Racial Differences in Cutaneous Events Among Patients Receiving Enfortumab Vedotin.

INTRODUCTION: Enfortumab vedotin (EV) is an antibody-drug conjugate approved alone and in combination with pembrolizumab for advanced urothelial cancer (UC). EV-related-cutaneous-events (EVCEs) are common and rarely life-threatening. Black patients are frequently under-represented in oncology trials, and dermatologic conditions may vary with race. METHODS: Therefore, this retrospective analysis investigated differences in EVCE frequency between Black and White patients in an urban cohort (Johns Hopkins [JH]) and a US-based, nationwide electronic health record (EHR)-derived deidentified database (Flatiron Health [FH]) with sub-group analysis of those who had received prior pembrolizumab. RESULTS: The study included 12 Black patients in the JH Cohort (17.1%) and 24 Black patients in the FH Cohort (7.6%). In both cohorts, the frequency of EVCEs among Black patients was higher compared to White patients (JH: 66.7% vs. 33.3%; FH: 25.0% vs. 15.8%), though not statistically significant. In the larger FH Cohort EVCEs were significantly more common among Black compared to White patients treated with prior pembrolizumab (Odds Ratio [OR]: 4.76 [95%CI: 1.42, 15.95]) and recent pembrolizumab (within 90 days of EV initiation) (OR 9.00 [95%CI: 1.94, 41.66]). CONCLUSION: This hypothesis-generating retrospective study, comprising the largest population of EV-treated Black patients reported to date, emphasizes the importance of attentiveness to EVCEs among Black patients, particularly with receipt of pembrolizumab.

The JAVELIN Bladder Medley trial: avelumab-based combinations as first-line maintenance in advanced urothelial carcinoma.

Results from JAVELIN Bladder 100 established avelumab (anti-PD-L1) first-line maintenance as the standard-of-care treatment for patients with advanced urothelial carcinoma (UC) that has not progressed with first-line platinum-based chemotherapy. We describe the design of JAVELIN Bladder Medley (NCT05327530), an ongoing phase II, multicenter, randomized, open-label, parallel-arm, umbrella trial. Overall, 252 patients with advanced UC who are progression-free following first-line platinum-based chemotherapy will be randomized 1:2:2:2 to receive maintenance therapy with avelumab alone (control group) or combined with sacituzumab govitecan (anti-Trop-2/topoisomerase inhibitor conjugate), M6223 (anti-TIGIT) or NKTR-255 (recombinant human IL-15). Primary end points are progression-free survival per investigator and safety/tolerability of the combination regimens. Secondary end points include overall survival, objective response and duration of response per investigator, and pharmacokinetics.

Urothelial cancer develops in the urinary tract, which contains the parts of the body that move urine from the kidneys to outside of the body. Urothelial cancer is called advanced when it has spread outside of the urinary tract. Chemotherapy is often the first main treatment given to people with advanced urothelial cancer. Avelumab is an immunotherapy drug that can help the body's immune system find and destroy cancer cells. Results from a trial called JAVELIN Bladder 100 looked at avelumab maintenance treatment, which is given after chemotherapy. The trial showed that avelumab maintenance treatment helped people with advanced urothelial cancer live longer than people who were not treated with avelumab. Avelumab also helped people have a longer time without their cancer getting worse. Avelumab is the only approved maintenance treatment available for people with advanced urothelial cancer that has not worsened after chemotherapy. The JAVELIN Bladder Medley trial will assess whether avelumab maintenance treatment given in combination with other anticancer drugs can help people with advanced urothelial cancer live longer and have a longer time without their cancer getting worse compared with avelumab alone. Researchers will also look at the side effects people have when they receive avelumab alone or combined with the other anticancer drugs in this trial. Results will show whether the benefit of avelumab maintenance treatment can be improved by combining avelumab with other anticancer drugs. People started joining this trial in August 2022. Results will be reported in the future. Clinical Trial Registration: NCT05327530 (ClinicalTrials.gov).

PrECOG PrE0807: A Phase 1b Feasibility Trial of Neoadjuvant Nivolumab Without and with Lirilumab in Patients with Muscle-invasive Bladder Cancer Ineligible for or Refusing Cisplatin-based Neoadjuvant Chemotherapy.

BACKGROUND AND OBJECTIVE: Neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy (RC) improves overall survival (OS) in muscle-invasive bladder cancer (MIBC). However, many patients are cisplatin ineligible; therefore, new treatment options are needed. Nivolumab without/with lirilumab prior to RC was investigated in cisplatin-ineligible patients in this phase 1b trial (NCT03532451) to determine its safety/feasibility. METHODS: Patients with localized MIBC received two doses of nivolumab (480 mg) alone (cohort 1) or with lirilumab (240 mg; cohort 2) prior to RC. Cohorts were enrolled sequentially. The key eligibility criteria were cT2-4aN0-1M0 stage and cisplatin ineligibility/refusal. The primary endpoint was the rate of grade (G) ≥3 treatment-related adverse events (TRAEs) as per Common Terminology Criteria for Adverse Events version 5.0. The key secondary endpoints included the proportion of patients who underwent RC >6 wk after the last dose, CD8+ T-cell density change between pretreatment transurethral resection of bladder tumor (TURBT) and post-treatment RC, ypT0N0, 6 wk. In cohorts 1 and 2, ypT0N0 rates for patients with MIBC and RC were 17% and 21%,

Antitumor immunity as the basis for durable disease-free treatment-free survival in patients with metastatic urothelial cancer.

Cisplatin-based chemotherapy has been associated with durable disease control in a small subset of patients with metastatic urothelial cancer. However, the mechanistic basis for this phenomenon has remained elusive. Antitumor immunity may underlie these exceptional responders. In a phase II trial evaluating a phased schedule of gemcitabine and cisplatin followed by gemcitabine and cisplatin with ipilimumab for metastatic urothelial cancer, 4 of 36 patients achieved durable disease-free treatment-free survival (DDFTFS) and remain in remission over 5 years after enrolment on the study. We sought to identify the genomic and immunological mechanisms associated with functional cures of such patients. Whole exome sequencing was performed on pretreatment archival tumor tissue. Neoantigen prediction and ranking were performed using a novel pipeline. For a subset of patients with available biospecimens, selected peptides were tested for neoantigen-specific T cell reactivity in peripheral blood CD4+ and CD8+ T cells cultured with autologous antigen-presenting cells at baseline, postchemotherapy, and postchemotherapy and ipilimumab timepoints. Multiplex assays of serum protein analytes were also assessed at each time point. Serum proteomic analysis revealed that pretreatment, patients achieving DDFTFS demonstrated an immune activated phenotype with elevations in TH1 adaptive immunity, costimulatory molecules, and immune checkpoint markers. After combination cisplatin-based chemotherapy and ipilimumab treatment, DDFTFS patients again displayed enrichment for markers of adaptive immunity, as well as T cell cytotoxicity. CD27 was uniquely enriched in DDFTFS patients at all timepoints. Neoantigen reactivity was not detected in any patient at baseline or post two cycles of chemotherapy. Both CD4+ and CD8+ neoantigen-specific T cell reactivity was detected in two of two DDFTFS patients in comparison to zero of five non-DDFTFS patients after combination cisplatin-based chemotherapy and ipilimumab treatment. Antitumor immunity may underlie functional cures achieved in patients with metastatic urothelial cancer treated with cisplatin-based chemotherapy and immune checkpoint blockade. Probing the mechanistic basis for DDFTFS may facilitate the identification of biomarkers, therapeutic components, and optimal treatment sequences necessary to extend this ultimate goal to a larger subset of patients.

Clinicopathologic and Survival After Cystectomy Outcomes in Squamous Cell Carcinoma of the Bladder.

BACKGROUND: Squamous cell carcinoma of the bladder (SqCC) is a rare disease with limited management data. Thus, we sought to characterize the clinicopathologic and survival outcomes amongst patients with SqCC and explore the association of squamous differentiation within urothelial carcinoma (UC w/Squam), as compared to muscle invasive pure UC. METHODS: We conducted a single-center retrospective cohort study of patients, stratified by histology, who underwent cystectomy for MIBC. Baseline clinicopathologic characteristics were compared, and overall survival was assessed using Kaplan-Meier method. RESULTS: We identified 1,034 patients; 37 (3.58%) with SqCC histology, 908 (87.81%) with UC histology, and 89 (8.61%) with UC w/ Squam histology. Among SqCC patients, a higher proportion were Black and similarly a higher proportion were women; amongst patients with UC w/ Squam a higher proportion had lower BMI; and amongst patients with UC a higher proportion had lower clinical (c) T, cN, pathological (p) T, and pN stages. Patients presenting with UC were more likely to receive intravesical therapy; patients presenting with SqCC were less likely to receive neoadjuvant chemotherapy (NAC). Adjuvant chemotherapy rates were similar. With post-hoc Bonferroni analysis, overall survival, cancer-specific survival, and recurrence-free survival were significantly worse for the UC w/ Squam cohort. CONCLUSIONS: UC w/ Squam histology was associated with worse survival outcomes after cystectomy for muscle invasive bladder cancer compared to UC. Our results suggest that UC w/ Squam is associated with more advanced disease compared to UC, warranting further prospective work on consideration of combination therapies for patients with this disease state.

Checkpoint Inhibitors in Urothelial Carcinoma-Future Directions and Biomarker Selection.

CONTEXT: Several recent phase 2 and 3 trials have evaluated the efficacy and toxicity of checkpoint inhibitor (CPI) therapy for urothelial carcinoma (UC) in the metastatic, localized muscle-invasive UC (MIUC), upper tract UC, and non-muscle-invasive bladder cancer (NMIBC) disease state. OBJECTIVE: To assess the outcomes and toxicity of CPIs across the treatment landscape of UC and contextualize their application to current real-world treatment. EVIDENCE ACQUISITION: We queried PubMed, Web of Science, and EMBASE databases and conference abstracts to identify prospective trials examining CPIs in UC. The primary endpoints included overall survival, recurrence-free survival, and toxicity (when available). A secondary analysis included biomarker evaluation of response. EVIDENCE SYNTHESIS: We identified 21 trials, 12 phase 2 and nine phase 3 trials, in which a CPI was used for metastatic UC (seven), MIUC (nine), and NMIBC (five). For first-line (1L) metastatic UC, concurrent chemotherapy with CPIs failed to show superiority. Improved overall and progression-free survival for switch maintenance avelumab (after achieving stable disease or response with induction systemic chemotherapy) has established the current standard of care for 1L metastatic UC. A single-agent CPI is a consideration for patients unable to tolerate chemotherapy. CPIs in the perioperative setting are limited to only the adjuvant treatment with nivolumab after radical surgery for MIUC in patients at a higher risk of recurrence based on pathologic stage. Only pembrolizumab is approved by the Food and Drug Administration for carcinoma in situ unresponsive to bacillus Calmette-Guérin (BCG) in patients who are not fit for or who refuse radical cystectomy. Trials investigating CPIs in combination with multiple immune regulators, antibody drug conjugates, targeted therapies, antiangiogenic agents, chemotherapy, and radiotherapy are enrolling patients and may shape the future treatment of patients with UC. CONCLUSIONS: CPIs have an established role across multiple states of UC, with broadened applications likely to occur in the future. Several combinations are being evaluated, while the development of predictive biomarkers and their validation may help identify patients who are most likely to respond. PATIENT SUMMARY: Our findings highlight the broad activity of checkpoint inhibitors in urothelial carcinoma, noting the need for further investigation for the best application of combinations and patient selection to patient care.

A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy.

PURPOSE: On the basis of preclinical evidence of epigenetic contribution to sensitivity and resistance to immune checkpoint inhibitors (ICI), we hypothesized that guadecitabine (hypomethylating agent) and atezolizumab [anti-programmed cell death ligand 1 (PD-L1)] together would potentiate a clinical response in patients with metastatic urothelial carcinoma (UC) unresponsive to initial immune checkpoint blockade therapy. PATIENTS AND METHODS: We designed a single arm phase II study (NCT03179943) with a safety run-in to identify the recommended phase II dose of the combination therapy of guadecitabine and atezolizumab. Patients with recurrent/advanced UC who had previously progressed on ICI therapy with programmed cell death protein 1 or PD-L1 targeting agents were eligible. Preplanned correlative analysis was performed to characterize peripheral immune dynamics and global DNA methylation, transcriptome, and immune infiltration dynamics of patient tumors. RESULTS: Safety run-in enrolled 6 patients and phase II enrolled 15 patients before the trial was closed for futility. No dose-limiting toxicity was observed. Four patients, with best response of stable disease (SD), exhibited extended tumor control (8-11 months) and survival (>14 months). Correlative analysis revealed lack of DNA demethylation in tumors after 2 cycles of treatment. Increased peripheral immune activation and immune infiltration in tumors after treatment correlated with progression-free survival and SD. Furthermore, high IL6 and IL8 levels in the patients' plasma was associated with short survival. CONCLUSIONS: No RECIST responses were observed after combination therapy in this trial. Although we could not detect the anticipated tumor-intrinsic effects of guadecitabine, the addition of hypomethylating agent to ICI therapy induced immune activation in a few patients, which associated with longer patient survival.

Enfortumab Vedotin-related Cutaneous Toxicity and Radiographic Response in Patients with Urothelial Cancer: A Single-center Experience and Review of the Literature.

Enfortumab vedotin (EV) is an antibody-drug conjugate approved for the treatment of refractory advanced urothelial cancer. Cutaneous toxicity is well described but has not been correlated with response. In this retrospective single-center study, data from patients treated with more than one dose of EV between December 2017 and June 2022 were analyzed. Of 56 patients with a median age of 69 yr, 41 (73.2%) were male and 27 (48.2%) had any-grade skin toxicity. For all 51 patients evaluable by physician-assessed Response Evaluation Criteria in Solid Tumors (RECIST) criteria, the response rate was 41.2%. For those with cutaneous toxicity, the response rate was 57.7%; for those without cutaneous toxicity, it was 24.0% (p = 0.0145). All three patients with complete response experienced cutaneous toxicity, and two of these responses remain durable 5 and 24 mo off EV. The median starting weight and body mass index (BMI) were, respectively, 80.86 kg and 26.53 kg/m2 among patients with cutaneous toxicity, and 69.37 kg and 23.29 kg/m2 in patients without (p = 0.0129 and 0.0014, respectively). In this small dataset, EV-related cutaneous toxicity was more common in patients with higher weight and BMI at baseline, and was associated with disease response. Confirmation in prospective trials may confirm this association and lead to an important clinical biomarker of response. Patient summary: We evaluated patients with urothelial cancer who were treated at our institution with enfortumab vedotin (EV). We found that patients who experienced the common side effect of any type of skin toxicity, such as rash or itching, were more likely to have improvement in their cancer from EV treatment than those who did not experience skin toxicity. Patients with higher weight and body mass index when starting EV tended to have more skin toxicity. We conclude that presence of skin toxicity might help doctors make decisions about how to manage the care of patients with EV in the future.

A Phase 1b/2 Study of Atezolizumab with or Without Bacille Calmette-Guérin in Patients with High-risk Non-muscle-invasive Bladder Cancer.

BACKGROUND: Bacille Calmette-Guérin (BCG) is the standard therapy after transurethral resection of bladder tumour for high-risk non-muscle-invasive bladder cancer (NMIBC). However, post-BCG recurrence/progression occurs frequently, and noncystectomy options are limited. OBJECTIVE: To evaluate the safety and clinical activity of atezolizumab ± BCG in high-risk BCG-unresponsive NMIBC. DESIGN, SETTING, AND PARTICIPANTS: This phase 1b/2 GU-123 study (NCT02792192) treated patients with BCG-unresponsive NMIBC who had carcinoma in situ with atezolizumab ± BCG. INTERVENTION: Patients in cohorts 1A and 1B received atezolizumab 1200 mg IV q3w for ≤96 wk. Those in cohort 1B also received standard BCG induction (six weekly doses) and maintenance courses (three doses weekly starting at month 3) with optional maintenance at 6, 12, 18, 24, and 30 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Coprimary endpoints were safety and 6-mo complete response (CR) rate. Secondary endpoints included 3-mo CR rate and duration of CR; 95% confidence intervals were calculated using the Clopper-Pearson method. RESULTS AND LIMITATIONS: At data cut-off (September 29, 2020), 24 patients were enrolled (cohort 1A, n = 12; cohort 1B, n = 12), and the recommended BCG dose was 50 mg in cohort 1B. Four patients (33%) had adverse events (AEs) leading to BCG dose modification/interruption. Three patients (25%) in cohort 1A reported atezolizumab-related grade 3 AEs; cohort 1B had no atezolizumab- or BCG-related grade ≥3 AEs. No grade 4/5 AEs were reported. The 6-mo CR rate was 33% in cohort 1A (median duration of CR, 6.8 mo) and 42% in cohort 1B (median duration of CR, not reached [≥12 mo]). These results are limited by the small sample size of GU-123. CONCLUSIONS: In this first report of the atezolizumab-BCG combination in NMIBC, atezolizumab ± BCG was well tolerated, with no new safety signals or treatment-related deaths. Preliminary results suggested clinically meaningful activity; the combination favoured a longer duration of response. PATIENT SUMMARY: We studied atezolizumab with and without bacille Calmette-Guérin (BCG) to determine whether this combination was safe and had clinical activity in patients with high-risk noninvasive bladder cancer (high-grade bladder tumours that affect the outermost lining of the bladder wall) that has previously been treated with BCG and is still present or occurred again. Our results suggest that atezolizumab with or without BCG was generally safe and could be used to treat patients unresponsive to BCG.

Comparison of clinicopathological characteristics, gene expression profiles, mutational analysis, and clinical outcomes of pure and mixed small-cell carcinoma of the bladder.

AIMS: Small cell bladder carcinoma (SCBC) is a rare, divergent form of urothelial carcinoma (UC). We aimed to determine whether pure (n = 16) and mixed (SCBC and UC; n = 30) tumours differed in pathology, gene expression characteristics, genetic alterations, and clinical outcomes. METHODS AND RESULTS: Forty (87%) patients received first-line chemotherapy. Twenty-nine patients had no metastatic disease at diagnosis and underwent radical cystectomy. There were no differences in age, sex, race distribution, tumour size, stage at presentation, therapy response with pathological downstaging to ≤ypT1N0, or overall or progression-free survival (PFS) between pure and mixed tumours. There was a longer PFS among downstaged chemotherapy-responding tumours ≤ypT2N0M0 than among unresponsive tumours ≥ypT2 ≥ yN1M1 (P = 0.001). Patients who achieved pathological downstaging with neoadjuvant chemotherapy (n = 10) were stage cT2N0M0 at the time of diagnosis and were alive at the last follow-up (median 37 months), while 46% of patients who failed to achieve pathological downstaging were alive at the last follow-up (median 38 months; P = 0.008). RNA sequencing showed that the UC of mixed SCBC had similar neural expression signatures to pure SCBC. DNA sequencing revealed alterations in TERT (83%), P53 (56%), ARID1A (28%), RB1 (22%), and BRCA2 (11%). Immunohistochemistry for RB1 showed loss of expression in 18/19 (95%) patients, suggesting frequent pathway downregulation despite a low prevalence of RB1 mutation. CONCLUSION: Patients with pure and mixed SCBC have similar outcomes and these outcomes are determined by the pathological stage at RC and are best among patients who have pathological downstaging after NAC.

A Phase 1 Trial of Durvalumab in Combination with Bacillus Calmette-Guerin (BCG) or External Beam Radiation Therapy in Patients with BCG-unresponsive Non-muscle-Invasive Bladder Cancer: The Hoosier Cancer Research Network GU16-243 ADAPT-BLADDER Study.

BACKGROUND: Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients. OBJECTIVE: To evaluate the safety and preliminary efficacy of anti-PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam radiation therapy (D + EBRT). DESIGN, SETTING, AND PARTICIPANTS: A multicenter phase 1 trial was conducted at community and academic sites. INTERVENTION: Patients received 1120 mg of D intravenously every 3 wk for eight cycles. D + BCG patients also received full-dose intravesical BCG weekly for 6 wk with BCG maintenance recommended. D + EBRT patients received concurrent EBRT (6 Gy × 3 in cycle 1 only). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Post-treatment cystoscopy and urine cytology were performed at 3 and 6 -mo, with bladder biopsies required at the 6-mo evaluation. The recommended phase 2 dose (RP2D) for each regimen was the primary endpoint. Secondary endpoints included toxicity profiles and complete response (CR) rates. RESULTS AND LIMITATIONS: Twenty-eight patients were treated in the D (n = 3), D + BCG (n = 13), and D + EBRT (n = 12) cohorts. Full-dose D, full-dose BCG, and 6 Gy fractions × 3 were determined as the RP2Ds. One patient (4%) experienced a grade 3 dose limiting toxicity event of autoimmune hepatitis. The 3-mo CR occurred in 64% of all patients and in 33%, 85%, and 50% within the D, D + BCG, and D + EBRT cohorts, respectively. Twelve-month CRs were achieved in 46% of all patients and in 73% of D + BCG and 33% of D + EBRT patients. CONCLUSIONS: D combined with intravesical BCG or EBRT proved feasible and safe in BCG-unresponsive NMIBC patients. Encouraging preliminary efficacy justifies further study of combination therapy approaches. PATIENT SUMMARY: Durvalumab combination therapy can be safely administered to non-muscle-invasive bladder cancer patients with the goal of increasing durable response rates.

Systemic therapy issues: Immunotherapy in nonmetastatic urothelial cancer.

Non-muscle-invasive bladder cancer is one of the most common malignancies. Patients with intermediate-risk or high-risk disease can be treated with intravesical Bacillus Calmette-Guerin, a vaccine against tuberculosis. However, many of these patients will experience tumor recurrence, despite appropriate treatment. 1 The standard of care in these patients is radical cystectomy (RC) with urinary diversion. 2 Patients diagnosed with muscle-invasive bladder cancer (MIBC) have traditionally faced 2 main treatment options: RC and urinary diversion, as in Bacillus Calmette-Guerin-unresponsive Non-muscle-invasive bladder cancer, or alternatively, trimodal therapy comprising maximal transurethral resection of bladder tumor plus chemoradiation. 3 For patients with MIBC and clinical (c)T2-T4a, neoadjuvant chemotherapy (NAC) preceding RC is supported by Level 1 evidence with a modest 5-year overall survival benefit of 5% with cisplatin-based regimens. 4-9 A number of factors preclude MIBC patients from standard treatment options. For example, patients with serious comorbidities might be unable to tolerate general anesthesia, while others might be unwilling to adapt to the lifestyle changes after RC. 10-12 Likewise, patients with extensive carcinoma in situ or poor bladder function might not be optimal candidates for trimodal therapy or be prepared for the ongoing risk that salvage RC might be ultimately required. Reasons for the underuse of NAC range from the fear of delaying potentially curative surgery in nonresponders to patient ineligibility to cisplatin-based NAC. 13,14 Despite best efforts, in both surgical and bladder-sparing approaches, the 5-year overall survival in treated patients with MIBC is only 35% to 50%. 3,15 Strategies to improve overall prognosis as well as to reduce the indications of RC are desperately needed. Trial results have demonstrated the unprecedented ability of immune-checkpoint inhibitors to induce durable remissions in some patients with metastatic urothelial carcinoma. 16-20 Furthermore, immune-checkpoint inhibitors have shown to be better tolerated than traditional chemotherapy. 16 These successful results have spearheaded the research on these agents in earlier curative settings, with the shared goal of improving overall outcomes, and potentially avoid surgery in patients who show complete response (pT0). Strategies to enhance the immune response by combining immunotherapy with immune sensitizers such as chemotherapy, immunotherapy, targeted therapy or radiation are on the rise.

Identification of a naturally-occurring canine model for early detection and intervention research in high grade urothelial carcinoma.

Background: Early detection and intervention research is expected to improve the outcomes for patients with high grade muscle invasive urothelial carcinoma (InvUC). With limited patients in suitable high-risk study cohorts, relevant animal model research is critical. Experimental animal models often fail to adequately represent human cancer. The purpose of this study was to determine the suitability of dogs with high breed-associated risk for naturally-occurring InvUC to serve as relevant models for early detection and intervention research. The feasibility of screening and early intervention, and similarities and differences between canine and human tumors, and early and later canine tumors were determined. Methods: STs (n=120) ≥ 6 years old with no outward evidence of urinary disease were screened at 6-month intervals for 3 years with physical exam, ultrasonography, and urinalysis with sediment exam. Cystoscopic biopsy was performed in dogs with positive screening tests. The pathological, clinical, and molecular characteristics of the "early" cancer detected by screening were determined. Transcriptomic signatures were compared between the early tumors and published findings in human InvUC, and to more advanced "later" canine tumors from STs who had the typical presentation of hematuria and urinary dysfunction. An early intervention trial of an oral cyclooxygenase inhibitor, deracoxib, was conducted in dogs with cancer detected through screening. Results: Biopsy-confirmed bladder cancer was detected in 32 (27%) of 120 STs including InvUC (n=29, three starting as dysplasia), grade 1 noninvasive cancer (n=2), and carcinoma in situ (n=1). Transcriptomic signatures including druggable targets such as EGFR and the PI3K-AKT-mTOR pathway, were very similar between canine and human InvUC, especially within luminal and basal molecular subtypes. Marked transcriptomic differences were noted between early and later canine tumors, particularly within luminal subtype tumors. The deracoxib remission rate (42% CR+PR) compared very favorably to that with single-agent cyclooxygenase inhibitors in more advanced canine InvUC (17-25%), supporting the value of early intervention. Conclusions: The study defined a novel naturally-occurring animal model to complement experimental models for early detection and intervention research in InvUC. Research incorporating the canine model is expected to lead to improved outcomes for humans, as well as pet dogs, facing bladder cancer.

Collaborative study from the Bladder Cancer Advocacy Network for the genomic analysis of metastatic urothelial cancer.

Urothelial Cancer - Genomic Analysis to Improve Patient Outcomes and Research (NCT02643043), UC-GENOME, is a genomic analysis and biospecimen repository study in 218 patients with metastatic urothelial carcinoma. Here we report on the primary outcome of the UC-GENOME-the proportion of subjects who received next generation sequencing (NGS) with treatment options-and present the initial genomic analyses and clinical correlates. 69.3% of subjects had potential treatment options, however only 5.0% received therapy based on NGS. We found an increased frequency of TP53E285K mutations as compared to non-metastatic cohorts and identified features associated with benefit to chemotherapy and immune checkpoint inhibition, including: Ba/Sq and Stroma-rich subtypes, APOBEC mutational signature (SBS13), and inflamed tumor immune phenotype. Finally, we derive a computational model incorporating both genomic and clinical features predictive of immune checkpoint inhibitor response. Future work will utilize the biospecimens alongside these foundational analyses toward a better understanding of urothelial carcinoma biology.

Phase II Clinical and Translational Study of Everolimus ± Paclitaxel as First-Line Therapy in Cisplatin-Ineligible Advanced Urothelial Carcinoma.

BACKGROUND: Treatment options have been historically limited for cisplatin-ineligible patients with advanced urothelial carcinoma (UC). Given the need for alternatives to platinum-based chemotherapy, including non-chemotherapy regimens for patients with both impaired renal function and borderline functional status, in 2010 (prior to the immune checkpoint blockade era in metastatic UC), we initiated a phase II trial to test the activity of everolimus or everolimus plus paclitaxel in the cisplatin-ineligible setting. METHODS: This was an open-label phase II trial conducted within the US-based Hoosier Cancer Research Network (ClinicalTrials.gov number: NCT01215136). Patients who were cisplatin-ineligible with previously untreated advanced UC were enrolled. Patients with both impaired renal function and poor performance status were enrolled into cohort 1; patients with either were enrolled into cohort 2. Patients received everolimus 10 mg daily alone (cohort 1) or with paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle (cohort 2). The primary outcome was clinical benefit at 4 months. Secondary outcomes were adverse events, progression-free survival (PFS), and 1-year overall survival (OS). Exploratory endpoints included genomic correlates of outcomes. The trial was not designed for comparison between cohorts. RESULTS: A total of 36 patients were enrolled from 2010 to 2018 (cohort 1, N = 7; cohort 2, N = 29); the trial was terminated due to slow accrual. Clinical benefit at 4 months was attained by 0 (0%, 95% confidence interval [CI] 0-41.0%) patients in cohort 1 and 11 patients (37.9%, 95% CI 20.7-57.7%) in cohort 2. Median PFS was 2.33 (95% CI 1.81-Inf) months in cohort 1 and 5.85 (95% CI 2.99-8.61) months in cohort 2. Treatment was discontinued due to adverse events for 2 patients (29%) in cohort 1 and 11 patients (38%) in cohort 2. Molecular alterations in microtubule associated genes may be associated with treatment benefit but this requires further testing. CONCLUSION: Everolimus plus paclitaxel demonstrates clinical activity in cisplatin-ineligible patients with metastatic UC, although the specific contribution of everolimus cannot be delineated. Patients with both impaired renal function and borderline functional status may be difficult to enroll to prospective trials. (ClinicalTrials.gov Identifier NCT01215136).

A Molecular Inquiry into the Role of Antibody-Drug Conjugates in Bacillus Calmette-Guérin-exposed Non-muscle-invasive Bladder Cancer.

The treatment landscape for advanced urothelial cancer has changed dramatically owing to the US Food and Drug Administration approval and introduction of antibody-drug conjugates (ADCs), including enfortumab vedotin and sacituzumab govitecan. Efforts have begun to use these therapies in earlier disease states, specifically bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). We assessed gene expression associated with these newly approved therapies in a novel cohort of treatment-naïve NMIBC tumors before and after BCG therapy. Multiple genes, including Nectin-4, Trop-2, and Her-2, exhibited increased expression after BCG therapy compared to baseline. However, few of the tumors with increased expression of ADC targets also exhibited increased PD-L1/PD-1 expression. Taken together, these data demonstrate the heterogeneous genomic landscape of BCG-exposed NMIBC, and provide evidence supporting the evaluation of ADCs in NMIBC. PATIENT SUMMARY: We evaluated the potential role of targeted therapies that have been approved in the USA for advanced non-muscle-invasive bladder cancer (NMIBC) that has recurred after treatment with bacillus Calmette-Guérin (BCG). By assessing levels of specific genes and proteins linked to the targeted therapies, we demonstrate that there is rationale for further evaluation of these therapies in NMIBC.

Four versus 3 Cycles of Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: Implications for Pathological Response and Survival.

PURPOSE: The ideal number of neoadjuvant chemotherapy (NAC) cycles for muscle-invasive bladder cancer is uncertain with 3 to 4 representing the standard of care (SOC). We compared ypT0 rates and survival between patients receiving 4 versus 3 cycles of NAC with evaluation of chemotherapy-related toxicity for correlation with tumor chemosensitivity and pathological response. MATERIALS AND METHODS: Patients receiving NAC followed by radical cystectomy for cT2-4N0M0 urothelial carcinoma from 2 institutions were included. Primary study groups included 4 cisplatin-based NAC cycles, 3 cisplatin-based NAC cycles, and nonSOC NAC (1-2 cycles or noncisplatin-based) to compare ypT0/≤ypT1 rates and survival. A cohort of patients not receiving NAC was included for pathological reference. RESULTS: Of 693 total patients, 318 (45.9%) received NAC. ypT0 and ≤ypT1 rates were 42/157 (26.8%) and 86/157 (54.8%) for 4 cycles, 38/114 (33.3%) and 71/114 (62.3%) for 3 cycles, and 6/47 (12.8%) and 13/47 (27.7%) for nonSOC (p=0.03 and p <0.01, respectively). Pathological response appeared higher among patients receiving 3 cycles due to toxicity (ypT0: 29/77 [37.7%]; ≤ypT1: 51/77 [66.2%]) but did not reach statistical significance. Toxicities leading to treatment modifications were thrombocytopenia (32.1%), neutropenia (27.2%), renal insufficiency (22.2%), and constitutional symptoms (18.5%). NonSOC patients had lower Kaplan-Meier survival (cT2-cT4N0M0: log-rank p=0.07; cT2N0M0: log-rank p=0.02). There were no statistically significant differences in survival between 4 and 3 cycles (HR 1.00 [95% CI 0.57-1.74], p=0.99). CONCLUSIONS: Patients completing 3 cycles of cisplatin-based NAC have similar pathologic response and short-term survival compared to 4 cycles. Further evaluation of patients experiencing toxicity as a potential marker of tumor chemosensitivity is needed.

Gender-specific Stratification of Survival Following Immune Checkpoint Inhibitor Therapy Based on Intratumoral Expression of a B cell Gene Signature.

BACKGROUND: There is a great need to identify biomarkers that can accurately identify patients who will obtain the most clinical benefit from immune checkpoint inhibitor (ICI) therapy. While high intratumoral B cell gene expression correlated with an ICI response in melanoma, whether it adds predictive value in other cancers is unknown. OBJECTIVE: To examine the relationship between B cell gene signature (BCGS) expression and overall survival (OS) following ICI treatment. DESIGN, SETTING, AND PARTICIPANTS: A total of 348 patients with advanced urothelial carcinoma from the IMvigor 210 phase 2 clinical trial of atezolizumab and 406 patients with muscle-invasive bladder cancer from The Cancer Genome Atlas (TCGA) were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We analyzed tumor RNA sequencing data of included patients to examine the relationships between a BCGS and clinical outcomes. RESULTS AND LIMITATIONS: Tumors with high levels of B cell and CD8+ T cell gene signatures (BCGS/CD8TGS or B8T high/high) were associated with the longest OS of all B8T groups. Moreover, the B8T cell signature stratified patients whose tumors had a high tumor mutational burden or high programmed death ligand 1 (PD-L1) into subsets with differential OS outcomes. Whereas the B8T high/high tumors were associated with the best clinical outcomes in ICI-treated men, they were not associated with better OS in women. Conversely, women with B8T high/high tumors had the best clinical outcomes in non-ICI-treated muscle-invasive bladder cancer. CONCLUSIONS: These data suggest that the B8T signature can enhance OS stratification in patients with advanced urothelial carcinoma who are treated with ICI therapy and that sex-specific differences in the tumor immune microenvironment may drive disparate outcomes. PATIENT SUMMARY: We examined whether the presence of two immune cell gene signatures within tumor samples impact survival in patients with bladder cancer. High levels of both of these signatures (B cells and CD8+ T cells) associate with superior survival in patients who receive immune therapy.

Neoadjuvant Nivolumab in Patients with High-risk Nonmetastatic Renal Cell Carcinoma.

Neoadjuvant immune checkpoint blockade represents a novel approach for potentially decreasing the risk of recurrence in patients with nonmetastatic renal cell carcinoma (RCC). In this early phase clincal tiral, we evaluated the safety and tolerability of neoadjuvant treatment with the programmed cell death protein 1 (PD-1) inhibitor nivolumab in patients with nonmetastatic high-risk RCC. Nonprimary endpoints included objective radiographic tumor response rate, immune-related pathologic response rate, quality of life alterations, and metastasis-free and overall survival. In total, 17 patients were enrolled in this study and underwent surgery without a delay after receiving three every-2-wk doses of neoadjuvant nivolumab. Adverse events (AEs) of any grade occurred in 14 (82.4%) patients, with two (11.8%) experiencing grade 3 events. Ten (58.8%) patients experienced an AE of any grade potentially attributable to nivolumab (all grade 1-2), and no grade 4-5 AEs occurred regardless of treatment attribution. The most common AEs were grade 1 fatigue (41.2%), grade 1 pruritis (29.4%), and grade 1 rash (29.4%). All evaluable patients had stable disease as per established radiographic criteria, with one (6.7%) demonstrating features of an immune-related pathologic response. Quality of life remained stable during treatment, with improvements relative to baseline noted at ≥6 mo postoperatively. Metastasis-free survival and overall survival were 85.1% and 100% at 2 yr, respectively. PATIENT SUMMARY: In this study, we evaluated the safety and tolerability of preoperative administration of three doses of the immune checkpoint inhibitor nivolumab in patients with clinically localized high-risk renal cell carcinoma. We demonstrated the safety of this approach and found that, although most patients will not experience a radiographic response to treatment, a subset may have features of an immune-related pathologic response.

New and topics: enfortumab vedotin mechanisms of response and resistance in urothelial cancer - What do we understand so far?

Enfortumab vedotin (EV) was FDA approved in December 2019 for platinum- and checkpoint-refractory urothelial cancer based on an exceptional 44% response rate, and is currently approved for use after platinum and checkpoint inhibitor therapy. Enfortumab is an antibody-drug conjugate that targets Nectin-4, which is widely expressed in urothelial cancer. Despite this ample target, clinical benefit is not achieved by all patients, and mechanisms of treatment resistance are undescribed. Herein we summarize what is known to date regarding coorelative findings and subgroup analysis and EV response, including novel biopsy data in patients with tumor progression post EV.