Urothelial Cancer Pts Research Articles

Analyzing disparities in socioeconomic factors, clinical characteristics, and outcomes in bladder cancer: Insights from the National Cancer Database (NCDB).

4572 Background: Social determinants of health can influence mortality in bladder cancer. We sought to understand the trends and survival differences for urothelial cancer (UC) and non-urothelial cancer (nUC) based on demographic, socioeconomic, clinical, and treatment from the NCDB. Methods: Using the NCDB database with patient-level data extraction from 2004 to 2020, we sought to identify the socioeconomic differences, clinical characteristics and examine survival trends for both UC and nUC bladder cancer. Results: Majority of UC patients (pts) were M (555107, 75.6%) and 178733 were F; nUC pts had 14296 M and 8835 F, median age was 72 years. 669,669 (or 91.3%) of UC pts were White (W), 5.4% (39444) were Black (B) and nUC pts had 19771 (85.5%) W and 2492 (10.8%) B. 41.2% of UC pts were treated at a Comprehensive Community Cancer Program (CCCP) followed by 28.3% at an academic/research program (ARP) with 20.7% at an integrated network cancer program (INCP) compared to nUC pts at 37.5%, 34.3% and 19.2%, respectively. Most UC pts (65.6%) had Medicare followed by 26.9% with private insurance and 3.2% with Medicaid. Distribution of stage at diagnosis for UC pts were: Stage 0 at 36.9%, Stage I at 16.3%, Stage II & III at 11.8% and Stage IV at 3.6%. While most (51.74%) of F UC pts had stage I, only 12.81% of F nUC had stage I. Majority had Charlson-Deyo Score (CDS) of 0 at 512237 (69.8%). Median Overall survival (mOS) in UC for M was 89.26 months (mos) (CI 88.8-89.76) and for F it was 94.88 mos (CI 93.83-95.93), Log-rank p=0.0011; worse for B = 73.03 mos (CI 71.03 – 74.84) vs W = 90.38 mos (CI 89.95-90.81), Log-rank p<0.0001; mOS was highest for ARP at 96.46 mos (CI 95.54-97.45); CDS of 0 at 108.29 mos (CI 107.66-108.85); private insurance at 185.79 mos (CI 183.98-188.16); mOS for nUC was better for M at 15.64 (CI, 15.05 -16.28) vs F at 12.68 (CI, 12.02, 13.31), Log-rank p<0.001. mOS for metastatic involvement for bone: UC: 5.03 (CI, 4.8, 5.39) vs nUC: 5.42 (4.4, 6.34), Log-rank p=0.2007; brain: U: 3.61 (CI 2.99, 4.3) vs nUC: 5.06 (2.5, 7.13); Log-rank p=0.5765; lung: U: 5.09 (CI, 4.76, 5.39) vs nUC: 4.8 (3.68, 5.78); Log-rank p=0.2163; liver: U: 3.32 (CI,3.06, 3.61) vs nUC: 5.42 (CI, 4.11, 6.44); Log-rank p=0.0009; LN: U: 7.1 (CI, 6.6, 7.56) vs nUC: 6.34 (5.36, 6.9); Logrank p=0.0007; Treatment using surgery, radiation, chemotherapy and immunotherapy all showed improvement in U vs nUC (all Log-rank p<0.0001). Conclusions: Women had better survival than men in UC but not in nUC. Factors including lower stages, Whites, private insurance, better CDS scores, treatment at academic/research facility, and lymph node metastases all showed improved survival. These data highlight the importance of bridging the gap between socioeconomic differences to improve outcomes for UC and nUC pts.

9MW2821, a nectin-4 antibody-drug conjugate (ADC), in patients with advanced solid tumor: Results from a phase 1/2a study.

3013 Background: 9MW2821 is a monoclonal ADC that delivers monomethyl auristatin E to cells expressing Nectin-4. Nectin-4 is an adhesion molecule that highly expressed in variety of solid tumors, especially urothelial cancer (UC), cervical cancer (CC), esophageal cancer (EC) and breast cancer. Here we report the updated safety and efficacy data of 9MW2821. Methods: 9MW2821 was administered by intravenous infusion at doses of 0.33-1.5mg/kg on days 1, 8 and 15 of each 28-day cycle. The study included dose escalation, dose expansion and cohort expansion period which included UC, CC, EC, triple negative breast cancer (TNBC) and other Nectin-4 positive solid tumors that progressed after ≥1 systemic treatments (Tx). Primary objectives were assessment of safety and preliminary efficacy. Results: As of Jan 15, 2024, 260 patients (pts) were enrolled with doses ranging from 0.33 to 1.5mg/kg. Only 1 out of 6 pts in 1.5mg/kg group had dose limiting toxicity (grade 4 neutropenia lasted more than 5 days). The maximum tolerated dose was not reached up to 1.5mg/kg and the RP2D was selected as 1.25mg/kg for tolerance. 240 pts were enrolled at dose of 1.25mg/kg. The most common TRAEs of 1.25mg/kg dose group (≥20%, all grade/≥5%, ≥G3) were white blood cell (WBC) count decreased (50.8%, 23.3%), neutrophil count decreased (46.3%, 27.9%), anemia (43.8%, 8.3%), aspartate aminotransferase increased (42.1%, 2.9%), alanine aminotransferase increased (35.4%, 2.1%), asthenia (32.1%, 2.9%), rash (30.0%, 5.0%), decreased appetite (28.8%, 1.3%), nausea (26.7%, 0%), hyperglycemia (25.4%, 2.1%), platelet count decreased (24.2%, 4.6%), alopecia (24.2%, 0%), hypoaesthesia (22.5%, 1.7%), constipation (21.3%, 0%), vomiting (20.9%, 1.3%), hypertriglyceridemia (20.4%, 2.1%), gamma-glutamyltransferase increased (15.8%, 5.4%). Among 190 pts treated with 9MW2821 at 1.25mg/kg or above and reached tumor assessment, objective response rate (ORR) and disease control rate (DCR) was 35.3% and 78.4%, respectively. 37 UC pts, 45 CC pts, 27 EC pts and 16 TNBC pts were enrolled at 1.25mg/kg and evaluable for tumor assessment. Median prior lines of Tx were 2 (range, 1-4). All UC, 51% CC and 93% EC pts progressed after platinum-based chemotherapy and immune checkpoint inhibitors, respectively. Objective responses were also observed in pts with other solid tumor types. Conclusions: The data indicated encouraging efficacy of 9MW2821 in advanced UC, CC, EC and TNBC. 9MW2821 is the first Nectin-4 targeting ADC showed antitumor activity in patients with CC, EC and TNBC. The safety profile showed adequate tolerability. Clinical trial information: NCT05216965 . [Table: see text]

COVID-19 vaccines in patients with urothelial cancers receiving immune checkpoint inhibitors.

491 Background: COVID-19 vaccination recommendations for cancer patients (pts) are similar to the general population. The interaction between checkpoint inhibitors (CPI) and Sars-COV-2 vaccines has been understudied. One potential complication in pts receiving CPI is the occurrence of immune-mediated adverse events (irAEs) resulting from overactivation of the immune system. This retrospective study examined the incidence of severe irAEs in pts with bladder urothelial cancer (UC) treated with CPI therapy who received concurrent vaccinations against Sars-CoV-2. Methods: Following IRB approval, UC pts who received any approved CPI treatment since FDA authorization of the first COVID-19 vaccine in December 2020 were identified via institutional electronic health record. Pts who received 1 or more doses of an authorized vaccine within 60 days of CPI treatment were included. The primary endpoint was to evaluate the incidence of severe irAE (defined as one or more of the following: grade 3 AE or above, multi-system involvement, need for hospitalization). Secondary endpoints included time between CPI and vaccination, need for immunosuppressive therapy, and rate of discontinuation. Data was analyzed using descriptive statistics. Results: Forty pts were included in our analysis with a median age of 72.5 years (IQR: 66.0-79.2); 82% pts were male. At the time of vaccination, 37 pts (92.5%) received CPI monotherapy, 2 pts (5.0%) received combination (combo) CPI therapy, and 1 pt (2.5%) received combo platinum-based chemotherapy and CPI. The vaccine manufacturer was Pfizer Bio-N-Tech in 22 pts (55.0%), Moderna in 17 pts (42.5%), and Johnson and Johnson in 1 pt (2.5%). Number of vaccinations received was >/= 3 in 27 pts, 2 in 11 pts, and 1 in 2 pts. Six pts (15.0%) experienced severe irAEs following vaccination, including nephritis, colitis, pneumonitis, DKA, and infusion-related reaction. Rates of severe irAEs were 16.2% (6/37) with CPI monotherapy, no severe irAEs occurred in the combo CPI and combo CPI-chemo groups. Severe irAEs occurred after the first vaccine dose in 1 pt (16.7%), second dose in 3 pts (50.0%), and third dose in 2 pts (33.3%) pts. The median time between CPI treatment and vaccination in this group was 22.0 days (IQR: 15.8-36.5. Hospitalization was required for all 6 patients (100%). Three pts (50.0%) required immunosuppressive therapy with a median therapy duration of 64.0 days (IQR 47.0-83.5). Five pts (83.3%) discontinued CPI therapy following severe irAEs. Conclusions: In this retrospective study, we observed a 15% rate severe irAE in UC pts receiving CPI concurrently with COVID-19 vaccines. Further investigation in pts with additional cancer types is warranted to help determine best practice guidelines for COVID-19 vaccination in cancer patients receiving CPI. NCI University of Colorado Cancer Center Support Grant 5P30CA046934-30, Health Data Compass Data Warehouse project (healthdatacompass.org).

Abstract 1273: Predicting pathological response after ipilimumab plus nivolumab in stage III urothelial cancer by liquid-biopsy assessment of plasma and urine ctDNA using the RaDaR assay

Abstract Patients (pts) with stage III (cT3-4aN0M0 or cT1-4aN1-3M0) urothelial cancer (UC) have a poor prognosis. In NABUCCO cohort 1, 24 stage III UC pts were treated with ipilimumab (ipi) plus nivolumab (nivo) followed by radical surgery (day 1: ipi 3 mg/kg; day 22: ipi 3 mg/kg + nivo 1 mg/kg; day 43: nivo 3 mg/kg). 14/24 (58%) of pts showed a pathological response (ypT0N0 or ypTisN0/ypTaN0). Currently, there are no good biomarkers to assess response before surgery, potentially leading to overtreatment and unnecessary surgical complications. Here, we investigated whether detection of circulating tumor DNA (ctDNA) in plasma and urine by the RaDaR™ personalized liquid biopsy assay was associated with treatment response and outcomes. EDTA-plasma and urine supernatant were collected before start of treatment (day 1; “baseline”), before each subsequent treatment cycle (day 22 and 43) and before radical surgery. WES was performed on tumor FFPE and peripheral blood germline DNA to identify somatic variants for designing patient-specific, multiplex PCR-based NGS RaDaR™ panels. Plasma and urine ctDNA was analyzed using these panels to determine ctDNA detection and its estimated variant allele frequency (eVAF). Tissue somatic variants were detected in all patients, a median of 48 variants was used per RaDaR™ panel (range: 43-51). ctDNA was detected in 50/94 plasma samples (53%) and in 74/93 urine samples (80%). Detection levels were higher in urine with a median eVAF of 1.98% (range: 0.00057%-35.85%) vs. 0.049% (range: 0.00026%-18.94%) in plasma. ctDNA was detected in baseline plasma in 10/14 (71%) responding pts (median eVAF: 0.325%) and in 8/10 (80%) non-responders (median eVAF: 0.107%). Changes in ctDNA levels reflected clinical responses. After treatment with ipi plus nivo, ctDNA was undetectable in 13/14 (93%) responding pts, and in only 4/10 (40%) of non-responders (p=0.0088). Of the 17 pts with undetectable ctDNA before surgery, 13 (76%) had a pathological response and 16/17 (94%) pts remained recurrence-free after a median follow-up of 34 months. Urine ctDNA was detected at baseline in 12/14 (86%) responding pts (median eVAF: 9.634%) and in 8/10 (80%) non-responders (median eVAF: 2%). After treatment with ipi plus nivo, urine ctDNA was detected in 8/14 (57%) responding pts (median eVAF: 0.87%), and in 8/10 (80%) non-responders (median eVAF: 0.162%). No association was observed between urine ctDNA detection and response (p=0.39). Detection of plasma ctDNA by RaDaR™ after neoadjuvant treatment was associated with pathological response and clinical outcome. In contrast, ctDNA detection in urine was not associated with outcomes. Absence of plasma ctDNA pre-surgery may predict complete response to ipi plus nivo at surgery and may be helpful in guiding clinical decisions in stage III UC, in particular to select pts for bladder-sparing strategies. Citation Format: Jeroen van Dorp, Christodoulos Pipinikas, Nick van Dijk, Greg Jones, Alberto Gil-Jimenez, Giovanni Marsico, Maurits L. van Montfoort, Sophie Hackinger, Linde Braaf, Kirsten McLay, Daan van den Broek, Bas W. Van Rhijn, Nitzan Rosenfeld, Michiel S. van der Heijden. Predicting pathological response after ipilimumab plus nivolumab in stage III urothelial cancer by liquid-biopsy assessment of plasma and urine ctDNA using the RaDaR assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1273.

Study EV-103 Cohort H: Antitumor activity of neoadjuvant treatment with enfortumab vedotin monotherapy in patients with muscle-invasive bladder cancer who are cisplatin-ineligible.

4582 Background: Up to 25% of all patients (pts) diagnosed with urothelial cancer present with muscle-invasive disease for whom the risk of progression or metastasis is substantial. Neoadjuvant chemotherapy prior to radical cystectomy and pelvic lymph node dissection (RC+PLND) has been shown to prolong overall survival for patients who are cisplatin (cis) eligible. The standard of care for cis-ineligible pts undergoing surgery does not include neoadjuvant therapy. Therefore, safe and effective neoadjuvant therapies are an unmet need for cis-ineligible pts with muscle invasive bladder cancer (MIBC). Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in urothelial cancer, and has been shown to benefit previously treated locally advanced or metastatic urothelial cancer pts in phase 2 and 3 trials, including cis-ineligible pts. Methods: Cohort H of the EV-103 phase 1b/2 trial (NCT03288545) enrolled pts with cis-ineligible cT2-T4aN0M0 MIBC who were eligible for RC+PLND and had an ECOG of 0-2. Pts received 3 cycles of neoadjuvant EV (1.25 mg/kg) on Days 1 and 8 of every 3-week cycle prior to RC+PLND. The primary endpoint of the study was pathological complete response rate (pCRR; ypT0N0) by central review. Key secondary endpoints included pathological downstaging (pDS) rate (ypT0,Tis,Ta,T1,N0) and safety. Results from a preliminary analysis are presented. Results: 22 pts were treated. Pts had cT2 (68.2%), cT3 (27.3%), and cT4 (4.5%) tumors. 68.2% pts had predominant urothelial cancer; 31.8% had a mixed histology. 19 pts completed all 3 cycles of EV. 21 underwent RC+PLND, and 1 had a partial cystectomy. 36.4% pts had a pCR. pDS was seen in 50.0% pts. The most common EV treatment-related adverse events (TRAEs) were fatigue (45.5%), alopecia (36.4%), and dysgeusia (36.4%). 18.2% pts had Grade ≥3 EV TRAEs. No surgeries were delayed due to EV administration. 3 pts had Grade 5 AEs while on study that were unrelated to EV; in 2 pts these AEs occurred > 30 days after RC+PLND. Conclusions: Observed pCRR after neoadjuvant EV showed promising activity in cis-ineligible pts with MIBC who have a high unmet need. Adverse events were consistent with the known safety profile of EV. This first disclosure of data supports the ongoing phase 2 and 3 programs evaluating EV in MIBC. Clinical trial information: NCT03288545.

Study EV-103 Cohort H: Antitumor activity of neoadjuvant treatment with enfortumab vedotin monotherapy in patients (pts) with muscle invasive bladder cancer (MIBC) who are cisplatin-ineligible.

435 Background: Up to 25% of all pts diagnosed with urothelial cancer present with muscle-invasive disease for whom the risk of progression or metastasis is substantial. Neoadjuvant chemotherapy prior to radical cystectomy and pelvic lymph node dissection (RC+PLND) has been shown to prolong overall survival for patients who are cisplatin (cis) eligible. The standard of care for cis-ineligible pts undergoing surgery does not include neoadjuvant therapy. Therefore, safe, and effective neoadjuvant therapies are an unmet need for cis-ineligible pts with MIBC. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in urothelial cancer, and has been shown to benefit locally advanced or metastatic urothelial cancer pts in Phase II and III trials, including cis-ineligible pts. Methods: Cohort H of the EV-103 phase 1b/2 trial (NCT03288545) enrolled pts with cis-ineligible cT2-T4aN0M0 MIBC who were eligible for RC+PLND and had an ECOG of 0-2. Pts received 3 cycles of neoadjuvant EV (1.25 mg/kg) on Days 1 and 8 of every 3-week cycle prior to RC+PLND. The primary endpoint of the study was pathological complete response rate (pCRR; ypT0N0) by central review. Key secondary endpoints included pathological downstaging (pDS) rate (yp T0,Tis,Ta,T1,N0) and safety. Results from a preliminary analysis are presented. Results: 22 pts were treated. Pts had cT2 (68.2%), cT3 (27.3%), and cT4 (4.5%) tumors. 68.2% pts had predominant urothelial cancer; 31.8% had a mixed histology. 19 pts completed all 3 cycles of EV. 21 underwent RC+PLND, and 1 had a partial cystectomy. 36.4% pts had a pCR. pDS was seen in 50.0% pts, with 1 case pending central pathology review. The most common EV treatment-related adverse events (TRAEs) were fatigue (45.5%), alopecia (36.4%), and dysgeusia (36.4%). 18.2% pts had Grade ≥3 EV TRAEs. No surgeries were delayed due to EV administration. 3 pts had Grade 5 AEs while on study that were unrelated to EV; in 2 pts these AEs occurred > 30 days after RC+PLND. Conclusions: Observed pCRR after neoadjuvant EV showed promising activity in cis-ineligible pts with MIBC who have a high unmet need. Adverse events were consistent with the known safety profile of EV. This first disclosure of data supports the ongoing Phase II and III programs evaluating EV in MIBC. Clinical trial information: NCT03288545.

Healthcare resource utilization (HCRU), costs, and mortality in relation to select immune-related adverse events (irAEs) and line of therapy (LOT) in patients (pts) with advanced or metastatic urothelial cancer (UC) treated with immune checkpoint inhibitor (ICI) monotherapy.

427 Background: Data on HCRU and costs in US UC patients treated with ICIs is in its infancy, as there is little information by LOT or focused on irAEs due to ICI use. In addition, the relationship between irAEs and mortality is controversial, with some studies suggesting lower risk of mortality in pts with irAEs, whereas others have found no association between irAEs and mortality. We assessed the associations of 1) irAEs and 2) LOT with HCRU, costs, and mortality in UC pts treated with ICI monotherapy. Methods: This retrospective cohort study used administrative claims data linked with mortality data from the National Death Index and Social Security Death Index to identify US commercial and Medicare Advantage plan members with UC treated with ICI monotherapy between 1 Sep 2014 and 30 Apr 2019. The LOT number of ICI therapy was captured. Twenty-one irAEs were chosen a priori based on ASCO and NCCN guidelines and clinical input. Based on ICD codes from claims, newly occurring irAEs were captured from ICI initiation to the earliest of 6 months after initial ICI LOT ended, start of new treatment, death, disenrollment, or 30 Apr 2019; HCRU and costs were assessed during same time. Using Cox regression with ICI LOT and time-varying irAEs as the exposures, we computed adjusted hazard ratios (HRs). Lin’s regression analysis was used to calculate adjusted 6-month all-cause costs by irAE. Results: Among UC pts treated with ICI monotherapy (N=417; mean age 74 ± 10 years; 72% male; 17% received prior systemic steroids; 32% initiated ICI as LOT 1, 43% as LOT 2), 22% (n=90) had an irAE. Pts who received ICIs as 2L therapy were 1.5 (95% CI: 1.1-2.0) and 1.7 (95% CI: 1.2-2.4) times more likely to have an all-cause ER visit and inpatient stay, respectively, than those who received 1L. There was no difference in mortality risk between 2L and 1L subgroups (HR, 1.2 [95% CI: 0.9-1.6]). Pts with irAEs had a 60% higher risk of an all-cause ER visit (95% CI: 1.0-2.5) and more than double the risk of an all-cause inpatient stay (HR, 2.6 [95% CI: 1.7-4.0]) than pts without irAEs. Pts who experienced an irAE had higher mean all-cause healthcare costs over 6 months vs those without irAEs ($98,415 vs $75,300; p<0.001). Mortality rates were similar between UC pts with and without irAEs (HR, 1.2 [95% CI: 0.9-1.6]). Conclusions: Pts with irAEs had higher all-cause HCRU and costs than pts without, and pts who received ICIs as 2L therapy had higher HCRU and costs than those who received 1L. This real-world study did not find that irAEs were associated with mortality in UC pts treated with ICI monotherapy. To inform optimum use of ICIs and management of irAEs, future work should include longer follow-up and grade of severity and number of irAEs.

Biomarker analysis and updated clinical follow-up of preoperative ipilimumab (ipi) plus nivolumab (nivo) in stage III urothelial cancer (NABUCCO).

5020 Background: Encouraging pathological complete response (pCR) rates were observed in trials testing neoadjuvant pembrolizumab or atezolizumab in urothelial cancer (UC). In cT3-4N0 tumors, pCR to atezolizumab was only 17% and restricted to tumors showing characteristics of preexisting T cell immunity. In NABUCCO, we aimed to increase response to pre-operative checkpoint blockade, particularly in high risk patients (pts), by combining ipi plus nivo in stage III UC. We previously reported pCR in 46% and downstaging to no remaining invasive disease in 58% (ESMO2019). Here, we present biomarker analyses and updated clinical follow-up (FU) data. Methods: Twenty four stage III (cT3-4aN0 or cT2-4aN1-3) UC pts who were unfit to receive cisplatin-based chemotherapy or refused, were treated with ipi 3 mg/kg (day 1), ipi 3 mg/kg + nivo 1 mg/kg (day 22), and nivo 3 mg/kg (day 43), followed by resection. The primary endpoint was feasibility (resection < 12 weeks). Efficacy (pCR), safety and biomarker analysis were secondary endpoints. Whole-exome sequencing (WES) was done on baseline tumor samples and local lymph node (LN) metastases showing no response. RNA-seq and multiplex immunofluorescence (mIF) for immune cell markers were done pre- and post-therapy. Results: After a median FU of 15.6 months, 2 pts relapsed (both non-pCR); 1 of these 2 pts died of metastatic disease. Tumors showing complete response (CR, for biomarker analysis defined as pCR, CIS or pTa) had a significantly higher tumor mutational burden than non-CR tumors. CR to ipi+nivo was independent of baseline CD8 T-cell presence. There was no difference between CR and non-CR tumors in baseline immune gene signatures, such as interferon gamma and T-effector signatures. Surprisingly, exploratory gene expression analysis revealed that non-CR was associated with a baseline B cell immune signature, particularly immunoglobulins and genes involved in B cell receptor signaling. CD20 positive cells (by mIF) and presence of tertiary lymphoid structures (TLS) at baseline were also associated with non-CR. Upon treatment with ipi+nivo, early and mature TLS increased significantly in responding tumors. A subset of pts showed CR in the bladder, but non-CR in a local LN tumor focus. WES revealed that these LN metastases were genetically different from the primary tumor bulk. Conclusions: At 15.6 months follow-up, recurrence after pre-operative ipi+nivo was low. Pathological complete response was not restricted to tumors exhibiting preexisting T cell immunity. Clinical trial information: NCT03387761 .

Predictive value of fibroblast growth factor receptor (FGFR) alterations on anti-PD-(L)1 treatment outcomes in patients (Pts) with advanced urothelial cancer (UC): Pooled analysis of real-world data.

493 Background: The tumor microenvironment in UC harboring FGFR gene alterations is characterized by decreased T-cell infiltration and low immune marker expression, potentially implicating suboptimal response to immune checkpoint inhibitors. The association between FGFR gene mutations/fusions and anti-PD-(L)1 treatment outcomes in advanced UC was assessed using real-world pt data. Methods: A pooled dataset of matched clinical and genomic data for advanced UC pts treated with anti-PD-(L)1 in any line from the Bladder Cancer Research Initiative for Drug Targets in Germany (BRIDGE) Consortium and UNC-CH was assessed. FGFR status was defined by a prespecified panel of FGFR2/3 mutations and fusions. Overall survival (OS) was analyzed using Kaplan-Meier estimates and Cox proportional hazards models. Multivariate analyses were performed using potential prognostic covariates (sex, age, baseline tumor stage, urothelial histology, smoking history, primary tumor location, and ECOG) in a Cox regression model for OS to assess their impact on the effect of FGFR alterations. Results: Median OS for FGFR+ pts (n=28) who received any line of anti-PD-(L)1 therapy was 9.5 mo vs 7.5 mo for FGFR− pts (n=139) (HR: 1.03, 95% CI: 0.60-1.76, p=0.93). Median OS for pts treated with first-line anti-PD-(L)1 was 5.42 mo in FGFR+ pts (n=10) and was not reached for FGFR− pts (n=31) (HR: 2.06, 95% CI: 0.68-6.24, p=0.19); median OS in second-line anti-PD-(L)1 was 6.5 mo (FGFR+; n=14) vs 5.7 mo (FGFR−; n=86) (HR: 0.89, 95% CI: 0.44-1.81, p=0.74). The multivariate analyses showed a significant trend of poorer OS in FGFR+ pts with first-line anti-PD-(L)1 (HR: 10.42, 95% CI: 1.45-74.97, p=0.02); wide CI may be attributed to small sample size for some categories in several covariates. Conclusions: Treatment with first-line anti-PD-(L)1 in FGFR+ pts may be associated with poorer OS outcomes in FGFR+ pts; however, this trend was not observed in FGFR+ pts treated with any line and second-line anti-PD-(L)1. Investigation of the predictive value of FGFR alterations to immunotherapy outcomes in larger real-world pt datasets is warranted.

Feasibility of digital pathology of circulating tumor cells with morphologic analysis in localized bladder cancer.

525 Background: Circulating tumor cells (CTCs) are promising biomarkers in metastatic urothelial cancer (UC). Unfortunately, efforts in localized disease have been unsuccessful, in part due to limitations of existing technologies that rely on counting cells and epithelial-marker expression. Here, we applied a novel selection-free digital pathology platform in a localized UC cohort. To date, this platform has associated CTC morphology with differential therapeutic response in metastatic UC and castrate-resistant prostate cancer. If feasible in localized UC, we may potentially identify best candidates for adjuvant therapy or bladder sparing, as well as enable sensitive monitoring for recurrence. Methods: N=16 consecutive UC pts included 8 (50%) metastatic controls and 8 (50%) localized (3 (37%) at TURBT and 5 (63%) at cystectomy). Peripheral blood was processed with the Epic CTC platform (pan-CK/CD45/PD-L1/DAPI staining). Approximately 3 million cells per slide were imaged. Unsupervised clustering categorized CTCs into 5 subtypes based on 11 morphologic features (nuclear solidity, speckling, nucleoli and entropy; cytokeratin speckling and ratio; and cytoplasmic/nuclear circularity, area, and convex area ratio). Results: 119 CTCs were detected from 11/16 (69%) pts (5/8 (63%) localized (2 NMIBC, 6 MIBC) and 6/8 (75%) metastatic). All MIBC pts had cystectomy (4/6 (67%) received NAC). 2/8 (25%) metastatic pts had stable disease, 3/8 (38%) were progressing, and 3/8 (38%) had newly detected M1. Median (range) CTC count/mL was similar for localized and metastatic pts (0.4 (0-58.6), 0.75 (0-1.9)). CTCs were detected in a pt with CIS, but not in a pt with TaHG disease. 1/16 (6.3%) pts had a single PD-L1+ CTC. CTCs were successfully assigned into 5 subtypes with predominant features of large, small, or linear cells, high cytoplasmic circularity, and prominent nucleoli. Conclusions: Digital pathology and subtype assignment of CTCs is feasible in localized UC. Ongoing efforts at our center include application of this technology in localized patients receiving investigational checkpoint inhibitor therapy to potentially predict best responders or conversely those at the highest risk for recurrence.

904PD - Pre-operative ipilimumab and nivolumab in locoregionally advanced, stage III, urothelial cancer (NABUCCO)

BackgroundStage III (cT3-4aN0M0 or ≥cT1N+M0) urothelial cancer (UC) patients (pts) have a poor prognosis. Despite high response rates, pre-operative chemo shows limited survival benefit. Immunotherapy targeting PD-1/PD-L1 is active in metastatic UC; the combination of ipilimumab (ipi) and nivolumab (nivo) appears to increase response rates. Encouraging path Complete Response (pCR) rates are observed in trials testing neoadjuvant anti-PD-1/PD-L1 (mostly cT2-T3N0 pts). Here, we present the first clinical trial data on preoperative ipi+nivo. MethodsThis is a single-arm phase 1B trial testing the feasibility (primary endpoint) of pre-operative ipi+nivo in stage III UC pts (cis unfit/refusal). To mitigate the risk of immune-related toxicity, pts were treated with (based on melanoma data): ipi 3mg/kg (day 1), ipi 3 + nivo 1mg/kg (day 22), and nivo 3mg/kg (day 43), followed by resection. Secondary endpoints were efficacy (pCR) and translational parameters: PD-L1, TMB (by WES), and immune cell infiltrates at baseline vs on-treatment using multiplex immunofluorescence (mIF; pan-CK/CD3/CD8/FOXP3/CD20/CD68). Results24 pts (14 cT3-4N0; 10 cN+) were enrolled, of whom 23 (96%) had resection <12 weeks from 1st cycle. 1pt, responding radiologically, had a delay in surgery because of an irAE (hemolysis). 18/24 pts received all 3 cycles, 6 pts received 2 cycles due to irAEs. Grade 3/4 irAEs occurred in 54% of pts; 42% when excluding clinically insignificant lab deviations. 22 pts were available for efficacy assessment (1pt resection delayed, 1pt had resection 1day before abstract submission). 10/22 pts (45%) achieved a pCR. 3 additional pts (14%) had noninvasive cancer at resection (2 ypTis, 1 ypTa), resulting in an overall path downstaging (≤ypT1N0) rate of 59% (13/22). In recent neoadjuvant IO studies in melanoma and NSCLC, major path response (MPR) has been defined as≤10% vital tumor cells in the tumor bed. MPR was seen in 5/22 pts (23%). Nonresponse was seen in 4/22 (17%). Response was associated with massive infiltration of CD8+ T-cells in the tumour bed. ConclusionsPreoperative ipi+nivo is feasible (96% surgery <12 weeks) and shows promising efficacy in stage III UC pts. Updated results on all 24 pts, including mIF, PDL1 and TMB, will be presented. Clinical trial identificationNCT03387761, January 2, 2018. Legal entity responsible for the studyNetherlands Cancer Institute - Antoni van Leeuwenhoek. FundingBMS. DisclosureM.S. Van der Heijden: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Janssen. T.N. Schumacher: Advisory / Consultancy: Adaptive Biotechnologies; Advisory / Consultancy, Shareholder / Stockholder / Stock options: AIMM Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Allogene Therapeutics; Advisory / Consultancy: Amgen; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merus; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Neon Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Scenic Biotech; Advisory / Consultancy: Third Rock Ventures; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck KGaA. P. Kvistborg: Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy: Personalis; Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS. C.U. Blank: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: GSK; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: GenMab; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (institution): NanoString. B.W. van Rhijn: Advisory / Consultancy: Astellas; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Ferring. All other authors have declared no conflicts of interest.

Sites of metastases (mets) and their association with clinical outcomes (CO) in urothelial cancer patients (pts) treated with immunotherapy (IO).

473 Background: Several IO agents have been approved for treatment of advanced urothelial cancer pts. We investigated the association between sites of mets and CO in urothelial cancer pts treated with IO in the real world setting. Methods: We performed a retrospective review of 67 urothelial cancer pts treated with PD-1 or PD-L1 inhibitors at Winship Cancer Institute from 2015-2018. Overall survival (OS) and progression free survival (PFS) were measured from first dose of IO to date of death or hospice referral and radiographic or clinical progression, respectively. Sites of mets were collected from radiology and clinic notes at baseline. Univariate analysis (UVA) and multivariable analysis (MVA) used Cox proportional hazard. Results: The median age was 70 and most (79.1%) were men. Pts had mets to sites such as lymph node (73.1%), bone (29.9%), liver (20.9%), lung (31.3%), and brain (1.5%). Pts with bone or liver mets had significantly shorter OS and PFS in UVA. Pts with bone mets also had significantly shorter OS and PFS in MVA (Table). The median OS of pts with bone mets was 2.2 months (12-month survival=28.0%), while those without bone mets had a median OS of 21.9 months (12-month survival=52.5%) per Kaplan-Meier estimation. The median OS of pts with liver mets was 2.2 months (12-month survival=28.6%), while those without liver mets had a median OS of 12.8 months (12-month survival=50.1%) per Kaplan-Meier estimation. Conclusions: Bone and liver mets are poor prognostic factors in urothelial cancer pts receiving IO in the real world setting. These findings should be validated in a larger study. [Table: see text]

Safety and efficacy of immune checkpoint inhibitors (CPI) in metastatic renal cell cancer (RCC) and urothelial cancer (UC) patients (pts) with pre-existing autoimmune disorders (AD).

653 Background: The pivotal clinical trials of CPI generally excluded pts with AD given concern for serious exacerbations. There is limited data on the safety and efficacy of CPI in this population. Methods: We conducted a retrospective single center analysis of RCC and UC pts treated with CPI. Pts were grouped by presence or absence of AD. We catalogued the incidence of new irAEs (CTCAEv4), AD exacerbations, objective response rate (ORR, RECIST 1.1), and overall survival (OS, Kaplan Meier). Competing risk models estimated cumulative incidences of irAEs and CPI discontinuation using 6 months (mos) as a benchmark. Results: 271 RCC and 220 UC pts were identified. Median followup was 21 mos for RCC and 13 mos for UC. 25 (9%) RCC and 27 (12%) UC had pre-existing AD; most commonly dermatologic and rheumatologic. A minority (3% RCC/4% UC) had clinically active AD requiring concurrent immunomodulators. AD exacerbations occurred in 8 (32%) RCC and 12 (44%) UC; median time to exacerbation was 86 (25-270) and 27 (8-300) days, respectively. Cumulative incidence of new irAEs at 6 mos was numerically higher in RCC AD pts (50% vs 37%). CPI discontinuation and clinical outcomes were similar among AD and non-AD pts (Table). Conclusions: CPI are active in advanced RCC and UC pts with pre-existing AD. Exacerbations and new irAEs should be expected, but AD pts can experience similar outcomes and rates of drug discontinuation. Larger scale investigations are warranted. [Table: see text]

Inflammatory markers at baseline (C1) and cycle 3 (C3) and their association with clinical outcomes in urothelial cancer patients (pts) treated with immunotherapy (IO).

390 Background: Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) have been explored as biomarkers for response to IO. We investigated the association between these biomarkers and clinical outcomes in urothelial cancer pts treated with IO. Methods: We conducted a retrospective review of 67 urothelial cancer pts treated with PD-1 or PD-L1 inhibitors at Winship Cancer Institute from 2015-2018. Overall survival (OS) and progression free survival (PFS) were measured from first dose of IO to date of death or hospice referral and clinical or radiographic progression, respectively. MLR, NLR, and PLR were collected at C1 and C3. The nonlinear relationship between log-transformed biomarkers and OS or PFS was examined by martingale residual plot and optimal cutoff (OC) values were determined. Multivariable analysis (MVA) used Cox proportional hazard model. Results: OC for C1 and C3 NLR, MLR, and PLR were 2.06 and 1.42, -0.331 and -0.153, and 5.7 and 5.6, respectively. Pts with C1 NLR and PLR above OC had worse OS and shorter PFS (all p&lt;0.05) (Table). High C3 MLR portended shorter OS and PFS. NLR, MLR and PLR were highly correlated (Pearson correlation coefficients ≥ 0.67, p&lt;0.0001). Conclusions: High NLR, MLR, and PLR at C1 and at C3 are associated with worse clinical outcomes in this cohort. These values warrant a larger study for validation. MVA† of MLR, NLR, and PLR at C1 and at C3 with OS and PFS. [Table: see text]

Association between immune-related adverse events (irAEs) and clinical outcomes (CO) in advanced urothelial cancer patients (pts) treated with immunotherapy (IO).

472 Background: The increasing use of IO agents in the treatment of urothelial cancer has revealed irAEs during therapy. We investigated whether there is an association between treatment-related irAEs and CO in urothelial cancer pts treated with IO. Methods: We performed a retrospective analysis of 67 urothelial cancer pts treated with PD-1/PD-L1 inhibitors at Winship Cancer Institute from 2015-2018. Overall survival (OS) and progression free survival (PFS) were calculated from first IO dose to date of death or hospice referral and clinical or radiographic progression, respectively. Objective response (OR) was defined as partial or complete response per RECISTv1.1. Treatment-related irAEs were determined from clinic notes. The univariate association between irAE and clinical outcomes was generated using chi-square test and Fisher’s exact test. Results: The median age was 70 and 79.1% were men. 41.8% of pts had received 2 or more prior lines of therapy. Nine pts (13.4%) experienced irAEs including infusion reactions, rashes, and joint pain. Median follow-up from date of first dose of IO was 15 months (95% CI: 11-18 months). The overall death rate for pts who experienced irAE was 0%, while it was 62% for pts who did not experience irAE ( p&lt;0.001) (Table). Conclusions: Experiencing irAEs was associated with lower death rate and progression rate and higher rate of OR in this cohort. These findings should be validated in a larger study. Univariate association of irAEs with CO. [Table: see text]

Alterations of DNA damage response (DDR) genes correlate with favorable response and overall survival (OS) in anti-PD-1/PD-L1-treated advanced urothelial cancer (UC).

438 Background: DDR gene alterations may contribute to higher tumor mutational burden (TMB) via genomic instability in addition to APOBEC mutagenesis. We previously showed that ATM mutations correlated with shorter OS in UC, while Teo et al. showed patients (pts) with DDR alterations benefited from PD-1/PD-L1 blockade in advanced UC. Here, we aimed to validate those findings and further explore the prognostic role of ATM mutations in advanced UC treated with anti-PD-1/PD-L1 agents. Methods: The study included 53 pts who had FoundationOne tumor tissue genomic sequencing and anti-PD-1/PD-L1 therapy. Fisher exact test was used to test difference in objective response rate (ORR). OS was measured from time of initial UC diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI). Results: The cohort had a median age of 66 (range 21–81) with 34% females and 64.2% platinum-based chemotherapy. DDR alterations (including ATM) were present in 49.1% pts (26/53) and favored a higher ORR (37.5% vs. 23.1%, p = 0.26). Compared with those without DDR alterations, pts with DDR alterations (excluding ATM) seemed to have longer OS, although significance was not reached likely due to a short follow-up time (HR = 0.53, 95% CI 0.20–1.38, p = 0.19). ATM alterations seemed to favor higher response rate to PD-1/PD-L1 blockade (ORR, 40% vs. 28.9%, p = 0.6), but was associated with significantly shorter OS (HR = 5.7, 95% CI 1.65–19.74, p = 0.006) in overall pts and in subgroups with/without platinum-based chemotherapy (data not shown). Pts with ≥ 3 DDR alterations (including ATM) had substantial higher TMB (13.9–72.2 perMb, median 22.6) and benefited the most from PD-1/PD-L1 blockade with 80% ORR vs. 24.4% ORR in pts with &lt; 3 DDR alterations. Conclusions: Our study supported that DDR alterations are associated with higher response rate and prolonged OS in advanced UC pts receiving anti-PD-1/PD-L1 agents, likely from impact on TMB. However, ATM alterations correlated with poor prognosis also in those pts. Further studies are needed to assess the clinical utility of DDR alterations in directing therapies in UC.

Rogaratinib treatment of patients with advanced urothelial carcinomas prescreened for tumor FGFR mRNA expression.

494 Background: Activation of FGFR signaling is involved in a variety of malignancies including advanced urothelial cancer (UC). Rogaratinib is an oral pan-FGFR kinase inhibitor. We report here the results from a phase I expansion cohort in UC patients prescreened for FGFR1-3 mRNA expression levels and activating mutations. (NCT01976741) Methods: Patients with advanced urothelial carcinomas were selected based on high FGFR1-3 mRNA expression in biopsy specimens. Selected patients were treated with rogaratinib 800mg twice daily until tumour progression, untolerable toxicity, or withdrawal. Tumor response was assessed by RECIST, v1.1. Adverse events were reported using CTCAE v4.03 criteria. Results: A total of 219 UC patients were prescreened for FGFR1-3 mRNA expression levels and FGFR3 activating mutations, with 99 samples (45%) found to be FGFR-positive. Of those, 87% of samples were positive for FGFR3 mRNA, 5% for FGFR1 mRNA and 8% were double FGFR mRNA-positive (FGFR1/2, 1/3 or 2/3). Frequency of FGFR3 activating mutations in UC samples was 7%, all of which also had high FGFR3 mRNA. Fifty two patients (median prior line of treatment 2) started treatment and 51 were evaluable for response. Rogaratinib was generally well tolerated and AEs manageable with dose modification. The most common AEs were diarrhea (49%) and hyperphosphatemia (49%). Objective response rate (ORR) was 24% (12/51; all PRs) and disease control rate (DCR) was 73% (37/51). Eleven of 12 pts with a PR were positive for FGFR3 mRNA, 5 of whom also had FGFR3 mutations, and one patient was positive for FGFR1 mRNA. Ten FGFR-positive UC patients had prior immuno-oncology (I/O) treatment, 9 of whom had progressive disease as best response. For these 10 patients the ORR was 30% and the DCR 80%. Conclusions: Selection of pts for treatment with rogaratinib based on FGFR mRNA expression levels was feasible and identified drug-sensitive patients with and without underlying DNA alterations. Rogaratinib had a favorable safety profile and showed promising anti-tumor activity in UC patients. Responses and disease stabilization were observed with rogoratinib in UC pts refractory to prior I/O treatment. Clinical trial information: NCT01976741.

Radium-223 and atezolizumab in platinum refractory urothelial carcinoma with bone metastases: NCT03208712.

TPS543 Background: Immunologically, radiation increases tumor antigen release, cytotoxic CD8+ T cell infiltration while reducing myeloid derived suppressor cells (MDSCs), with distant abscopal responses occasionally reported. Radium-223 is a systemically administered bone-targeted alpha emitter that causes double-stranded DNA breaks and may induce similar immune effects. Anti-PD(L1) immune checkpoint inhibitor monotherapy with Atezolizumab demonstrates objective responses in metastatic urothelial cancer. In mouse models, radiotherapy and checkpoint immune inhibitor in combination synergistically reduce tumor growth. We hypothesized that the combination of Atezolizumab and Radium-223 in metastatic urothelial cancer pts with bone metastases would target bone metastases more effectively and yield higher response rates. Methods: Eligibility criteria for this single-site, phase 2 trial of Radium-223 in combination with Atezolizumab include diagnosis of advanced urothelial carcinoma with ≥1 bone metastasis, RECIST 1.1 measurable disease, progression of disease after/on platinum-containing chemotherapy in the metastatic or perioperative setting, ECOG PS of 0-2 and adequate organ function. Twenty-two pts will be treated with Radium-223 at a dose of 55 kBq/kg IV and Atezolizumab 1200mg IV both on day 1 of 21 day cycles. Up to 6 doses of Radium-223 will be administered. Atezolizumab will be continued until lack of clinical benefit or intolerable toxicity for up to 17 cycles. Routine response assessment will be performed every 12 weeks. Primary endpoint is best overall response per RECIST 1.1. Secondary objectives are to determine the safety and tolerability; determine the overall survival, progression free survival, clinical benefit rate, complete response rate and duration of response; and changes in quality of life as assessed by the EORTC QLQ-C30 score. Exploratory objectives are PD-L1 status by IHC, changes in bone scan per EXINI bone scan index and efficacy measures by irRC. If ≥6 pts respond, corresponding to an ORR of 27% with 80% confidence limits of 15%-43%, further study of the combination would be warranted. Blood and archival tissue will be collected for correlative studies. Clinical trial information: NCT03208712.

IFNγ mRNA signature (IFNγ sig), circulating tumor DNA (ctDNA), and survival in NSCLC or urothelial cancer (UC) treated with durvalumab (D).

51 Background: Associations between early reduction in plasma ctDNA, pretreatment tumoral IFNγ sig, liver metastases and outcomes, and between tumor mutational burden (TMB) and CD274 (PD-L1) mRNA or IFNγ sig in TCGA were evaluated in NSCLC and UC pts treated with D. Methods: Pts received 10 mg/kg Q2W of D in a Phase 1/2 study in advanced solid tumors. RNAseq measured a 4-gene IFNγ sig; top tertile was IFNγ sig+. Pts with PD-L1 expression (Ventana SP263) ≥ 25% tumor cells in NSCLC or ≥ 25% tumor or immune cells in UC were PD-L1+. 70 genes were assayed for DNA variants (Guardant360) in plasma ctDNA pre/posttreatment. TCGA was used to calculate TMB; ≥ median TMB was high. Results: IFNγ sig+ NSCLC or UC pts had higher response and longer median PFS and OS compared with PD-L1+, PD-L1- and IFNγ sig- pts (Table). Responders showed significant decreases in ctDNA mean variant allele frequency (VAF) posttreatment with D; pts with progressive disease showed increased VAF. Pts with decreased VAF at week 6 had longer median PFS and OS compared with those with VAF increases. VAF changes were not associated with IFNγ sig. NSCLC without liver metastases had higher IFNγ sig (P &lt; 0.001) than pts with liver metastases. In TCGA NSCLC and UC, IFNγ sig+ correlated with high TMB; CD274 mRNA did not. Conclusions: IFNγ sig correlated with outcomes and with TMB in NSCLC and UC. CtDNA VAFs were reduced in NSCLC or UC responders after treatment and correlated with longer survival, suggesting utility as an early indicator of clinical benefit. Clinical trial information: NCT01693562. [Table: see text]

Biologic and clinical relevance of an IFNG mRNA signature (IFNGS) and PD-L1 protein expression in tumor and immune cells in urothelial cancer (UC) patients (pts) treated with durvalumab (D).

3037 Background: PD-L1 can be induced by IFNG in tumor cells (TC) and immune cells (IC). TC PD-L1 expression prevalence in UC is low and the relevance of scoring TC (in addition to IC) is not fully understood. We recently reported a positive correlation between high levels of an IFNGS and outcome in a cohort of 30 UC pts treated with D. Here, we assessed the potential predictive value of the IFNGS in an additional 32 pts (total N = 62) and further explored the relationship between the IFNGS and TC and/or IC PD-L1 IHC expression patterns. Methods: Study CP1108 was a phase 1/2 trial evaluating D in pts with solid tumors; 191 UC pts received 10 mg/kg D with median follow up of 8.4 mo. 144 of these pts have available ORR and PD-L1 data and 62 pts have ORR, PD-L1 and IFNGS data. Pts with ≥25% TC or IC were scored as PD-L1 high (TC+ or IC+). Pts within the top tertile of IFNGS ( LAG3, PDL1, CXCL9, and IFNG mRNAs) tumor expression were scored positive. Cox proportional hazards models were used adjusting for age, gender, ECOG, smoking status, line of therapy, and liver metastasis at baseline. ORR was evaluated using RECIST v1.1. Results: IFNGS+ pts had increased ORR (45 vs 16%) and improved PFS (adj HR 0.3; p = 0.005) and OS (adj HR 0.18; p = 0.016) over IFNGS- pts. IFNGS expression was significantly higher in pts who were PD-L1 high (TC+/IC+) compared with TC-/IC- (low/negative) pts (mean IFNGS expression 3.5 vs 1.1; p = 0.0155) and also in TC+ or IC+ vs TC-/IC- (mean IFNGS 2.2 vs 1.1; p = 0.000127). TC-/IC+ and TC+/IC- groups had a mean IFNGS expression of 2 and 2.2 respectively. ORR in all 1108 UC pts with available IHC and ORR data (N = 144) was 29% for TC+/- pts, 36% in TC-/IC+ pts, and 7% in the TC-/IC- pts. Conclusions: IFNGS predicted improved outcomes in a cohort of 62 2L+ UC pts treated with D. TC-/IC- PD-L1 pts had lowest levels of IFNGS expression. Observations that TC+ (and IC+) pts contribute to IFNGS enrichment and that TC+/IC-, and TC-/IC+ pts have increased response vs TC-/IC-pts provides rationale for TC+ inclusion (in addition to IC+) in the SP263 PD-L1 scoring algorithm for UC. IFNGS is an additional potential predictive biomarker in UC pts that warrants further investigation.