bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma DNA and deoxyribonuclease in testicular germ cell tumors.
Authors: Mego Michal , Vlkova Barbora , Kalavska Katarina , Cierna Zuzana , Rejlekova Katarina , Udvorkova Natalia , Majtanova Kristina , Lesko Peter , Obertova Jana , Orszaghova Zuzana , Palacka Patrik , Sycova-Mila Zuzana , Mardiak Jozef , Chovanec Michal , Kucerova Lucia , Celec Peter
Published: January 2024

518

Background: Despite high cure rate, small proportion of patients with germ cell tumors (GCTs) experience relapse and eventually die as a consequence of their disease. Tumor-derived DNA, but also total extracellular DNA (ecDNA) in plasma were found to be associated with the prognosis in different types of cancer. Deoxyribonuclease (DNase) catalyzes the cleavage of ecDNA and is likely the main metabolic pathway of ecDNA degradation. We hypothesized that DNase activity might modulate the association between ecDNA and prognosis. This study aimed to determine the prognostic value of ecDNA of different subcellular origin and plasma DNase activity in GCTs. Methods: This study included 117 patients with testicular GCTs starting a new line of therapy and 19 healthy controls. Plasma ecDNA was quantified using fluorometry (total ecDNA) and using PCR (nuclear – ncDNA and mitochondrial DNA – mtDNA). DNase activity was assessed using the single radial enzyme diffusion method in a DNA-containing gel. An in vivo experiment in mice was conducted to evaluate the effect of DNase I treatment alone and in combination with cisplatin on the xenografts derived from the human embryonal carcinoma cell line variant NTERA-2 CisR. Results: Plasma ecDNA was higher in patients with GCTs compared to healthy controls (mean ng/ml ± SEM: 6.2 ± 0.6 vs.1.2 ± 2.2). Patients with high total ecDNA, ncDNA but not mtDNA had inferior PFS and OS compared to patients with low ecDNA (all p < 0.05). There was an inverse relationship between plasma DNase and ecDNA as well as between plasma DNase and clinical outcome (HR=2.96, 95%CI 1.39-6.32, P = 0.01 for PFS and HR=4.88, 95%CI 2.06-11.53, p = 0.005 for OS, respectively). Our experiments on selected model human GCT cell lines confirmed the lack of cytotoxic or inhibitory effects of DNase I in vitro. The animal experiment showed that the combination treatment with DNase I and cisplatin substantially reduced the growth of the NTERA-2 cisplatin-resistant xenografts (by 30%). Conclusions: We confirmed the prognostic value of ecDNA and proved it for the first time for DNase in patients with GCTs. We suggest that based on the animal experiment there is strong rationale to add DNase to cisplatin in refractory GCTs. Although the mechanisms are unclear and could involve reduced inflammatory response to ecDNA, we hypothesize that degradation of ecDNA by DNase might contribute to a better control of the tumor progression by cisplatin in patients with progressing or relapsing GCTs.
Estimating the impact of adjuvant treatment with nivolumab on long-term survivorship rates compared with surveillance: Analyses of disease-free survival (DFS) from the phase 3 CheckMate-274 trial.
Authors: Geynisman Daniel M. , Yates Georgia , Chepynoga Kateryna , Teitsson Siguroli , Kurt Murat , Patel Miraj Y. , Mamtani Ronac
Published: January 2024

528

Background: Durable DFS and cure are the ultimate goals for the treatment of muscle invasive urothelial carcinoma (MIUC) with radical cystectomy. This analysis employed mixture cure models (MCMs) to estimate the underlying cure fraction among high-risk MIUC patients following radical resection in the Phase 3 CheckMate-274 study. Methods: MCMs were applied to patient-level DFS data from the trial (minimum follow-up: 31.6 months). Intention-to-treat (ITT) population and the subpopulation with tumor PD-L1 expression ≥1% were analyzed separately for nivolumab (NIVO) and placebo (PBO) arms. In MCMs, the patient populations were assumed to consist of two exclusive subgroups as cured and uncured. Cured subgroup was assumed to be free of disease recurrence and disease-related mortality risks. The uncured subgroup was at the risk of both disease recurrence and all-cause mortality. DFS for the cured subgroup was estimated using background mortality rates published by WHO matched to the trial’s demographic characteristics. DFS for the uncured subgroup was modelled using parametric distributions, which were characterized along with the cure fraction by maximum likelihood methods. Model selection was primarily based on clinical plausibility of estimated DFS for the uncured subgroup. Visual comparison of the fits from the MCMs to the reported DFS data from the trial and goodness-of-fit statistics also assisted model selection. Results: In the trial, 353 patients were treated with NIVO (mean age: 65.3; male: 75.1%; PD-L1≥1%: 39.7%) and 356 patients were in PBO control (mean age: 65.9; male: 77.2%; PD-L1≥1%: 39.9%). Selected models estimated almost all uncured patients to experience recurrence within 5 years. The estimated cure fraction in the ITT population ranged from 43.1%-45.1% in the NIVO arm (95% CI: 36.7%-51.6%), and 36.4%-37.0% in the PBO arm, (95% CI: 30.9%-43.0%) for clinically plausible models. Projected range of 10-year mean DFS for the ITT patients was 4.38-4.47 years in the NIVO arm and 3.61-3.64 years in the PBO arm. Estimated cure fractions in the PD-L1≥1% subpopulation ranged from 59.1%-61.0% in the NIVO arm (95% CI: 48.9%-72.0%), and 35.9%-36.9% in the PBO arm, (95% CI: 27.5%-45.9%). Projected range of 10-year mean DFS for the PD-L1≥1% subpopulation was 5.54-5.65 years in the NIVO arm and 3.54-3.57 years in the PBO arm. Conclusions: In the adjuvant treatment of MIUC, relative to radical resection only, systemic therapy with NIVO is associated with a 6-9 percentage points higher cure fraction in the ITT population. Tumor PD-L1≥1% expression was associated with higher cure fractions in the NIVO arm but had only negligible impact on the underlying cure fraction in the PBO arm. Clinical trial information: NCT02632409 .
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]
Datopotamab deruxtecan in locally advanced/metastatic urothelial cancer: Preliminary results from the phase 1 TROPION-PanTumor01 study.
Authors: Lisberg Aaron , Drakaki Alexandra , Meric-Bernstam Funda , Alhalabi Omar , Kojima Takahiro , Kato Manabu , Spira Alexander I. , Salkeni Mohamad Adham , Heist Rebecca , Gao Xin , Bhave Manali A. , Klauss Gunnar , Sakaki Hayato , Kakurai Yasuyuki , KOGAWA TAKAHIRO
Published: January 2024

603

Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor payload via a plasma-stable, tumor-selective, tetrapeptide-based cleavable linker. Dato-DXd has shown encouraging antitumor activity and a manageable safety profile in patients (pts) with solid tumors. We report preliminary results in pts with advanced/metastatic (a/m) urothelial cancer from the ongoing phase 1 TROPION-PanTumor01 study (NCT03401385). Methods: Pts with unresectable a/m urothelial cancer treated with ≥1 prior line of therapy received intravenous Dato-DXd 6 mg/kg Q3W. Primary study objectives were safety and tolerability. Secondary endpoints were objective response rate (ORR; complete response [CR] + partial response [PR]), and disease control rate (DCR; CR + PR + stable disease) per RECIST 1.1 by BICR. This is the first data disclosure from this cohort in an ongoing expansion cohort study. Results: At data cutoff (May 18, 2023), 18 pts had received Dato-DXd. Median follow-up was 9.1 (range 5–17) months; 6 (33.3%) pts were receiving ongoing treatment. Median age was 63.5 (range 46–79) yrs. Pts were heavily pretreated, 15 (83.3%) had received ≥3 prior regimens. All pts received prior immunotherapy, 17 (94.4%) prior platinum-based chemotherapy, and 4 (22.2%) prior taxanes. Treatment-emergent adverse events (TEAEs) occurred in 100% (any grade [gr]) and 44.4% (gr ≥3) of pts, and drug-related TEAEs occurred in 94.4% (any gr) and 16.7% (gr ≥3) of pts. No drug-related serious AEs were reported, and no TEAEs associated with death were observed. Any gr TEAEs associated with reduction, interruption, and discontinuation of treatment were reported in 11.1%, 33.3%, and 5.6% of pts, respectively (Table). Adjudicated drug-related interstitial lung disease (gr 2) occurred in 1 (5.6%) pt. Confirmed ORR was 27.8% (95% CI 9.7–53.5); 1 pt achieved a CR and 4 achieved a PR. DCR was 77.8% (95% CI 52.4–93.6). Clinical evaluation of this cohort is ongoing and updated results will be presented. Conclusions: In heavily pretreated pts with a/m urothelial cancer, Dato-DXd demonstrated a tolerable and manageable safety profile with encouraging antitumor activity. Dato-DXd is being evaluated in pts with urothelial cancer as part of the phase 1/2 TROPION-PanTumor02 (NCT05460273) and the phase 2 TROPION-PanTumor03 (NCT05489211) studies. Clinical trial information: NCT03401385 . [Table: see text]
Performance of the OncoUrine test on predicting patients who can avoid Re-TURBT and prognosis: A prospective, multicenter clinical study.
Authors: Yang Xiao , Cai Lingkai , Zhen Bing , Yuan Lin , Qin Zhenqian , Chen Xinfeng , Han Jie , Jiang Xuping , Xin Yaqun , Yuan Hongling , Cao Dandan , Lu Qiang
Published: January 2024

623

Background: According to European Association of Urology (EAU) guidelines, repeated transurethral resection of bladder tumor (re-TURBT) is recommended in a large percentage of non–muscle-invasive bladder cancers (NMIBC) due to possibility of incomplete initial TURBT. However, no reliable predictors have been developed to help select patient candidates who could avoid Re-TURBT in NMIBC. Methods: This was a blinded, observational, prospective multicenter study (NCT05112523). A total of 162 patients who underwent initial TURBT and were scheduled for Re-TURBT were enrolled in this study between June 2021 and August 2023 from four centers. Urine sample of each patient was collected prior to Re-TURBT. High-throughput sequencing of 17 genes and methylation analysis for ONECUT2 CpG sites were combined as a liquid biopsy test panel named OncoUrine. The OncoUrine test results were compared to pathological results at Re-TURBT to assess the performance in predicting residual tumor and predictive value of risk stratification. Patients who received intravesical infusion chemotherapy or BCG were followed up for recurrence analysis. Results: 151 patients were finally included for performance analysis. At Re-TURBT, 48 (31.8%) samples had residual tumor and 103 (68.2%) had no residual tumor. 1 Ta and 2 T1 patients were up staged to T2 at Re-TURBT. Overall, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of OncoUrine test were 77.1%, 77.7%, 61.7%, and 87.9%. Compared to OncoUrine, Cytology prior to Re-TURBT yielded a high specificity of 95.8% but lower sensitivity of 20% and combined with OncoUrine improved the sensitivity to 75.6%. In the overall OncoUrine test results, variants from 12 genes showed positive mutations. TERT, TP53, ERBB2, FGFR3, and PIK3CA were on the top 5 of the lists with other mutations from ERBB3, ERCC2, U2AF1, HRAS, KDM6A, KRAS, and ROHA. 132 were followed up with a median of 362 days (range 21 to 953). 19 patients were found recurred. The pathological results at Re-TURBT, OncoUrine, methylation and TERT results were risk stratification approaches for the recurrence analysis (positive vs. negative, p＜0.05). Conclusions: OncoUrine test after initial TURBT for NMIBC showed promise as to guide patient selection for Re-TURBT and risk stratification in the management of NMIBC. Clinical trial information: NCT05112523 .
Phase Ib trial of erdafitinib (E) combined with enfortumab vedotin (EV) following platinum and PD-1/L1 inhibitors for metastatic urothelial carcinoma (mUC) with FGFR2/3 genetic alterations (GAs).
Authors: Jain Rohit K. , Heiligh Jazlyn , Kim Youngchul , Piekarz Richard , Pelosof Lorraine Cheryl , Yang Yuanquan (Aaron) , D'souza Anishka , Wong Risa Liang , Graham Laura , Gupta Sumati , Park Anna , Synold Timothy W. , Sonpavde Guru P.
Published: January 2024

625

Background: Erdafitinib (E) is a treatment option in mUCpatients with somatic FGFR2/3 GAs after progression on platinum-based chemotherapy (PBC). Enfortumab Vedotin (EV) is approved as a single agent to treat mUC patients following prior PBC and PD1/L1 inhibitors or as second-line therapy for cisplatin-ineligible patients. Retrospective studies suggest that the activity of EV is not compromised by FGFR2/3 GAs. E and EV have different mechanisms of activity, and toxicities are mostly non-overlapping. Hence, there is rationale to evaluate the feasibility of combination E + EV, to overcome the difficulties of resistance and sequencing agents in mUC patients with FGFR2/3 GAs. Methods: This is an ongoing, single arm, multicenter, dose-escalation and expansion study of combination E + EV evaluating the safety, tolerability, pharmacokinetics (PK), and antitumor activity in patients with mUC harboring somatic FGFR2/3 GAs who have progressed after PBC and/or PD1/L1 inhibitor therapies. Dose escalation phase aims to identify the maximum tolerable dose and recommended phase 2 dose of EV at dose levels of 1 mg/kg and 1.25 mg/kg in combination with E at 8 mg/day as shown in the table. Preliminary safety, PK, and efficacy data for Dose Level (DL) 1 and 2 are presented in this abstract. Results: As of data cutoff, based on 3+3 design, total 8 patients are enrolled and finished dose limiting toxicity (DLT) period (1st cycle). Six patients were enrolled in DL1 with 1 DLT (skin rash) and 2 patients in DL2. The most common treatment-related adverse events (TRAE) included hyperphosphatemia (88%), mucositis (88%), hypercalcemia (75%), high AST (75%), hand foot syndrome (75%), peripheral neuropathy (75%), alopecia (63%), diarrhea (63%), hypoalbuminemia (63%) and hypomagnesemia (63%). Grade 3 TRAE included hand foot syndrome (50%), anemia (17%), rash (17%), anorexia (17%) and paronychia (17%). One patient developed grade 4 Stevens-Johnson syndrome related to EV which subsequently improved. PK data are available for all 6 subjects in DL1. The average steady-state Cmin of E and monomethyl auristatin E (MMAE) was 1430 ± 639 ng/mL and 1.4 ± 0.9 ng/mL, respectively, and the average Cmax of MMAE was 3.9 ± 0.9 ng/mL at DL1. All 8 patients are evaluable for response, and best response is partial response in all. Detailed safety and additional efficacy data will be presented. Conclusions: Combination E + EV is feasible and preliminarily exhibits antitumor activity. Dose escalation is ongoing to identify the MTD or recommended dose for expansion of the trial. Clinical trial information: NCT04963153 . [Table: see text]
Association of ARID1A deficiency with invasive transformation in metastatic bladder cancer.
Authors: D'Andrea Vincent , Hanlon Timothy , Chroneos Rea , Bekele Raie , Clinton Timothy , Carvalho Filipe L.F. , Mouw Kent William
Published: January 2024

656

Background: ARID1A is an essential component of the BAF complex, a large SWI/SNF chromatin-remodeling complex which is implicated in bladder cancer (BC) pathogenesis. While ARID1A mutations are more highly represented in metastatic rather than localized tumors, the biological consequences of ARID1A loss in BC remain to be elucidated. We hypothesize that ARID1A deficiency primes an invasive transformation in BC, thus increasing the likelihood of disease progression and metastases. We used CRISPR/Cas9-mediated gene editing to knockout (KO) the ARID1A gene in several BC cell lines, thus providing a platform for cellular function assays. We show that ARIDA1 loss potentiates an invasive phenotype in these cell lines, giving evidence for its transformative role in the development of higher stage and metastatic BC. Methods: A CRISPR-Cas9 KO was performed with three cell lines with wild-type (WT) ARID1A (T24, SW1710, and 5637). This was accomplished by developing sgRNAs against ARID1A with a GFP marker and carrying out single-cell fluorescence-activated cell sorting (FACS) following nucleofection to identify ARID1A-deficient clones. Western blot analysis was performed on the resulting clones to confirm complete loss of ARID1A. Baseline proliferation studies were performed on the KO and WT cell lines. Finally, invasion studies were performed on the KO and WT cells with a scratch assay. Results: CRISPR-Cas9 directed KO of ARID1A yielded ARID1A-deficient clones for SW1710, T24, and 5637. The proliferation rates for each cell line were analyzed and compared which showed no significant differences. A scratch assay was performed with the cell lines in triplicate, with each ARID1A-deficient cell line showing a trend towards more rapid wound closure than its matched WT cell line (WT=31.5% vs. KO=53.5% for SW1710, p=0.15; WT=17.2% vs. KO=52.0% for T24, p=0.07; WT=10.4% vs. KO=13.9% for 5637, p=0.59). Conclusions: To explore the increased frequency of ARID1A alterations in metastatic BC compared to non-invasive tumors, we developed a model of ARID1A-deficient BC using CRISPR-Cas9. We compared the relative invasiveness of the lines using a scratch assay. All lines trended towards a more invasive phenotype following ARID1A KO, which was especially pronounced in T24. Taken together, these data suggest that ARID1A deficiency in BC may prime tumors for a more invasive phenotype, which may help to explain the higher frequency of ARID1A alterations in higher stage and metastatic samples.
The role of androgen response pathway in association with tumor biology and response to neoadjuvant immune-checkpoint inhibitors (ICI) in muscle-invasive urothelial bladder carcinoma (MIBC).
Authors: Tateo Valentina , Gibb Ewan , Mercinelli Chiara , Raggi Daniele , Cigliola Antonio , Patanè Damiano Alfio , Crupi Emanuele , Giannatempo Patrizia , Colecchia Maurizio , Moschini Marco , Avesani Giulio , Briganti Alberto , Montorsi Francesco , Santini Daniele , Necchi Andrea
Published: January 2024

662

Background: Emerging findings from ICI trials are suggestive of differential outcomes in females compared with males. Sex-specific differences in tumor biology, microbiome, and outcomes in MIBC are well-established. Conversely, limited data are available regarding the role of the androgen response pathway in explaining subtype differences between males and females and, most importantly, response to ICI. Methods: We retrospectively evaluated the biomarker findings of the transurethral resection of the bladder tumors (TURBT) and baseline clinical characteristics of patients (pts) with cT2-4N0M0 MIBC who received neoadjuvant pembrolizumab and radical cystectomy (RC) in the PURE-01 study. Transcriptome-wide expression profiling was performed on 102 TURBT samples. We focused on androgen receptor (AR) gene expression and the hallmark androgen response pathway expression quantifying 117 different genes related to the androgen response pathway as previously reported (PMID: 26771021). Pt and tumor characteristics were compared between subgroups using χ2 tests and two-sided Wilcoxon rank-sum tests. Kaplan-Meier curves and log rank tests evaluated gene expression and signature scores in association with the event-free survival (EFS), calculated from start of pembrolizumab treatment. Signature scores were analyzed as continuous values and were split by median and quartile values. Results: Pts received pembrolizumab and RC from 2017 to 2022. There were 87 (85.3%) males and 15 (14.7%) females. AR gene expression was not significantly different between males and females (p = 0.5), whereas androgen response signature was significantly higher in male (p = 0.03). The AR gene expression and androgen response signature scores were more highly expressed in luminal tumors vs rest of molecular subtypes (p = 0.005 and p < 0.001). Despite AR gene expression was not associated with ypT0N0 response (p = 0.425), hallmark androgen response signature scores were significantly lower in ypT0N0 responders (p = 0.033). Higher hallmark androgen response signature scores were statistically significantly associated with shorter EFS (p = 0.028), whereas AR gene expression was not (p = 0.152). Conclusions: For the first time to our knowledge, we reported the androgen response pathway expression to be a potential biomarker of ICI benefit in MIBC. This signature was also associated with a luminal subtype, linked to inferior responsiveness to ICI. If confirmed at a larger scale these analyses will strengthen the need for sex-specific approaches and potentially new combination therapies in MIBC.
Enfortumab vedotin (EV) in combination with pembrolizumab (P) versus chemotherapy in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC): Subgroup analyses results from EV-302, a phase 3 global study.
Authors: Van Der Heijden Michiel Simon , Powles Thomas , Gupta Shilpa , Bedke Jens , Kikuchi Eiji , De Wit Ronald , Galsky Matt D. , Duran Ignacio , Necchi Andrea , Retz Margitta , Yu Evan Y. , Hoffman-Censits Jean H. , Iyer Gopa , Park Se Hoon , Su Wen-Pin , Parmar Hema , Guan Xuesong , Gorla Seema Rao , Homet Moreno Blanca , Valderrama Begoña Pérez
Published: January 2024

LBA530

Background: EV-302/KEYNOTE-A39 (NCT04223856) is a phase 3, open-label, randomized, global study comparing EV+P with platinum-based chemotherapy for first-line (1L) treatment of patients (pts) with la/mUC regardless of cisplatin eligibility or PD-L1 expression status. In EV-302, EV+P demonstrated a statistically significant and clinically meaningful benefit compared with platinum-based chemotherapy for the dual primary endpoints of progression-free survival (PFS) (hazard ratio [HR]: 0.45; P<0.00001) and overall survival (OS) (HR: 0.47; P<0.00001) in the overall pt population (Powles ESMO 2023). Here we present results not previously presented of prespecified subgroup analyses. Methods: Pts with previously untreated la/mUC were randomized 1:1 to receive 3-week cycles of EV (1.25 mg/kg; Days 1 and 8; IV) and P (200 mg; Day 1; IV) or gemcitabine with cisplatin or carboplatin. Select secondary endpoints included confirmed objective response rate (cORR), duration of response, and safety. For PFS and OS, an HR between treatment arms was estimated using a stratified Cox proportional hazards regression model controlling for the stratification factors (cisplatin eligibility, PD-L1 status [high/low], liver metastases [yes/no]) for each predefined subgroup. Results: 886 pts (EV+P: 442, chemotherapy: 444) were randomized; baseline pt and disease characteristics were balanced between groups. PFS and OS were prolonged for EV+P among prespecified subgroups, including race, cisplatin eligibility, PD-L1 expression, metastatic site, liver involvement, and renal function. Select subgroup data not previously presented for OS are presented in the Table. Kaplan-Meier curves for PFS (liver metastases, cisplatin eligibility, and PD-L1 status) and OS (liver metastases) will also be presented. Conclusions: EV+P significantly improved outcomes in pts with previously untreated la/mUC compared with chemotherapy; OS benefit was consistently observed across select prespecified subgroups, including those historically associated with poor prognosis. The results of these subgroup analyses support the findings of the primary analysis, which indicate that EV+P is a potential new standard of care for 1L la/mUC. Clinical trial information: NCT04223856 . [Table: see text]