Abstract Background: Immune checkpoint inhibitors (ICIs) are well-described to augment T cell responses and boost anti-tumor immune responses, with increased survival benefits of patients with a number of different indications treated with a variety of PD-1, PD-L1, or CTLA-4 targeting monoclonal antibodies. While the combination of nivolumab (nivo) and ipilimumab (ipi) is currently one of the standard-of-care treatments for patients with metastatic renal cell carcinoma (mRCC), the majority of patients still suffer disease progression. CBM588 is a live biotherapeutic product that has previously demonstrated ability to enhance clinical responses to nivo+ipi treatment in patients with mRCC. In our current study, we sought to explore immune correlatives of patients treated with nivo+ipi alone as compared to those treated with CBM588+nivo+ipi. Methods: Peripheral blood was collected from patients with mRCC treated across two clinical trials: the initial CBM588+nivo+ipi study (NCT0382911) and an ongoing CBM588 dose finding study of patients with (NCT06399419). Both trials enrolled treatment-naïve patient with mRCC with clear cell and/or sarcomatoid histology. The initial trial enrolled patients with or without CBM588 co-treatment at a 2:1 ratio. The initial trial enrolled patients treated with or without CBM588 at 4 × 108 CFU/dose, while the dose escalation study followed a 3+3 design with three dose levels of CBM588 (4 × 108 CFU, 1.2 × 109 CFU, and 4 × 109 CFU). Cryopreserved blood was thawed and analyzed by high parameter spectral flow cytometry for overall immune composition and detailed T cell phenotyping. Results: No significant differences were observed in myeloid cell or innate lymphocyte changes between patients treated with or without CBM588. Increased frequencies of proliferating CD8+ T cells (Ki-67+) were observed across all patients from baseline to Cycle 3 Day 1. The expansion of proliferating CD8+ T cells was significantly less accelerated in patients treated with CBM588+nivo+ipi as compared to those treated with nivo+ipi alone. Notably, the expanding Ki-67+ CD8+ T cell population identified demonstrated features of T cell exhaustion with less expression of CD127 (IL-7R) and higher expression of CD38, KLRG1, TIM-3 relative to other circulating CD8+ T cell populations. Conclusions: Our results suggest that CBM588 may improve patient responses to ICIs by restraining CD8+ T cell amplification and attenuating features of T cell exhaustion. The CBM588+nivo+ipi dose escalation study is still ongoing with further immune correlative analyses pending. Citation Format: Colt A. Egelston, Miguel Zugman, Hedyeh Ebrahimi, Regina Barragan Carrillo, Nazli Dizman, Salvador Jaime-Casas, Xiaochen Li, Daniela V. Castro, Benjamin Mercier, Marice Alcantara, Motomichi Takahashi, Atsushi Hayashi, Tom Parks, Sumanta Kumar Pal, Peter P. Lee, Alexander Chehrazi-Raffle. Microbiome modulation via CBM588 dampens T cell exhaustion in patients with metastatic renal cell carcinoma on dual immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6476.

e17096 Background: Therapy intensification has expanded combination strategies in metastatic prostate cancer (mPC) with improved outcomes in clinical trials. However, it remains unclear which patients derive incremental benefit from the addition of upfront docetaxel to androgen receptor pathway inhibitor (ARPI)–based doublet therapy. Methods: We identified adults with prostate cancer in the Patient360 Prostate dataset, a U.S.-based de-identified data source derived from electronic health records, linked claims, and mortality data. Patients initiating ARPI doublet (ARPI + androgen deprivation therapy [ADT]), docetaxel doublet (docetaxel + ADT), or triplet (ARPI + ADT + docetaxel) were included. Patient characteristics and treatment regimens were summarized descriptively; overall survival (OS) was estimated using Kaplan–Meier methods. Results: Patients with mPC were diagnosed between 1990 and 2025. Among patients without privacy-compliant date of birth suppression, median age was 67 years; 79.4% were White and 14.3% Black. ECOG performance status was 0–1 in 86.4%. ARPI doublet was the most common regimen (n = 7,676), followed by triplet (n = 1,389) and docetaxel doublet (n = 1,282; total n = 10,347). Compared with ARPI doublet, patients who received docetaxel-containing regimens had higher prevalence of adverse baseline features, including de novo metastatic disease (triplet 65.7%; docetaxel doublet 68.4% vs ARPI doublet 55.2%), liver metastases (14.8% and 17.9% vs 8.7%), and high-grade disease (Gleason 8–10: 55.5% and 57.2% vs 49.2%). Bone-supportive therapy use was also higher (66.7% and 73.4% vs 56.9%, respectively). A PSA nadir < 0.2 ng/mL was achieved in 42.9%, 29.1% and 30.2% of patients receiving ARPI doublet, docetaxel doublet and triplet, respectively. Median OS from regimen start was 109 months (mo) for ARPI doublet, 79 mo for triplet and 64 mo for docetaxel doublet. When stratified by PSA nadir < 0.2 ng/mL, median OS was substantially longer across all regimens (202, 128 and 104 mo, respectively), whereas among patients not achieving PSA nadir < 0.2 ng/mL, differences between regimens were attenuated (86, 71 and 59 mo, respectively). In multivariable Cox regression, baseline disease characteristics independently associated with worse OS included de novo metastatic disease (HR 3.71), liver metastases (HR 1.87), baseline PSA > 200 ng/mL (HR 1.39), and Gleason score 8–10 (all p < 0.0001). Conclusions: In the largest cohort to date comparing ARPI doublet and triplet therapy, ARPI doublet was the most common regimen and was associated with more favorable outcomes, even after multivariable adjustment. Non-achievement of PSA nadir identifies a population with poorer survival in whom docetaxel triplet therapy may be associated with improved outcomes, supporting the rationale underlying the TRIPLE-SWITCH (SWOG/CCTG-PR26) clinical trial.

Immunohistochemical expression for 21 cell surface markers across testicular germ cell tumor subtypes and histologic components.

INTRODUCTION:Belzutifan, a HIF-2α inhibitor, is approved for von Hippel-Lindau (VHL)-tumors and sporadic metastatic renal cell carcinoma (mRCC) after prior immunotherapy (IO) and tyrosine kinase inhibitor (TKI) therapy. Real-world data on outcomes and adverse events (AEs) of belzutifan in patients not represented in clinical trial settings remain limited. PATIENTS AND METHODS:A multicenter retrospective study of patients with mRCC treated with belzutifan was performed. Clinical efficacy outcomes included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Treatment-related AEs were also recorded. RESULTS:A total of 43 patients received belzutifan (26% Hispanic). Median age was 67 years (range, 21-86). Clear cell histology was predominant (91%); other histologies included mixed clear cell/papillary (n = 1); chromophobe with somatic VHL alteration (n = 1); unclassified RCC (n = 1). Common sites of metastases at belzutifan start included liver (33%), bone (30%), and peritoneum (19%). The median number of prior therapies was 3 (range, 0-6) including prior IO (95%) and TKI (88%). Among 36 evaluable patients, ORR was 25% (9 partial responses). At a median follow-up of 8.2 months, the median PFS was 5.7 months (95% CI, 3.3-10.7) and median OS was not reached (95% CI, 12.0-NR). Any AE was reported in 93% with all-grade anemia (79%), fatigue (30%); hypoxia (14%) being most common. The most frequent grade 3 to 5 AEs were anemia (30%) and hypoxia (7%). Discontinuation due to AE occurred in 12%. CONCLUSIONS:In this diverse, heavily pre-treated mRCC cohort with frequent visceral metastases, belzutifan had consistent clinical outcomes and toxicity profile with prior reports.

PURPOSE:Clinical trial availability often varies between countries, independent of the local burden of disease. We aimed to evaluate the current global availability of prostate cancer clinical trials and the factors affecting it. METHODS:We searched for clinical trials involving prostate cancer between June 2019 and June 2024 through Clinicaltrials.gov. Noninterventional trials were excluded. Countries were classified according to the World Bank Ranking (WBR) as high-, upper-middle-, lower-middle-, and low-income countries (HICs, UMICs, LMICs, and LICs). Multivariable negative binomial regression was used to evaluate the association between the number of trials and country's characteristics. Multivariable logistic regression was used to evaluate the association between trial availability and country's characteristics. In addition, we collected data on sponsorship, funding, intervention, intervention intent, end point selection, trial phase, and cancer stage. RESULTS:Of the 1,531 trials identified, 1,413 met the eligibility criteria. Most trials were conducted exclusively in HICs (80.4%), included patients with metastatic disease (55.4%), and were sponsored by academia (68.8%). Pharma-funded trials had a higher number of participating countries (mean 2.7 v 1.0, P < .001) and were more likely to include metastatic disease (72.0% v 32.3%, P < .001) and to investigate systemic therapy (76.3% v 29.4%, P < .001). In the multivariable analysis, WBR, gross national income (GNI), and annual health expenditure were all associated with the presence of at least one trial (P < .001). Only GNI was independently associated with the number of trials within a country (P < .001). CONCLUSION:Prostate cancer trials are disproportionately concentrated in HICs despite a lower burden of disease. Intentional efforts are needed to ensure global representation and long-term benefits for populations historically excluded from research.

Antibodies used for immunohistochemistry, including clone, catalog number, and vendor.

Importance:The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk criteria stratify metastatic renal cell carcinoma (mRCC) into favorable, intermediate, and poor risk groups, but heterogeneity within the favorable risk category remains poorly understood. Objective:To evaluate a proposed very favorable subgroup (tier 1: Karnofsky Performance Status ≥90%; diagnosis to treatment ≥3 years; and no brain, liver, and bone metastases) and characterize its molecular and clinical features. Design, Setting, and Participants:This retrospective cohort study analyzed IMDC data, from January 2015 to September 2024, of patients with favorable risk mRCC (tier 1 and tier 2 [favorable and not tier 1]). Molecular profiling leveraged IMmotion151 (A Study of Atezolizumab in Combination With Bevacizumab Versus Sunitinib in Participants With Untreated Advanced Renal Cell Carcinoma) trial data with whole-exome sequencing, RNA sequencing, and programmed cell death ligand 1 immunohistochemistry. Exposures:Systemic standard of care treatments for mRCC, which include vascular endothelial growth factor receptor targeted therapy (VEGF-TT [sunitinib or pazopanib]), immune-oncology-VEGF (IO-VE [pembrolizumab and axitinib, pembrolizumab and lenvatinib, nivolumab and cabozantinib, or avelumab and axitinib]), and 2 IO (IO-IO [ipilimumab and nivolumab]) regimens. Main Outcomes and Measures:The primary end point of this study was overall survival (OS) at 2 years of the favorable risk group and in the tier 1 and tier 2 subgroups with the different treatment options. Secondary end points included time to next treatment, treatment duration, and overall response rate. Outcomes were compared across treatment types: VEGF-TT, IO-VE, and IO-IO. Results:Among 641 patients with favorable risk mRCC (median [IQR] age, 65 [58-71] years; 475 males [74.1%]), 176 (27.5%) were in tier 1, and 465 (72.5%) were in tier 2. Those in tier 1 met criteria for a very favorable subgroup, characterized by similar age and treatment distribution but lower rates of sarcomatoid features; more patients with only 1 metastatic site; and an absence of brain, bone, and liver metastases compared with patients in tier 2 with favorable risk. Patients in tier 1 showed a median OS of 79.1 (95% CI, 73.7 to not reached) months vs 54.5 (95% CI 45.5-67.7) months in tier 2 (P < .001) and distinct molecular features: high polybromo-1 alterations (64.7%), low BRCA1-associated protein 1 alterations (8.8%), and programmed cell death ligand 1 positivity (21.9%); transcriptomics revealed less immune-infiltrated tumors (8.5% immunogenic clusters) than in the other subgroups. Clinically, IO-IO underperformed in tier 1, with a 2-year OS of 73.1% (95% CI, 49.1%-97.1%) vs 89.1% (95% CI, 79.0%-99.2%) with IO-VE and 92.4% (95% CI, 86.5%-98.3%) for VEGF-TT (IO-IO hazard ratio, 3.64 [95% CI, 1.49-9.06]; P = .005), and a lower overall response rate (26.3% vs 63.3% in IO-VE and 57.0% in VEGF-TT). Conclusions and Relevance:In this cohort study, the very favorable risk subgroup had a less immunogenic molecular profile and superior outcomes from VEGF-containing regimens (VEGF-TT and IO-VE) compared with the favorable risk group. The IO-IO combination showed significantly worse survival in this population, suggesting that VEGF inhibition remains essential for optimal outcomes.

Abstract Background. Prostate cancer (PC) is the second most common cancer among men in the US, with adenocarcinomas being the most prevalent histologic subtype (≥99%). Emerging evidence suggests that BRAF alterations, mostly annotated by protein altering mutations, may be drivers of prostate cancer progression in up to 6% of patients. Here we characterized, to our knowledge, the largest cohort of whole-exome and -transcriptome sequenced BRAF-altered PCs. We aimed to interrogate molecular features and clinical outcomes in BRAF-altered PCs. Methods. The Tempus Lens Platform (Tempus AI, Inc., Chicago, IL) was used to query the Tempus multimodal de-identified database and establish a cohort of 485 patients with prostate adenocarcinoma with xT (DNA) and xR (RNA) testing. Of those, 137 had BRAF alterations while the remaining 348 were considered BRAF wildtype (wt). BRAF alterations were defined as including a copy number alteration (CNA) or a single nucleotide variant (SNV) resulting in a short variant mutation. Of the BRAF-wt group, 94 were primary-tumor biopsies while 43 were metastatic biopsies. Within the BRAF-wt group, there were 210 primary tumors and 138 metastatic biopsies. RNA expression data was normalized and quantified as transcripts per million (TPM). BRAF mRNA expression from metastatic tissue were grouped as ultra-low (10th percentile), low (25th percentile), mid (50th percentile), and high (75th percentile). Overall survival (OS) was defined as the time from biopsy collection to death or loss to follow up and conducted using risk set adjustment through Cox proportional hazard analysis and reported by hazard ratios (HR). Results. We confirmed prior studies in that Class 2 BRAF mutations (p.K601) were the predominant form of alteration in PC (46%, 63 of 137). CN gains were the second most common BRAF alteration (15%, 21 of 137). Patients with BRAF Class 1, 2, 3 mutations demonstrated no significant difference in OS. However, metastatic PC patients with BRAF CN gain had worse OS relative to BRAF-wt (HR: 2.4, CI 95% 1.18-4.85, p=0.01). Among BRAF-wt PCs from metastatic tissues, those with ultra-low BRAF mRNA expression (bottom 10% within metastatic patients) exhibited worse OS compared to mid BRAF expression (HR:2.43, CI 95% 1.22-4.84, p=0.01). The median OS for PC patients with CN gain and ultralow BRAF gene expression were at 9.4 and 6.6 months, as compared to the wt group of metastatic patients at 15.6 months. Conclusions. The current paradigm for reporting BRAF status in PC patients requires revision. In addition to SNVs (class 1,2,3), we recommend reporting BRAF CN gain and BRAF mRNA ultralow expression - both may be indicative of a subset of prostatic adenocarcinomas with very poor OS. Future studies should examine the functional consequences of these BRAF perturbations in larger cohorts of PC patients as well as their therapeutic implications. Citation Format: Jesenia Marie Perez, David R. Moline, Hedyeh Ebrahimi, Ella Boytim, Eamon Toye, Stamatina Fragkogianni, Emmanuel S. Antonaraki, Alexander Chehrazi-Raffle, Justin Hwang. BRAF copy number alterations and ultralow BRAF mRNA expression are prognostic for poor overall survival in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1179.

Purpose Aberrant alternative splicing (AS) events have been implicated in cancer progression; however, their role in metastatic renal cell carcinoma (mRCC) remains underexplored. This study aims to identify AS events associated with clinical benefits from immune checkpoint inhibitors and targeted therapies in mRCC. Materials and methods We conducted a retrospective analysis on 101 patients with mRCC who received systemic therapy and underwent RNA sequencing. Patients were divided into subgroups based on ICIs (alone or in combination) and targeted therapies. Responders and non-responders were classified according to Response Evaluation Criteria in Solid Tumors V.1.1 criteria. Differential gene expression and splicing analyses were performed between responders and non-responders in each cohort. Novel AS events were analyzed for their potential to generate peptide neoantigens through major histocompatibility complex (MHC) class I binding predictions. Results Outlier splicing analysis identified 10 aberrant splice events specific to mRCC. AS analysis revealed 461 differentially spliced events between responders and non-responders in the ICI cohort and 253 in the targeted therapy cohort, with intron retention as the predominant motif. Thirteen unique AS events were enriched in responders, including PTPN6 and ACTN1. Predictive neoantigen analysis identified high MHC class I binding potential in peptides from AS events in IFFO1 and ZNF692. High splice burden was linked to an immunogenic tumor microenvironment, characterized by enriched antigen processing and adaptive immune responses. Conclusions This study provides a comprehensive analysis of AS events in mRCC, highlighting intron retention as potential biomarkers for treatment response. Identified AS-derived neoantigens may serve as potential targets for adoptive cell therapy strategies.

507 Background: Two randomized phase I trials demonstrated that CBM588, a live biotherapeutic, may enhance the antitumor efficacy of frontline ICI-based regimens in mRCC (Dizman et al Nat Med 2022; Ebrahimi et al Nat Med 2024). For the first time, we present an updated, pooled analysis of long-term clinical outcomes from a combined cohort of these two studies. Methods: Data from two open-label, randomized phase I clinical trials were analyzed. Eligible patients were adults with advanced or metastatic RCC, Karnofsky performance status ≥70%, no prior systemic therapy, and measurable disease per RECIST 1.1. Participants were randomized to receive nivolumab/ipilimumab or nivolumab/cabozantinib alone (standard of care [SOC]) or with CBM588 (SOC + CBM588). The pooled clinical outcomes including objective response rate (ORR; complete response [CR] or partial response [PR]), disease control rate (DCR; CR, PR, or stable disease [SD] ≥ 6 months), progression-free survival (PFS), and overall survival (OS), were compared between treatment groups, using Fisher’s Exact test and Kaplan Meier log rank test, respectively. The TOPOSCORE, a measure of microbial dysbiosis associated with poor prognosis with ICIs, was derived for all stool samples collected across both studies, using previously published bioinformatic methods (Derosa et al Cell 2024). Results: Fifty-nine patients were included: 20 received SOC and 39 received SOC + CBM588. The median age was 65 years (range 36-90); 69.5% were male, 88.1% had clear-cell mRCC, and 67.8% had intermediate/poor IMDC risk. Baseline characteristics were similar in both arms. Pooled ORR and DCR were 66.7% and 82% with SOC + CBM588 versus 20% and 55% with SOC alone (p = 0.001 and p = 0.019, respectively). Median follow-up was 43.9 months (95% CI 42.5-73) for SOC+CBM and 44.1 months (95% CI 35.4-NE) for SOC. Median PFS was 32.0 months (95% CI 16.6-NE) with SOC + CBM588 and 3.7 months (95% CI 2.6-17.0) with SOC, with a hazard ratio (HR) of 0.36 (95% CI 0.19-0.67; p = 0.001). Median OS was 52.7 months (95% CI 37.3-NE) with SOC+CBM588 and 45.7 months (95% CI 29.2-NE) with SOC (HR 0.69, 95% CI 0.32-1.47, p = 0.33). Exploratory analysis using the TOPOSCORE microbiome metric showed that baseline microbiota profiles were similar between SOC and SOC + CBM588 in both trials. Notably, however, baseline gut microbiota composition was associated with treatment response in the dual ICI subgroup, but not in the ICI + VEGFR-TKI subgroup. Conclusions: In this pooled analysis of two randomized phase I trials, the addition of CBM588 to frontline ICI-based therapy was associated with higher ORR and prolonged PFS compared with SOC alone, supporting the design of the upcoming phase III SWOG BIOFRONT study. We also identify baseline TOPOSCORE as a potential predictor of benefit with dual ICI regimens. Clinical trial information: NCT05122546 , NCT03829111 .

Abstract Background: N/I is a standard first-line therapy for mRCC. Our group has shown that gut microbiome modulation may enhance immune checkpoint inhibitor (ICI) efficacy in mRCC (Dizman et al, 2022; Ebrahimi et al, 2024). In preclinical models, camu camu, a polyphenol-rich Amazonian berry, enriched Ruminococcus spp. in the gut microbiome and improved responses to ICI in mice (Messaoudene et al 2022). We prospectively evaluated the biological and clinical effects of adding camu camu to N/I for mRCC therapy. Methods: This single-center, randomized, phase I trial enrolled pts. ≥18 years with clear-cell mRCC, IMSC intermediate- or poor-risk disease, ECOG 0-1, measurable disease, and adequate organ function. Prior systemic therapy was not allowed, except adjuvant or neoadjuvant therapy completed ≥6 months without prior ICI exposure. Patients were randomized 2:1 to receive standard-dose N/I (3 mg/kg plus 1 mg/kg every 3 weeks for 4 doses, then N 480 mg every 4 weeks) with or without camu camu 1500 mg PO daily. The primary endpoint was the change in Ruminococcus spp. abundance in stool from baseline to week 13. Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), safety, changes in microbiome diversity, and plasma cytokine assessment. A 2-group t-test with a 1-sided type I error of 0.05 was used to assess the primary endpoint, increase in Ruminococcus spp. with camu camu. Results: We enrolled 31 patients (21 N/I plus camu camu; 10 N/I alone) with a median follow-up of 15.9 months. Median age was 64 years (range 45-84),10% had sarcomatoid features, 35% had a nephrectomy, and 29% presented poor-risk disease. Median PFS was 16.4 months (95% CI 5.5-not estimable [NE]) in the camu camu arm vs 5.4 months (95% CI 2.6-NE) with N/I alone (p=0.04). ORR was 33% in the experimental and 10% in the control arm (p=.2). Median OS was not reached in either arm. No significant differences in Ruminococcus spp. abundance present. Alpha diversity as measured by species richness in the placebo arm decreased from baseline to week 13 (p=0.02), whereas it remained stable in the camu camu arm (p=0.5). In the N/I arm, there was an increased differential abundance at week 13 compared to baseline in deleterious bacteria such as Collinsella aerofaciens, Veillonella rogosae, and Enterococcus gallinarum, while beneficial bacteria including Ruminococcus lactaris remained enriched at week 13 in the camu camu arm. The proportion of beneficial SIG2 TOPOscore (Derosa et al., Cell 2024) bacteria significantly increased at week 13 in responders (15% vs. 29%, p<0.001), not observed in the N/I group. The most frequent adverse events (AEs) in both arms were fatigue and anemia. Patients in the camu camu arm displayed a distinct pattern of immune-related AEs (irAEs), including cerebritis (n=2),immune thrombocytopenic purpura (n=1), and adrenal insufficiency (n=6). Cytokine assessment showed significant changes at week 13 compared with baseline in this group, with increased IL-10 and IL-17A, and reduced IL-8 levels. Conclusion: In this first randomized trial evaluating a natural prebiotic with ICI in first-line mRCC, the addition of camu camu prolonged PFS and beneficially shifted the gut microbiome. The irAEs observed with camu camu, together with associated cytokine alterations, emphasize the need for close monitoring in future studies. Citation Format: Regina Barragan Carrillo, Miguel Zugman, Bertrand Routy, Mallia Geiger, Xiaochen Li, Nazli Dizman, Hedyeh Ebrahimi, Salvador Jaime-Casas, Nicholas Salgia, Joann Hsu, Daniela V. Castro, Benjamin D. Mercier, Koral Sha, Sreya Duttagupta, Tanya B. Dorff, Neal S. Chawla, Ruchi Agarawal, Ekta Kapoor, Marcin Kortylewski, Alex Chehrazi-Raffle, Arielle Elkrief, Sumanta K. Pal. Camu camu plus nivolumab/ipilimumab (N/I) as first-line therapy for metastatic renal cell carcinoma (mRCC): A randomized phase I trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT182.

Abstract Background First-line therapies with combinations of ICI-ICI and ICI-tyrosine kinase inhibitor (TKI) are commonplace in mRCC. Frequency of irAEs in patients receiving first-line ICI-based therapies is high, with grade ≥ 2 (G ≥ 2) typically warranting active management. Although prognostication based on irAEs has been demonstrated, prediction of irAE occurrence in mRCC remains a challenge. We investigated the role of baseline hematologic markers to predict G ≥ 2 irAE occurrence with first-line ICI-based therapies in mRCC. Methods We used the City of Hope database (encompassing 5 centers across 4 states) to retrospectively identify mRCC patients treated with first-line ICI-based therapies from September 2015 to September 2025. Baseline patient demographics, including age, gender, Karnofsky Performance Status (KPS), pre-existing autoimmune condition, IMDC risk group and first-line ICI-based regimen were collected. We stratified baseline hematologic markers, including neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-eosinophil ratio (NER), platelet-to-lymphocyte ratio (PLR), systemic inflammatory index (SII) and absolute eosinophil count (AEC), into high and low levels using recursive partitioning, and evaluated their association with occurrence of first-line ICI-related G ≥ 2 irAEs. Results A total of 198 patients with mRCC were treated with first-line ICI-based therapy, of which 5 were excluded due to insufficient data. Of the 193 evaluable patients, the mean age was 61, 131 patients (67.9%) were male, 100 patients (51.8%) received ICI-ICI and 93 patients (48.2%) received ICI-TKI. G ≥ 2 irAEs were observed in 55 patients (28.5%), requiring systemic steroid use in 32 patients (16.6%) and treatment discontinuation in 30 patients (15.5%). The most common G ≥ 2 irAE was ALT/AST elevations, seen in 16 patients (8.3%). Of the baseline hematologic markers studied, increased PLR and SII were most strongly associated with occurrence of G ≥ 2 irAEs (P < 0.005 for each). Conclusions Our results point to a novel potential role of PLR and SII as predictive biomarkers of G ≥ 2 irAEs, with ICI-based therapies in mRCC, meriting further validation in prospective studies.

4519 Background: The Clostridium butyricum -based live biotherapeutic, CBM588, demonstrated signals for enhanced clinical activity with first-line ICB combinations in two randomized phase I trials for mRCC. However, impact of microbial dysbiosis on the benefit of CBM588 supplementation is unclear. Herein, we examined prognostic and predictive value of microbial dysbiosis with CBM588. Methods: We analyzed clinical outcomes and stool whole-genome sequencing data from a combined cohort from two randomized phase I clinical trials. Both enrolled treatment-naïve patients with mRCC and randomized them to receive nivolumab/ipilimumab (NCT03829111) or nivolumab/cabozantinib (NCT05122546) alone (standard of care [SOC]), or with CBM588 (SOC+CBM588). Baseline TOPOSCORE, a stool metagenomic dysbiosis index linked to ICB outcomes, was analyzed continuously (S score positively correlated with dysbiosis) and categorically (SIG1+ [dysbiosis phenotype] vs SIG2+ [non-dysbiosis]). Associations with progression free survival (PFS) and objective response rate (ORR, per RECIST 1.1) with SOC and SOC + CBM588 were assessed. Results: Fifty-nine patients were included: 39 in the SOC + CBM588 arm and 20 in the SOC arm. Median age was 65 (range 36-90), with the majority male (69.5%), clear-cell (88.1%) and intermediate/poor risk (67.8%) mRCC. Baseline clinical characteristics were comparable across arms. ORR was 66.7% in SOC+CBM588 arm versus 20.0% in the SOC arm (p = 0.001). Median PFS was 32.1 months (95% CI 16.6-NR) with SOC+CBM588 versus 3.7 months (95% CI 2.6-17.0) with SOC (HR 0.36 [95% CI 0.19, 0.67], p = 0.001). At baseline, S score was similar across arms (p = 0.16), and SIG1+ was seen in 55.6% of patients in the SOC+CBM588 arm versus 44.4% in the SOC arm (p = 0.441). While differences in PFS were not statistically significant in the SIG2+ cohort between SOC+CBM588 and SOC alone (32.0 vs 10.9 months, HR 0.49 [95% CI 0.19-1.3], p = 0.149), in the SIG1+ setting, a PFS improvement was seen for SOC+CBM588 versus SOC alone (24.9 vs 2.8 months, HR 0.19 [95% CI 0.07-0.53], p < 0.001). Notably, S score was associated with response to SOC+CBM588 among patients who received nivolumab/ipilimumab backbone (median S score 0.668 in response vs 0.540 in no response, p = 0.046), while no such association was observed in patients treated with nivolumab/cabozantinib backbone (median S score 0.681 vs 0.821, p = 0.554, respectively). Conclusions: Addition of CBM588 to ICB-based first-line combinations conferred a disproportionately greater benefit in patients with a dysbiotic stool phenotype, underscoring actionability of TOPOSCORE as a potential predictive biomarker in this setting. The upcoming phase III randomized placebo-controlled BIOFRONT trial will assess clinical activity of CBM588 and advance microbiome-based predictive biomarker development in mRCC.

503 Background: CBM588 has shown potential to improve clinical outcomes when combined with immune checkpoint inhibitors (ICIs) in untreated mRCC (Dizman et al Nat Med 2022; Ebrahimi et al Nat Med 2024). Since no significant treatment-related adverse events were related to CBM588 in previous studies, we sought to determine if CBM588 capsules, a novel formulation of this live biotherapeutic, designated MO-03, could be delivered at higher doses with similar tolerability and greater biologic effect. Methods: Patients (pts) with treatment-naïve mRCC and any international mRCC Database Consortium (IMDC) risk were treated with nivo (3 mg/kg q3w ×4, then 480 mg q4w) and ipi (1 mg/kg q3w ×4) plus CBM588 at one of three dose levels (4 × 10⁸, 1.2 × 10⁹, or 4 × 10⁹ CFU BID) in a 3+3 dose-escalation design. The primary endpoint was safety, with secondary endpoints including response rate and progression-free survival. Stool samples collected at baseline and Week 13 were analyzed by metagenomic sequencing to assess microbial composition across CBM588 dose levels. Plasma samples collected at baseline and Cycle 3 were analyzed for soluble mucosal addressin cell adhesion molecule-1 (sMAdCAM-1), a biomarker associated with dysbiosis (Fidelle et al Science 2023). Results: Twelve pts were treated between 6/26/2024 and 9/15/2025. Median age was 69 (range 48-80). All had clear cell histology without sarcomatoid features; two had rhabdoid features. Half the cohort had ≥3 metastatic sites, most commonly involving the lung, lymph nodes, and contralateral kidney. Most patients had favorable (50%) or intermediate (42%) IMDC risk. No dose-limiting toxicities (DLTs) were observed at any dose level, and no dose-dependent increase in immune-related toxicity was noted with CBM588 escalation. Notably, Bacteroides thetaiotaomicron showed a dose-dependent increase in relative abundance across escalating CBM588 levels (P = 0.0043 for Level 3 vs Level 1 and P = 0.0047 for Level 3 vs Level 2, Mann–Whitney U), suggesting a selective modulation of gut microbial composition. Among 11 pts with evaluable disease, 3 were responders (1 complete response, 2 partial responses), 6 had stable disease, and 2 had progressive disease. Baseline sMAdCAM-1 levels were similar between responders (Rs) and non-responders (NRs) (median: 205,196 vs. 206,462 pg/mL). However, percent change from baseline to Cycle 3 demonstrated a diverging pattern, with an early increase in Rs and relative stabilization in NRs (median: +8.2% vs –0.1%). Conclusions: No DLTs were encountered with CBM588 capsules at the highest dose level (MO-03) in combination with nivo/ipi, supporting the dosing strategy in the upcoming phase III SWOG study S2419 (BioFront). Translational studies indicate a dose effect upon microbiome composition, and sMAdCAM-1 dynamics suggest a potential association with response. Clinical trial information: NCT06399419 .

Background: Bladder cancer disproportionately affects non-high-income countries, yet clinical trials underrepresent global diversity. We assessed global availability of bladder cancer trials, their alignment with disease burden, and barriers to equitable care. Methods: We queried ClinicalTrials.gov for adult bladder cancer trials from June 2019 to June 2024, excluding observational and non-oncologic trials. Trial characteristics were summarized descriptively, and country data came from the Global Cancer Observatory. Countries were classified per World Bank Ranking (WBR) into high-income (HICs), upper middle-income (UMICs), lower middle-income (LMICs), and low-income countries (LICs). Trials were categorized as HIC-only, non-HIC, or mixed-income trials. Fisher's exact and Kruskal-Wallis tests compared groups. Multivariable logistic regression assessed associations between trial availability and WBR, national health expenditure, and gross national income (GNI). Univariable linear regression and ANOVA assessed the association between the mortality-to-incident ratio and WBR. Results: Of 611 trials, 75.1% were HIC-only, 16.9% non-HIC, and 8.0% mixed-income trials. Non-HIC trials were mainly academic-sponsored (80.6%), while all mixed-income trials had pharmaceutical sponsorship (p < 0.001). Non-HIC trials had lower enrollment, less pharmaceutical funding, fewer multinational collaborations, and fewer basket, multi-arm, early-phase designs (all p < 0.001). Mixed-income trials were larger, led by HICs, had broader eligibility criteria, more novel therapies, and more frequent use of overall survival endpoints. Trial availability was lower in UMICs (p = 0.011), LMICs (p = 0.024), and absent in LICs, and positively associated with higher national health expenditure (p = 0.007) and GNI (p = 0.001). Conclusions: Bladder cancer trials remain concentrated in HICs. Mixed-income trials expand access in non-high-income countries, but are exclusively led by HICs and require balanced sponsorship, early-phase research, and lasting local benefits.

Abstract To characterize clinically actionable cell surface proteins in testicular germ cell tumors (GCT), we retrospectively analyzed archival formalin-fixed, paraffin-embedded orchiectomy specimens from 30 patients, including 11 with pure seminoma and 19 with mixed GCTs. Immunohistochemistry was performed for 21 surface antigens using an automated platform. Staining intensity (0 to 3+) and the percentage of positive tumor cells were used to derive H-scores (0–300). Expression was summarized by patient classification and histologic component; high expression was defined as H-score ≥100. Claudin-6 (CLDN6) was diffusely and strongly expressed, with H-score ≥100 in 100% of pure seminomas and 89.5% of mixed GCTs. At the component level, 100% of seminoma and 92.9% of embryonal carcinoma samples reached this threshold. Epidermal growth factor receptor (EGFR) showed high expression in 68.4% of mixed GCTs and 45.5% of pure seminomas, with most enrichment in teratoma components (73.3%, ≥100; mean H-score, 212). TROP2 was markedly upregulated in mixed GCTs (78.9%, ≥100; mean, 194.7), particularly in teratoma components (86.7%, ≥100). Nectin-4 and glycoprotein nonmetastatic melanoma B (GPNMB) were expressed in smaller but notable subsets, including teratoma and seminoma, whereas most remaining antigens, including CD19, DLL3, FOLR1, and BCMA, showed minimal or no expression. These findings demonstrate a distinct surface antigen landscape in testicular GCTs, with CLDN6, EGFR, and TROP2 emerging as leading candidates for further translational evaluation. The enrichment of these targets highlights antigenic heterogeneity within GCTs and supports further validation in appropriate disease settings, including metastatic, posttreatment, and relapsed or refractory disease. Significance: Relapsed or refractory testicular GCT remains a clinical challenge with limited treatment options. We evaluated cell surface antigens of primary GCTs and identified CLDN6, EGFR, and TROP2 as candidate targets for antigen-directed approaches. These findings provide a rationale for future validation in metastatic and posttreatment disease settings.

Immunohistochemical staining of selected cell surface markers across testicular GCT subtypes. A, CLDN6 (membranous staining) in seminoma, (B) CLDN6 (membranous staining) in yolk sac tumor, (C) EGFR (membranous staining) in seminoma, (D) EGFR (membranous staining) in teratoma, (E) TAG72 (membranous and cytoplasmic staining) in seminoma, (F) TAG72 (membranous and cytoplasmic staining) in choriocarcinoma, (G) TROP2 (membranous staining) in seminoma, (H) TROP2 (membranous staining) in teratoma, (I) Nectin-4 (membranous and cytoplasmic staining) in seminoma, (J) Nectin-4 (membranous and cytoplasmic staining) in teratoma, (K) GPNMB (membranous and cytoplasmic staining) in seminoma, (L) GPNMB (membranous and cytoplasmic staining) in embryonal carcinoma, (M) c-MET (nuclear staining) in seminoma, (N) c-MET (nuclear staining) in embryonal carcinoma, (O) HER2 (membranous staining) in teratoma, and (P) c-MET (membranous and cytoplasmic staining) in choriocarcinoma.

862 Background: Sarcomatoid variant of UTUC (S-UTUC) is a rare and aggressive malignancy. Due to the paucity of reported literature, the molecular landscape and potentially targetable alterations harbored by these tumors are not well described. We aimed to comprehensively compare the clinical, pathological, and genomic profiles of S-UTUC and conventional UTUC. Methods: We leveraged the Tempus LENS genomic dataset to extract clinical, pathologic, and somatic genomic alteration data from patients with UTUC and S-UTUC. Patients with any-stage disease who underwent either blood- or tissue-based next-generation sequencing were included. Baseline clinical and demographic characteristics were summarized using descriptive statistics. Comparisons between groups were performed using Chi-square or Fisher’s exact tests for categorical variables, and Student’s t-test or ANOVA for continuous variables, as appropriate. Mutational frequencies and pairwise comparisons were performed to assess significant differences between histological groups. Results: In total, 1721 patients were included, of which 1600 (93%) had UTUC and 121 (7%) had S-UTUC. Patients with S-UTUC were younger at diagnosis, 61 years (IQR 54, 69), compared to UTUC (71 years, IQR 64, 77) (p < 0.001). Compared to UTUC, patients with S-UTUC were more likely to have node-positive (24% vs 10%), pT4 (13% vs 11%), and stage 4 disease (37% vs 0.5%) (all p < 0.05). Patients with S-UTUC were more likely to have visceral metastasis to the lung (44% vs 30%), bone (19% vs 10%), and brain (7% vs 1%) compared to patients with UTUC (all p < 0.05). Among patients with S-UTUC, the most common genomic alterations were TERT (30%), TP53 (29%), NF2 (19%), PTEN (13%), SETD2 (12%), PBRM1 (12%), and BAP1 (8%). Among patients with UTUC, the most common genomic alterations were TERT (52%), TP53 (52%), KMT2D (30%), FGFR3 (25%), ARID1A (20%), and KDM6A (18%). S-UTUC group was significantly enriched with NF2, SETD2, PBRM1, PTEN, and BAP1 (all p < 0.05), with lower prevalence of FGFR3 (0% vs 8%) and FGFR4 (0% vs 8%) mutations compared to UTUC (both p < 0.05). Alterations in genes with potentially actionable targets were observed in S-UTUC, including NF2 (19%), SETD2 (12%) , PTEN (13%), and PI3KCA (2%). Conclusions: Compared to UTUC, S-UTUC demonstrated a more aggressive clinical and genomic profile, characterized by a younger age at onset, more aggressive metastatic tropism, relative enrichment in NF2, SETD2, PTEN and PI3KCA alterations , and an absence of FGFR- family mutations. These findings underscore the divergent molecular landscape of S-UTUC and highlight potentially targetable genomic alterations to guide precision oncology strategies for this rare disease.

449 Background: Clinical trials are the cornerstone for developing novel therapies and diagnostic tools. Due to advancements from clinical trials, the median overall survival (OS) of patients with metastatic RCC has increased 4-fold in the last 20 years (Lancet 2024). However, clinical trial availability remains disproportionately concentrated in high-income regions, limiting the inclusion of a diverse patient population (JCO CCI 2020). We aimed to assess the current state of the global availability of clinical trials for RCC. Methods: Using the National Clinical Trials database, we identified all clinical trials enrolling patients with RCC from 6/1/2019 to 6/1/2024. We initially screened all trials and excluded those involving non-interventional studies, pediatric patients, and non-RCC neoplasms. Per trial, we annotated which countries had at least one active site. We classified them based on income using the World Bank Ranking (WBR) into high-income (HICs), upper-middle-income (UMICs), lower-middle-income (LMICs), and low-income (LICs) countries. Additionally, we registered information on RCC type, sponsor, phase, cancer stage, and primary and secondary endpoints. We used descriptive statistics to summarize the characteristics of each trial. The association between RCC trial availability and WBR was assessed using the Kruskal-Wallis test. We applied Poisson regression analysis to evaluate the association between clinical trial availability and incidence, mortality, WBR, health expenditure, and gross national income (GNI). Results: Out of 558 identified RCC trials, 357 met the eligibility criteria and 201 were exclude. The median number of countries per trial was 2.6. Most trials were conducted exclusively in HICs (76%), with fewer trials available in UMICs (23%), LMICs (3%), and none in LICs. The majority of trials included patients with clear cell RCC (52%) and metastatic disease (80%). Furthermore, 47% of trials were sponsored by academic institutions and 81% were early-phase trials. We found that the WBR was significantly associated with RCC clinical trial availability (p < .001). UMICs, LMICs, and LICs had significantly lower odds of hosting RCC clinical trials than HICs (OR 0.2, 0.05, and 0.013, respectively). Moreover, trials in non-HICs were more frequently funded by pharma (64% vs 40%), were part of multinational trials (45% vs 16%) and were late-phase trials (25% vs 8%). Poisson regression analysis revealed that GNI, health expenditure, and mortality rates were significantly associated with the number of clinical trials in a country. Conclusions: RCC clinical trials are disproportionately concentrated in HICs, with a direct association between GNI, health expenditures and trial availability. Expanding access to a broader range of trials, including early-phase and academic-sponsored studies, in underserved regions will promote more equitable advancements for all RCC patients.