Advanced Urothelial Bladder Cancer Research Articles

P260 Real-world data on treatment patterns and guideline adherence in patients with locally advanced and metastatic urothelial bladder cancer (la/mUC) in Germany

P260 Real-world data on treatment patterns and guideline adherence in patients with locally advanced and metastatic urothelial bladder cancer (la/mUC) in Germany

The metastatic and advanced upper tract urothelial carcinoma-a separate entity or bladder cancer's younger sibling?

Upper tract urothelial carcinoma (UTUC) is acancer that is often already in an advanced stage at the time of initial diagnosis. Although urothelial carcinoma of the upper and lower urinary tracts both originate from the urothelium and have similar genetic alterations, there are significant differences in their distribution. In localized high-risk UTUC, radical nephroureterectomy is the gold standard therapy. In metastatic UTUC, major changes are emerging in sequential therapy due to the investigation of new classes of drugs. In addition to platinum-based combination chemotherapy and immunotherapy, new substances such as antibody-drug conjugates (ADCs) and FGFR inhibitors are used.

The Value and Safety of Adjuvant Radiation Therapy After Radical Cystectomy in Locally Advanced Urothelial Bladder Cancer: A Controlled Randomized Study

BackgroundAdjuvant radiotherapy after radical cystectomy in locally advanced bladder cancer was revived after the advancement in precise radiotherapy that decreased the normal pelvic tissue radiation hazards. However, there are still scarce controlled randomized studies addressing this issue. Patients and methodsOne hundred thirty-one cystectomized urothelial bladder cancer patients were enrolled; a hundred and twenty-two were randomized to receive adjuvant radiotherapy (ART) 50 Gy/25 fractions, 4 weeks’ post-cystectomy or cystectomy alone (CY). Sixty-two were included in the ART arm and sixty in the CY arm. Twenty-four ART and 30 CY patients received Neoadjuvant chemotherapy. Eleven patients (9%) had cotenant neo-bladder diversion, 6 in ART, and 5 in CY arms. All ART patients were treated with intensity-modulated radiotherapy (IMRT) with daily verification cone-beam CT (CBCT). The median follow-up was 42.7 months. ResultsThe 3-year adjusted Locoregional relapse-free survival (LRFS) rate was higher in the ART arm, measuring 81% (95%CI: 69-94) compared to 71% (95% CI: 60-80) (p=0.0457). ART significantly improved the locoregional relapse-free rate in the cystectomy bed and the pelvic side wall (p= 0.016 and 0.001, respectively). The overall survival, event-free, and distant metastasis-free survival did not rank to the level of statistical significance in the 2 arms. Even though the acute side effects were slightly higher in ART, the late toxicities were almost equal in the two groups. ConclusionsAdjuvant radiotherapy is safe and quite tolerable after radical cystectomy when using precise radiation techniques. These techniques significantly improved the LRFS but had insignificant improvement on the overall survival. ART did not affect the distant metastasis-free survival. Similar studies are performed in different centers around the world to confirm the value of ART in urothelial bladder cancer.

Preliminary results from a multi-center phase Ib/II study of RC48-ADC combined with tislelizumab as neoadjuvant treatment in patients with HER2 positive locally advanced muscle-invasive urothelial bladder cancer (Hope-03).

e16595 Background: To evaluate the safety and efficacy of RC48-ADC, a humanized anti-HER2 antibody conjugated with monomethyl auristatin E, and tislelizumab, a PD-1 antibody, as a novel neoadjuvant treatment combination in patients with HER2 positive locally advanced muscle-invasive bladder cancer (MIBC). The study design has been presented at 2022 ESMO Asia meeting. The preliminary results would be reported this time. Methods: This is a Ib/II, multi-center, open-label, single-arm study (ChiECRCT20210564). 51 patients with pathological and imaging diagnosed cT2-4bN0-3M0-1a HER2 positive MIBC will be included. RC48-ADC is given every 2 weeks with a maximum dose of 120mg intravenously, and tislelizumab is given every three weeks at the dose of 200mg intravenously. Treatment efficacy will be performed by imaging and transurethral resection of tumors after the neoadjuvant treatment. Patients without disease progression will receive radical cystectomy or bladder-sparing therapies based on individual risk profiles and preferences. The primary endpoints are clinical complete remission rate (cCR, T0/Ta/Tis), pathological complete remission rate (pCR) and safety. The secondary endpoints are disease control rate (DCR), overall survival (OS), local recurrence free survival (LRFS), distant metastasis free survival (DMFS) and quality of life. Results: Until now, 18 patients were included successfully, with 3 female patients and 15 male patients. And the median age was 64.47 years old. Of them, 7 patients were HER2(2+), and 11 patients were HER2(3+). The clinical stages were T2-4aN0-3M1a. Sixteen patients had the primary efficacy evaluation by now. After the neoadjuvant treatment, 7 patients were T0, 4 patients Tis, 2 patients partial response (PR), 2 patients stable disease (SD) and 1 patient suffered from progress of local disease. Hence the cCR rate was 68.75%, and the DCR was 90.91%. Fourteen patients chose radiotherapy as bladder-sparing therapy and no evidence of tumor in 6 patients who received treatment efficacy after radiotherapy. Two patients received radical cystectomy and pT3N0M0 was achieved for both. No patient died so far. For safety analysis, 4 patients suffered from immune-related adverse event, namely, grade 2 myositis, grade 1 elevated transaminase and grade 1 hyperthyroidism which led to treatment interruption of tislelizumab. And 10 patients experienced RC48-ADC related toxicities, including grade 1 elevated transaminase, grade 1 erythra and grade 1 paresthesia. No treatment related dose reduction happened. Conclusions: The novel neoadjuvant combination of RC48-ADC and tislelizumab showed promising down stage efficacy in patients with HER2 positive locally advanced MIBC and the toxicities were manageable, which would be verified by the final analysis. Clinical trial information: ChiECRCT20210564.

Targeted and immunotherapy for the management of advanced urothelial carcinoma of the bladder.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. The activity of targeted and immunotherapy for the management of advanced bladder cancer is reviewed. Platinum-based chemotherapy is standard first-line treatment for advanced bladder cancer. Pembrolizumab is approved alone as first-line therapy for patients who are ineligible for any platinum-based chemotherapy and with enfortumab for patients ineligible for cisplatin-based chemotherapy. Avelumab is approved for maintenance therapy in patients who have not progressed with first-line platinum-containing therapy. Pembrolizumab, avelumab, and nivolumab are approved second-line therapy in patients who experience progression during or after platinum-containing chemotherapy. Erdafitinib is indicated for advanced disease that has susceptible FGFR2 or FGFR3 genetic alterations and has progressed during or after treatment with at least one line of platinum-containing chemotherapy. Enfortumab vedotin and sacituzumab govitecan are antibody-drug conjugates. They are both approved for patients who have received anti-PD-L1 or anti-PD-1 therapy and treatment with platinum-containing chemotherapy. Enfortumab is also indicated for patients who are ineligible to receive cisplatin-based therapy and have received one or more prior lines of therapy. Six targeted and immunotherapeutic agents have been approved for patients with advanced urothelial bladder cancer. They all have demonstrated activity in patients for whom disease has progressed during or after platinum-based therapy. Pembrolizumab, with and without enfortumab, has demonstrated first-line activity, and avelumab is a key maintenance therapy after first-line treatment. The results of additional clinical trials should provide evidence to establish the exact role in therapy of each agent in patients with advanced disease.

Cisplatin-Resistant Urothelial Bladder Cancer Cells Undergo Metabolic Reprogramming beyond the Warburg Effect.

Advanced urothelial bladder cancer (UBC) patients are tagged by a dismal prognosis and high mortality rates, mostly due to their poor response to standard-of-care platinum-based therapy. Mediators of chemoresistance are not fully elucidated. This work aimed to study the metabolic profile of advanced UBC, in the context of cisplatin resistance. Three isogenic pairs of parental cell lines (T24, HT1376 and KU1919) and the matching cisplatin-resistant (R) sublines were used. A set of functional assays was used to perform a metabolic screening on the cells. In comparison to the parental sublines, a tendency was observed towards an exacerbated glycolytic metabolism in the cisplatin-resistant T24 and HT1376 cells; this glycolytic phenotype was particularly evident for the HT1376/HT1376R pair, for which the cisplatin resistance ratio was higher. HT1376R cells showed decreased basal respiration and oxygen consumption associated with ATP production; in accordance, the extracellular acidification rate was also higher in the resistant subline. Glycolytic rate assay confirmed that these cells presented higher basal glycolysis, with an increase in proton efflux. While the results of real-time metabolomics seem to substantiate the manifestation of the Warburg phenotype in HT1376R cells, a shift towards distinct metabolic pathways involving lactate uptake, lipid biosynthesis and glutamate metabolism occurred with time. On the other hand, KU1919R cells seem to engage in a metabolic rewiring, recovering their preference for oxidative phosphorylation. In conclusion, cisplatin-resistant UBC cells seem to display deep metabolic alterations surpassing the Warburg effect, which likely depend on the molecular signature of each cell line.

Efficacy and safety of disitamab vedotin combined with toripalimab as neoadjuvant treatment in patients with HER2 positive locally advanced muscle-invasive urothelial bladder cancer.

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

RC48-ADC combined with tislelizumab as neoadjuvant treatment in patients with HER2-positive locally advanced muscle-invasive urothelial bladder cancer: a multi-center phase Ib/II study (HOPE-03).

Bladder cancer with high expression of human epidermal growth factor receptor-2 (HER2) is related to pathological malignancy and poor prognosis. The standard care for muscle-invasive urothelial bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) with pelvic lymph node dissection. For HER2-positive MIBC, the efficacy of cisplatin-based NAC is unsatisfactory, and adverse reactions are inevitable or even intolerable. New regimens with higher efficiency and lower toxicity need to be explored in the neoadjuvant setting for this population. HOPE-03 is a multi-center, open-label, single-arm, phase Ib/II study aiming to evaluate the safety and efficacy of RC48-ADC (disitamab vedotin (DV)), a humanized anti-HER2 antibody conjugated with monomethyl auristatin E, and tislelizumab (PD-1 antibody) as a novel neoadjuvant treatment combination in patients with HER2-positive locally advanced urothelial MIBC. Fifty-one patients with cT2-4bN0-3M0-1a pathology- and imaging-diagnosed HER2 positive (immunohistochemistry status 3+ or 2+ or 1+) MIBC were recruited. Of these patients, six were enrolled in the dose-escalation phase (three patients in the RC48-ADC 1.5 mg/kg group and three patients in the 2.0 mg/kg group), and 45 patients were enrolled in the phase II study (the expected recommended phase II dose for RC48-ADC was 2.0 mg/kg). Patients without disease progression received radical cystectomy or bladder-sparing therapies as their preference after neoadjuvant treatment. The primary endpoints were clinical complete remission rate (cCR rate; T0/Ta/Tis), pathological complete remission rate (pCR rate), and safety. The secondary endpoints were overall survival (OS), local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and quality of life. The HOPE-03 trial provides a description of the safety profile of RC-48 and tislelizumab combination in the neoadjuvant treatment of HER2-positive locally advanced urothelial MIBC, and the efficacy is explored as well in this population. https://www.chictr.org.cn/showproj.html?proj=137111, identifier ChiCTR2200060153.

Associations of TACSTD2/TROP2 and NECTIN-4/NECTIN-4 with molecular subtypes, PD-L1 expression, and FGFR3 mutational status in two advanced urothelial bladder cancer cohorts.

Treatment options for advanced urothelial carcinoma (aUC) rapidly evolved: besides immunomodulative therapeutic options and inhibitors targeting Fibroblast growth factor receptor (FGFR) alterations, two new antibody-drug conjugates (ADC), sacituzumab govitecan (SG) and enfortumab vedotin (EV), have been approved. However, little is known about the associations of specific aUC properties and the surface target expression of TROP2 and NECTIN-4. Our aim was to characterize associations of TACSTD2/TROP2 and NECTIN-4/NECTIN-4 protein and gene expression with morphomolecular and clinicopathological characteristics of aUC in two large independent cohorts. The TCGA BLCA (n = 405) and the CCC-EMN (n = 247) cohorts were retrospectively analysed. TROP2/TACSTD2 and NECTIN-4/NECTIN-4 are highly expressed at the protein and transcript level in aUC, and their expression status did not correlate with patient survival in both cohorts. NECTIN-4/NECTIN-4 expression was higher in luminal tumours and reduced in squamous aUCs. NECTIN-4 was negative in 10.6% of samples, and 18.4% of samples had low expression (H-score <15). The TROP2 negativity rate amounted to 6.5%. TACSTD2 and NECTIN-4 expression was reduced in neuroendocrine-like and/or protein-based double-negative tumours. TROP2- and NECTIN-4-negative tumours included one sarcomatoid and four neuroendocrine aUC. FGFR3 alterations and PD-L1 expression on tumour and immune cells did not associate with TROP2 or NECTIN-4 expression. TACSTD2/TROP2 and NECTIN-4/NECTIN-4 are widely expressed in aUC, independent of FGFR3 alterations or PD-L1 expression, thus representing a suitable target for ADC treatment in the majority of aUC. The expression loss was associated with aggressive morphomolecular aUC subtypes, i.e. neuroendocrine(-like) and sarcomatoid aUC.

Impact of consensus molecular subtypes on survival with and without adjuvant chemotherapy in muscle-invasive urothelial bladder cancer

AimsAdjuvant chemotherapy after radical cystectomy can reduce the risk of recurrence and death in advanced muscle-invasive urothelial bladder cancer (MIBC). Molecular subtypes have been shown to be associated with survival....

Patterns of Utilization and Outcomes of Perioperative Chemotherapy in Patients With Locally Advanced-urothelial Bladder Cancer (LABC)-Real World Data From an Indian Tertiary Care Cancer Center.

Optimal utilization of perioperative systemic therapy in locally advanced bladder cancer (LABC) holds the key in improving the survival outcomes. We aim to analyze the oncological outcomes of clinically locally advanced urothelial bladder cancer patients treated with neoadjuvant (NACT) or adjuvant chemotherapy or without any systemic therapy in the perioperative period of radical cystectomy. We retrospectively analyzed the medical records of patients with cancer of the urinary bladder diagnosed between 2012 and 2020. The demographic profile, and the treatment received, was recorded for all patients. Oncological outcomes of the patients based on these variables were analyzed. Two hundred and twenty nine (229) locally advanced bladder cancer patients were included in the study. Eighty eight (38%) of them underwent upfront radical cystectomy and 141 (62%) received neoadjuvant chemotherapy (NACT). With a median follow-up of 27 months, the 2-year DFS in either of the groups was 65.4% and 67.1% respectively (P - 0.373). In the multivariate analysis, the pathological lymph nodal status and lymph vascular invasion (LVI) status influenced the DFS. The initial modality of management chosen did not affect the outcome. (HR - 0.688; 95% CI: 0.38-1.21). The commonest reason for not receiving NACT was Cisplatin ineligibility due to malignant obstructive uropathy and a subgroup analysis of this set of patients also did not show any significant difference in 2 year DFS compared to those who received NACT. A significant proportion of patients with LABC are unable to receive the recommended neoadjuvant chemotherapy and obstructive uropathy is the commonest reason for this in our centre. In our single centre series upfront radical cystectomy followed by adjuvant platinum based therapy had an outcome similar to neoadjuvant chemotherapy in LABC patients, in patients who were unable to receive the same due to various reasons.

Treatment patterns, survival, and healthcare utilisation and costs in patients with locally advanced and metastatic bladder cancer in Denmark 2015–2020

Background Treatment patterns in locally advanced and metastatic urothelial bladder cancer (La/mUBC) is changing, but little is known about current treatment patterns, survival, and costs of these patients. Our aim was to describe treatment patterns, survival, and healthcare utilisation/costs in Danish La/mUBC patients in a routine clinical care setting. Methods Registry-based nationwide cohort study including all bladder cancer patients aged 18 years or older with a La/mUBC tumour in the pathology register and a concomitant bladder cancer diagnosis in the Danish National Patient Registry in the period 2015–2020. We categorised the patients according to (1) La/mUBC at time of first bladder cancer diagnosis (de novo La/mUBC) and (2) non-invasive or localised muscle-invasive bladder cancer at time of diagnosis which had progressed to La/mUBC. All patients were included at date of pathology-confirmed La/mUBC. Follow-up ended 30 September 2022. Results We identified 1278 patients (69% men) with La/mUBC and no other previous cancer. Of these, 212 (17%) had de novo La/mUBC, while 1066 (83%) had progressed to La/mUBC. Median age was 72 years. Patients were followed for a median of 13.0 months (interquartile range 4.7;32.0). During follow-up, 651 (51%) patients started first-line treatment, of these, 285 progressed to second-line treatment, and 112 also started third-line treatment. Median survival was 13.0 months from La/mUBC diagnosis, 12.1 months from start of first-line treatment, 9.8 months from start of second-line treatment, and 8.6 months from start of third-line treatment. The mean number of days admitted to hospital was 3.47, 3.97, and 4.07 per month following initiation of first-line, second-line, and third-line treatment, respectively. Conclusion Patients with La/mUBC have a poor prognosis, and in routine clinical care only around half of the patients received systemic anti-cancer treatment suggesting an unmet need for novel treatments. The overall costs only increased slightly from first to third-line treatment.

Induction therapy with ipilimumab and nivolumab followed by consolidative chemoradiation as organ-sparing treatment in urothelial bladder cancer: study protocol of the INDIBLADE trial.

Studies that assessed the efficacy of pre-operative immune checkpoint blockade (ICB) in locally advanced urothelial cancer of the bladder showed encouraging pathological complete response rates, suggesting that a bladder-sparing approach may be a viable option in a subset of patients. Chemoradiation is an alternative for radical cystectomy with similar oncological outcomes, but is still mainly used in selected patients with organ-confined tumors or patients ineligible to undergo radical cystectomy. We propose to sequentially administer ICB and chemoradiation to patients with (locally advanced) muscle-invasive bladder cancer. The INDIBLADE trial is an investigator-initiated, single-arm, multicenter phase 2 trial. Fifty patients with cT2-4aN0-2M0 urothelial bladder cancer will be treated with ipilimumab 3 mg/kg on day 1, ipilimumab 3 mg/kg plus nivolumab 1 mg/kg on day 22, and nivolumab 3 mg/kg on day 43 followed by chemoradiation. The primary endpoint is the bladder-intact event-free survival (BI-EFS). Events include: local or distant recurrence, salvage cystectomy, death and switch to platinum-based chemotherapy. We will also evaluate the potential of multiparametric magnetic resonance imaging of the bladder to identify non-responders, and we will assess the clearance of circulating tumor DNA as a biomarker for ICB treatment response. This is the first trial in which the efficacy of induction combination ICB followed by chemoradiation is being evaluated to provide bladder-preservation in patients with (locally advanced) urothelial bladder cancer. The INDIBLADE trial was registered on clinicaltrials.gov on January 21, 2022 (NCT05200988).

CDH1-mutated clinically advanced urothelial bladder cancer (UBC): A genomic landscape and real-world clinical outcome study (RWCOS).

4587 Background: CDH1 mutated bladder cancers are characterized by plasmacytoid histology and are associated with an aggressive clinical course. Methods: Cohort 1: 6,676 clinically advanced UBC patients underwent hybrid capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA) as well as microsatellite instability (MSI), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH, high ≥16%). Tumor cell PD-L1 expression was determined by immunohistochemistry (Dako 22C3). GAs were compared between CDH1 mutated and wild-type (WT) patients using Chi-square. Cohort 2: 586 UBC patients underwent a RWCOS using the de-identified Flatiron Health-Foundation Medicine urothelial clinicogenomic database. The de-identified data originated from approximately 280 US cancer clinics (~800 sites of care) between January 2011 and April 2022. Differences in real-world progression-free survival (rwPFS) and overall survival (rwOS) were evaluated by Cox proportional hazard models. Results: Cohort 1: 217 UBC patients featured a CDH1 short variant mutation with 65.2% featuring plasmacytoid histology (PLC). The PLC cohort was slightly younger, with a higher proportion of male patients, and MSI-High status. Cell-Cycle regulatory GAs were significantly higher in the non-PLC cohort, specifically CDKN2A (25.5% vs 9.7%, p=0.01) and CDKN2B (23.6% vs 5.8%, p&lt;0.01). CDH1-mutated UBCs featured a higher MSI high frequency (2.7% vs 0.8%; p=.002), mean TMB (14.8 vs 9.9mut/Mb p&lt;.0001), RB1 GA (52.5% vs 20.3%; p&lt;.0001), PTEN GA (9.2% vs 4.3%; p=.006) and PIK3CA GA (29.5% vs 21.8%; p=.02), but lower gLOH (6.8% vs 15.9%; p=.009), CDKN2A loss (12.4% vs 38.3%; p&lt;.0001), MTAP loss (10.1% vs 25.1%; p&lt;.0001), and FGFR3 GA (9.7% vs 18.1%; p=.002). TP53 GAs and PD-L1 expression levels were similar between groups. From cohort 2: 22 (3.7%) patients featured CDH1 mutations. When compared with the CDH1 WT patients, the age, gender, ethnicity and ECOG status were similar. CDH1 mutation was associated with less favorable outcomes for 270 UBC patients treated with immune checkpoint inhibitors (ICPI) including rwPFS (2.8 vs 3.5 months; p=.096) and rwOS (3.3 vs 9.5 months; p=.03). Similar comparisons for 316 UBC patients treated with chemotherapy showed no significant adverse impact of CDH1 mutation status on either rwPFS (7.9 vs 6.2 months; p=.11) and rwOS (13.4 vs 13.4 months; p=0.83). Conclusions: In addition to its classic association with PLC histology, CDH1-mutated UBC features an unique genomic landscape including higher MSI and TMB, activating GAs in the MTOR pathway, but lower frequency of FGFR3 GAs. RWCOS further supports that CDH1 mutation predicts resistance to ICPI-based treatment, but does not systemic chemotherapy. These findings support CGP to guide therapeutic approaches based on the personalized genomic signature of UBC.

Correlation between fibroblast growth factor receptor mutation, programmed death ligand-1 expression and survival in urinary bladder cancer based on real-world data.

Background: Programmed cell death (PD)-1/PD-ligand 1 (PD-L1) inhibitors have made a breakthrough in the therapy of advanced urothelial bladder cancer (UBC). The impact of Fibroblast Growth Factor Receptor 3 (FGFR3) mutation on the effectiveness of PD-L1 treatment remains still unclear. Objective: Our study aimed to investigate the frequency of FGFR mutations at different tumor stages, and their relation to PD-L1 status and survival. Methods: 310 patients with urothelial bladder cancer and subsequent radical cystectomy were included in a retrospective study over a 10-year study period at the University of Szeged, Hungary. FGFR3 mutations from the most infiltrative areas of the tumor were analyzed by targeted next-generation sequencing and PD-L1 (28-8 DAKO) tests (tumor positive score -TPS and combined positives score-CPS). In T0 cases FGFR3 mutations were analyzed from the earlier resection samples. Survival and oncological treatment data were collected from the National Health Insurance Fund (NHIF). Neoadjuvant, adjuvant and palliative conventional chemotherapies were allowed; immunotherapies were not. The relationship between the covariates was tested using chi-square tests, and survival analysis was performed using the Kaplan-Meier model and Cox proportional hazards regression. Results: PD-L1 and FGFR could be tested successfully in 215 of the 310 UBC samples [pT0cyst 19 (8.8%); St.0-I 43 (20%); St.II 41 (19%); St.III-IV 112 (52%)]. Significant pairwise dependency was found between tumor stage, FGFR3 mutation status and PD-L1 expression (p < 0.01). Samples with FGFR mutation were more common in less advanced stages and were also less likely to demonstrate PD-L1 expression. The effect of all investigated factors on survival was found to correlate with tumor stage. Conclusion: FGFR alteration frequency varied between the different stages of cancer. Higher positivity rates were observed at early stages, but lower levels of PD-L1 expression were detected in patients with FGFR mutations across at all stages of the disease.

Single Drug Therapy of PD-1/PD-L1 Checkpoint Inhibitors for Advanced Urothelial Bladder Cancer

Since the first approval of Atezolizumab in May 2016, immunotherapy, PD-1/PD-L has completely changed the way bladder cancer is treated, as chemotherapy was the sole available choice as a treatment for bladder cancer, and the results still was not optimistic, with five licensed drugs treating bladder cancer. Despite the generally poor prognosis of advanced bladder cancer, some patients show persistent responses to immune checkpoint inhibitors. This review summarizes the efficacies and safety of the five drugs: Durvalumab, Atezolizumab, Avelumab and other drugs - from different studies respectively for treating advanced bladder cancer and mentions the side effects and future perspectives. For the treatment, all inhibitors that was licensed have akin efficacy and safety traits, but they differ in terms of dosage, frequency, and financial burden. Only Pembrolizumab, to date, has revealed advantage over conventional chemotherapy in a stochastic Phase III scenario. Pembrolizumab and Atezolizumab are also well tolerated and approved for patients who are unable to receive cisplatin treatment. Patients with bladder cancer now have some hope, thanks to immunotherapy. The current environment is continuously evolving, and new immunotherapy-combination trials are being conducted to further enhance results.

A phase 2, open-label study of neoadjuvant chemotherapy plus tislelizumab followed by radiotherapy-based, bladder-preserving treatment for high risk/locally advanced muscle invasive urothelial bladder cancer (HOPE-02).

516 Background: Tri-modality therapy (TMT) is an alternative to radical cystectomy for selected muscle-invasive bladder cancer (MIBC) patients with bladder-preserving will. Neoadjuvant treatment makes chance for imperfect patients to turn into ideal bladder-sparing patients. This phase 2 study aimed to explore the efficacy of neoadjuvant chemotherapy plus tislelizumab followed by radiotherapy as a strategy of bladder-sparing therapy for high risk/locally advanced MIBC (Trial registration number: ChiCTR2100045213). Methods: Pathological and imaging diagnosed cT2-4bN0-3M0-1a MIBC received 3-4 cycles of neoadjuvant chemotherapy (gemcitabine and cisplatin or carboplatin) plus tislelizumab (200mg every three weeks for one year). Radiotherapy (60.4-64.4 Gy /1.8Gy/33-35f to bladder with 50.4 Gy/1.8Gy/28f to pelvic) were given to patients with non- progressed disease (PD) after neoadjuvant therapy. The primary endpoint was complete response rate (CR, including T0/Ta/Tis), and the secondary endpoints were progression-free survival (PFS), bladder-intact disease free survival (BI-DFS), overall survival (OS) and toxicity. Results: The simple size is 43 participants. Until now, 28 patients were included, of which 23 patients received radiotherapy and 16 patients finished efficacy evaluation with imaging and cystoscopic biopsy after radiotherapy. Median follow-up time was 14.2 (1.5-17.4) months (m). Two of the 16 patients were Tis and 14 were T0 after radiotherapy, indicating the primary CR rate were 100%. For the 2 patients with Tis received BCG vaccine intravesical perfusion, and T0 was achieved when the second therapy evaluation. No patient died and only one patient had distant metastasis. The one-year PFS rate, one-year BI-DFS and one-year OS were 100%. Grade 3 and 4 hematological system adverse events were 23.3% and 2.3%. One patient had reduced bladder capacity (100-200 mL) with 2-h intervals of micturition, and 3 patients had frequency with urgency, nocturia and dysuria. Three patients had grade1 immunotherapy related abnormality of thyroidal function and 3 patients suffered from grade 2 myositis. The current bladder-preserving therapies research were well-tolerated with acceptable and manageable toxicities. Conclusions: Neoadjuvant chemotherapy plus tislelizumab followed by radiotherapy showed perfect efficacy and acceptable toxicities, which maybe an optimal strategy for high risk/locally advanced MIBC patients with bladder-preserving willingness. Clinical trial information: ChiCTR2100045213 .

Associations of TACSTD2/TROP2 and NECTIN-4/NECTIN-4 with molecular subtypes, PD-L1 expression and FGFR3 mutational status in two advanced urothelial bladder cancer cohorts.

554 Background: Treatment options for advanced urothelial carcinoma (aUC) rapidly evolved in recent years. Besides immunomodulative therapeutic options like anti-PD-(L)1 inhibitors and inhibitors targeting FGFR alterations, two new antibody-drug conjugates (ADC), sacituzumab govitecan (SG) and enfortumab vedotin (EV), have been approved for treatment. However, little is known about associations of specific aUC properties and the surface target expression of TROP2 and NECTIN-4. This study characterizes associations of TACSTD2/TROP2 and NECTIN-4/NECTIN-4 gene and protein expression with morphomolecular and clinico-pathological characteristics of aUC in two large independent cohorts. Methods: The TCGA BLCA (n=405) and the CCC-EMN (n=247) cohorts were retrospectively analyzed. Expression of mRNA and protein for TACSTD2/TROP2 and NECTIN-4/NECTIN-4 was measured and correlated with clinico-pathological characteristics, molecular subtypes, FGFR3 alterations and PD-L1 expression. Results: TACSTD2/TROP2 and NECTIN-4/NECTIN-4are highly expressed at protein and transcript level in aUC, and their expression status did not correlate with patient survival in two independent cohorts. NECTIN-4/NECTIN-4 expression was higher in luminal tumors and reduced in squamous aUCs. NECTIN-4 was negative in 10.6% of samples, and 18.4% of samples had low expression (H-Score &lt; 15). TROP2 negativity rate amounted to 6.5%. TACSTD2 and NECTIN-4 expression was reduced in neuroendocrine-like and/or protein-based double negative tumors. TROP2 and NECTIN-4 negative tumors (protein level) included one sarcomatoid and four neuroendocrine aUC. FGFR3 alterations and PD-L1 expression on tumor and immune cells did not associate with TROP2 or NECTIN-4 expression. Conclusions: TACSTD2/TROP2 and NECTIN-4/NECTIN-4 are widely expressed in aUC, independent of FGFR3 alterations or PD-L1 expression. Expression loss is associated with aggressive morphomolecular aUC subtypes, i.e. neuroendocrine(-like) and sarcomatoid aUC. TROP2 and NECTIN-4 are widely expressed in aUC thus representing suitable targets for novel ADC treatment for the majority of aUC patients.

CDH1-mutated clinically advanced urothelial bladder cancer (UBC): A genomic landscape and real-world clinical outcome study (RWCOS).

564 Background: CDH1 mutated UBCs are characterized by plasmacytoid histology and are associated with an aggressive clinical course at the time of diagnosis. Methods: Cohort 1: 6,676 clinically advanced UBC patients (pts) underwent comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA), microsatellite instability (MSI), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH, high ≥16%). Predominant genetic ancestry was determined using a SNP-based approach and classified as one of the 5 categories: African (AFR), European (EUR), Central and South American (AMR), South Asian (SAS), or East Asian (EAS). Cohort 2: 586 UBC pts underwent a RWCOS using the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine urothelial clinico-genomic database (FH-FMI CGDB). The de-identified data originated from approximately 280 US cancer clinics (~800 sites of care) Jan 2011-Apr 2022. Differences in real-world progression-free survival (rwPFS) and overall survival (rwOS) were evaluated by Cox proportional hazard models. Results: Cohort 1: 217 (3.3%) of UBC had a CDH1 short variant (SV) mutation with 65.2% featuring plasmacytoid histology. When compared with CDH1 wild-type (WT) UBC, the CDH1-mutated UBC had similar age, gender, and genetic ancestry. The CDH1-mutated UBC featured a higher frequency of MSI (2.7% vs 0.8%; p=.002), mean TMB (14.8 vs 9.9 mut/Mb p&lt;.0001), RB1 GA (52.5% vs 20.3%; p&lt;.0001), PTEN GA (9.2% vs 4.3%; p=.006) and PIK3CA GA (29.5% vs 21.8%; p=.02), but less gLOH high (6.8% vs 15.9%; p=.009), CDKN2A loss (12.4% vs 38.3%; p&lt;.0001), MTAP loss (10.1% vs 25.1%; p&lt;.0001) and FGFR3 GA (9.7% vs 18.1%; p=.002). TP53 GA were similar (62.3% vs 60.3%). Cohort 2: 22 (3.7%) featured CDH1 mutations. Compared with the CDH1 WT pts, the age, gender, ethnicity and ECOG status were similar. Evaluation of the RWCOS showed that CDH1 mutation was associated with less favorable outcomes for 270 UBC pts treated with immune checkpoint inhibitors (ICPI) including rwPFS (2.8 vs 3.5 months; p=.096) and rwOS (3.3 vs 9.5 months; p=.03). Similar comparisons for 316 UBC pts treated with chemotherapy showed no significant adverse impact of CDH1 mutation status on either rwPFS (7.9 vs 6.2 months) and rwOS (13.4 vs 13.4 months). Conclusions: In addition to its classic association with plasmacytoid histology, CDH1-mutated UBC features a unique CGP pattern including higher MSI and TMB status and activating GA in the MTOR pathway while harboring a lower FGFR3 GA frequency. RWCOS further supports that CDH1 mutation predicts resistance to ICPI-based treatments but does not impact responsiveness to chemotherapy. These results further support that CGP has the potential to customize the treatment and improve outcomes for UBC patients based on the determination of their genomic signatures.

Association of liver metastases, tumor microenvironment, and treatment outcomes in patients with urothelial bladder cancer treated with tislelizumab.

537 Background: Tislelizumab, a humanized monoclonal antibody that targets programmed cell death protein 1 (PD-1), has shown promising activity in the treatment of advanced urothelial bladder cancer (UBC). Recent studies suggest that liver metastases (LM) are associated with reduced effectiveness of PD-1/PD-L1 therapies (Yu, et al. Nat Med. 2021;27[1]:152-164). We evaluated how LM correlate with survival outcomes and the tumor immune microenvironment in UBC patients treated with tislelizumab in the BGB-A317-204 trial (NCT04004221). Methods: Cox regression was used to evaluate the effect of LM on overall survival (OS). Other key baseline characteristics were further included as covariates in the model to investigate the adjusted effect of LM and the interactions of LM with them. Gene expression profiling and multiplex immunohistochemistry (mIHC) analysis were performed on baseline tumor samples. Gene expression differences between LM positive (LM+) and LM negative (LM–) patients were compared by Wilcoxon rank-sum test for continuous biomarkers, and Fisher’s exact test for categorical biomarkers. All P-values reported in this post-hoc exploratory analysis were descriptive, without multiplicity adjustment. A result of P&lt;0.05 was considered statistically significant. Results: A total of 113 patients were included in the analysis. LM were present in 27/113 (23.9%) of them. Cox regression analysis showed the presence of LM was a negative prognostic factor for overall survival (OS) in UBC patients treated with tislelizumab, OS (hazard ratio (HR), 3.7; 95% CI, 2.3-6.2; P&lt;0.001). The LM negative prognostic value remained unaffected after adjustment for other baseline covariates. Next, we investigated immune cell infiltration and gene expression as potential indicators of impaired response in LM+ patients included in this analysis. Significantly fewer circulating lymphocytes at baseline were found in LM+ compared to LM– patients ( P&lt;0.05), while no differences were observed in other immune cell types. Reduced expression of gene signatures of CD4 Th1 ( P&lt;0.05), CD8+T cells ( P&lt;0.05) and NK cells functions ( P&lt;0.05) within tumor tissues was observed in samples from LM+ patients. Reduced CD8+ T-cell infiltration within the tumor and the intra-tumor stroma was also observed in LM+ patients based on mIHC analysis. No significant differences were observed in tumor mutational burden level between LM+ and LM– patients. Conclusions: LM were associated with worse outcomes of UBC patients treated with tislelizumab in the A317-204 study. Diminished number and impaired function of CD8+ T cells and NK cells in the tumor microenvironment of LM+ patients may have contributed to the worse survival observed in this subset of patients. Clinical trial information: NCT04004221 .