bluuebunny/crossref_metadata_2025 huggingface dataset:
Study of real-world treatment patterns and adherence to bacillus Calmette-Guerin (BCG) in the context of guideline recommendations for patients with high-risk non-muscle invasive bladder cancer (NMIBC).
Authors: Gaylis Franklin D , Emond Bruno , Manceur Ameur M , Tardif-Samson Anabelle , Morrison Laura , Pilon Dominic , Lefebvre Patrick , Ellis Lorie , Balaji Hiremagalur parthasarathy , Ireland Andrea
Published: March 2023

470

Background: Intravesical BCG is considered a first-line (1L) treatment for high-risk NMIBC patients. Since the presence of carcinoma in situ (CIS) in NMIBC is associated with increased disease progression rates and poor clinical outcomes, BCG is prioritized in clinical guidelines for NMIBC patients with CIS. However, BCG’s US shortage may negatively affect clinical outcomes in patients. This study evaluated the adequacy of BCG treatment patterns among NMIBC patients, including a subgroup with CIS. Methods: Adults with NMIBC treated with BCG were selected from de-identified IBM MarketScan Commercial, Medicare, and Medicaid Databases (1/1/2010-2/28/2021). Treatment patterns were assessed from the first BCG claim (triggering the start of 1L treatment) until the end of the patient’s observation. Consistent with real-world literature, adequate BCG induction was defined as ≥5 BCG claims within 70 days of the first BCG claim whereas adequate BCG induction and maintenance was defined as ≥7 BCG claims within 274 days of the first BCG claim. Proportions of patients with adequate BCG induction and maintenance were compared between CIS subgroup and overall NMIBC cohorts using chi square tests. Results: Of 5,803 NMIBC patients treated with 1L BCG, 1,182 (20.4%) had documentation of CIS. Overall and CIS cohorts had similar mean age (67 years; range 18-101 years). After 1L BCG, 56.6% and 71.8% of the overall and CIS cohorts had another treatment (P<.001; table). While 86.9% and 90.0% of the overall and CIS cohorts had adequate BCG induction (P=0.003), only 41.5% and 50.8% had adequate BCG maintenance (P<.001). More patients in the CIS versus overall cohort had a cystectomy (13.9% vs 9.7%; P<.001). Conclusions: In this study, most NMIBC patients treated with BCG received adequate induction; however, BCG maintenance was inadequate and most patients had another treatment following 1L BCG. Patients with CIS were more likely to have cystectomy after BCG, suggesting higher risk of progression in this subgroup. Results of this study further emphasize a need for additional available treatment options that are safe, efficacious, and tolerable. [Table: see text]
Cost savings associated with palliative care among patients with genitourinary malignancies.
Authors: Chansriwong Phichai , Thokanit Nintita Sripaibookij , Semsarn Siriporn , Utthiya Pinyo , Kasemsup Vijj
Published: March 2023

474

Background: The cost of cancer treatment has increased significantly in recent decades, and highest costs incurred in the last 6-months of life. Patients’ health insurance status is a factor influencing to cost of care in different from individuals’ ability to access hospital care. 80% of Thai people use the Thailand’s Universal Coverage Scheme (UCS), about 15% use the Civil Servants Medical Benefit Scheme (CSMBS). Only CSMBS can reimburse all costs of in-patient care, but UCS had to co-pay at some cost. All health scheme is equality accessibility to palliative care. Early integrated palliative care services improve the GU malignancy patients care experience, decreases healthcare utilization, and improved quality of life. Study aim was to examine Hospital-based palliative care interventions in GU malignancy patients may reduce costs. Methods: A retrospective claims database in Ramathibodi Hospital was analyzed, that included cancer patients had a medical claim for death between Jan 1, 2016 - Dec 31, 2020. Our study compared cost in patients receiving palliative care (PC) and patients receiving usual care. Costs were determined by summing paid amounts on all hospital services used within the last 6, 3 and 1 months before death, including cancer-related inpatient service, emergency room visits, cancer-related outpatient services and other hospital services with cancer diagnosis. Results: Of the 1,772 cancer patients who died, 289 (16.3%) integrated treated with PC matched to 1,483 (83.7%) were usual care patients. 107 Genitourinary Malignancies patients including 44 TCC, 36 Prostate, 22 RCC and 2 Testicular cancer, that 22 (20.6%) integrated treated with PC. Median age was 72.4 years. Patients categorized as CSMBS 48% and UCS 44.4%. The PC group had $10,244.1 (+/- 8,705.6) in last 3 months hospital costs that significantly less than in usual care $(17,174.3 +/-14,262.5) (P= 0.032) that PC group had significant reductions in medications, laboratory, and intensive care unit costs compared with usual care patients. Direct costs of inpatient care in the last 3 months of life for patients were lower in patient who received earlier PC that patients who received PC consults < 90 days was $9,728.8 (+/- 1,044.5) and patients received PC consults < 30 days cost was $12,517.7 +/- 1,476. Patients in SSS and UCS had a significantly saving cost when they received PC consultation, P=0.032. However, there was no difference in CSMBS. Conclusions: Integrated palliative care in caring GU malignant patients associates with significant hospital cost savings. Insurance status not limited in access to palliative care consultation, but influences in cost of end-of-life care.
Outcomes with immune checkpoint inhibitor (ICI) therapy in patients with FGFR2/3 alterations in advanced urothelial carcinoma (aUC).
Authors: Talukder Rafee , Bakaloudi Dimitra Rafailia , Makrakis Dimitrios , Tripathi Nishita , Agarwal Neeraj , Jindal Tanya , Koshkin Vadim S , Johnson Jeffrey , Zakharia Yousef , Brown Jason , Rey-Cárdenas Macarena , Castellano Daniel , Alva Ajjai Shivaram , Zakopoulou Roubini , Korolewicz James , Drakaki Alexandra , Barata Pedro C. , Grivas Petros , Khaki Ali Raza
Published: March 2023

478

Background: Erdafitinib is FDA-approved for patients (pts) with advanced urothelial carcinoma (aUC) with FGFR2/3 mutation or fusion and progression after platinum-based chemotherapy. It is postulated that FGFR3-altered aUC may be a “cold tumor” and associated with non-T cell-inflamed phenotype and, thus, may be less responsive to ICI. We hypothesized that pts with aUC that harbor FGFR2/3 alterations would have lower response and shorter survival on ICI. Methods: We performed a retrospective cohort study of pts with aUC treated with ICI and available genomic data in 11 institutions; pts with pure non-UC, treated with combinations or on clinical trial were excluded. Outcomes (overall response rate [ORR], progression free survival [PFS] and overall survival [OS] were compared in pts with and without FGFR2/3 alterations. PFS and OS was compared using Cox proportional hazards. All analyses were performed in the overall population and also categorized by treatment line (1st line [1L] vs salvage [2+L]). Multivariable models were adjusted for an internally developed risk score for 1L and Bellmunt risk score for 2+L; p<0.05 was significant. Results: 310 pts met inclusion criteria; 217 pts, 206 pts, and 204 pts were included in ORR, OS and PFS analyses, respectively. Median follow up time was 37 months [mo]. Overall, median age at ICI initiation was 69, 74% men, 85% White, 27% mixed histology, 24% upper tract, 15% liver metastases, 55% ECOG PS 0-1; 101 pts (33% of total population) had FGFR2 or FGFR3 mutation/fusion. ORR to ICI in pts with FGFR2/3 alteration was 25% (95% CI 15-37%) vs 46% (95% CI 38-55%) in pts without such alterations. PFS was shorter for pts with FGFR2/3 alteration (median [m] PFS 4 mo vs 7 mo without such alterations; HR=1.53 [95% CI 1.09-2.15], p=0.015). However, OS was similar in both groups (mOS 14 mo in both groups; HR=1.09 [95% CI 0.75-1.58], p=0.65). ORR, PFS and OS analyses stratified by ICI treatment line (1L vs 2+L) are shown in the Table. Conclusions: In this multisite retrospective study, the presence of FGFR2/3 alterations was associated with lower ORR and shorter PFS in pts with aUC treated with ICI. Limitations include retrospective nature, lack of randomization and central scan review, selection bias, missing data, and possible residual confounding. Findings suggest that FGFR2/3 alterations may impact response and PFS with ICI and might inform discussion on the optimal sequence of therapies in aUC but need external validation and ideally clinical trial data. [Table: see text]
Neoadjuvant chemotherapy (NAC) versus adjuvant chemotherapy (AC) in patients with clinically node-positive upper tract urothelial cancer (UTUC) who underwent radical nephroureterectomy (RNU).
Authors: Jatwani Karan , Roy Arya Mariam , Attwood Kristopher , George Anthony , Faisal Muhammad Salman , Muthusamy Kumarasamy Vasanthan , Perimbeti Stuthi , Jiang Changchuan , Chatta Gurkamal S. , Gopalakrishnan Dharmesh
Published: March 2023

486

Background: UTUC is less common and associated with poorer stage-for-stage prognosis compared to urothelial bladder cancer. AC is regarded as a standard-of-care in high-risk UTUC based on superior disease-free survival compared to observation in the POUT trial, though fewer than 10% of patients in this trial had lymph node involvement.1 CheckMate 274 revealed lesser magnitude of benefit with adjuvant nivolumab in UTUC compared to bladder cancer on post hoc analysis.2 The preferred sequence of perioperative systemic therapy in node positive UTUC remains unclear. Methods: We queried the National Cancer Database for adult patients with clinically node positive (cTanyN1-3M0) UTUC diagnosed between 2004 and 2018. Patients were divided into two groups based on the perioperative treatment strategy - NAC or AC. Patients who did not undergo RNU were excluded from analyses. Fisher’s exact and Mann Whiney U tests were used to compare frequency distributions. Cox Proportional Hazards regression was employed for multivariate analysis of factors associated with overall survival. Models were adjusted for age, sex, race, income, educational level, clinical T stage, insurance status, and the Charlson Comorbidity Index. Results: A total of 862 patients were identified - 362 (42%) underwent NAC while 500 (58%) received AC. No significant differences were noted between the groups regarding age, sex, or insurance status. Patients with cT1-2 UTUC more often received NAC (27.9% vs 11.8%, P <0.001) while those with cT3-4 disease more frequently received AC (38.9% vs 57.4%, p<0.001). Rates of NAC vs AC were not significantly different based on clinical N stage (P = 0.35). Overall survival in the NAC group was significantly longer than the AC group (median of 47.1 vs. 20.2 months, log-rank P < 0.001). On multivariable analysis, only the sequence of perioperative chemotherapy was independently predictive of overall survival (Hazard Ratio of 1.38 for AC, with 95% CI 1.14-1.68, P = 0.001). Conclusions: In this large retrospective analysis of outcomes among patients with clinically node positive UTUC who underwent RNU, NAC was associated with significantly longer overall survival compared to AC. References: 1) Birtle A, Lancet 2020; 2) Bajorin DF, NEJM 2021.
Comparative real-world survival outcomes of muscle-invasive bladder cancer treated with bladder-only vs. whole-pelvis concurrent chemoradiation.
Authors: Riveros Carlos , Ranganathan Sanjana , Haque Waqar , Xu Jiaqiong , Geng Michael , Anis Maryam , Muhammad Taliah , Farach Andrew M. , Teh Bin S. , Wallis Christopher J.D. , Sonpavde Guru P. , Satkunasivam Raj
Published: March 2023

488

Background: Elective nodal irradiation for patients with muscle-invasive bladder cancer (MIBC) undergoing trimodal therapy (TMT) is controversial. In patients with node-negative (N0) MIBC, the benefit of elective whole-pelvis concurrent chemoradiotherapy (WP-CCRT) compared to bladder-only (BO)-CCRT has not been demonstrated. Currently, the National Comprehensive Cancer Network (NCCN) guidelines do not recommend whether to include pelvic nodes in the radiation field. Using real-world data from the National Cancer Database (NCDB), we sought to compare the overall survival (OS) between BO-CCRT and WP-CCRT for MIBC. Methods: Using the 2019 NCDB Participant User File, we identified cases of MIBC diagnosed between 2017 and 2018. We selected patients with clinical T2-T4N0M0 disease receiving TMT as first-line treatment. TMT was defined as transurethral resection of bladder tumor followed by CCRT: 60–65 Gy of RT delivered to the bladder with concurrent single- or multiple-agent chemotherapy. Patients were stratified into BO-CCRT vs. WP-CCRT. Overall survival (OS) analysis was performed using Kaplan-Meier estimates and multivariable Cox proportional hazards regression analysis. The variables included in the multivariable Cox regression model were age, sex, race, comorbidity burden (as per the Charlson-Deyo comorbidity index), facility type, insurance status, median income quartile, rurality, distance from facility, and clinical T stage. Results: A total of 605 patients receiving TMT for MIBC were identified: 162 (26.8%) BO-CCRT and 443 (73.2%) WP-CCRT. The median follow-up time was 25.6 months (interquartile range [IQR]: 4.8-42.6) and 28.7 months (IQR: 3.0-51.6) for BO-CCRT and WP-CCRT, respectively. The median OS was 32.9 months (95% confidence interval [CI] 30.8 – not reached) and 48.3 months (95% CI 39.6 – not reached) for BO-CCRT and WP-CCRT, respectively. However, multivariable Cox regression analysis failed to find an association between WP-CCRT (hazard ratio [HR] 1.08, 95% CI 0.76-1.54) and improved OS, compared to BO-CCRT. Conclusions: Elective nodal-irradiation (WP-CCRT) in the setting of TMT for MIBC was not associated with a benefit in OS compared to BO-CCRT.
68GaPSMA-11 PET/CT to monitor treatment response in patients with metastatic prostate cancer: The concordance between biochemical response and PSMA response.
Authors: Esen Baris , Seymen Hulya , Tarim Kayhan , Köseoğlu Ersin , Bolukbasi Yasemin , Falay Okan , Demirkol Mehmet Onur , Tilki Derya , Esen Tarik
Published: March 2023

49

Background: The aim of this study was to assess whether PSMA PET is associated with flares, with discordant results in regard to biochemical response, and with positivity rates at low PSA values while monitoring metastatic prostate cancer (mPCa) receiving systemic treatment. Methods: A total of 96 patients with PSMA PET-detected mPCa who underwent at least one follow-up scan after receiving systemic treatment were included in the study. PSA levels at baseline PSMA PET-CT (bPSMA) and follow-up PSMA PET scans (fPSMA) were recorded. Any significant PSMA uptake at prostate and/or metastatic lesions were considered PSMA positivity. PSMA response were decided according to PSMA PET Progression (PPP) criteria . Biochemical progression was defined as ≥25% increase in PSA (1 ng/dL was the minimal starting value). PSMA PET and PSA response were dichotomized into progressive disease (PD) vs non-PD. Discordant responses among different metastases and prostate were defined as the condition when some metastatic lesions (or prostate) are responding (CR or PR) to systemic treatment while others had progressed. Results: A total of 346 serial PSMA PET/CT (96 bPSMA and 249 fPSMA) scans were evaluated. The median time between consecutive PSMA PET scans was 6.3 months (IQR: 4.7 – 10.6) Overall PSMA PET positivity rate of fPSMA scans was 88.4% (220/249). PSMA positivity rates according PSA levels were summarized. PPP was detected in 93 cases (37.8%) and biochemical progression was observed in 73 cases (30.2%). PSA and PSMA responses were highly concordant (Cohen’s K=0.623, p<0.001). PSA-PSMA discordant responses were detected in 39 scans (17%). The possible causes could be identified in 34 of 39 scans (87%) while no obvious reason for discordance could be shown in the remaining 5. Conclusions: PSMA PET/CT showed very high detection rates of malignant lesions even in very low PSA values when monitoring treatment response in patients receiving systemic treatment for mPCa. PSA and PSMA responses were highly concordant. In cases with discordance, the reason seems to be the discordant behaviour of intraprostatic and metastatic lesions and not necessarily PSMA flares. PSMA PET is a promising biomarker to assess treatment response in patients with mPCa. [Table: see text]
The Bristol Bladder Trial: Five year outcomes in patients treated with neoadjuvant cabazitaxel and cisplatin chemotherapy for muscle invasive transitional cell carcinoma of the urinary bladder.
Authors: Challapalli Amarnath , White Paul , Masson Susan , Foulstone Emily , Renninson Emily , Bravo Alicia , Pearson Sylvia , Dailami Narges , Persad Raj , Koupparis Anthony , Rowe Edward , Oxley Jon , Kabala Julian , Ash-Miles Janice , Bahl Amit
Published: March 2023

493

Background: Neoadjuvant cisplatin-based combination chemotherapy (NAC) improves survival in muscle invasive bladder cancer (MIBC). However, response rates and survival remain suboptimal. We sought to evaluate the efficacy of cabazitaxel with cisplatin in this patient group. These patients have now been followed for survival status for 5 years post NAC and radical cystectomy. Methods: This was a single arm (Simon 2 stage), phase 2 study. Patients with MIBC were included if fit to receive NAC and to undergo radical cystectomy. 26 evaluable patients were required to detect an objective response rate (ORR) of >35% with 80% power. ORR was defined as pathological complete response (pCR) plus partial response (pathological downstaging, ≥T2 at diagnosis to ≤T1 at cystectomy). Treatment was with cisplatin 70mg/m2 and cabazitaxel 15mg/m2 on day 1 of a 21-day cycle, for 4 cycles prior to surgery. Toxicity was recorded using CTCAE v.4.03. QoL data was assessed during and after chemotherapy using EQ-5D-5L and EORTC-QLQ-C30, BLM30 questionnaires. Patients were followed for 5 years post cystectomy for progression free survival (PFS) and overall survival (OS). Results: ORR was seen in 15 out of 26 evaluable patients, 57.7%, with 24.6% achieving pCR. 1 out of 15 patients who achieved ORR died due to disease progression in the 5 year follow up period. The median PFS and OS were not reached by the 5 year follow up time point with a 5 year survival rate of 65.4% being seen in this patient cohort. Median OS in non-responders (11 patients) was 20.5 months and 5 year survival rate for the non-responders was 36.4% compared to 93.3% for responders. Conclusions: Neoadjuvant cabazitaxel with cisplatin chemotherapy is an effective regimen with 65.4% patients alive and progression-free at 5 years. It also indicates that ORR (and not just pCR), is a good predictor of patient survival at 5 years post radical cystectomy with only 1 out of 15 patients who achieved ORR progressing and dying in this period. However, in current clinical practice, there are no validated predictive biomarkers regarding potential response to NAC. Taken together with our previously published data, cabazitaxel with cisplatin as neoadjuvant chemotherapy is a safe, well-tolerated and effective regimen and should be compared to the regimens e.g. cisplatin/gemcitabine considered as standard in this setting. Clinical trial information: NCT01616875 .
A pilot study of tazemetostat and pembrolizumab in advanced urothelial carcinoma (ETCTN 10183).
Authors: Hussain Maha H. A. , Kocherginsky Masha , Singh Parminder , Myint Zin , Jiang Di Maria , Wulff-Burchfield Elizabeth Marie , Sharon Elad , Piekarz Richard , Meeks Joshua J , VanderWeele David James
Published: March 2023

506

Background: Despite response to systemic therapy, few metastatic urothelial carcinoma (mUC) patients (pts) achieve durable responses. Mutations in the COMPASS-related proteins KMT2D, KMT2C, and KDM6A are found in 66% of UC patients suggesting histone regulation may be an acquired mechanism of tumor viability. We previously found regression of UC in mice when treated with EZH2 inhibitor, tazemetostat. In vivo administration of tazemtostat enhanced the immune response with direct regulation of cytokines and antigen recognition machinery (MHCI and MHCII). We hypothesized that restoration of epigenetic imbalance, combined with immunotherapy, may improve outcomes in mUC pts. Methods: ETCTN 10183 (NCT03854474) is a pilot study evaluating the efficacy of tazemetostat 800 mg BID + pembrolizumab 200 mg every 3 weeks for cisplatin-refractory (Cohort A) or cisplatin/chemo-ineligible advanced UC (Cohort B) pts, with N=12 pts in each cohort. The primary objective is to identify the recommended phase two dose (RP2D) of tazemetostat in combination with pembrolizumab. Secondary objectives include RECIST-based response rate, safety, and progression-free survival. The maximum planned treatment duration is 2 years. Translational objectives include defining total and COMPASS-related genes tumor mutational burden, tumor subtyping, TCR clonality, T cell infiltration, and PDL-1 expression. Results: In the safety lead-in phase, 6 mUC pts were treated. There were no dose-limiting toxicities (DLTs). The RP2D for tazemetostat was established at 800 mg BID. Here we report results of fully accrued cohort A (N=12); 67% males, 33% females, 83% white, 8.3% Black, and 25% Hispanic/Latino ethnicity. The primary sites of UC were: bladder (n=9, 75%), renal pelvis (n=2, 17%), and ureter (n=1, 8.3%). The median (interquartile range, IQR) time since primary diagnosis was 1.1 years (0.7, 1.9); 11/12 patients had non-nodal metastatic disease; 10/12 had 1 or more visceral/bone metastasis. Median number of treatment cycles was 5 (IQR: 3-11; range 1-35). Median duration on protocol treatment was 12 weeks (IQR: 7-30; range 3-107 weeks). Three pts had treatment related grade 3/4 AEs: grade 4 sepsis (n=1), grade 3 lymphopenia (n=2); anemia, increased alkaline-phosphatase, and HSV oral infection (n=1 each). Best response was partial response (PR) in 3 pts (25%) and 3 (25%) had stable disease. Median PFS was 3.1 months (95%CI: 2.3-NA), and median overall survival was 8.0 months (95% CI: 4.7 – NA). Conclusions: The RP2D dose for tazemetostat is 800 mg + 200 mg Pembrolizumab q 3 weeks. The combination was feasible, well tolerated, and resulted in durable responses in poor-risk chemo-refractory UC patients. Clinical trial information: 03854474 .
Intravesical gemcitabine and docetaxel in the treatment of BCG-naïve non–muscle invasive urothelial carcinoma of the bladder: Updates from a phase 2 trial.
Authors: Patel Sunil H. , Gabrielson Andrew , Collins Connie , Singla Nirmish , Bivalacqua Trinity , Hahn Noah M. , Kates Max R.
Published: March 2023

507

Background: Combination intravesical Gemcitabine and Docetaxel (GEMDOCE) has demonstrated benefit for bacillus Calmette-Guérin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) in retrospective series and is now being widely utilized as salvage therapy. BCG therapy is fraught with frequent drug shortages and some patients are unable to tolerate BCG due to side effects. Given ongoing BCG shortages as well as the promising efficacy and tolerability of GEMDOCE as a salvage therapy, our objective was to investigate the safety and efficacy of intravesical GEMDOCE for high-risk (HR) BCG-naïve NMIBC in a prospective manner. Methods: This study is an IRB-approved prospective single-arm open-label phase II trial for patients with BCG-naïve HR NMIBC. Intravesical gemcitabine (1,000 mg)/docetaxel (40 mg) in 100mL normal saline is given weekly for 6 weeks as induction followed by monthly maintenance therapy for 2 years among responders. The primary endpoint was 3-month complete response (CR), defined as a negative bladder biopsy 6 weeks after induction treatment. Secondary endpoints included adverse events (AE) and 12-month CR. Results: To date, the study has fully accrued with 25 patients enrolled from July 2020-August 2022. The pre-trial pathologic stages in our cohort were as follows: HGT1 with CIS (n = 7), HGT1 without CIS (n = 6), HGTa (n = 9), and CIS alone (n = 3) (Table). All 25 patients who completed induction therapy demonstrated CR at 3 months. Eight out of 9 (89%) patients with at least 12 months of follow-up demonstrated continued CR. One patient with HGT1 + CIS on enrollment developed a recurrence at 9 months with HGTa. No enrolled patients have undergone radical cystectomy. Grade 1 AEs were common (19/25 patients, 76%) including hematuria, urinary frequency, urgency, and fatigue. Two patients (8%) experienced a Grade 3 AE including urinary retention and UTI requiring hospitalization and intravenous antibiotics. Conclusions: In this ongoing single-arm phase II trial, GEMDOCE appears to be well-tolerated with promising short-term efficacy for patients with BCG-naïve HR NMIBC. [Table: see text]
Preliminary clinical outcomes of ADP-A2M4CD8, a next-generation autologous T-cell receptor T-cell therapy, in patients with advanced urothelial cancer.
Authors: Aggen David H , Hong David S. , Clarke Jeffrey Melson , Asch Adam Steven , Calvo Emiliano , Zugazagoitia Jon , Butler Marcus O. , Moreno Victor , Cervantes Andres , Van Tine Brian Andrew , Lawrence Donald P. , Johnson Melissa Lynne , Brophy Francine Elizabeth , Broad Robyn , Isabelle Martin , Gunn Alasdair , Navenot Jean-Marc , Saro Jose , Norry Elliot , Charlson John A.
Published: March 2023

517

Background: ADP-A2M4CD8 is a specific peptide enhanced affinity receptor mixed CD4+ and CD8+ T-cell therapy targeting the cancer testis antigen MAGE-A4 and modified with addition of a CD8α co-receptor designed to provide additional functionality to CD4+ T-cells. ADP-A2M4CD8 has demonstrated an acceptable benefit to risk profile in the Phase 1 SURPASS trial (NCT04044859) in HLA A*02–eligible patients with unresectable or metastatic tumors positive for MAGE-A4.1 Here we report updated clinical outcomes in patients with urothelial cancer (UC). Methods: SURPASS is a first-in-human trial consisting of a modified 3+3 dose-escalation design and an expansion cohort. Autologous T-cells are obtained by leukapheresis, transduced with a self-inactivating lentiviral vector expressing the MAGE-A4-specific T-cell receptor and the CD8α co-receptor, and infused back to the patients as ADP-A2M4CD8 following lymphodepleting chemotherapy. Primary and secondary objectives are safety and anti-tumor activity, respectively. Results: At ESMO 2022, we reported promising results from SURPASS in several tumour types.2 In the 43 evaluable patients, the overall response rate was 28%, including 1 complete response and 11 partial responses (PR), and an additional 2 unconfirmed PRs awaiting confirmatory scans (as of August 1, 2022). Data from the 7 evaluable patients in the UC subset (updated September 6, 2022) showed that 3 (43%) had a best overall response of PR, and 1 (14%) had an unconfirmed PR. Disease control rate was 100% (3 PR + 1 unconfirmed PR + 3 stable disease). Adverse events have been consistent with those typically observed with lymphodepletion chemotherapy or cellular therapy. This trial is ongoing; data from additional patients with UC treated by January 2023 and updated translational data will be presented. Conclusions: ADP-A2M4CD8 continues to show an acceptable benefit to risk profile in multiple MAGE-A4+ unresectable or metastatic tumors, and preliminary encouraging evidence of efficacy in UC. An additional treatment cohort has been included in the updated trial protocol to evaluate ADP-A2M4CD8 combined with nivolumab. 1. Hong DS, et al. E-poster 540P: ESMO 2021; Virtual. 2. Hong DS, et al. Ann Oncol 33(suppl_7); S331-S355, Abstract 735MO. ESMO 2022. Clinical trial information: NCT04044859 .
A phase II clinical study of intravesical photo dynamic therapy in patients with BCG-unresponsive NMIBC (interim analysis).
Authors: Kulkarni Girish S. , Richards Kyle A , Black Peter C. , Rendon Ricardo A. , Chin Joseph , Shore Neal D. , Jayram Gautam , Kramolowsky Eugene V. , Saltzstein Daniel , Agarwal Piyush K. , Belkoff Laurence , O'Donnell Michael A. , Kamat Ashish M. , Jewett Michael A.S. , Lamm Donald L. , DeGruttola Victor , Mandel Arkady , Dumoulin-White Roger , Kassouf Wassim
Published: March 2023

528

Background: Novel therapies are required for BCG-unresponsive, high risk non-muscle invasive bladder cancer. We report the interim results of a Phase II Clinical Study of Intravesical Photo Dynamic Therapy (PDT) in patients with BCG-Unresponsive Carcinoma In-Situ (CIS) with or without papillary disease. Methods: Out of a planned 125 patients, 42 patients have been enrolled and treated with two Study Treatments (Day 0 and Day 180) consisting of an intravesical instillation of the photosensitizer TLD-1433 (0.70 mg/cm2) followed by activation with a 520 nm intravesical laser under general anesthesia (Study Device TLC-3200) to a total of 90 J/cm2 of laser light. The primary outcome assessed was efficacy, evaluated by Complete Response (CR), at any point in time. The secondary outcome was duration of CR at 12 months, post initial CR. A tertiary objective is safety, evaluated by the incidence and severity of Adverse Events, Grade 4 or higher that do not resolve within 450 days post treatment. Patients with a negative cystoscopy and positive cytology have been defined as indeterminate response (IR), as these patients remain under investigation for lower and upper tract urothelial carcinoma. Results: Interim analyses included the first 42 patients, along with 3 patients treated in a preceding Phase Ib NMIBC clinical study assessing the safety of TLD-1433 PDT who weretreated at the same parameters, for a total of 45 patients. Data for the primary and secondary outcomes are listed in the table.The interim clinical data demonstrates a 90 day CR of 50% and a duration of response at 360 and 450 days of 35% and 21%, respectively.There have been eight Serious Adverse Events (SAE) identified (2 Grade II (tachycardia, hematuria), 3 Grade III (acute kidney injury, cellulitis), 2 Grade IV (urosepsis, depression/anxiety) and 1 Grade V). None of the SAEs were deemed to be directly related to the PDT. Conclusions: The interim data support that treatment with Photo Dynamic Therapy provides a viable treatment option for patients with BCG unresponsive CIS (+/- papillary disease) with an acceptable ongoing safety profile. Clinical trial information: NCT03945162 . [Table: see text]
Prognostic value of integrated liquid biopsies in patients (pts) with metastatic urothelial cancer (mUC).
Authors: Stahlfeld Charlotte , Emamekhoo Hamid , Kaufmann Katherine , Grivas Petros , Ornstein Moshe Chaim , Sheng Iris Yeong- Fung , Burkey Caroline , Sperger Jamie , Bade Rory M. , Schehr Jennifer L. , Taylor Amy K , Shi Yue , Zhao Shuang , Lang Joshua Michael
Published: March 2023

547

Background: Despite recent therapeutic advancements for patients with mUC, including checkpoint inhibitors (CPIs), anti-FGFR and antibody-drug conjugates (ADCs), biomarker data to predict therapeutic response and identify mechanisms of resistance remain limited. Ongoing randomized clinical trials evaluating the combination of CPIs and ADCs in these pts underscore the need to develop biomarkers to better understand who might best respond to these therapies. Here, we employ a liquid biopsy approach to molecularly characterize circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), including those isolated with Trop-2, the target of the novel drug Sacituzumab Govitecan and Datopotamab Deruxtecan. Methods: 104 blood samples serially collected from pts being treated for mUC were used for CTC collection using anti-EpCAM and Trop-2 antibodies in parallel. CTCs were isolated and stained for immune markers PD-L1 and HLA I using the VERSA (Versatile Exclusion-based Rare Sample Analysis) platform. Plasma was isolated for paired analysis of CTC and ctDNA content. CTCs were analyzed for enumeration and single-cell protein analysis. Overall survival (OS) was defined from time of sample collection, and survival analyses were performed using the Kaplan-Meier method. Results: We observed significantly shorter OS in pts with higher CTC burden (≥ 20 CTCs/7.5 mL blood) in samples captured with either EpCAM (median 34.1 vs 3.1 mo, P < 0.01) or Trop-2 (median 34.1 vs 6.2 months, P < 0.01). Furthermore, EpCAM and Trop-2 CTC burdens were higher at progression timepoints relative to responding or stable timepoints, when stratified according to treatment modality (table). Inter and intra-patient heterogeneous PD-L1 and HLA I expression and co-expression was observed on CTCs although no significant differences were seen globally between EpCAM and Trop-2 CTCs. In a cohort of pts treated with CPIs, we observed dynamic phenotypic changes in the ratio of HLA:PD-L1 that differed between EpCAM and Trop-2 CTCs. ctDNA analysis identified concordant increases in tumor fraction and acquired genomic mutations. When examined longitudinally across individual pts, these findings in tandem with changes in enumeration, suggest the emergence of different CTC subpopulations that may serve as biomarkers of resistance. Conclusions: We identify the prognostic significance of CTC enumeration with parallel EpCAM and Trop-2 CTC isolation and demonstrate the utility of a liquid biopsy assay that can detect pharmacodynamic changes in CTC burden and immune marker expression throughout the course of treatment. [Table: see text]
Systematic literature review and testing of HER2 status in urothelial carcinoma (UC).
Authors: Koshkin Vadim S , Boyiddle Christine , Schwartz Naomi , Yu Judy , Yu Kristina S. , Kang Ashley , Bloudek Lisa , Fang Qijun , Schafer Johanna M. , Baker Amanda F. , Sayedian Farzaneh H. , Scherrer Emilie
Published: March 2023

556

Background: Recent clinical trials suggest an emerging role for HER2-targeted therapy in locally advanced and metastatic UC (LA/mUC). The prevalence of HER2 expression and gene amplification (encoded by ERBB2) in LA/mUC has not been well defined, as testing for HER2 expression in LA/mUC is not part of current routine practice and is not standardized. We report (1) findings of a systematic literature review (SLR) of HER2 status in LA/mUC and (2) preliminary results of an ongoing evaluation of HER2 status in UC assaying HER2 protein expression by immunohistochemistry (IHC) and gene amplification by in situ hybridization (ISH). Methods: (1) The SLR used databases PubMed and EMBASE to identify English-language studies of LA/mUC HER2 status published Jan2000 – Oct2021. We used the following definitions: HER2-positive (HER2+) was defined as IHC 3+, or IHC 2+ with HER2 gene amplification (Amp+). HER2-low was defined as IHC 2+/Amp–, or as IHC 1+. HER2-zero was defined as IHC 0. Weighted averages were calculated to estimate population prevalence. (2) Commercially sourced, formalin-fixed paraffin-embedded surgical resections of primary UC were evaluated by trained readers for HER2 protein expression using the VENTANA HER2/neu (4B5) Rabbit Monoclonal Primary Antibody IHC assay and for HER2 gene amplification using the VENTANA HER2 Dual ISH DNA Probe Cocktail that detects both ERBB2 and its residing chromosome, chromosome 17 (Chr17), using a two-color chromogenic stain. HER2 IHC staining was scored based on an established scoring algorithm for gastric cancer. HER2 gene amplification was defined by a HER2/Chr17 ratio ≥2.0. Results: (1) Of 744 records screened for the SLR, 45 studies reported HER2 status, including 10,602 patients (pts) with LA/mUC. A variety of assays and scoring guidelines were used. In the 4 studies (862 pts) reporting data applicable to our predefined criteria for HER2 status, the percentage of HER2+ ranged from 6.7% to 37.5% (weighted average, 13.1%; 95% CI, 7.3%–18.8%). (2) Of 252 UC samples evaluated, 38 were HER2+ (15.1%; 95% CI, 11.2%–20.0%), 74 were HER2-low (29.4%; 95% CI, 24.1%–35.3%), and 140 were HER2-zero (55.5%; 95% CI: 49.4%–61.6%; Table). The HER2 gene was amplified in 31 (12.3%), among them 24 (77.4%) at stage III or IV muscle-invasive UC (MIUC). Conclusions: The SLR revealed wide variability of HER2 status in LA/mUC, highlighting a lack of standardized methods for assessing and defining HER2 status. In our large study using standardized laboratory methods, 44% of UC samples were HER2+ or HER2-low, and HER2 status distribution was consistent with that reported for pts with LA/mUC. Results suggest a potentially important role for HER2-targeted therapy for UC. [Table: see text]
Evaluating technical feasibility of a urine cell-free DNA (cfDNA) NGS assay for identifying biomarkers in bladder cancer.
Authors: Kim Il-Jin , Quiroz Michelle , Zhao Zhixin , Mo Wei , Zheng Tiantian , Wang Amy , Singh Usha , Beeharry Neil , Smirnov Denis , Wang Songbai , Tate Renee , Zhang Tom , Liu Fang , Hanumanthe Seema , Xiang Binggang , Luo Shujun , Kuklin Alexander , Wirtz Ralph M. , Du Pan , Jia Shidong
Published: March 2023

565

Background: Bladder cancer is one of the most common cancers worldwide. In 2022, about 81,000 people were diagnosed with this disease and 17,000 died from it (www.cancer.org). Despite significant breakthroughs in targeted medicines (i.e., Erdafitinib, FGFR2/3 kinase inhibitor) and clinical care over the past decade, non-invasive molecular testing remains an unmet clinical need for the treatment of bladder cancer patients. By contrasting the results with those from the FDA-approved tissue-based CDx assay, we assess the clinical utility of a urine NGS assay for identifying biomarkers, including mutations from FGFR genes. Methods: Paired urine and tissue samples were collected from 107 (muscle and non-muscle invasive) bladder cancer patients from the Bladder BRIDGister clinical trial in Germany. Tissue specimens were analyzed using the FDA approved Qiagen therascreen FGFR RGQ RT-PCR kit while matched urine samples were processed using the PredicineCARE urine (cell-free DNA) cfDNA NGS assay with detection sensitivity of 0.3% (0.1% for hotspot mutations). One hundred seven bladder cancer urine cfDNA NGS and tissue RT-PCR results were analyzed to determine the concordance (PPA and NPA) between these two assays. A smaller sample set was also used to compare tissue NGS to therascreen RT-PCR and tissue NGS to urine cfDNA NGS. A subset of discordant mutations were additionally validated by ddPCR. Results: For the concordance analysis between PredicineCARE Urine cfDNA NGS and therascreen tissue RT-PCR assay of 107 samples, PPA was 100% (20/20, 95% CI: 83.2-100) and NPA was 94.1% (48/51, 95% CI: 83.8-98.8). Three discrepant samples (tissue FGFR negative but urine positive for FGFR genes) were further analyzed by independent orthogonal ddPCR (Bio-Rad ddPCR Mutation Detection Assay). All tissue FGFR negative but urine positive samples were confirmed positive by ddPCR. PPA and NPA between PredicineCARE Urine cfDNA and Tissue NGS were 100% (19/19, 95% CI: 82.4-100) and 94.2% (49/52, 95% CI: 84.1-98.8) respectively. PPA and NPA between PredicineCARE Tissue NGS and Therascreen FGFR RGQ RT-PCR kit were both > 95%. Conclusions: High concordance between FGFR alterations detected with an FDA approved tissue CDx and urine cfDNA NGS assay demonstrates that the PredicineCARE urine cfDNA NGS assay may represent a novel, accurate, and non-invasive clinical application for molecular diagnostic testing to identify biomarkers in bladder cancer.
Extracellular domain ERBB2 (ERBB2 ECD+) mutations in urothelial bladder cancer (UBC).
Authors: Basin Michael , Jacob Joseph M , Bratslavsky Gennady , Grivas Petros , Spiess Philippe E. , Li Roger , Necchi Andrea , Pavlick Dean C. , Huang Richard S.P. , Lin Douglas I. , Danziger Natalie , Sokol Ethan , Sivakumar Smruthy , Ross Jeffrey S.
Published: March 2023

566

Background: Given the recent approval in lung cancer for the first anti-HER2 targeted therapy directed against activating kinase domain exon 20 ERBB2 insertion mutations, considerable interest has arisen in targeting additional locations in the ERBB2 gene in other tumor types. Methods: 5,485 UBC samples were sequenced using a hybrid capture-based comprehensive genomic profiling (CGP) assay to assess all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genomic loss of heterozygosity (gLOH), trinucleotide signatures and predominant genetic ancestry. Statistical comparisons utilized the Bonferroni correction. Results: 548 (10.0%) of UBC featured ERBB2 gene amplification (amp) and 219 (4.0%) featured an ERBB2 ECD+ sequence mutation (74% S310F and 26% S310Y). ERBB2 ECD+ mutations and ERBB2 amplification were mutually exclusive. 16.4% of ERBB2 ECD+ UBC had more than one E RBB2 sequence mutation. Central pathology review of the 219 ERBB2 ECD+ UBC revealed that 63 (28.8%) featured a micropapillary histologic appearance (MPUC). ERBB2 ECD+ UBC featured more patients with European ancestry than both ERBB2 WT (90.9% vs 84.2%; p=.03) and ERBB2 amp (90.9% vs 83.2%; p=.04). ECD mut+ UBC also featured lower association with African ancestry than ERBB2 amp (2.7% vs 7.8%; p=.04) and lower frequency of gLOH > 16% (9.3% vs 19.1%; p=.04). MSI-High status was similar and rare in all 3 groups (range 0 to 0.9%). ERBB2 ECD+ UBC had a higher frequency of APOBEC signature than ERBB2 amp (82.9% vs 72.4%; p=.03). TMB > 10 mut/mb was higher in ERBB2 amp (49.2% vs 31.4%; p<.0001) and ERBB2 ECD+ (59.8% vs 31.4%; p<.0001) compared to ERBB2 WT as was the mean TMB (11.8 and 17.4 mut/Mb respectively vs 8.9 mut/Mb, p<0.001 for both). Among important UBC individual genes, FGFR3 GA were significantly higher in ERBB2 WT than both ERBB2 amp (19.9% vs 6.2%; p<.0001) and ERBB2 ECD+ (19.9% vs 10.5%; p=.0002). CDKN2A GA were significantly higher in ERBB2 amp (39.1% vs 27.9% ERBB2 WT; p<.0001) only. The higher frequency of KMT2D GA in MPUC+ ECD+ and MPUC- ECD+ UBC (63.4% vs 27.6%; p=.02) was the only genomic difference between these cohorts. Conclusions: ERBB2 ECD mutation driven UBC is a unique form of UBC featuring enrichment of MPUC histology and a unique clinical and genomic landscape including genomic signatures and ancestry.
Identification of lineage-specific transcription factor defined subtypes in small cell/neuroendocrine bladder cancer.
Authors: Choi Woonyoung , Feng Mingxiao , Epstein Gabriel , Hoffman-Censits Jean H. , Kates Max R. , Czerniak Bogdan , Comperat Eva , Matoso Andres , Kim Seungchan , McConkey David James
Published: March 2023

568

Background: Small cell/neuroendocrine bladder cancer (SCBC) is a rare and clinically aggressive disease. However, its molecular characteristics are poorly studied; hence, biology-based therapeutic options are not available. Strong pan-cancer similarity in gene expression signature of neuroendocrine (NE) tumors including SCBC and small cell lung cancer (SCLC) has been reported. Recent genomics studies discovered that SCLC can be grouped into lineage- specific transcription factor (TF)-defined subtypes. Therefore, we explored whether TF-defined molecular subtypes could also be observed in SCBC with the goal of developing subtype-specific therapeutic strategies. Methods: Whole transcriptome RNAseq on a cohort of n = 44 pure SCBCs collected at Johns Hopkins (n=20) and Tenon Hospital (Paris) (n=24) and DNA panel sequencing on subset of the tumors (n=24) were performed. Two expert genitourinary pathologists selected the cases for the analyses based on the histopathological characteristics of the tumor tissue. Results: SCBC tumors displayed overexpression of canonical NE markers and high mutation rates in TERT, TP53 and RB1 with 92%, 75% and 38%, respectively, confirming the concordance between genomic features and histopathologic characteristics.Lineage-specific TFs (ASCL1, NEUROD1, and POU2F3) defined three molecular subtypes of SCBC that resembled the previously reported SCLC subtypes. The three subtypes expressed variable levels of NE biomarkers and were heterogeneous with respect to distinct downstream therapeutic targets. The ASCL1 and NEUROD1 subtypes expressed the highest levels of NE lineage-specific gene expression and were associated with expression of known regulators of the neuroendocrine phenotype including FOXA2 and HES6, respectively. The ASCL1 subtype was also enriched with DLLs and other genes that control oncogenic Notch signaling, whereas tumors enriched with POU2F3, a master regulator of the NE-low SCBC subtype, expressed TRPM5, SOX9 and CHAT. Finally, an inverse association between NE lineage-specific gene expression and immune signatures associated with response to immunotherapy was observed. Conclusions: Three lineage-specific TFs (ASCL1, NEUROD1, and POU2F3) defined discrete molecular subtypes in SCBC. Each subtype was characterized by distinct therapeutic targets and gene expression signatures associated with response to immunotherapy. Future studies will be required to test the clinical relevance of these observations.
Exploratory analysis of predictive biomarkers for immune-related adverse events (irAEs) due to checkpoint inhibitors (CPIs) in patients with genitourinary (GU) cancers.
Authors: Vosoughi Elham , Kaakour Dalia , Chen Wen-Pin , Mar Nataliya
Published: March 2023

569

Background: CPIs targeting PD-1/PD-L1 and CTLA-4 have transformed management of GU cancers. These agents are associated with a unique type of immune-mediated toxicities that may affect any organ, which may be severe or life-threatening. Development of irAEs may in part depend on type of CPI used, type of solid tumor, and individual patient factors including presence of subclinical inflammatory states. However, distinct biomarkers predictive of irAE development are poorly defined. This study aimed to examine possible associations between tumor mutation burden (TMB) and PD-L1 expression with occurrence of irAEs. Methods: A retrospective chart review was performed of all patients with urothelial carcinoma (UC) and renal cell carcinoma (RCC), who received therapy with CPIs from 1/2019 to 9/2022 at our institution and developed associated irAEs. Severe irAEs were defined as those necessitating initiation of immunosuppressive therapies or other supportive therapies. TMB and PDL-1 expression patterns were analyzed, if available. Given lack of standardized cutoffs for PD-L1 positivity across different GU cancer types, tumors were considered positive if a combined positive score of greater than 10 was present in UC or a total positive score of greater than 1% was present in RCC. Results: A total of 60 patients were included in this analysis - 33 with UC and 27 with RCC. Severe irAEs occurred in 19 patients with UC and 25 patients with RCC. Median TMB was 8.7 in patients with UC, while it was 2.5 in patients with RCC. PD-L1 positivity was seen in 39.3% (13/33) of UC patients and 40.7% (11/27) of RCC patients. In the UC cohort, 57.8% (11/19) had severe irAEs and TMB less than 10, while 36.8% (7/19) had severe irAEs and TMB greater than 10. Further, 47.3% (9/19) of UC patients had severe irAEs and positive PD-L1, while 42.1% (8/19) had severe irAEs and negative PD-L1. In the RCC cohort, 88% (22/25) had severe irAEs and TMB less than 10, while 8% (2/25) had severe irAEs and TMB greater than 10. Additionally, 40% (10/25) RCC patients had severe irAEs and positive PD-L1, while 56% (14/25) had severe irAEs and negative PD-L1. The incidence of TERT promoter mutations and TMB is noted in the table. Conclusions: Identification of predictive biomarkers of irAEs from CPIs is a major area of need in GU malignancies. Definitive conclusions from this dataset are limited by its small sample size. Interestingly, there appear to be differences in baseline expression of traditional immune biomarkers between UC and RCC, with lower prevalence of TMB greater than 10 and positive PD-L1 noted in the RCC cohort. As such, their utility when making treatment decisions in clinical practice may be of limited value. [Table: see text]