CI): IMVigor test 1.23 (0.96-1.57); UCGENOME 1.35 (0.99-1.85); Gide 1.50 (1.02-2.2)]. By comparison, no association was seen in the TCGA test set in which patients received non-ICI SOC treatment (HR = 0.96 (0.73-1.3). Patients with high TMB had extended survival in both IMVigor210 and non-ICI SOC TCGA datasets (P = 0.02 and 0.001). Conclusions: Herein we describe the development of a novel ICI-PRS and initial demonstration that it provides ICI-treatment specific prognostic value for bladder cancer patients. ICI-PRS status was associated with extended survival in patients treated with anti-PD-L1 but not non-ICI SOC therapy. These results support the further evaluation of the ICI-PRS and potential development as a diagnostic test for selecting UC patients most likely to benefit from ICI therapy.
Estimating Bayesian priors for a non-inferiority randomized trial of gemcitabine-based chemoradiation for muscle invasive bladder cancer.
Authors: Pepin Abigail , Maitre Priyamvada , Wang Xingmei , Murthy Vedang , Mamtani Ronac , Christodouleas John Paul 
Published: January 2024

575 Background: Gemcitabine (gem) is a convenient radiosensitizer for muscle invasive bladder cancer (MIBC). However, the effectiveness and toxicity of gem have not been studied in a randomized control trial (RCT) against non-gem radiosensitization. This analysis aims to generate informative Bayesian prior distributions for effectiveness and toxicity outcomes to be used in a non-inferiority RCT of gem versus non-gem radio-sensitizers. Methods: We extracted all patients (pts) treated with curative intent concurrent chemoradiotherapy for node negative MIBC at a single institution between 2010-2022 and divided into gem vs non-gem cohorts. To minimize impact of confounding, we used freedom from distant metastases (FFDM) as our primary measure of effectiveness, censoring for both loss to follow up and death. We used a non-informative uniform prior to estimate the posterior distribution of hazard ratios (HR) for FFDM. We used a non-informative Jeffrey’s prior to estimate the posterior distribution of odds ratios (OR) for dichotomized acute grade 2 or higher gastrointestinal (G2+ GI) and genitourinary (G2+ GU) toxicities. We adjusted for age, T-stage, prior non-MIBC, neoadjuvant chemotherapy in all analyses. Results: A total of 106 pts were included (50 = gem, 56 = non-gem, of which 27 [48%] received mitomycin/5FU); 81% had cT2 disease and median radiation dose was 6480 cGy (range 4500-6480 cGy). Compared to pts in non-gem cohort, pts in gem cohort were older (mean age: 80 vs 76), had less advanced primaries (T3-T4: 14% vs 23%), were less likely to get neoadjuvant chemotherapy (12% vs 29%), were less likely to have prior non-MIBC (10% vs 13%), were less likely to complete full course radiotherapy (88% vs 94.6%), and had shorter follow-up (median 1.3 versus 2.3 years). The 2-year FFDM for the gem and non-gem were 62% and 66%. Table 1 shows rates of acute GI/GU toxicity. The median posterior HR (high probability density (HPD)) for FFDM was 1.54 (0.63-2.86). The OR (HPD) for grade 2+ GI toxicity was 2.4 (HPD 0.78-5.44) and grade 2+ GU toxicity was 0.91 (HPD 0.29-1.82) in gem vs non-gem cohorts. Conclusions: Our analysis suggests skeptical priors for FFDM (50% chance of at least 54% worse HR) and acute G2+ GI toxicity (50% chance of at least 140% worse OR) toxicity and a neutral prior for acute G2+ GU toxicity for a non-inferiority RCT of gem vs non-gem radiosensitization. Validation in a second institutional cohort will be available for our presentation. [Table: see text]
Unraveling the web of frailty: A novel approach to frailty using a CGA-derived spider plot.
Authors: Cavanaugh Dana , Holt Sarah K , Petersen Erin , Jannat Samia , Wright Jonathan L. , Gore John L. , Schade George , Psutka Sarah P. 
Published: January 2024

579 Background: Frailty in bladder cancer predicts increased complications and mortality. Measuring frailty is challenging because relying on one frailty instrument risks oversimplifying patients’ multidimensional vulnerability profiles. Current guidelines recommend using a comprehensive geriatric assessment (CGA) to quantify frailty across domains of physical function, mental health/cognition, nutrition, and multimorbidity in older adults. However, the CGA’s extensive data can be hard to synthesize and integrate into busy clinical practice. We propose a novel CGA-derived Frailty Spider Plot, synthesizing CGA-identified vulnerabilities into a clinically useful frailty profile. Methods: Urothelial cancer patients, prospectively enrolled between 9/2020 and 7/2021 in a multidisciplinary bladder cancer clinic, completed a CGA incorporating validated assessments of functional status, multimorbidity, nutrition, cognition, and mental health, augmented with CT-derived assessments of muscle mass and adiposity. Spearman Correlation Coefficients were used to quantify relationships between frailty tools and domains. Novel Frailty Spider plots were then created to visualize individuals’ distinct frailty phenotypes. The CGA instruments, grouped by domain, were the spokes of the plot, with each node determined by validated thresholds. Outer ring values indicated greater frailty. Results: The cohort included 67 patients (median age 71, 16.4% female), most with muscle-invasive bladder cancer (77.6%; cN+: 20.9%, M1: 7.6%). The CGA identified 31.4% vulnerable-to-moderately frail, 23.9% at risk for falls, 13.4% with mild depression, 7.5% with moderate-severe depression, 3% with mild/moderate dementia, 34% at risk for malnutrition, and 6% malnourished. Frailty measures were generally weakly correlated (rho <|0.5|). Individuals’ specific risk profiles were plotted on the novel Frailty spider plot which visually distinguished patients according to their frailty phenotypes. For instance, a patient with a high risk Mini-nutritional Assessment score, hypoalbuminema, and sarcopenic skeletal muscle mass, is distinguished with a Spider plot dominated by nutritional frailty spokes. Conclusions: In this prospective observational cohort, a CGA identified key vulnerabilities beyond a standard risk assessment. Frailty domains provide unique risk insights beyond relying on simple frail/not frail nomenclature. Notably, even within a domain, instruments had low correlations, contributing distinct insights into a patient’s vulnerability profile. Our novel Spider plot approach visually synthesizes this data in a single depiction of the predominant components of frailty that can be targeted by personalized prehabilitation interventions. Future work will refine risk assessment instruments to best predict clinical outcomes, creating parsimonious Frailty spider plots for clinical use.
Treatment patterns and outcomes by age in metastatic urothelial carcinoma (mUC): A retrospective tertiary cancer center analysis.
Authors: Tripathi Nishita , Gebrael Georges , Sahu Kamal Kant , Balasubramanian Ishwarya , Caparas Constance , Mathew Thomas Vinay , Cohan Jessica N. , Pelletier Kaitlyn , Maughan Benjamin L. , Agarwal Neeraj , Swami Umang , Gupta Sumati 
Published: January 2024

582 Background: Older adults with locally advanced or mUC often do not receive optimal first-line (1L) therapy (Rx) and subsequent treatments (Lara et al. ASCO 2016). There are limited randomized data for age-appropriate Rx in older mUC adults. Through our real-world study, we describe the clinical characteristics, treatment patterns, and outcomes among pts with mUC, comparing older to younger adults receiving 1L systemic Rx. Methods: This retrospective IRB-approved study included pts receiving care between 2014 and 2023 at the University of Utah, Huntsman Cancer Institute, a tertiary care National Cancer Institute-Designated Comprehensive Cancer Center. Eligible pts had a confirmed diagnosis of mUC and received 1L chemotherapy or 1L immunotherapy-based regimens. Based on age at receipt of 1L Rx, pts aged 70 years or above were grouped in the ‘older’ group, while rest were included in the ‘younger’ cohort. Survival and Rx-related outcomes of those enrolled inwere excluded. Overall survival (OS) between the two groups was compared using Kaplan-Meier and Cox Regression analysis. All statistical analyses were implemented in R-Studio (v.4.2). Results: We identified 212 eligible mUC pts (103 older vs. 109 younger). Older pts received more immunotherapy-based Rx in the 1L (52.4% vs 35.7%, p=0.02), were more likely to be (73.6% vs. 45.4%, p<0.001), less likely to receive subsequent lines of Rx (median; range: 0 (0-3) vs 1 (0-5), p=0.005) and had lower clinical trial participation (69.9% vs 81.6%, p=0.04)compared to younger pts. For survival outcomes and treatment-related analysis, 160 patients (72 older vs. 88 younger) undergoing approved standard of care were included. Among mUC treated with 1L chemotherapy (n=108), more pts required dose adjustments in older group (23/43 vs 15/65 younger). Older adults received less number of cycles of chemotherapy (median; range: 4 (0-6) vs 5 (1-12), p= 0.03). Older pts had OS comparable to younger pts (11.2 mos vs. 14 mos, p=0.06). Pts from both age groups had similar rates of Rx-related toxicity and healthcare visits, independent of the type of systemic Rx. Conclusions: Older pts with mUC tend to be cis-ineligible and have lower bone marrow reserve. Nevertheless, select pts can be treated with risk-adjusted regimens of chemotherapy and with immunotherapy with comparable outcomes to younger mUC pts in terms of toxicity and outcomes. Validated tools to predict vulnerabilities and excessive chemotherapy-related toxicity in older adults with mUC are available and may help mitigate toxicity by informing Rx adjustments.
De novo financial toxicity following radical cystectomy for bladder cancer and its impact on health-related quality of life.
Authors: Westhofen Thilo , Buchner Alexander , Eismann Lennert , Rodler Severin , Becker Armin , Stief Christian G. , Kretschmer Alexander 
Published: January 2024

587 Background: Financial toxicity (FT) is a patient-reported outcome measure (PROM), defined as the detrimental effect of financial burden caused by a cancer diagnosis on a patient’s well-being. Although FT is common among cancer patients, little is known about FT following radical cystectomy for bladder cancer in countries with universal health coverage. We aimed to assess de novo FT and its impact on health-related quality of life (HRQOL) in a large prospective cohort of patients undergoing RC with a systematic follow-up of up to 10 yrs. Methods: 1606 consecutive patients who underwent RC at a large tertiary care center were included. PROMs were prospectively assessed preoperatively, postoperatively at 3mo, then annually until a maximum follow-up of 120mo, applying the validated EORTC QLQ-C30 questionnaire, and the bladder cancer-specific QLQ-BLM30 and FACT-BL-questionnaires. FT was assessed by the “financial toxicity subscale” (FTS) of the EORTC QLQ-C30. Based on previous reports, meaningful FT was defined as FTS ≥ 17. Multivariable regression analysis was used to identify predictors for the development of de novo FT. Separate modeling of longitudinal HRQOL was performed for patients with de novo FT (FT-cohort) and without FT (no-FT-cohort). Results: 93 Patients reporting FT prior RC were excluded from further analysis. 37.6% of the included patients reported de novo FT within 12 months after RC with a mean FTS-score of 55.2 (SD 26.3). Baseline clinicopathological characteristics did not differ between the FT-cohort and the no-FT-cohort (p-range .072-.370). Multivariable logistic regression analysis revealed male gender (OR 3.448, 95%CI 1.10-11.49, p=.045), urban neighborhood (OR 1.532, 95%CI 1.01-2.53, p=.049), a positive smoking history (OR 2.491, 95%CI 1.18-5.26, p=.017) and ileal conduit urinary diversion (OR 2.179, 95%CI 1.03-4.61, p=.042), to independently predict de novo FT following RC. Longitudinal analysis of HRQOL revealed no significant difference in baseline general HRQOL assessed by the global health status domain (GHS) between both cohorts (p=.934). Postoperatively, patients with de novo FT reported significantly worse general HRQOL compared to patients without FT (p= .001). In the longer term, the FT-cohort reported significantly worse GHS scorer up to 84mo after RC. Conclusions: The current study provides prospective data from a unique contemporary patient cohort, which reveals independent predictors for de novo FT following RC. Furthermore, it displays the natural course of general HRQOL for patients who develop de novo FT.
Role of thromboprophylaxis during neoadjuvant chemotherapy before radical cystectomy in patients with bladder cancer: Results of a multicenter retrospective cohort study.
Authors: Antonelli Luca , Wendel Garcia Pedro David , Deforth Manja , Afferi Luca , Borghesi Marco , Antonelli Alessandro , Tully Karl , Mari Andrea , Pichler Renate , Claps Francesco , Teoh Jeremy Yuen-Chun , Schulz Gerald Bastian , Soria Francesco , Alrumayyan Majed , Rink Michael , Zamboni Stefania , Lavallee Luke , Moschini Marco , Held Ulrike , Fankhauser Christian Daniel 
Published: January 2024

598 Background: Patients undergoing radical cystectomy are at risk of developing venous thromboembolic events (VTE), with most VTEs occurring during neoadjuvant chemotherapy. The ASCO Clinical Practice Guideline Update recommends thromboprophylaxis in cancer patients with a high risk of VTE and a low risk of bleeding. However, the risks of VTE and bleeding with or without thromboprophylaxis in bladder cancer patients scheduled for radical cystectomy have not been well evaluated. Methods: We conducted a retrospective cohort study of patients with non-metastatic bladder cancer undergoing cystectomy across 28 centers in 13 countries between 1990 and 2021. Inverse probability weighting analyses were performed to estimate the effect of thromboprophylaxis during neoadjuvant chemotherapy on VTE and bleeding. Results: Of 4886 patients, 4631 (95%) received neither thromboprophylaxis nor anticoagulation during chemotherapy. Thromboprophylaxis during neoadjuvant chemotherapy was prescribed in 151 (3%) patients mainly being enoxaparin (80%) with a median duration of 94 (range 38 to 104) days. In inverse probability weighting analyses, patients with thromboprophylaxis compared to patients without thromboprophylaxis during chemotherapy had not only a lower VTE (HR 0.32 [95% CI, 0.12 to 0.81], p-value = 0.016) but also a lower bleeding risk (HR 0.03 [95% CI, 0.09 to 0.12], p-value: <0.0001). Conclusions: In this retrospective analysis, the benefit of thromboprophylaxis during neoadjuvant chemotherapy before cystectomy is in line with data from randomized trials in other malignancies. Our data suggests thromboprophylaxis seems protective against VTEs during neoadjuvant chemotherapy in bladder cancer patients planned for cystectomy. The ASCO guidelines recommending thromboprophylaxis during chemotherapy should therefore also be regarded as a standard of care in patients treated with neoadjuvant chemotherapy before cystectomy.
Association of HER2 expression in advanced urothelial carcinoma (aUC) and treatment outcomes with immune checkpoint inhibitors and enfortumab vedotin.
Authors: Shipp Chase Allain , Jindal Tanya , Reyes Kevin R , Zhu Xiaolin , Ding Chien-Kuang Cornelia , Chan Emily , Stohr Bradley A. , Deshmukh Prianka , Fitzgerald Kelly N. , Kwon Daniel , Bose Rohit , Desai Arpita , de Kouchkovsky Ivan , Aggarwal Rahul Raj , Small Eric J. , Fong Lawrence , Porten Sima P. , Friedlander Terence W. , Chou Jonathan , Koshkin Vadim S 
Published: January 2024

599 Background: HER2 immunohistochemistry (IHC) is not routinely assessed in patients (pts) with aUC, but it is an emerging predictive biomarker with the advent of HER2-targeting agents. aUC outcomes with respect to HER2 status following treatment with immune checkpoint inhibitors (ICIs) and enfortumab vedotin (EV) are unknown. Methods: We retrospectively identified pts with aUC and available biopsies tested for HER2 IHC and fluorescence in situ hybridization (FISH). HER2 status was assessed using modified GI criteria as HER2 high (IHC 3+ or IHC 2+/FISH+), HER2 low (IHC 2+/FISH- or IHC 1+) or HER2 negative (IHC 0). Pt characteristics and outcomes were abstracted from chart review. We compared outcomes following ICI monotherapy and EV-based regimens in pts with HER2-high or HER2-low tumors relative to HER2-negative, and HER2-positive (≥IHC 1+) tumors relative to HER2-negative. Observed response rate (ORR) evaluated by local investigator was compared in pts with scans after ≥1 treatment cycles using logistic regression, while progression-free survival (PFS) and overall survival (OS) from treatment start were assessed using the Kaplan-Meier method and Cox proportional hazards model. Results: Biopsies from 181 pts with aUC obtained from 3/2016 – 3/2023 were tested for HER2 (34 high, 88 low, 58 negative, 1 indeterminate). In this group, 43 pts received ICI [38 (88%) pembrolizumab; 5 (12%) atezolizumab] and 37 EV [31 (82%) monotherapy; 6 (18%) combination regimen]. Pt characteristics and outcomes are shown in the Table. Among pts treated with EV, HER2-negative pts had decreased PFS (HR: 0.18, 95% CI 0.03 – 0.94, p=0.04) relative to HER2-high. No other differences were noted for any cross-group comparison. For pts treated with ICI, no differences in outcomes were observed for any comparisons based on HER2 status. Conclusions: In this single institution retrospective analysis, pts with aUC and HER2-high IHC expression had longer PFS relative to pts with HER2-negative expression when treated with EV-based regimens. No differences were observed in ICI outcomes based on HER2 expression. These hypothesis-generating results should be validated in larger cohorts. [Table: see text]