Muscle-invasive bladder cancer (MIBC) is traditionally managed with neoadjuvant chemotherapy followed by radical cystectomy. Although bladder preservation offers substantial quality-of-life advantages, clinically validated biomarkers to guide organ-sparing strategies are lacking. Here, we report results from RETAIN-2, a phase II trial evaluating neoadjuvant AMVAC plus nivolumab followed by response-adapted management, alongside an integrated tumor-informed circulating tumor DNA (ctDNA) analysis spanning 111 patients across RETAIN-1 and RETAIN-2. Whereas prior ctDNA studies in MIBC have been limited to cystectomy- or chemoradiation-based paradigms and largely limited to binary assessment at discrete timepoints, this integrated analysis uniquely captures longitudinal ctDNA dynamics in patients forgoing any immediate definitive local therapy, representing the largest prospective ctDNA dataset in any bladder-preservation trial. RETAIN-2 met its primary endpoint, with 70% of patients metastasis-free at 2 years. The Kaplan–Meier analysis estimated 2-year MFS was 83.5% and 68% of active surveillance patients remained metastasis-free with intact, non-irradiated bladders. Baseline and post-treatment ctDNA positivity were strongly associated with inferior metastasis-free and overall survival. Critically, ctDNA-negative patients managed with active surveillance had outcomes comparable to those undergoing cystectomy (24-month MFS 91% vs. 84%; OS 97% vs. 89%), providing the first prospective evidence that ctDNA negativity can identify patients who safely avoid radical cystectomy without compromising metastatic control. Importantly, plasma ctDNA reflected systemic metastatic risk rather than intravesical disease burden, underscoring the need for complementary bladder-directed surveillance. These results establish ctDNA as a clinically actionable biomarker for response-adapted organ preservation in MIBC. Trial registration number: NCT02710734

INTRODUCTION:Enfortumab vedotin (EV) has emerged as a key treatment for metastatic bladder cancer. The treatment paradigm is to treat until unacceptable toxicity or progression, but acute and cumulative toxicity adversely impacts quality of life (QOL). We hypothesized that dose reductions may improve QOL without sacrificing efficacy. We conducted a single-center, retrospective study to assess association of EV dose reduction with treatment duration, treatment-related adverse events (TRAEs), and survival. METHODS:Patients with metastatic bladder cancer treated with EV ± pembrolizumab were divided into three groups: standard dose (1.25 mg/kg); on-treatment dose reduction (1.25 mg/kg and dose-reduced); and upfront dose reduction (started EV < 1.25 mg/kg). We evaluated the electronic medical record for data on survival, TRAEs, and number of doses received. Kaplan-Meier and Cox proportional hazards regression models were used to compare progression-free survival (PFS) and overall survival (OS) between the three groups and evaluate treatment dose (1.25 or < 1.25 mg/kg) as a time-varying covariate. TRAEs and number of doses received were examined using logistic and negative binomial regression. Regression models adjusted for age, ECOG status, concurrent pembrolizumab, histology, and site of metastasis. RESULTS:A total of 152 patients comprised the groups: standard dose, n = 47; on-treatment dose reduction, n = 72; upfront dose reduction, n = 33. Upfront dose reduction, patients were significantly older (P < .001) and had worse ECOG status (P = .054). Patients receiving on-treatment dose reduction had significantly more cutaneous AEs (26.4%, P = .005) and neuropathy (34.7%, P < .001) than standard dose patients. In 4-month landmark analyses, patients receiving on-treatment dose reduction had significant improvement in PFS (HR: 0.49, P = .027) but no difference in OS (HR: 0.60, P = .106) compared to standard dose patients. Time-varying analyses showed dose-reduced EV patients had improved PFS (HR: 0.57, P = .018) and OS (HR: 0.53, P = .017) compared to standard dosing. CONCLUSION:EV dose reduction decreases AEs while maintaining efficacy, warranting prospective evaluation.

4505 Background: First-line nivolumab plus ipilimumab (NIVO+IPI) provided substantial long-term survival benefits over sunitinib (SUN) in patients (pts) with advanced renal cell carcinoma (aRCC) in the CheckMate 214 trial. We now report final efficacy and safety data in the intent-to-treat (ITT) population and by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk. Methods: Pts with clear cell aRCC were randomized 1:1 to NIVO 3 mg/kg + IPI 1 mg/kg Q3W×4 then NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN 50 mg once daily for 4 weeks on, 2 weeks off. Efficacy endpoints included overall survival (OS), and independent radiology review committee (IRRC)-assessed progression-free survival (PFS) and objective response rate (ORR) in intermediate/poor-risk (I/P; primary), ITT (secondary), and favorable-risk (FAV; exploratory) pts. Response was assessed using RECIST v1.1. Results: With 9 years median follow-up, OS was improved with NIVO+IPI vs SUN in ITT (HR 0.71) and I/P (HR 0.69) pts. The probability of OS at 108 months was 31% vs 20% in ITT pts and 30% vs 19% in I/P pts, respectively. In pts with FAV risk, the HR for OS improved from 1.45 at first report (Motzer NEJM 2018) to 0.80 at 9 years, showing a delayed benefit with NIVO+IPI vs SUN. OS probabilities at 108 months were 35% vs 22% in FAV pts, respectively (Table). The probability of PFS at 96 months with NIVO+IPI vs SUN was 23% vs 9% in ITT pts, 25% vs 9% in I/P pts, and 13% vs 11% in FAV pts. The probability of remaining in response through 96 months with NIVO+IPI vs SUN was 48% vs 19% in ITT pts, 50% vs 23% in I/P pts, and 36% vs not available (NA) in FAV pts. No new treatment-related deaths occurred in either arm. Additional subgroup analyses will be presented. Conclusions: In the longest and final phase 3 follow-up (9 years) of a first-line checkpoint inhibitor combination in aRCC, milestone rates of OS and PFS and durable response remained higher with NIVO+IPI vs SUN. No new safety signals emerged. NIVO+IPI remains a standard first-line option in aRCC. Clinical trial information: NCT02231749 . ITT I/P FAV Arm; n NIVO+IPI; 550 SUN; 546 NIVO+IPI; 425 SUN; 422 NIVO+IPI; 125 SUN; 124 mOS (95% CI), mo 53 (46–64) 38 (32–44) 47 (35–56) 26 (22–33) 78 (65–92) 67 (56–80) 108-mo OS probabilities (95% CI), % 31 (27–35) 20 (16–23) 30 (26–35) 19 (15–23) 35 (27–44) 22 (15–30) mPFS (95% CI), mo 12 (10–16) 12 (10–15) 12 (9–17) 9 (7–11) 13 (10–18) 29 (23–43) 96-mo a PFS probabilities (95% CI), % 23 (18–27) 9 (5–15) 25 (20–31) 9 (4–15) 13 (6–22) 11 (3–27) ORR per IRRC (95% CI); CR, % 39 (35–44); 12 33 (29–37); 3 42 (38–47); 12 27 (23–32); 3 30 (22–38); 13 52 (43–61); 6 mDOR (95% CI), mo 76 (59–NE) 25 (20–33) 83 (54–NE) 20 (16–26) 61 (23–NE) 33 (25–51) 96-mo a DOR probabilities (95% CI), % 48 (39–55) 19 (10–31) 50 (41–58) 23 (13–36) 36 (17–56) NA b a 96-mo probabilities reported due to small numbers of pts at risk at 108 mo. b No pts remain at risk. CR, complete response; DOR, duration of response; m, median; NE, not estimable.

Supplementary Figure 8: PD-L1 levels in tumor or tumor microenvironment does not associate with tumor progression or control.

548 Background: Combination tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (IO) are an established standard of care for patients with metastatic renal cell carcinoma (mRCC). We report updated analysis of a multi-center, investigator-initiated (IIT), phase I/II study of axitinib (axi) with nivolumab (nivo) in the previously treated patient cohort. Methods: The study investigated the combination of axi/nivo in an initial dose finding phase I portion and a phase II portion including 2 parallel arms: treatment naïve mRCC patients and mRCC patients previously treated with TKIs or IO/IO combination (NCT03172754). We are presenting final results from the previously treated cohort. Included patients had pathology with any clear cell component, ECOG performance status of 0-1, no known or symptomatic brain metastases, and no history of autoimmune disease. The recommended phase 2 dose of axi was 5 mg BID and patients were treated for up to 2 years then could stop one or both therapies. The primary endpoint of the phase II portion was objective response rate (ORR) per investigator assessment. Results: Twenty-six patients were accrued to the previously treated arm, all evaluable for efficacy and toxicity. The median age was 62 yrs (range: 42-81), 80.8% were male and 88.5% were white. Twenty pts had 1 prior line of therapy (18 TKI alone), 6 pts had 2 or more prior lines of Tx. Two pts had prior nivo with ipilimumab. Median follow-up was 47.2 months. The ORR was 30.8% (all PRs) and 57.7% achieved stable disease. The primary PD rate was 11.5%. Median OS was 48.4 months and median PFS was 13.0 months. Six pts (23.1%) completed two years of Tx on trial and elected to stop one or both drugs (2 elected to stay on axi alone). Five pts remain progression-free and have received no subsequent therapy with a median progression-free interval of 23.2 months. None had received prior IO. Adverse event (AE) data was similar to published data for IO/TKI combinations. There was one Gr4 TRAE of elevated lipase and 12 pts (46%) experienced a Gr3 TRAE. One pt (4%) discontinued the study due to TRAEs. Conclusions: Final results from the previously treated cohort of this IIT of axi/nivo for pts with mRCC demonstrated an ORR of 30.8% and a DCR of 88.5% with no unexpected AEs. Though there were no CRs, disease control rate and median OS were encouraging in this previously treated population. This is the only reported IO/TKI trial that allowed for stopping of all Tx at 2 years, with 6 pts (23.1%) meeting this milestone, 5 of whom (19% of all pts) remain progression-free for a median period close to 2 years. Clinical trial information: NCT03172754 .

Understanding how health-related quality of life (HRQOL) concerns vary by disease stage is essential for developing patient-reported outcome measures (PROMs) that reflect the lived experiences of individuals with renal cell carcinoma (RCC). This study aimed to explore differences in the perceived relevance of HRQOL domains between patients with localized and metastatic RCC using a provisionally grouped item set derived from validated instruments. This is a secondary analysis of a prospective international study conducted from August 2022 and October 2024, with participants from the United States, Europe, and Brazil (Bergerot et al., JCO 2025). In Phase 1, a 54-item was developed using the Functional Assessment of Cancer Therapy–Kidney Symptom Index (FKSI-19), the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30), and the EuroQol (EQ-5D). Items were provisionally grouped into four conceptual domains: physical disease-related symptoms (DRS-P), emotional symptoms (DRS-E), treatment side effects (TSE), and function/well-being (FWB). Patients with localized or metastatic RCC rated item relevance. We calculated the mean number of relevant items per domain and conducted ANOVAs to compare groups, reporting partial eta squared (η²) for effect size. A total of 200 patients (localized n = 83; metastatic n = 117) were included. Patients with metastatic RCC reported greater relevance of physical symptoms (DRS-P: M = 39.2, SD = 6.0) compared to those with localized disease (M = 35.3, SD = 6.7; F(1,198)=17.53, P < .001, η²=0.081). Similarly, metastatic patients reported higher treatment side effect burden (TSE: M = 12.2, SD = 2.3 vs. 10.6, SD = 2.5; F(1,198)=19.47, P < .001, η²=0.089). No significant difference was observed in emotional symptoms (DRS-E; P = .260). Conversely, patients with localized RCC more often endorsed concerns related to function and well-being (FWB: M = 17.6, SD = 3.5) than those with metastatic disease (M = 15.5, SD = 2.9; F(1,198)=20.52, P < .001, η²=0.094). Given the differences in trajectory and treatment modalities across localized and metastatic RCC, our findings underscore the evolving nature of HRQOL concerns across the RCC continuum. While physical symptoms and treatment side effects were highly relevant across both groups, their prominence among metastatic patients suggests the burden of advanced disease and systemic therapies. In contrast, patients with localized disease prioritized functional limitations and emotional concerns, potentially linked to surveillance-related anxiety. These insights support the need for stage-specific PROMs and highlight the importance of integrating both physical and emotional dimensions of care in RCC. Validation of such a tool for both localized and metastatic RCC is underway in forthcoming studies.

BACKGROUND AND OBJECTIVE:Despite significant advances in treatments for renal cell carcinoma (RCC) over the past decade, health-related quality of life (HRQOL) assessments have not been updated to reflect these developments. The aim of our study was to refine assessment of HRQOL for patients with localized or metastatic RCC. METHODS:We conducted a four-phase international study (August 2022-October 2024). Phase 1 involved a patient survey identifying relevant HRQOL issues. In phase 2, an expert panel refined items, followed by patient advocate feedback in phase 3. Phase 4 harmonized items with the Functional Assessment of Chronic Illness Therapy library for consistency across RCC stages. Data analysis included descriptive statistics and qualitative analysis of the content. KEY FINDINGS AND LIMITATIONS:Of 54 items from the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, and EuroQol Group-Five Dimension questionnaires, the metastatic RCC cohort endorsed 15 items, while the localized RCC cohort endorsed six. Expert panel review and patient advocate feedback resulted in a revised 23-item FKSI questionnaire with targeted subsets of 11 items for localized RCC and 12 items for metastatic RCC. Application of a relevance threshold of 66% ensured clinical significance but limited the sensitivity. Future studies could explore complementary approaches to refine item selection and enhance score interpretability. Study limitations include a potentially limited patient sample and reliance on patient recall of patient-reported outcomes. CONCLUSIONS AND CLINICAL IMPLICATIONS:We successfully developed item subsets of the FKSI-23 questionnaire that address the multifaceted impact of localized and metastatic RCC on patients' HRQOL. These two clinical settings required distinct tools for optimal measurement of HRQOL. Validation of the resulting FKSI-23 tool is under way in forthcoming clinical trials.

At the first interim analysis of the phase 3 KEYNOTE-426 trial, first-line pembrolizumab plus axitinib showed superior overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) over sunitinib for advanced renal cell carcinoma (RCC). To assess long-term durability of clinical outcomes and elucidate predictive biomarkers for RCC, we performed efficacy and prespecified exploratory biomarker analyses from KEYNOTE-426 with ≥5 years of follow-up. Pembrolizumab plus axitinib showed sustained benefits in OS (hazard ratio: 0.84; 95% confidence interval: 0.71–0.99), PFS (hazard ratio: 0.69; 95% confidence interval: 0.59–0.81) and ORR (60.6% versus 39.6%) compared to sunitinib. An 18-gene T-cell-inflamed gene expression profile (Tcell inf GEP) was positively associated with OS ( P = 0.002), PFS ( P < 0.0001) and ORR ( P < 0.0001) within the pembrolizumab plus axitinib arm. An angiogenesis signature was positively associated with OS ( P = 0.004) within the pembrolizumab plus axitinib arm and with OS ( P < 0.0001), PFS ( P < 0.001) and ORR ( P = 0.002) within the sunitinib arm. Across arms, programmed cell death ligand 1 combined positive score was only associated (negatively) with OS within the sunitinib arm ( P = 0.025). Additionally, PBRM1 (polybromo-1) mutation had a positive association with ORR ( P = 0.002) within the pembrolizumab plus axitinib arm. Within the sunitinib arm, OS was positively associated with VHL (von Hippel–Lindau tumor suppressor gene) ( P = 0.040) and PBRM1 ( P = 0.010) mutations and was negatively associated with BAP1 ( BRCA1- associated protein 1) mutation ( P = 0.019). Results showed a sustained clinical benefit with pembrolizumab plus axitinib over sunitinib and provide valuable information on biomarkers for immunotherapy-based treatment combinations in advanced RCC. Prospective clinical investigations are needed for biomarker-directed treatment for advanced RCC. ClinicalTrials.gov identifier: NCT02853331 .

Purpose Altmetric Attention Score (AAS) is a measure of the quantity of attention that a scholarly work receives, and evidence about gender gaps in AAS in oncology is lacking. Our objective was to analyze potential disparities in the AAS within oncology by comparing research publications authored by women first and last authors with those authored by men. Secondarily, we aimed to quantify the extent of over-/undercitation by gender. Materials and Methods The initial data set was compiled from the Altmetric database through Application Programming Interface (API) using oncology-related search terms. Author gender categories were assigned on the basis of the Gender Guesser API. For example, those with first and last authors labeled woman were categorized as woman first author/woman last author (WW). Over-/undercitation was calculated using observed citations and expected citations. Analyses were completed both for the oncology literature as a whole and for prominent subspecialty peer-reviewed journals. Results Our search yielded 652,834 articles published between January 1, 2009, and January 31, 2024. For AAS, women in the first author position had a 15.2% lower score compared with men counterparts and women in the last author position had an 8.3% lower score than men (P < .01 for both). Although the proportion of WW authors in oncology publications increased over time, the man first author/man last author combination was overcited (mean citation percentage difference [MCD] = +16.2%), whereas WW was undercited (MCD = -7.7%). There was variation in both proportion of WW papers and over-/undercitation among oncologic subspecialties. Conclusion Significant gender disparities in citation rates and AAS exist across various fields within oncology. This highlights a systemic issue where woman-authored research is undercited and receives less attention compared with man-authored work, with the potential to affect career advancement, funding opportunities, and academic recognition.

Supplementary Figure 2: Modest treatment-induced DNA methylation changes in UC tumors.

BACKGROUND AND OBJECTIVE:The rs4680 single-nucleotide polymorphism (SNP) of the COMT gene leads to a reduction in dopamine clearance, resulting in better mood and a decrease in symptoms in noncancer populations, but its influence on quality of life (QOL) during cancer treatment is undefined. We hypothesized that in comparison to wildtype (WT) COMT, the rs4680 SNP is associated with better QOL among men with metastatic hormone-sensitive prostate cancer receiving androgen deprivation therapy ± docetaxel (ADT ± D). METHODS:In this post hoc analysis, we tested the association between COMT rs4680 status and Functional Assessment of Cancer Therapy-Prostate (overall QOL), Functional Assessment of Chronic Illness Therapy-Fatigue, and Brief Pain Inventory scores at baseline and at 3, 6, 9, and 12 mo using Fisher's exact test and the Wilcoxon rank-sum test. Blood samples for genotyping were collected before treatment initiation. KEY FINDINGS AND LIMITATIONS:COMT SNP data were available for 550/790 men. Across the overall cohort, 3-mo pain severity was lower for rs4680 versus WT COMT (0.5 vs 1.25; p = 0.04). In the ADT arm, rs4680 versus WT COMT was associated with better overall QOL at 6 mo (128.9 vs 118.5; p = 0.04), less pain at 3 mo (no pain: 70.4% vs 41.5%; p = 0.01), and less pain interference at 3 mo (no interference: 76% vs 51.3%; p = 0.03), 6 mo (75% vs 48.7%; p = 0.02), and 9 mo (83.3% vs 52%; p = 0.02), with similar fatigue scores. Patients in the ADT + D arm had similar QOL regardless of COMT status. CONCLUSIONS AND CLINICAL IMPLICATIONS:Patients with the COMT rs4680 SNP experienced less pain and better global QOL after starting ADT alone. This is the first study to show that inherited genetic traits may influence treatment tolerability in men with prostate cancer.

815 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) or chemoradiation (CRT) is the standard of care for patients (pts) with muscle invasive bladder cancer (MIBC). Mutations in DNA damage repair genes enrich for pathologic downstaging after NAC. In RETAIN-1, a risk-adapted approach was employed to identify patients for cystectomy-sparing active surveillance (AS) following NAC, reporting a 73% 2-year MFS rate. RETAIN-2 employs a similar approach but incorporates neoadjuvant chemoimmunotherapy. Methods: This is a phase II, multi-institutional trial in which pts with cT2-T3N0M0 MIBC, ECOG PS 0-1 and CrCl≥50 mL/min received neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) with nivolumab. Pre-NAC transurethral bladder resection (TURBT) specimens were sequenced for mutations (pathogenic or VUS) in ATM , ERCC2 or RB1 . Pts with >1 mutation and clinical complete response (cCR) post-NAC (based on restaging TUR, urine cytology and CT imaging) initiated active surveillance (AS). Remaining pts underwent bladder-directed therapy: intravesical therapy (< cT2 post-NAC), CRT or RC. The primary endpoint is 2-year metastasis-free survival (MFS) for ITT pts which is not mature. This interim analysis reports clinically meaningful secondary endpoint outcomes. Results: A total of 80 pts were treated over 40 months at four academic centers and 71 were evaluable per protocol. The median age was 69 years (range: 66-86), 77% were male, 80% had ECOG PS 0 and 87% were cT2. Of 80 treated pts, 60 (75%) completed 3 cycles of AMVAC with nivolumab; 7 tolerated only 1 cycle, and 2 died shortly after completing 3 cycles from treatment-related adverse events and were not evaluable for the primary endpoint. Grade 3-4 TRAEs occurred in 19% of all treated pts. Of 71 evaluable ITT pts, 31 (44%) had a mutation of interest and the cCR rate in those pts was 71%; 35 pts proceeded directly to RC, 10 received CRT, 3 received intravesical therapy and 23 pts started per protocol AS. Of 23 AS pts, 4 did not have mutation. Similarly, 3 pts with tumor mutation and cCR chose RC. In pts who underwent RC, pT0 rate was 46%,

Supplementary Figure 3: Copy number variation detected by SeSAMe from DNA methylation data.

Despite the success of immune checkpoint inhibitors (ICI) for the treatment of renal cell carcinoma (RCC), many patients do not receive durable clinical benefit. Therefore, an understanding of resistance to ICIs is critical for the treatment of this disease. Using scRNA-seq, we previously found increased tissue-resident ZNF683 + (Hobit) SLAMF7+ CD8+ exhausted T cells (T-exh-SLAMF7) in human RCC resistant to PD-1 blockade in the HCRN GU16-260 trial. A T-exh-SLAMF7 gene expression signature (GES) was associated with worse clinical outcomes with PD-1 blockade in multiple validation cohorts. Here, through bulk RNA-seq of RCC biospecimens from 90 patients enrolled in this trial, we identified higher tertiary lymphoid structures (TLS) in patients responsive to PD-1 blockade and investigated the interplay between TLS and T-exh-SLAMF7 in shaping therapeutic responses. Bulk RNA sequencing was performed on tumor samples from 90 RCC patients enrolled in the HCRN GU16-260 clinical trial. GES scores were calculated for each sample by z-scoring all genes and then computing the average expression of the genes comprising each signature of interest. To validate TLS presence at the protein level, 19 FFPE RCC tumor samples were analyzed using a 7-plex multiplex immunofluorescence panel targeting DAPI, CD20, CD3, CD21, CD4, PD-1, and FOXP3. TLS were manually quantified based on the colocalization of B and T cell markers in organized structures. Patients were stratified by high versus low TLS and T-exh-SLAMF7 GES scores (≥ or < median) for downstream analyses of clinical response and progression-free survival. Patients with complete/partial response had a higher (≥ median) TLS GES score compared to patients with progressive disease (P = .0004). Similarly, high TLS signature scores were associated with improved progression-free survival (PFS; HR = 2.08, 95% CI: 1.28–3.4, P = .0032), indicating significantly higher risk of progression in patients with low TLS scores. We confirmed that tumors with a high TLS GES score had a higher number of TLS detected by multiplex immunofluorescence (P = .028). Finally, we analyzed the interplay between TLS and tissue-resident exhausted CD8+ T cells. We divided patients into four categories based on median split TLS and T-exh-SLAMF7 GES score values: TLS high SLAMF7 low (n = 28), TLS high SLAMF7 high (n = 15), TLS low SLAMF7 high (n = 28), and TLS low SLAMF7 low (n = 15). Patients with both high TLS and low T-exh-SLAMF7 GES scores had substantially improved PFS compared to all other patients (HR = 0.45, 95% CI: 0.26-0.79, P = .0052), with 60.7% PFS at 12 months compared to 25.9% in the remaining groups. These findings support a paradigm where both high TLS and low T-exh-SLAMF7 cells are required for optimal response to PD-1 blockade in RCC. Ongoing studies will use spatial transcriptomics and functional assays to evaluate the interaction between TLS and T-exh-SLAMF7 cells and to define the roles of SLAMF7 and Hobit in regulating CD8+ T cell effector functions within the RCC tumor microenvironment. Note: Encore Presentation; recently published in Cancer Discovery (PMID: 39992403)

526 Background: Existing HRQOL measures may not fully capture the experiences of patients with localized and advanced RCC. This study aimed to develop a validated, patient-centered HRQOL metric by incorporating insights from patients, advocates, and clinical experts for both localized and advanced RCC. We previously developed a questionnaire for advanced RCC (Bergerot et al., JCO 2024). In this study, we integrate it into the FKSI-19 model and create a new questionnaire. Methods: A four-phase approach was used. Previous work in advanced RCC assessed item relevance from established HRQOL measures (FKSI-19, EORTC QLQ-C30, EQ-5D), refined through patient feedback and expert review. This phase expanded to include localized RCC in the adjuvant setting. In Phase 1, patients with localized RCC rated the the relevance of 54 items from the metastatic cohort. Phase 2 included a panel of 11 expert refining the adjuvant-specific items. Phase 3 gathered feedback from patient advocates, and Phase 4 further refined the items by harmonizing them with the FACT library for consistency across RCC stages. Results: In Phase 1, 6 of 54 items were rated as most relevant by patients with localized RCC. Phase 2 refined these further, excluding redundant items and adding 4 new questions focused on adjuvant therapy. Phase 3 led to minor revisions after advocate review, and Phase 4, the new items were harmonized with validated FACT library questions. The final adjuvant-specific questionnaire comprises 10 items, addressing concerns such as long-term side effects, surveillance anxiety, and post-surgery emotional distress. The advanced-specific version includes 13 items. Both versions deemed to be of utmost importance to patients with localized and advanced disease. These items can be used as standalone scoring options, resulting in the creation of a novel FKSI-23 metric, allowing for customized questionnaires tailored to specific clinical scenarios. Conclusions: Through collective input from patients, advocates and experts, novel items that aid in capturing the experience of RCC patients were identified and existing metrics were refined to generate separate “scoring options” for patients with localized and metastatic disease. Validation of the resulting FKSI-23 tool is underway in forthcoming studies in RCC.

4576 Background: Enfortumab Vedotin (EV), an antibody drug conjugate targeting Nectin-4, has emerged as first-line treatment for advanced Urothelial Carcinoma (UC) in combination with pembrolizumab. Acute and cumulative toxicity due to EV can adversely impact quality of life. Treatment related adverse events (TRAEs) are managed with dose and schedule modifications. Current treatment paradigm is to treat until unacceptable toxicity or progression. Our single center, retrospective study, aims to assess the impact of EV dose reduction on treatment duration, AEs, and survival. Methods: We conducted a retrospective analysis of patients with UC treated with EV +/- pembrolizumab. Patients were divided into 3 groups: A) 1.25 mg/kg dose and not dose-reduced; B) 1.25 mg/kg dose and dose-reduced; C) EV < 1.25 mg/kg. Data was collected from the EMR and we evaluated OS, PFS, TRAEs, and number of doses received. Kaplan Meier and Cox proportional hazards regression models were used to compare PFS and OS between the 3 groups, and to evaluate treatment dose (1.25 mg or <1.25 mg) as a time-varying covariate. TRAEs (y/n) and number of doses received were examined using logistic and negative binomial regression respectively. Regression models adjusted for age, ECOG status, and receipt of concurrent pembrolizumab. Results: 153 patients comprised the 3 groups: A) n= 47; B) n=73; C) n=33. The cohort was majority male (78.4%) and white (79.1%) with no significant difference across groups. Median age and ECOG score were both significantly higher in group C (p<0.001 and p=0.033, respectively). Overall, 52.9% of patients received prior immunotherapy, while 35.9% of patients received concurrent pembrolizumab (similar across groups). Patients started on full dose EV then reduced (B) had significantly more TRAEs than groups A and C (Neuropathy; A: 15.2%, B:34.2%, C: 12.1%, p<0.001; Cutaneous AE; A: 4.3%, B:27.4%, C:2.1%, p=0.004). In unadjusted Kaplan Meier analyses (months), there was a trend but no statistically significant difference in PFS (A:6.4, B:10.1, C:13.1; p=0.1) or OS (A:10.5, B:15.6, C:22.9; p=0.22). In adjusted analyses (minimum 5 doses of EV), there was no difference in total doses received across groups(p=0.6867). Adjusted Cox proportional hazards regression (HR) showed significantly improved PFS and OS for the dose-reduced groups by both landmark (Table 1) and time-covarying analyses (<1.25 PFS, HR: 0.6 p=0.032; <1.25 OS, HR: 0.59 p=0.039). Conclusions: In adjusted analyses dose reduced groups had significantly improved PFS and OS. These results suggest that changes in dose can decrease overall AEs while maintaining efficacy, warranting prospective evaluation. 1.25 mg/kg dose and dose-reduced Significance Started < 1.25 mg/kg Significance Landmark Analyses PFS (HR) 0.48 p=0.019 0.44 p=0.049 Landmark Analyses OS (HR) 0.53 p=0.038 0.47 p=0.063

Supplementary Figure 10: Peripheral immune cell dynamics induced by combination therapy.

Supplementary Figure 12: HLA-DR and NKG2D abundance on peripheral lymphocytes associate with longer progression free survival.

Supplementary TablesSupplementary Table 1: Patient and tumor sample informationSupplementary Table 2: Tumor mutation burdenSupplementary Table 3: Unfiltered whole exome sequencing mutation analysisSupplementary Table 4: Filtered whole exome sequencing mutation analysisSupplementary Table 5: Immunohistochemistry scores of tumorsSupplementary Table 6: FACS panel for PBMC analysisSupplementary Table 7: Geometric mean fluorescence intensity (GMFI) from PBMC FACSSupplementary Table 8: Representativeness of Study Participants