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We present our institutional experience with 46 patients diagnosed with micropapillary bladder carcinoma compared to conventional urothelial carcinoma, alongside data from Surveillance, Epidemiology, and End Results (SEER)-Medicare. We identified comparable pathologic response to neoadjuvant chemotherapy (NAC) across histologic subtypes, while micropapillary bladder carcinoma was not independently associated with worse outcomes, despite presenting with more aggressive features. The role of NAC should be further evaluated with additional studies in this setting. BACKGROUND: Micropapillary urothelial carcinoma (MPC) is a rare urothelial carcinoma variant with conflicting data guiding clinical practice. In this study, we explored oncologic outcomes in relation to neoadjuvant chemotherapy (NAC) in a retrospective cohort of patients with MPC, alongside data from Surveillance, Epidemiology, and End Results (SEER)-Medicare. PATIENTS AND METHODS: We retrospectively identified patients with MPC or conventional urothelial carcinoma (CUC) without any variant histology undergoing radical cystectomy (RC) in our institution (2003-2018). SEER-Medicare was also queried to identify patients diagnosed with MPC (2004-2015). Clinicopathologic data and treatment modalities were extracted. Overall survival (OS) was estimated with the Kaplan-Meier method. Mann-Whitney-Wilcoxon and chi-square tests were used for comparative analysis and Cox regression for identifying clinical covariates associated with OS. RESULTS: Our institutional database yielded 46 patients with MPC and 457 with CUC. In SEER-Medicare, 183 patients with MPC were identified, and 63 (34%) underwent RC. In the institutional cohort, patients with MPC had significantly higher incidence of cN+ (17% vs. 8%), pN+ stage (30% vs. 17%), carcinoma-in-situ (43% vs. 25%), and lymphovascular invasion (30% vs. 16%) at RC versus those with CUC (all P < .05). Pathologic complete response (ypT0N0) to NAC was 33% for MPC and 35% for CUC (P = .899). Median OS was lower for institutional MPC versus CUC in univariate analysis (43.6 vs. 105.3 months, P = .006); however, MPC was not independently associated with OS in the multivariate model. Median OS was 25 months in the SEER MPC cohort for patients undergoing RC, while NAC was not associated with improved OS in that group. CONCLUSION: Pathologic response to NAC was not significantly different between MPC and CUC, while MPC histology was not an independent predictor of OS. Further studies are needed to better understand biological mechanisms behind its aggressive features as well as the role of NAC in this histology variant.

Background: While immune checkpoint inhibitors (ICIs) are approved in the first-line (1L) setting for cisplatin-unfit patients with programmed death-ligand 1 (PD-L1)-high tumors or for platinum (cisplatin/carboplatin)-unfit patients, response rates remain modest and outcomes vary with no clinically useful biomarkers (except for PD-L1). Objective: We aimed to develop a prognostic model for overall survival (OS) in patients receiving 1L ICIs for advanced urothelial cancer (aUC) in a multicenter cohort study. Design, setting, and participants: Patients treated with 1L ICIs for aUC across 24 institutions and five countries (in the USA and Europe) outside clinical trials were included in this study. Outcome measurements and statistical analysis: We used a stepwise, hypothesis-driven approach using clinician- selected covariates to develop a new risk score for patients receiving ICIs in the 1L setting. Demographics, clinicopathologic data, treatment patterns, and OS were collected uniformly. Univariate Cox regression was performed on 18 covariates hypothesized to be associated with OS based on published data. Variables were retained for multivariate analysis (MVA) if they correlated with OS (p < 0.2) and were included in the final model if p < 0.05 on MVA. Retained covariates were assigned points based on the beta coefficient to create a risk score. Stratified median OS and C- statistic were calculated. Results and limitations: Among 984 patients, 357 with a mean age of 71 yr were included in the analysis, 27% were female, 68% had pure UC, and 13% had upper tract UC. Eastern Cooperative Oncology Group performance status ≥2, albumin 5, and liver metastases were significant prognostic factors on MVA and were included in the risk score. C index for new 1L risk score was 0.68 (95% confidence interval 0.65-0.71). Limitations include retrospective nature and lack of external validation. Conclusions: We developed a new 1L ICI risk score for OS based on data from patients with aUC treated with ICIs in the USA and Europe outside of clinical trials. The score components highlight readily available factors related to tumor biology and treatment response. External validation is being pursued. Patient summary: With multiple new treatments under development and approved for advanced urothelial carcinoma, it can be difficult to identify the best treatment sequence for each patient. The risk score may help inform treatment discussions and estimate outcomes in patients treated with first-line immune checkpoint inhibitors, while it can also impact clinical trial design and endpoints. TAKE HOME MESSAGE: A new risk score was developed for advanced urothelial carcinoma treated with first- line immune checkpoint inhibitors. The score assigned Eastern Cooperative Oncology Group performance status ≥2, albumin 5, and liver metastases each one point, with a higher score being associated with worse overall survival.

Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance.In a phase 3 trial, we randomly assigned patients with unresectable locally advanced or metastatic urothelial cancer who did not have disease progression with first-line chemotherapy (four to six cycles of gemcitabine plus cisplatin or carboplatin) to receive best supportive care with or without maintenance avelumab. The primary end point was overall survival, assessed among all patients who underwent randomization (overall population) and among those with tumors positive for programmed cell death ligand 1 (PD-L1). Secondary end points included progression-free survival and safety.Among all 700 patients who underwent randomization, the addition of maintenance avelumab to best supportive care significantly prolonged overall survival as compared with best supportive care alone (control). Overall survival at 1 year was 71.3% in the avelumab group and 58.4% in the control group (median overall survival, 21.4 months vs. 14.3 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.86; P = 0.001). Avelumab also significantly prolonged overall survival in the PD-L1-positive population; overall survival at 1 year was 79.1% in the avelumab group and 60.4% in the control group (hazard ratio, 0.56; 95% CI, 0.40 to 0.79; P0.001). The median progression-free survival was 3.7 months in the avelumab group and 2.0 months in the control group in the overall population (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75) and 5.7 months and 2.1 months, respectively, in the PD-L1-positive population (hazard ratio, 0.56; 95% CI, 0.43 to 0.73). The incidence of adverse events from any cause was 98.0% in the avelumab group and 77.7% in the control group; the incidence of adverse events of grade 3 or higher was 47.4% and 25.2%, respectively.Maintenance avelumab plus best supportive care significantly prolonged overall survival, as compared with best supportive care alone, among patients with urothelial cancer who had disease that had not progressed with first-line chemotherapy. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Bladder 100 ClinicalTrials.gov number, NCT02603432.).

Background Infigratinib (BGJ398) is a potent, selective fibroblast growth factor receptor (FGFR) 1–3 inhibitor with significant activity in metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations. It can cause hyperphosphatemia due to the “on-target” class effect of FGFR1 inhibition. Objective To investigate the relationship between hyperphosphatemia and treatment response in patients with mUC. Intervention Oral infigratinib 125 mg/d for 21 d every 28 d. Design, setting, and participants Data from patients treated with infigratinib in a phase I trial with platinum-refractory mUC and activating FGFR3 alterations were retrospectively analyzed for clinical efficacy in relation to serum hyperphosphatemia. The relationship between plasma infigratinib concentration and phosphorous levels was also assessed. Outcome measurements and statistical analysis Clinical outcomes were compared in groups with/without hyperphosphatemia. Results and limitations Of the 67 patients enrolled, 48 (71.6%) had hyperphosphatemia on one or more laboratory tests. Findings in patients with versus without hyperphosphatemia were the following: overall response rate 33.3% (95% confidence interval [CI] 20.4–48.4) versus 5.3% (95% CI 0.1–26.0); disease control rate 75.0% (95% CI 60.4–86.4) versus 36.8% (95% CI 16.3–61.6). This trend was maintained in a 1-mo landmark analysis. Pharmacokinetic/pharmacodynamic analysis showed that serum phosphorus levels and physiologic infigratinib concentrations were correlated positively. Key limitations include retrospective design, lack of comparator, and limited sample size. Conclusions This is the first published study to suggest that hyperphosphatemia caused by FGFR inhibitors, such as infigratinib, can be a surrogate biomarker for treatment response. These findings are consistent with other reported observations and will need to be validated further in a larger prospective trial. Patient summary Targeted therapy is a new paradigm in treating bladder cancer. In a study using infigratinib, a drug that targets mutations in a gene called fibroblast growth factor receptor 3 (FGFR3), we found that elevated levels of phosphorous were associated with greater clinical benefit. In the future, these data may help inform treatment strategies.

Background: Immune checkpoint inhibitor (ICI) therapy predisposes patients to immune-related adverse events (irAEs). Data are limited regarding the incidence, management, and outcomes of one such irAE: mucositis. In this study, we evaluated the clinical characteristics, disease course, treatment, and outcomes of ICI-mediated mucositis. Methods: This was a retrospective, single-center study of patients who received ICI therapy and developed oral mucositis at The University of Texas MD Anderson Cancer Center from January 2009 to September 2019. Inclusion criteria included age ≥18 years, a diagnosis of oral mucositis and/or stomatitis based on ICD-9 and ICD-10 codes, and therapy using CTLA-4 or PD-1/L1 inhibitors alone or combined with other agents. Results: We identified 152 patients with a mean age of 60 years, 51% of whom were men. Of the sample patients, 73% had stage IV cancer, with melanoma the most common (28%). Median time from ICI initiation to mucositis was 91 days. The most common clinical presentation of mucositis was odynophagia and/or oral pain (89%), 91% developed CTCAE grade 1–2 mucositis, and 78% received anti–PD-1/L1 monotherapy. Compared with anti–PD-1/L1–based therapy, anti–CTLA-4–based therapy was more frequently associated with earlier onset of mucositis (73 vs 96 days; P=.077) and a lower rate of symptom resolution (76% vs 92%; P=.029); 24% of patients required immunosuppressive therapy, which was associated with longer symptom duration (84 vs 34 days; P=.002) and higher mucositis recurrence rate (61% vs 32%; P=.006). ICI interruption was associated with worse survival (P=.037). Mucositis recurrence, immunosuppressant use, and presence of other irAEs did not affect survival. Conclusions: For ICI-mediated mucositis, a diagnosis of exclusion has not been well recognized and is understudied. Although the clinical symptoms of mucositis are mostly mild, approximately 25% of patients require immunosuppression. Mucositis recurrence can occur in approximately 39% patients. Our results showed that ICI interruption compromises overall survival.

Immune-related adverse events (IRAEs) are becoming increasingly common as use of immune checkpoint inhibitors (ICIs) expands into more tumor types and treatment settings. Although the majority of IRAEs are mild and can be managed in the outpatient setting by the medical oncologist, severe IRAEs can be life-threatening and often require complex care coordination among multiple providers. These providers include a variety of non-oncology specialists who have interest and expertise in managing IRAEs. Multiple systems-based solutions have been proposed in the literature, but these need to be tailored to the needs and resources of each practice setting. In this article, we highlight the challenges of IRAE care by presenting an illustrative case from our institution. We then describe the format and structure of the IRAE Tumor Board established at the University of Washington/Seattle Cancer Care Alliance/Fred Hutchinson Cancer Research Center. Finally, we discuss how this tumor board attempts to address clinical issues related to complex IRAE presentations and provide IRAE education.

Objective To assess the effect of patient's sex on response to neoadjuvant chemotherapy (NAC) in patients with clinically nonmetastatic muscle-invasive bladder cancer (MIBC). Methods Complete pathologic response, defined as ypT0N0 at radical cystectomy, and downstaging were evaluated using sex-adjusted univariable and multivariable logistic regression modeling. We used interaction terms to account for age of menopause and smoking status. The association of sex with overall survival and cancer-specific survival was evaluated using Cox regression analyses. Results A total of 1,031 patients were included in the analysis, 227 (22%) of whom were female. Female patients had a higher rate of extravesical disease extension (P = 0.01). After the administration of NAC, ypT stage was equally distributed between sexes (P = 0.39). On multivariable logistic regression analyses, there was no difference between the sexes or age of menopause with regards to ypT0N0 rates or downstaging (all P > 0.5). On Cox regression analyses, sex was associated with neither overall survival (hazard ratio 1.04, 95% confidence interval 0.75–1.45, P = 0.81) nor cancer-specific survival (hazard ratio 1.06, 95% confidence interval 0.71–1.58, P = 0.77). Conclusion Our study generates the hypothesis that NAC equalizes the preoperative disparity in pathologic stage between males and females suggesting a possible differential response between sexes. This might be the explanation underlying the comparable survival outcomes between sexes despite females presenting with more advanced tumor stage.

Patients with cancer who developed severe, grade 3 or 4 immune-related adverse events (irAEs) during therapy with immune checkpoint inhibitors are at risk for developing severe toxicities again on rechallenge with checkpoint inhibitors. Consequently, medical oncologists and multidisciplinary teams are hesitant to retreat in this scenario, despite the fact that a number of patients may derive clinical benefit from this approach. Balancing such clinical benefit and treatment-related toxicities for each patient is becoming increasingly challenging as more and more patients with cancer are being treated with checkpoint inhibitors. In this manuscript, we provide an extensive overview of the relevant literature on retreatment after toxicity, and suggest prophylactic approaches to minimize the risk of severe irAE following rechallenge with immune checkpoint blockade, since treatment may be lifesaving in a number of occasions.

Durvalumab is a programmed death-ligand 1 (PD-L1) inhibitor with clinical activity in advanced urothelial cancer (AUC)1. AUC is characterized by several recurrent targetable genomic alterations2–5. This study ( NCT02546661 , BISCAY) combined durvalumab with relevant targeted therapies in biomarker-selected chemotherapy-refractory AUC populations including: (1) fibroblast growth factor receptor (FGFR) inhibitors in tumors with FGFR DNA alterations (FGFRm); (2) pharmacological inhibitor of the enzyme poly-ADP ribose polymerase (PARP) in tumors with and without DNA homologous recombination repair deficiency (HRRm); and (3) TORC1/2 inhibitors in tumors with DNA alteration to the mTOR/PI3K pathway3–5.This trial adopted a new, biomarker-driven, multiarm adaptive design. Safety, efficacy and relevant biomarkers were evaluated. Overall, 391 patients were screened of whom 135 were allocated to one of six study arms. Response rates (RRs) ranged 9–36% across the study arms, which did not meet efficacy criteria for further development. Overall survival (OS) and progression-free survival (PFS) were similar in the combination arms and durvalumab monotherapy arm. Biomarker analysis showed a correlation between circulating plasma-based DNA (ctDNA) and tissue for FGFRm. Sequential circulating tumor DNA analysis showed that changes to FGFRm correlated with clinical outcome. Our data support the clinical activity of FGFR inhibition and durvalumab monotherapy but do not show increased activity for any of the combinations. These findings question the targeted/immune therapy approach in AUC. The adaptive, biomarker-driven BISCAY trial evaluating durvalumab with targeted agents in patients with metastatic urothelial carcinoma based on tumor genomic alterations finds no added clinical benefit over durvalumab monotherapy.

Background DNA damage response (DDR) genomic alterations may play an important role in clinical outcomes of patients with urothelial cancer (UC). However, data on the prognostic role of DDR gene alterations in patients with advanced UC remain unclear. Materials and Methods We retrospectively collected data of three independent patient cohorts with relapsed or advanced UC including 81 and 91 patients from four institutions who underwent FoundationOne genomic sequencing as well as 129 patients selected from The Cancer Genome Atlas bladder cohort. Fisher's exact test was used to determine differences of mutation frequency among the three cohorts. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI. Results DDR genomic alterations were present in 76.5% (62/81), 40.7% (37/91), and 51.2% (66/129) of the three cohorts. ATM alterations consistently correlated with significantly shorter OS, whereas other DDR alterations (excluding ATM) were associated with better prognosis. In 152 patients treated with platinum pooled from the three cohorts, the prognostic value of alterations in ATM as compared with other predefined DDR genes was substantially different (ATM: adjusted HR [HR], 2.03; 95% CI, 1.03–4; p = .04; other DDR: adjusted HR, 0.49; 95% CI, 0.31–0.8; p = .003). Conclusions Genomic alterations in ATM and other DDR genes may have opposite prognostic value in relapsed and/or advanced UC. ATM may have a complex role in UC progression. Implications for Practice Somatic mutations of DNA damage response (DDR) genes are frequently found in urothelial cancer and appear to play an important role in tumorigenesis, progression, treatment response, and outcomes. In a set of DDR genes, ATM alterations were associated with worse survival, while other alterations were associated with better survival in advanced urothelial cancer. The results of this study suggest a complex role of ATM in tumor progression and call for further studies to determine the underlying mechanisms and biomarker clinical utility.

INTRODUCTION AND OBJECTIVE:Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is the standard and recommended treatment for clinical T2-T4aN0M0 bladder cancer. Howev...

INTRODUCTION AND OBJECTIVE:Binding of HLA-E to CD94/NKG2A expressed on NK and CD8 T cells is strongly associated with impaired anti-tumor immunity. We aimed to demonstrate that HLA-E expression is ...

At JADPRO Live 2019, Petros Grivas, MD, PhD, and Jeannette Hammond, PA-C, reviewed data regarding mechanistic activity, efficacy, and safety of approved and emerging therapies for advanced or metastatic urothelial carcinoma, the selection of appropriate lines of therapy, and strategies for managing adverse events.

Introduction There is no current standard of care for patients with high-risk muscle-invasive urothelial carcinoma (MIUC) after neoadjuvant chemotherapy and surgical resection or for those who cannot receive or decline cisplatin-based perioperative chemotherapy. Understanding current, real-world treatment patterns may help inform decisions from clinical, research, and population health management perspectives. We examined real-world treatment patterns, survival outcomes, and prognostic factors among Medicare beneficiaries with high-risk MIUC who did not receive adjuvant treatment after surgical resection. Methods We identified patients with high-risk MIUC in the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database who underwent surgical resection (radical cystectomy and/or radical nephroureterectomy). Eligible patients had indicators of high-risk MIUC and surgical resection between 2001 and 2013. Demographic and clinical characteristics, including comorbidities, American Joint Commission on Cancer (AJCC) stage, tumor stage/grade and nodal status, and distribution of neoadjuvant treatment by the year of surgical resection were evaluated. Overall survival (OS) and disease-free survival (DFS) were assessed for the full cohort and by subgroups using Kaplan-Meier survival analysis. Adjusted Cox proportional hazards models were used to evaluate patient demographics and clinical characteristics associated with OS and DFS. Results A total of 665 patients were included in the analysis, with a mean age of 75.5 years; most were men (61%) and had AJCC stage IIIA disease (69%). Neoadjuvant treatment increased over the entire study period, both overall (from 12% to 46%) and cisplatin based (from 5% to 38%). Median OS for the entire cohort was 23.1 months (95% confidence interval: 18, 27); median DFS was 13.5 months (95% confidence interval: 11.3, 16.8). AJCC stage IIIB/IVA was the most significant predictor of poor prognosis for both OS and DFS, followed by non-white race and comorbidity burden. Conclusion The prognosis for high-risk patients with MIUC remains poor, with significant risk of mortality within 2 years of radical cystectomy despite increasing use of neoadjuvant treatment. Unmet treatment needs persist for this difficult-to-treat patient population despite the increasing use of cisplatin-based neoadjuvant chemotherapy.

Background The clinical impact of addressing potential germline alterations from tumor-only next-generation sequencing (NGS) is not well characterized. Current guidelines for cancer genetic testing may miss clinically actionable germline changes, which may have important implications for cancer screening, treatment, and prevention. We examined whether increasing involvement of the clinical genetics service during somatic tumor-only NGS review at Molecular Tumor Board (MTB) increases the detection of germline findings. Methods In a retrospective evaluation of patients who underwent tumor-only NGS and were reviewed at MTB, we quantified genetic counseling (GC) referrals as well as germline testing uptake and results across three cohorts: before (C1) and after (C2) the addition of tumor-only NGS review and after (C3) instituting a formal process to coordinate NGS-based genetics referrals to preexisting oncology appointments. All statistical tests were two-sided. Results From 2013 to 2017, 907 tumor-only NGS reports were reviewed at MTB (nC1 = 281, nC2 = 493, nC3 = 133); gastrointestinal (22.5%), lung (19.7%), genitourinary (14.8%), and breast (14.1%) were the most common index cancers. GC visits due to MTB increased with each successive cohort (C1 = 1.1%, C2 = 6.9%, C3 = 13.5%; P for trend [Ptrend] < .001), as did germline testing (C1 = 0.7%, C2 = 3.2%, C3 = 11.3%; Ptrend < .001). Diagnosis of germline pathogenic variants increased with each successive cohort (C1 = 1.4%, C2 = 2.0%, C3 = 7.5%; Ptrend = .003) and with germline pathogenic variants found by MTB review (C1 = 0.4%, C2 = 0.4%, C3 = 2.3%; Ptrend = .12). Conclusions Both review of tumor-only NGS by genetics and the institution of a process coordinating GC with oncology appointments increased the discovery of germline pathogenic variants from tumor-only NGS testing. Furthermore, this process identified germline pathogenic variant carriers who would not have otherwise met standard criteria for germline testing.

Patients with cancer and with preexisting active autoimmune diseases (ADs) have been excluded from immunotherapy clinical trials because of concerns for high susceptibility to the development of severe adverse events resulting from exacerbation of their preexisting ADs. However, a growing body of evidence indicates that immune-checkpoint inhibitors (ICIs) may be safe and effective in this patient population. However, baseline corticosteroids and other nonselective immunosuppressants appear to negatively impact drug efficacy, whereas retrospective and case report data suggest that use of specific immunosuppressants may not have the same consequences. Therefore, we propose here a two-step strategy. First, to lower the risk of compromising ICI efficacy before their initiation, nonselective immunosuppressants could be replaced by specific selective immunosuppressant drugs following a short rotation phase. Subsequently, combining ICI with the selective immunosuppressant could prevent exacerbation of the AD. For the most common active ADs encountered in the context of cancer, we propose specific algorithms to optimize ICI therapy. These preventive strategies go beyond current practices and recommendations, and should be practiced in ICI-specialized clinics, as these require multidisciplinary teams with extensive knowledge in the field of clinical immunology and oncology. In addition, we challenge the exclusion from ICI therapy for patients with cancer and active ADs and propose the implementation of an international registry to study such novel strategies in a prospective fashion.

PURPOSE Neuroendocrine (NE)-like carcinoma is a newly recognized molecular subtype of conventional urothelial carcinoma of the bladder with transcriptomic profiles and clinical outcomes highly similar to histological NE carcinoma. The identification of NE-like tumors is challenging, as these tumors often appear histologically like urothelial carcinoma and can be missed by routine morphological criteria. We previously developed a single-sample classifier to identify NE-like tumors, which we aimed to validate in an independent cohort. MATERIALS AND METHODS A single-sample genomic classifier was performed on transurethral specimens from a retrospective multicenter cohort of 234 patients who underwent cisplatin-based neoadjuvant chemotherapy and subsequent radical cystectomy. Outcomes were compared for NE-like vs. non-NE-like. RESULTS We identified 10 patients with urothelial tumors of the NE-like subtype, all of which had robust gene expression of neuronal markers, but did not express markers associated with basal or luminal tumors. The cancer-specific mortality rates were significantly higher compared to non-NE-like tumors (P < 0.001), with 5 of the 10 patients dying within 12 months from surgery. CONCLUSIONS The single-sample classifier was able to identify urothelial carcinomas with NE-like subtype. These NE-like tumors have demonstrated transcriptomic profiles and clinical behavior similar to histological NE tumors across multiple patient cohorts. We propose that NE-like tumors should be managed similarly to histological NE tumors, and that standard treatments for small cell lung cancer as well as novel strategies may be evaluated in these patients.

Background: Characterization of the different genomic alterations (GAs) in urothelial carcinoma (UC), by site of origin, may identify contrasting therapeutic opportunities and inform distinct putative pathogenetic mechanisms. Objective: To describe the genomic landscape of UC based on the anatomic site of the primary tumor. Design, setting, and participants: In total, 479 upper tract UC (UTUC) and 1984 bladder UC (BUC) patients underwent comprehensive genomic profiling (CGP) to evaluate all classes of GAs, tumor mutational burden (TMB), and microsatellite instability (MSI) status. Targetable GAs and signatures were assessed according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT). Intervention: Hybrid-capture–based CGP. Outcome measurements and statistical analysis: Descriptive analyses and differences between anatomic subgroups were reported. Results and limitations: In total, 39% of patients with UC harbored one or more tier 1–2 GAs, suggesting potential benefit from approved or investigational therapies. UTUC cases were enriched in FGFR3 short variant (SV) GA (20% vs 13%) and HRAS SV GA (7.3% vs 3%), the latter attributed specifically to enrichment in renal pelvis UC (9.5%) versus ureteral UC (1.8%, p = 0.002). RB1 GAs were more frequent in BUC than in UTUC (21% vs 7.8% p < 0.001). Non-FGFR3 kinase fusions were observed in 1% of patients, including BRAF/RAF1 fusions in 0.5%. BRAF mutations/fusions were observed in 2% of cases and were mutually exclusive with FGFR3 GA (p = 0.002). There were no differences of TMB high/MSI high for primary tumor and metastatic sites, but UTUC was enriched for MSI high (3.4%) relative to BUC (0.8%, p < 0.001). Conclusions: Differences in the genomic landscapes of UTUC and BUC were modest; however, patients with UTUC were enriched for FGFR3 and HRAS SV relative to BUC. Further investigation on UC, stratified by the site of origin, is warranted. In addition, these results suggest an opportunity for the routine incorporation of CGP prior to systemic therapy initiation in metastatic UC. Patient summary: Genomic profiling of advanced urothelial carcinoma can inform several therapeutic opportunities for patients, particularly those with upper tract urothelial carcinoma, an infrequent and generally aggressive tumor entity with nonoverlapping clinical features compared with its bladder counterpart, which is often treated based on the data extrapolated from bladder cancer.

Advanced urothelial carcinoma (UC) is a very important cause of cancer-related morbidity and mortality with, until recently, only a few available therapeutic options. The treatment landscape has dramatically changed in recent years with the introduction of immune checkpoint inhibitors and the development of novel targeted agents, such as erdafitinib, and antibody-drug conjugates, such as enfortumab vedotin. Cost-effective utilization of this rapidly expanding therapeutic armamentarium can be further optimized via the identification and validation of reliable prognostic and predictive biomarkers that inform prognostication and patient selection. In this review, we aim to summarize examples of recent developments in the rapidly expanding field of emerging biomarkers in UC, outlining challenges and opportunities.

TPS582 Background: Treatment options are limited for pts with LA unresectable or mUC who progress after prior PLT-based and CPI therapies. SG is an antibody-drug conjugate (ADC) composed of an anti-trophopblast cell surface antigen 2 (Trop-2) antibody coupled to SN-38 (a topoisomerase-I inhibitor) via a proprietary hydrolyzable linker. In the phase 2 registrational study TROPHY-U-01 (NCT03547973), SG demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.9 months in pts with mUC who progressed after prior PLT-based and CPI therapies (n = 113; median, 3 prior lines of therapy; 84% with ≥1 Bellmunt risk factors; Tagawa et al, J Clin Oncol. 2021). These results compared favorably with historic data for single-agent chemotherapy (ORR, ̃18%; OS, 9 months; Powles et al. J Clin Oncol. 2021) and led to accelerated approval of SG by the US Food and Drug Administration for pts with LA or mUC who previously received a PLT-containing chemotherapy and CPI. The phase 3 TROPiCS-04 trial has been initiated to confirm these findings. Methods: TROPiCS-04 (NCT04527991) is a global, multicenter, open-label, randomized, controlled trial in pts with LA unresectable or mUC who progressed after prior PLT-based and CPI therapies. Key eligibility requirements include Eastern Cooperative Oncology Group performance status 0-1; no prior CPI or ADC therapy within 4 weeks of study drug initiation; no history of active interstitial lung disease or noninfectious pneumonitis; and adequate hematologic, hepatic, and renal function. Pts will be randomly assigned 1:1 to receive SG 10 mg/kg intravenously (IV) on days 1 and 8 of 21-day cycles or single-agent treatment of physician’s choice (paclitaxel 175 mg/m2, docetaxel 75 mg/m2, or vinflunine 320 mg/m2 IV on day 1 of 21-day cycles) until progressive disease, unacceptable toxicity, or withdrawal of consent. Treatment beyond progressive disease may be permitted in pts deemed to be receiving clinical benefit per investigator assessment. Approximately 600 pts will be enrolled across ̃280 sites in 3 regions (North America, Europe, and Asia-Pacific) to provide 90% power on the primary endpoint of OS. Secondary endpoints include progression-free survival, ORR, clinical benefit rate, duration of response (all per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review and investigator assessment), safety, and quality of life. Study enrollment started in January 2021 and is ongoing with pts currently enrolled at 30 sites across all 3 regions. Clinical trial information: NCT04527991.

[No Abstract Available], Merck Sharp Dohme Corp.; Eisai Inc., Woodcliff Lake, NJ, USA, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and Eisai Inc., Woodcliff Lake, NJ, USA.

511 Background: PD(L)1 inhibitors can achieve durable responses in aUC but only in a minority of patients (pts). Combination strategies with agents that “prime and stimulate” the immune system may improve outcomes. CV301 comprises 2 recombinant poxviruses, Modified Vaccinia Ankara (MVA) and Fowlpox (FPV), encoding the human transgenes for CEA, MUC-1, and a Triad of Co-stimulatory Molecules (TRICOM: ICAM-1, LFA-3, and B7-1). MVA-CV301 is used for priming and FPV-CV301 is used for booster doses. Preliminarily, BN-platform vaccine plus PD-(L)1 inhibitors exhibited synergistic preclinical anti-tumor efficacy and the combination of CV301 and anti-PD-(L)1 agent demonstrated an acceptable safety profile. We hypothesized that this combination would be safe and effective in cisplatin-ineligible or platinum-refractory pts with aUC. Methods: A Phase 2, single-arm multicenter trial was designed to study CV301 + atezo as 1st-line treatment in pts with aUC ineligible for cisplatin-based chemotherapy regardless of PD-L1 status (Cohort 1; C1) and in pts progressing on/after platinum-based chemotherapy (Cohort 2; C2). MVA-CV301 was given subcutaneously (SC) on Days 1 and 22 and FPV-CV301 SC from day 43 every 21 days for 4 doses, then every 6 weeks until 6 months, then every 12 weeks until 2 years. Atezo 1200mg IV was given every 21 days. Primary endpoint: objective response rate (ORR). Secondary endpoints: OS, PFS, response duration, AEs and antigen-specific T-cell responses to CEA and MUC-1 by ELISPOT. Using 1-sided α 2.5%/cohort, a 2-stage design with 14/19 and 13/22 stage 1/2 subjects, respectively, will achieve ≥70% power if the true ORR for C1 is 43% and C2 is 33%. 3 C1 and 2 C2 responders were required in stage 1 to move forward. Results: 43 evaluable pts were enrolled and received therapy: 19 in C1; 24 in C 2. Overall, 9 pts experienced ≥ Grade 3 AEs related to the combination of treatment: 5 in C1, and 4 in C2. In C1, 1 pt had partial response (PR), for ORR 5.3% (90%CI: 0.3, 22.6) and 5 (26.3%, 90%CI: 11.0, 47.6) had stable disease (SD) as best response. In C2, 1pt had CR and 1 had PR, for ORR 8.3% (90%CI: 1.5, 24.0) and 3 (12.5%, 90%CI: 3.5, 29.2) had SD as best response. Median PFS and OS in C1 were 2.0 mo and 13.8 mo, and in C2 1.95 and 8.13 mo, respectively. The trial was halted for futility. Responding pts in C2 exhibited T-cell responses to CEA and pts with SD exhibited responses to MUC-1. Conclusions: CV301 + atezo exhibited an acceptable safety profile but did not demonstrate sufficient efficacy in pts with aUC as 1st-line therapy in cisplatin-ineligible pts or in the platinum-refractory setting. The development of effective vaccines to generate robust and durable responses as single agents and/or combined with anti-PD(L)1 remains an unmet need in aUC. Clinical trial information: NCT03628716.

TPS585 Background: Trilaciclib is an intravenous (IV) CDK4/6 inhibitor that has been shown to help protect hematopoietic stem and progenitor cells from chemotherapy (CT)-induced damage (myeloprotection) via transient cell cycle arrest. Trilaciclib is approved in the US to decrease the incidence of CT-induced myelosuppression (CIM) in adult patients with extensive-stage small cell lung cancer receiving certain treatment regimens. An exploratory phase 2 study (NCT02978716) in patients with triple-negative breast cancer showed improved overall survival (OS) in patients receiving trilaciclib prior to CT vs CT alone, regardless of PD-L1 expression. The aim of this exploratory, randomized, open-label, multicenter, phase 2 trial (PRESERVE 3; NCT04887831) is to assess whether trilaciclib administered with standard-of-care platinum-based CT and avelumab maintenance can improve antitumor efficacy and reduce CIM versus CT and avelumab without trilaciclib, in patients with locally advanced or metastatic urothelial carcinoma (mUC). Methods: Adult patients with measurable disease per RECIST v1.1, no prior systemic treatment for mUC, and ECOG performance status ≤2 will be randomized 1:1 to receive gemcitabine 1000 mg/m2 plus cisplatin 70 mg/m2 or carboplatin area under the curve 4.5 (± trilaciclib 240 mg/m2 IV over 30 minutes, ≤4 hours prior to CT) in 21-day cycles. Patients will receive 4–6 cycles of CT. Those without progressive disease per RECIST v1.1 can receive avelumab 800 mg maintenance therapy (± trilaciclib) in 14-day cycles until disease progression, unacceptable toxicity, investigator/patient decision, or end of trial. Patients will be followed for survival. The sample size was calculated to support the primary endpoint of progression-free survival (PFS), using a stratified log-rank test accounting for two stratification factors (visceral metastasis and platinum agent [cisplatin/carboplatin]). 63 PFS events will be required to achieve 77% power to detect a hazard ratio of 0.6 with a 2-sided significance of 0.2, corresponding to a median PFS of 11.7 months for the trilaciclib arm. Assuming a 10-month enrollment period, final PFS analysis approximately 22 months after the first randomization, and 5% loss to follow-up, 90 patients are required for randomization. PFS will be analyzed in the intention-to-treat population. Secondary endpoints include objective response rate, disease control rate, PFS during maintenance, OS, multilineage myeloprotective effects, and safety/tolerability. Exploratory endpoints will assess pharmacodynamic parameters, including those related to immune-based mechanisms, and efficacy by CDK4/6-dependence. Enrollment opened in June 2021. As of September 29, 2021, 8 sites are open, and 1 patient randomized. Clinical trial information: NCT04887831.

516 Background: Pembro showed antitumor activity in 1L and 2L for pts with UC in the single-arm, phase 2 KEYNOTE-052 study (NCT02335424) and the randomized phase 3 KEYNOTE-045 (NCT02256436) study, respectively. This post hoc exploratory analysis evaluated whether primary tumor location affected efficacy and safety of pembro (KEYNOTE-052; KEYNOTE-045) and chemotherapy (chemo; KEYNOTE-045). Methods: KEYNOTE-052 enrolled cisplatin-ineligible pts with advanced/metastatic UC who had not previously received systemic therapy; they received pembro (200 mg IV Q3W). KEYNOTE-045 enrolled pts with advanced/metastatic UC who had received platinum-containing chemo; pts were randomly assigned 1:1 to receive pembro (200 mg IV Q3W) or investigator’s choice of chemo (paclitaxel, docetaxel, or vinflunine). Both studies required pts to have measurable disease per RECIST v1.1. Upper tract (UT) UC included primary tumors in the renal pelvis or ureter; lower tract (LT) UC included primary tumors in the bladder or urethra. Pts with UT and LT disease (UT/LT) were classified as LT. Pts receiving pembro were treated until disease progression, unacceptable toxicity, or withdrawal of consent, for up to 2y. End points were PFS, ORR, and DOR per RECIST v1.1 by central radiology assessment and OS. Results: A total of 369 pembro-treated pts (68 UT; 301 LT [79 UT/LT]) from KEYNOTE-052 plus 270 pembro-treated pts (93 UT; 177 LT [33 UT/LT]) and 272 chemo-treated pts (94 UT; 178 LT) from KEYNOTE-045 were evaluated. Median follow-up from randomization to data cutoff (09/26/20 and 10/1/20, respectively) was ≥56 mo. Both studies enrolled a similar percentage of pts with PD-L1–positive tumors (25%-30%). PFS, ORR, DOR, and OS for pembro were consistent regardless of tumor location, although ORR for KEYNOTE-045 was lower for the UT group (Table). In the chemo arm of KEYNOTE-045, similar efficacy was observed regardless of tumor location or regimen. Grade 3-5 TRAEs occurred at similar rates in KEYNOTE-052 (19.1% UT; 21.6% LT) and KEYNOTE-045 (17.2% UT; 16.8% LT). Conclusions: In this exploratory analysis, pembro showed similar clinical activity and manageable safety regardless of primary UC tumor location. Clinical trial information: NCT02256436 and NCT02335424. [Table: see text]

553 Background: UCS is a common entity and usually managed similarly to pure UC but requires focused study. Limited data are available on the genomic profile of UCS. We hypothesized that UCS would have a distinct genomic landscape compared to UC. Methods: In this IRB-approved retrospective study, pts) with advanced UCS and UC undergoing tumor based comprehensive genomic profiling from a CLIA-certified laboratory were included. An independent genitourinary pathologist reviewed all cases. Pts were determined to have UCS based on presence of any component of squamous differentiation. Pts with UC having any other secondary histology variant were excluded. Genes with alterations (GA) in less than 5% of pts and variants of unknown significance were excluded from the analysis. test was used to compare gene aberration frequency and the p-values were adjusted for false using Benjamini-Hochberg (BH) correction. Results: 87 pts were eligible and included. UCS (n=31) vs UC (n=56): median age, 66 vs 68 years; male vs female: 21/10 vs 48/8Genomic aberrations in both groups are listed in the. GA in KMT2D was found to be significantly enriched in UCS vs UC (15/31 vs 0/56, FDR

TPS580 Background: Radical surgery is the mainstay of treatment for muscle-invasive upper tract urothelial cancer (UTUC) and urothelial bladder cancer (UBC). However, even when surgery is combined with cisplatin‐based (neo)adjuvant chemotherapy, recurrence rates are high. Many patients (pts) are ineligible for, do not respond to, or refuse cisplatin-based chemotherapy because of toxicity concerns. Fibroblast growth factor receptor 3 ( FGFR3) genetic alterations occur in 21–38% of muscle-invasive UTUC, and in approx. 20% of invasive UBC. Infigratinib (BGJ398) is an ATP-competitive FGFR1–3 selective oral tyrosine kinase inhibitor that has clinical activity and tolerability in pts with advanced/metastatic urothelial carcinoma (UC) harboring susceptible FGFR3 alterations. PROOF 302 was designed to investigate the efficacy and safety of adjuvant infigratinib in pts with high-risk, muscle-invasive UC (85% UTUC) and susceptible FGFR3 alterations. Methods: PROOF 302 is a global, multicenter, randomized, double-blind, placebo-controlled, phase 3 trial (NCT04197986). Eligible pts have high-risk, muscle-invasive UTUC (85%) or UBC (15%) with susceptible FGFR3 alterations (mutations, gene fusions or rearrangements) confirmed by FoundationOne CDx test, and are ≤120 days following nephroureterectomy, distal ureterectomy, or cystectomy. The study protocol was amended to include pts with carcinoma in situ at surgical margins and those who refuse cisplatin-based chemotherapy (in addition to pts allowed to enroll if ineligible for perioperative cisplatin-based chemotherapy). Eligible pts are M0 and have either disease stage ≥ypT2 and/or yN+ after cisplatin-based neoadjuvant chemotherapy or ≥pT2 pN0–2 or pN+ (UTUC); and ≥pT3 or pN+ (UBC) if not treated with cisplatin-based neoadjuvant chemotherapy. Pts are randomized 1:1 to receive oral infigratinib 125 mg or placebo QD on days 1–21 of a 28-day cycle for up to 52 weeks (13 cycles) or until recurrence, unacceptable toxicity, or death. Primary endpoint: centrally reviewed disease-free survival (DFS) analyzed via stratified log-rank test and Cox model (hazard ratio). Secondary endpoints: investigator-reviewed DFS, metastasis-free survival, overall survival, safety/tolerability. Exploratory endpoints: quality of life, pharmacokinetics, determination of the prevalence of genomic alterations and correlation with features of UC, genomic and proteomic assessment of tumor tissue and cell-free DNA samples from baseline and at recurrence to identify the predictive/prognostic value of biomarkers. PROOF 302 is actively enrolling as of Sep 2021. A second Data Monitoring Committee meeting is planned for Dec 2021. The last pt is expected to complete treatment in 2024. Clinical trial information: NCT04197986.

505 Background: Current standard therapy for most pts with aUC is first-line (1L) platinum-based chemotherapy followed by ICI maintenance (or 2L if progression). Shorter time on 1L or between therapy lines may be a surrogate of more aggressive disease and poor outcome, but its prognostic role in ICI response is unclear. We hypothesized that shorter time until start of 2L ICI would be associated with worse outcomes in aUC. Methods: We performed a retrospective multi-institution cohort study in pts with aUC treated with 1L platinum-based chemotherapy, who later received 2L ICI. Pts receiving maintenance ICI were excluded. We calculated the time from start of 1L platinum chemotherapy to start of 2L ICI, dichotomizing the exposure into ≤6 months and >6 months. We compared overall response rate (ORR) to 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI between the two populations. ORR was compared among groups using multivariable logistic regression and PFS, OS using cox regression. Analysis was adjusted for calculated Bellmunt score. Results: From a total of 1283 pts, 462 received 1L platinum chemotherapy; among those, 350 received 2L ICI. After exclusions, 270, 269 and 260 pts were included in the ORR, PFS and OS analyses, respectively. Median age was 70 years, 78% men, 75% White, 74% with pure urothelial histology, 21% upper tract, 60% received cisplatin in 1L. Pts with time to 2L ICI ≤6 months had significantly higher Bellmunt scores (32% vs 22% score=2, 9% vs 3% score=3). ORR and PFS were comparable between pts with ≤ and >6 months to 2L ICI. However, OS was significantly longer for pts with >6 months to 2L ICI (median [m]OS 13 vs 7 months, p=0.002), (Table). Conclusions: Among pts with aUC treated with 2L ICI, time to 2L ICI ≤6 months from 1L platinum based chemotherapy was associated with similar ORR and PFS but shorter OS. Limitations include retrospective nature, patient selection, confounding factors. More studies are needed on the impact of platinum resistance in pts with aUC treated with ICIs.[Table: see text]

TPS5099 Background: Approximately 30% of patients (pts) treated with definitive surgical and/or radiation therapy for localized prostate adenocarcinoma develop biochemical recurrence (BCR). The optimal time to initiate androgen deprivation therapy (ADT) for such patients is controversial and depends on patient and provider preference, absolute PSA value, and PSA doubling time (PSADT), which has been associated with time to metastasis. Because the time from BCR to metastasis can be long in many cases, strategies allowing pts to avoid ADT while extending metastasis-free survival are desirable. Prior studies have shown that a high tumor neoantigen load correlates with response to anti-PD(L)1. We hypothesized that PARP inhibitor-induced genomic instability may sensitize tumors to anti-PD(L)1 through: i) increasing mutational burden and subsequent tumor neoantigen formation, and/or ii) through activation of other immunogenic pathways (e.g. the STING pathway). This trial investigates an ADT-sparing approach for men predicted to have high neoantigen load and who have BCR prostate cancer. Methods: This is a phase 2 clinical trial testing durvalumab (1500 mg IV every 4 weeks) and olaparib (300 mg PO twice a day) (one cycle = 4 weeks) in men with BCR (PSADT≤10 months) whose tumors are predicted to have high neoantigen load based on: biallelic CDK12 mutations (Cohort A), mismatch repair deficiency (MMRd)/high microsatellite instability (MSI-H) (Cohort B), or loss of function mutations in homologous recombination repair (HRR) genes (Cohort C). Cohorts A and B will receive 3 cycles of durvalumab followed by 3 cycles of the combination of durvalumab and olaparib. Given the proven efficacy of olaparib in prostate cancer patient whose tumors posses an HRR gene mutation, Cohort C will receive 6 full cycles of the combination. Ten patients will be enrolled in each cohort (total n = 30) at two collaborating sites. This study was designed to provide preliminary efficacy data across eligible cohorts, with a primary objective of estimating the proportion of pts with an undetectable PSA at 12 months within each cohort. Secondary objectives include safety, proportion of patients with ≥50% decline in PSA from baseline and quality of life measures. Correlative studies will assess blood and tissue molecular biomarkers for association with outcomes. The study is open with two patients enrolled at the time of abstract submission. Clinical trial information: NCT04336943.

479 Background: Commonly utilized risk stratification tools demonstrate inconsistent associations with salient clinical outcomes in bladder cancer leading to a disproportionate reliance on providers’ subjective impression of a patient’s fitness for therapy. Current guidelines advocate for use of a CGA to quantify vulnerabilities in older ( > 65 years) patients before treatment selection. Our objective was to prospectively evaluate CGA in our Bladder Cancer Multidisciplinary Clinic (BCMC). We hypothesized that CGA implementation would be feasible and that discussion of the results during shared decision-making would be associated with reduced patient-reported decisional conflict. Methods: Patients seen in BCMC were prospectively enrolled from 6/1/20 to 7/20/21. In the first 3 months, participants underwent non-standardized risk stratification (“Routine cohort”, N = 27). Between 9/1/20 and 7/20/21, participants completed a CGA incorporating validated assessments of frailty, functional status, multimorbidity, nutrition, cognition, and mental health (“CGA cohort”, N = 67). Results were shared with patients during BCMC visits. All patients and providers (three physicians per clinic from: Uro-Oncology, Medical Oncology, and Radiation Oncology) completed a follow-up survey including the Decisional Conflict Scale (DCS). Time required to complete the CGA, completion rates, and patient-reported burden were assessed. Concordance of patient- and provider-reported decisional conflict was compared between Routine and CGA cohorts. Results: Of 138 eligible patients, 94 patients were successfully enrolled (68%) with median age of 72 years, ECOG PS ≥3 in 13%, and Charlson Comorbidity Index ≥3 in 18%, of whom 18% were women. Most patients had pT2 bladder cancer (87%; cN+ and M1 in 23.4% and 9.6%, respectively). CGA component completion rates were 79-100%. Survey response rates were high (patients: 77%, providers: 86%), and most (86%) patients felt that the CGA was, at most, minimally burdensome. Vulnerabilities detected across CGA domains triggered relevant referrals. Patient-reported median (IQR) DCS scores were numerically higher (e.g. greater decisional conflict) for the CGA cohort: (27 [14-33] vs 16 [2-30] for Routine patients, p = 0.28). Provider- and provider reported DCS score was correlated in the CGA (p = 0.04), but not the Routine cohort (p = 0.07). Conclusions: We prospectively evaluated use of CGAs in bladder cancer care and found that CGAs were successfully implemented with high rates of completion and low rates of perceived burden. Notably, in this pilot cohort of 94 patients, DCS scores did not differ significantly between patients and providers with CGA use. Future work will evaluate associations between individual instruments, treatment decisions, clinical outcomes and patient-reported quality of life measures.

512 Background: Pembrolizumab (pembro) has shown efficacy in advanced/unresectable and metastatic UC (mUC). There is interest in determining whether pts should be treated subsequently with checkpoint inhibitors such as anti–PD-1 therapy if mUC responds then later progresses. Pembro retreatment after disease progression has shown efficacy in melanoma and NSCLC. This post hoc exploratory analysis investigated the efficacy of pembro retreatment for pts with advanced UC or mUC enrolled in KEYNOTE-045 and KEYNOTE-052 with a best overall response (BOR) of SD or better and whose disease progressed after discontinuation or completion of 2 y of therapy. Methods: The phase 3 KEYNOTE-045 trial (NCT02256436) was designed to compare the efficacy and safety of pembro vs chemotherapy (chemo) in pts with mUC that recurred/progressed on platinum containing chemo; ≤2 prior lines of systemic chemo for mUC were permitted. The phase 2 KEYNOTE-052 trial (NCT02335424) was designed to evaluate the efficacy and safety of first-line pembro in cisplatin-ineligible pts with advanced UC. In both studies, pembro was administered for up to 2 y; pts were eligible for retreatment if they stopped pembro after CR or had a BOR of CR, PR, or SD and completed 2 y of treatment. Pts must have investigator-confirmed radiographic PD after therapy cessation, have ECOG PS score 0-1, and not have received anticancer treatment after the last pembro dose. BOR to retreatment is reported. Results: At data cutoff for KEYNOTE-045 (Oct 1, 2020), 11 pts were retreated: 5 (45%) achieved objective response to retreatment (3 CR; 2 PR; Table) and 6 had SD, for a disease control rate (DCR; CR+PR+SD) of 100%. Median treatment-free interval was 7.7 mo (IQR, 3.6-16.5); median duration of retreatment was 11.4 mo (IQR, 7.6-12.0). Seven pts (64%) were alive at cutoff. At data cutoff for KEYNOTE-052 (Sep 26, 2020), 10 pts were retreated; 5 (50%) had objective response to retreatment (1 CR; 4 PR) and 4 had SD, for a DCR of 90%. Retreatment BOR was PD for 1 pt (10%). Median treatment-free interval was 13.0 mo (9.2-16.6); median duration of retreatment was 6.0 mo (IQR, 4.9-9.2). Four pts (40%) were alive at cutoff. Conclusions: Although the number of pts who received retreatment was small, objective responses were observed. The findings are generally consistent with observations from retreatment in other tumor types (e.g., melanoma). Clinical trial information: NCT02256436 and NCT02335424. [Table: see text]

TPS581 Background: Cis-based combination chemotherapy regimens with gemcitabine or methotrexate, vinblastine, and doxorubicin are commonly used as initial treatment for mUC. However, only a fraction of pts maintain a durable response. Alternative Cis-based combinations with improved efficacy while maintaining tolerability are needed. SG is an antibody-drug conjugate (ADC) composed of an anti-trophoblast cell-surface antigen-2 (Trop-2) antibody coupled to SN-38 (a topoisomerase-I inhibitor) via a proprietary hydrolyzable linker. In vitro/in vivo urinary bladder cancer models suggest that the combination of SG and Cis resulted in additive antitumor activity over either agent alone (data on file). In the phase 2 registrational TROPHY-U-01 study, SG monotherapy resulted in a 27% objective response rate (ORR) and a median overall survival (OS) of 10.9 months with a manageable, mostly non–Cis-overlapping toxicity profile in heavily pretreated pts with mUC (Tagawa et al, J Clin Oncol. 2021). These results led to accelerated approval of SG by the FDA in 2021 for pts with locally advanced or mUC who previously received PLT-containing chemotherapy and a checkpoint inhibitor. We hypothesized that SG and Cis in combination may improve efficacy/safety over available first-line mUC regimens. TROPHY-U-01 Cohort 4 study will evaluate the safety, tolerability, and clinical activity of this novel combination. Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, global phase 2 trial. Cohort 4 will evaluate combination SG and Cis in PLT-naive pts with mUC or unresectable locally advanced disease. Key eligibility requirements include Eastern Cooperative Oncology Group performance status 0–1; no prior anticancer monoclonal antibody or ADC therapy within 4 weeks of study drug initiation; no history of active interstitial lung disease or noninfectious pneumonitis; adequate hematologic, hepatic, and renal function. Pts will be treated with Cis at 70 mg/m2 on day 1 of a 21-day cycle (if creatinine clearance [CrCl] ≥60 mL/min) or at a split dose of Cis at 35 mg/m2 on days 1 and 8 of a 21-day cycle (if CrCl 50-59 mL/min) followed by SG (5, 7.5, or 10 mg/kg) on days 1 and 8 of a 21-day cycle. The recommended phase 2 dose will be the dose in which ≤30% dose-limiting toxicities are noted in cycle 1. Combination therapy will continue for up to 6 cycles, followed by SG and avelumab maintenance given until progression. Prophylactic granulocyte colony-stimulating factor is not allowed in cycle 1 of the safety lead-in phase. Primary endpoint is ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints include progression-free survival, duration of response, and clinical benefit rate per BICR and investigator assessment. OS and safety will be assessed. Enrollment is ongoing; ̃60 pts expected across ̃30 sites in North America and Europe. Clinical trial information: NCT03547973.

164 Background: Novel treatments for clinically advanced GUca including castrate resistant prostate ca (PC), bladder urothelial ca (BUC) and clear cell renal ca (ccRCC) are widely needed. Recently, the targeting of cancer cells with arginine accumulation caused by MTAP loss has emerged as a new synthetic lethality-based anti-cancer program. Methods: 8,436 mCRPC, 2,683 BUC and 841 ccRCC underwent hybrid-capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. PD-L1 tumor cell expression was determined by IHC (Dako 22C3). Results: 1.3% of PC, 24.2% of BUC and 5.5% of ccRCC featured MTAP loss. There were no significant age or gender differences associated with MTAP loss. CDKN2A/B loss ranged from 94% in ccRCC to > 99% in PC and BUC. The GA/tumor frequencies were similar when CDKN2A/B GA are excluded. In PC, GA in TP53, PTEN and BRCA1 were more frequent, while GA in AR, CDK12, RB1 and BRCA2 were less frequent in cases with MTAP loss. In BUC, GA in TSC1 and FGFR3 were more frequent and GA in RB1and TP53 were less frequent in cases with MTAP loss. In ccRCC, GA in NF2 were more frequent in cases with MTAP loss, while GA in VHL and PBRM1 were less frequent in cases with MTAP loss. “Targetable” kinase GA were rare in all groups, except for FGFR3 GA in MTAP loss BUC. Immunotherapy (IO) putative biomarkers varied among tumors, with MSI-high status less frequent and TMB ≥ 10 mut/Mb more frequent in BUC MTAP-intact than BUC with MTAP loss. PD-L1 expression was similar except for high PD-L1 expression more frequent in MTAP-intact BUC. Conclusions: When compared with PC and ccRCC, the clinical development of novel drugs, such as PRMT5 and MTA2 inhibitors in GUca will likely be focused on BUC given the 24% frequency of MTAP loss in that tumor type. CGP of PC, BUC and ccRCC reveal significant differences in GA in MTAP-intact and tumors with MTAP loss, which may impact future combinatorial clinical trial designs.[Table: see text]

476 Background: Low skeletal muscle index (SMI) is associated with an increased risk of mortality in muscle-invasive bladder cancer (MIBC) and chemotherapy-related adverse events (AE) across numerous other malignancies. Small case series suggest neoadjuvant chemotherapy (NAC) is associated with a significant decline in SMI in patients with MIBC. However, limited data exists regarding changes in fat mass during NAC. Herein, we examine changes in SMI, visceral fat index (VFI), and subcutaneous fat index (SFI) in patients receiving NAC for MIBC before radical cystectomy (RC). We describe associations between body composition changes and NAC-associated AE and all-cause mortality (ACM) in patients with MIBC. Methods: Retrospective review of patients with MIBC (≥pT2 N0/x/1 M0) who received NAC (2006-2019). Patients with digitized abdominal computed tomography scans (CT) within 75 days prior (T1) and 75 days following completion (T2) of NAC were included. We segmented and calculated the indices (cm2/m2) for SMI, VFI, and SFI at the third lumbar vertebra level at T1 and T2 using validated methodology. Associations with AE during NAC and ACM were evaluated with multivariate logistic regression and Cox proportional hazards models. Results: Included 170 patients, median age 63 years receiving a median of 4 (IQR 3-5) cycles of Gemcitabine/Cisplatin (52%), MVAC (28%), or other NAC (20%). Absolute and relative changes in SMI, VFI, and SFI over a median of 112 days (IQR 94-146) between measurements are presented in the Table. 117 (69%) patients experienced grade ≥3 chemotherapy-related AE. No associations between baseline body composition or change in body composition during NAC with chemotherapy-related AE. T1 SMI (HR: 0.98; 0.97-0.99, p = 0.008), as well as T2 SMI (HR: 0.98; 0.96-0.99, p = 0.003), T2 VFI (HR: 0.99; 0.99-1.0, p = 0.05) and T2 SFI (HR: 0.99; 0.98-1.0, P = 0.03) were associated with ACM after adjusting for age, clinical T and N stage, and performance status. Conclusions: Patients undergoing NAC prior to RC experienced a 6.4% decrease in SMI and a 5.2% decrease in VFI during an average of 112 days. Chemotherapy-related AE were not associated with a change in body composition. Baseline SMI and T2 SMI, SFI, and VFI were associated with ACM on multivariable analysis. Future work is needed to understand the mechanisms underpinning such changes and the extent to which potentially detrimental changes in body composition may be mitigated before surgery.[Table: see text]

521 Background: First-line treatment with pembrolizumab (pembro) monotherapy has shown durable clinical activity in selected patients (pts) with advanced/unresectable or metastatic urothelial carcinoma (UC). In a pooled population of pts with advanced UC from the single-arm phase 2 KEYNOTE-052 (NCT02335424) and the randomized, open-label, phase 3 KEYNOTE-361 (NCT02853305) studies, this exploratory analysis evaluated the relationship between baseline characteristics and clinical outcomes of first-line pembro monotherapy. Methods: Cisplatin-ineligible pts with advanced UC were enrolled in KEYNOTE-052 and chemotherapy-naive pts with advanced UC were enrolled in KEYNOTE-361. For analysis of predictive factors for ORR and OS in pembro-treated pts, the purposeful selection method was used to build the multivariable logistic regression model (ORR) and multivariable Cox model (OS), beginning with a univariable analysis of each independent variable. Any variable in the univariate model with P < 0.10 was a candidate for the multivariate model. The stepwise selection method was used to select the variables in the final model. Significance of the final model was set at P < 0.05. Data cutoff dates were September 26, 2020 (KEYNOTE-052) and April 29, 2020 (KEYNOTE-361). Results: This pooled analysis included 681 pts treated with pembro monotherapy (KEYNOTE-052, N = 374; KEYNOTE-361, N = 307 [170 were cisplatin ineligible]). Median follow-up was 51.9 mo (range, 22.0-65.3). ORR was 29.4% (95% CI, 26.0-32.9; 69 CRs, 131 PRs), and median DOR was 33.2 mo (range, 1.4+ to 60.7+). Median OS was 12.5 mo (95% CI, 11.0-14.6). By multivariate analysis, independent factors significantly associated with higher ORR were PD-L1 status (combined positive score [CPS] ≥10 vs CPS < 10; odds ratio [OR], 1.90 [95% CI, 1.33-2.71]; P = 0.0004), site of metastasis (lymph node only vs visceral disease; OR, 1.66 [95% CI, 1.06-2.59]; P = 0.0265), liver involvement (absent vs present; OR, 1.75 [95% CI, 1.06-2.89]; P = 0.0294), and baseline hemoglobin level ≥10 vs < 10 g/dL; OR, 2.17 [95% CI, 1.09-4.31]; P = 0.0276). Multivariate analysis of OS is displayed in the Table. Conclusions: This exploratory multivariate analysis identified numerous factors, including PD-L1–positive status (CPS ≥10), lymph node only metastasis, and lower ECOG PS score, associated with improved clinical outcomes in pts with advanced UC treated with first-line pembro monotherapy. Clinical trial information: NCT02335424 and NCT02853305. [Table: see text]

532 Background: It is not known whether serial circulating tumor DNA (ctDNA) can augment imaging for assessing treatment response in patients (pts.) with advanced urothelial carcinoma (UC). We hypothesized that serial ctDNA measurements predict the clinical progression of advanced UC and map its evolutionary trajectories. Methods: We analyzed 182 serial ctDNA samples from 53 pts. with advanced UC sequenced by the Guardant360 ctDNA platform. The aggregate variant allele frequency (aVAF) was defined as the sum of VAFs of all genomic alterations (GAs) in a ctDNA sample. Clinical response status was categorized into progressive disease (PD) and non-PD based on imaging. Progression-free survival (PFS) was defined as the time from treatment start till PD or death. The Mann-Whitney test was used to compare radiologic response status (PD vs. non-PD) and the ctDNA aVAF collected within 4 weeks of restaging imaging. Results: Pts. with lower initial ctDNA aVAF (≤0.2) had longer overall survival (OS) (hazard ratio (HR): 0.31, 95%CI: 0.11-0.90, p = 0.03). Pts. who achieved clearance of their ctDNA aVAF at the time of any subsequent ctDNA sample (n = 19/53) had longer OS (HR: 0.26, 95%CI: 0.08-0.85, adjusted p = 0.027). Combining ctDNA aVAF values from two consecutive samples improved the performance of a clinical prognostic model based on age, sex, and liver metastasis (C-statistic improved from 0.65 to 0.84). The mean ctDNA aVAF and the median number of GAs per ctDNA sample significantly increased at the time of PD vs. non-PD (12.31 vs. 2.10, p < 0.0001, and 3 vs. 1, p = 0.0006, respectively). Delta ctDNA aVAF increases predicted radiologic PD with an area under the receiver operating characteristic curve of 0.84 (95%CI: 0.65-0.95, p < 00.1). Delta ctDNA aVAF improved the patient risk stratification, pts with both decreased delta ctDNA aVAF and non-PD had the longest overall survival (Log-rank p = 0.05). A subgroup of 20 pts. had increasing ctDNA aVAF and ≥ 1 available subsequent radiologic scans within six months. Increasing ctDNA VAF ≥1 predicted PD in 90% (18/20) of pts with a median lead time of 92 days over imaging. APOBEC3-induced mutations (A3-m) were identified in ctDNA samples of (23%) 12/53 pts. Pts. with ctDNA A3-m had longer median PFS on immune checkpoint blockade than pts. without (17 vs. 3 months, Log-rank p = 0.01). There was no significant difference in OS according to ctDNA A3m status (Log-rank p = 0.37). Serial ctDNA provided insights into the clonal dynamics of treatment resistance, including the acquisition of ERBB2 S653C resistance mutation at the time of PD on lapatinib. Conclusions: Serial ctDNA predicts clinical outcomes and provides real-time assessment of treatment effectiveness in pts. with advanced UC. This has the potential to guide future adaptive therapy paradigms.

TPS596 Background: Radical cystectomy (RC) without neoadjuvant chemotherapy remains SOC for cis-ineligible pts (and those refusing cis) with MIBC and T1-T4aN1 disease. Yet, many pts progress to incurable, metastatic disease. Preventing disease recurrence for these pts remains an unmet need. Immune checkpoint inhibitors (ICIs) are approved in Bacillus Calmette-Guérin-unresponsive carcinoma in situ, in the adjuvant and metastatic urothelial cancer (UC) settings, and are being actively explored in the perioperative setting. In phase 2 single-arm trials, neoadjuvant ICIs showed promising pathologic complete response (pCR) rates (approximately 30%–40%). The phase 3 CheckMate 274 study showed improved disease-free survival with adjuvant NIVO vs placebo in MIBC. BEMPEG, an immunostimulatory interleukin-2 (IL-2) cytokine prodrug, is engineered to deliver a controlled, sustained, and preferential signal to the clinically validated IL-2 pathway. Preferential binding of BEMPEG to the IL-2 heterodimeric receptor (IL-2Rβγ) activates and expands CD8+ T cells and natural killer cells over immunosuppressive regulatory T cells. The combination of BEMPEG + NIVO demonstrated deep responses and a tolerable safety profile in pts with metastatic UC in the phase 1/2 PIVOT-02 trial and is being further explored in the phase 2 PIVOT-10 (NCT03785925) study. The PIVOT IO 009 study, presented here, aims to evaluate the hypothesis that perioperative treatment with BEMPEG + NIVO will provide higher pCR and longer event-free survival (EFS) vs SOC in cis-ineligible pts with MIBC and T1-T4aN1 disease. Methods: PIVOT IO 009 (NCT04209114) is an open-label, phase 3 trial of 540 cis-ineligible pts with MIBC and T1-4aN1 disease, who will be randomized 1:1:1 to receive SOC, neoadjuvant and adjuvant BEMPEG + NIVO, or neoadjuvant and adjuvant NIVO alone. Stratification factors include clinical stage (T2N0 vs T3-T4aN0 vs T1-T4aN1) and tumor cell PD-L1 status. Key inclusion criteria: adults with MIBC and T1-T4aN1 disease deemed eligible for RC and ECOG PS 0–1. Cis-ineligibility is defined as one of the following: glomerular filtration rate ≥30 but < 60 mL/min, or ≥grade 2 hearing loss or peripheral neuropathy. Key exclusion criteria: clinical evidence of ≥N2 or metastatic disease or UC in the upper urinary tract; prior systemic therapy, radiation therapy, or prior surgery for bladder cancer other than TURBT or biopsies. Primary endpoints: pCR rate (pT0N0) of neoadjuvant BEMPEG + NIVO vs no neoadjuvant therapy (SOC), and EFS of neoadjuvant and adjuvant BEMPEG + NIVO vs SOC. Secondary endpoints: pCR rate of neoadjuvant NIVO vs SOC; EFS of neoadjuvant and adjuvant NIVO vs SOC; overall survival and safety in each treatment arm vs SOC. The study is currently recruiting pts. Clinical trial information: NCT04209114.

563 Background: Immunohistochemistry (IHC) to determine PD-L1 expression level has been proposed a companion assay related to the approval of immune checkpoint inhibitors in UBC. We hypothesized that the GA profiles would differ between UBC featuring high vs negative PD-L1 expression. Methods: 102 cases of advanced UBC with known PD-L1 expression underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Tumor cell (TC) PD-L1 expression was determined by IHC (Dako 22C3). Only PD-L1 high (H) (≥50% TC expression) and negative (N) (0% TC expression) cases were included with PD-L1 Low (1-49% TC expression) cases excluded from this study. Results: Overall, only 2 (8.3%) of the 24 PD-L1H UBC featured CD274 ( PD-L1) amplification (mean 19 copies) and none of 78 PD-L1N had CD274 amp (P =.05). The gender, age was similar in the groups. When compared with the PD-L1H UBC cases, FGFR3 GA were significantly more frequent in the UBC PD-L1N cases (p =.02). Currently “untargetable” GA that were more frequent in the PD-L1H UBC, but did not reach statistical significance, included TP53, TERT and RB1. MTAP loss, a potential target for PRMT5 and MTA2 inhibitors, were 3X more frequent in the PD-L1N UBC. ERBB2 amplification and ERBB3 and PIK3CA short variant (SV) GA were more frequent in the PD-L1N UBC with differences not reaching significance. Other ICPI-associated potential biomarkers, including MSI status, TMB level and GA in PBRM1, STK11 and MDM2 were not significantly different in the groups. For UBC cases where a mutational signature could be determined, 10/12 (83%) of PD-L1H and 21/29 (72%) of PD-L1N UBC featured APOBEC signature; 2 PD-L1N featured MMR signature and 6 PD-L1N UBC featured no dominant signature. Conclusions: PD-L1H and PD-L1N subtypes of UBC differ in their genomic profiles:PD-L1N UBC features greater frequencies of potentially “targetable” GA, including FGFR3, ERBB2, ERBB3 and PIK3CA. PD-L1 IHC may thus not only play a role in the selection of ICPI for advanced UBC but also in designing trials that may combine ICPI with targeted therapies. Limitations include small sample size, possible selection bias and lack of clinical annotation.[Table: see text]

487 Background: The phase 3 JAVELIN Bladder 100 trial (NCT02603432) showed significantly longer overall survival (OS) with avelumab + best supportive care (BSC) vs BSC alone in patients (pts) with advanced UC that had not progressed with 1L platinum-containing chemotherapy. Avelumab 1L maintenance is now considered standard of care in treatment guidelines. We report trial data with ≥2-years follow-up in all pts (additional 19 months from the initial analysis). Methods: Pts with unresectable locally advanced or metastatic UC without disease progression with 4-6 cycles of 1L gemcitabine + cisplatin or carboplatin were randomized 1:1 to receive avelumab + BSC or BSC alone. The primary endpoint was OS, assessed from randomization in all pts and in pts with PD-L1+ tumors (Ventana SP263 assay). Secondary endpoints included progression-free survival (PFS) and safety. Results: 700 pts were randomized (350 per arm); 358 (51.1%) had PD-L1+ tumors. With extended follow-up (median, ≥38 months in both arms for all pts; data cutoff, June 4, 2021), OS remained significantly longer in the avelumab + BSC vs BSC alone arm in all randomized pts and in pts with PD-L1+ tumors (Table). An OS benefit was observed across prespecified subgroups. PFS (by investigator) was longer with avelumab + BSC vs BSC alone in all randomized pts and in pts with PD-L1+ tumors (Table). In the avelumab + BSC and BSC alone arms, respectively, 185 (52.9%) vs 252 (72.0%) pts received a subsequent anticancer drug therapy, including a PD-(L)1 inhibitor in 40 (11.4%) vs 186 (53.1%) pts. Long-term safety was consistent with previous avelumab monotherapy studies, with no new safety signals. Conclusions: Long-term follow-up from the JAVELIN Bladder 100 trial continues to show prolonged OS with avelumab + BSC vs BSC alone. These results further support the standard-of-care role for avelumab as 1L maintenance in pts with advanced UC that has not progressed with 1L platinum-containing chemotherapy. Clinical trial information: NCT02603432. [Table: see text]

TPS578 Background: The randomized phase 3 JAVELIN Bladder 100 trial demonstrated overall and progression-free survival (OS and PFS) benefit with Ave 1LM for la/mUC not progressed with platinum-containing chemotherapy (PCT). PATRIOT II aims to understand real-world treatment (tx) patterns, patient-reported outcomes (PRO), and healthcare resource utilization (HCRU; eg, hospitalizations and emergency department visits) before and during Ave 1LM treatment. Methods: PATRIOT II is an ongoing, real-world, observational study in ≤25 US oncology centers with 1) an ambispective cohort of patients (pts) initiating PCT (n = 100), a subset of whom may continue to Ave 1LM and 2) a retrospective cohort initiated on Ave 1LM (n = 150). Sample size assumes noninferiority in HCRU and PRO pre and post 1LM initiation using paired t-tests with effect size of ≤0.3 as noninferior: ≥71 patients continuing to 1LM. In the ambispective cohort, pts with histologically confirmed la/mUC newly initiating 1L PCT are enrolled. While pts are receiving PCT and 1LM (for those who receive it), data will be collected on disease characteristics, response to tx, survival, adverse events (AEs), and HCRU for ≤52 wks after study initiation. PROs are captured using Rand SF-36 question 1, FACT Bladder Symptom Inventory – 18 and Cancer Treatment Satisfaction Questionnaire. Primary outcomes include OS and PFS from both PCT and 1LM initiation; secondary outcomes are changes in PROs and HCRU from PCT to 1LM. Analysis will be conducted at following time points: 1) baseline characteristics after full enrollment; 2) 6 months after study initiation to assess tx changes and rationale, OS, PFS, HCRU, and PRO changes from baseline; 3) at study conclusion (wk 52 after study initiation). In the retrospective cohort, pts with la/mUC who initiated Ave 1LM are enrolled. Chart data encompasses PCT and 1LM periods. Disease characteristics, response to tx, survival, AEs, and HCRU are collected. Primary outcomes are OS and PFS from initiation of PCT and 1LM start. Secondary outcomes are changes in HCRU before and after 1LM. Analysis will be conducted at following time points: 1) baseline characteristics after full enrollment, PCT, and response to tx; 2) 6 months after study initiation to assess tx changes since baseline, including dose changes, tx discontinuation/change rationale, survival rates (censoring for differential duration of follow-up), and HCRU outcomes; 3) at study conclusion to analyze endpoints up to wk 52 following study initiation. Analyses for both cohorts include Kaplan-Meier and Cox regression for time-to-event endpoints and paired t-tests for pre/post 1LM. Enrollment commenced in June 2021. 5 and 18 pts are enrolled to date in the ambispective and retrospective cohorts, respectively, from 6 of 11 activated sites. Initial results are anticipated in May 2022.

292 Background: FLCN is a tumor suppressor gene associated with cutaneous hair follicle development. FLCN germline mutations are linked to inherited chrRCC in the Birt-Hogg-Dube (BHD) syndrome. We queried whether clinically sporadic chrRCC featured FLCN mutations by comparing the genomic profiles of chrRCC with ccRCC. Methods: 108 chrRCC and 2110 ccRCC underwent hybrid-capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: Patients (pts) with chrRCC were more frequently female and younger than pts with ccRCC p

The treatments for metastatic urothelial carcinoma (mUC) have advanced substantially since 2016. Prognostic tools have been used to inform clinical trial designs and treatment decisions. Historically, prognostic tools were developed for mUC based on older clinical trials involving cytotoxic chemotherapy. As novel therapies emerged, there are studies investigating prognostic factors in the era of immune checkpoint inhibitors (ICI), antibody-drug conjugates, and targeted therapies. This review aims to highlight prognostic factors in mUC and their potential in clinical decision-making and research. In the setting of chemotherapy, patient performance status, site of metastatic burden, and specific laboratory findings were found to have prognostic value in mUC. In the era of ICI, newer models identified variables such as neutrophil to lymphocyte ratio, platelet count, and lactate dehydrogenase to also have potential prognostic value. In addition to clinical biomarkers, molecular biomarkers, such as PD-L1 assay and fibroblast growth factor receptor 2 and 3 genomic testings, may have promising prognostic and predictive implications. Current methods of identifying clinical and molecular prognostic factors involve clinician insight. As large complex datasets emerge, machine learning and artificial intelligence may help data analysis and detect important prognostic features. With careful validation, such machine learning-based strategies may help create more robust prognostic and/or predictive models in the future.

Purpose Precision oncology is widely discussed, but cohort studies are limited. We previously reported our prospective experience of precision oncology in solid tumors, and here we report our longitudinal experience, focusing on therapeutic impact. Patients and Methods We conducted a retrospective review of 600 consecutive patients seen at Cleveland Clinic from 2013 to 2016 for treatment of incurable solid tumor malignancies for whom tumor genomic profiling was ordered using FoundationOne (Cambridge, MA). Results were discussed at our multidisciplinary genomics tumor board. Data analyzed included subsequent therapy and overall survival (OS). Results Median age was 59 years (range, 18 to 94 years), 308 (51.3%) were female, and 533 (88.8%) were white. Targeted therapy was recommended in 310 patients (51.7%). After results, 313 patients (52.2%) started any subsequent therapy; of these, 95 (30%; 15.8% overall) received genomics-driven therapy (G), and 218 (70%) received non–genomics-driven treatment (NG). For the G versus NG group, the on-label, off-label, and clinical trial therapy breakdowns were 23% versus 88%, 47% versus 3%, and 30% versus 9%, respectively. Median OS for patients receiving no therapy after tumor genomic profiling was 5.5 months; for the G and NG groups, it was 18 ( P < .001) and 14.4 ( P < .001) months, respectively ( P = NS for G v NG). The use of G increased from 10% in the first 250-patient cohort (reported earlier) to 20% in the subsequent 350-patient cohort. Conclusion Tumor genomic profiling influenced treatment in 15.8% of patients. More patients received treatment via clinical trials in the G cohort, and although not statistically significant, there was a trend toward increased OS in the G ( v NG) group. These data can further guide real-world applications of precision oncology.

Introduction: Treatment delay among patients with muscle invasive bladder cancer is associated with reduced survival. With limited existing literature examining institutional causes of treatment delay, we identified such causes of delay to radical cystectomy among patients with high risk bladder cancer.Methods: We conducted a retrospective review of 176 patients with bladder cancer who underwent radical cystectomy at our tertiary referral center in 2013 to 2014. Process mapping was used to define each step in the path to cystectomy and the time interval between each step was quantified. Patients experiencing treatment delay (more than 90 days to cystectomy or chemotherapy initiation) were identified and the causes of delay examined.Results: Median time from diagnosis to referral was 17 days (IQR 9–36). Following referral the urology and medical oncology evaluations occurred at a median of 5 (IQR 2–9) and 6 days (IQR 1–9), respectively. Median time from urological evaluation to transurethral resect...

Myeloid-derived suppressor cells (MDSC) have immunosuppressive activity and enhance tumor progression. We hypothesized that lower blood MDSC would correlate with pathologic complete response and better outcomes in nonmetastatic urothelial carcinoma (UC).Before cystectomy, blood MDSC were measured in whole blood (WB) and peripheral blood mononuclear cells using flow cytometry. MDSC were defined as CD33Overall, 109 patients were included: 86% men with median (range) age of 67 (30-88) years, 76% with pure UC, 29% intravesical therapy, and 41% neoadjuvant chemotherapy. Twenty-one patients (19%) had pT0N0 and 23 (24%) pT2N0. Median (range) follow-up time was 17.4 (0.4-42.4) months. Total MDSC and polymorphonuclear MDSC percentage in peripheral blood mononuclear cells was significantly lower in patients with pT0N0 disease (P = .03). One- and 2-year OS rates were 94% (95% confidence interval [CI], 90-99) and 83% (95% CI, 75-93), respectively. In the multivariate Cox model after adjusting for age and gender, patients with higher WB M-MDSC and UnC-MDSC had shorter OS (optimal cutoff points by recursive partitioning analysis, hazard ratio = 7.5 [95% CI, 2.5-22.8], P = .0004; hazard ratio = 3.4 [95% CI, 1.0-11.0], P = .046, respectively).In patients with nonmetastatic UC of bladder, higher WB M-MDSC and UnC-MDSC before cystectomy had negative prognostic value. Prospective validation is warranted.