OBJECTIVES:To review how response to neoadjuvant therapy (NAT) is assessed in clinical trials of muscle-invasive bladder cancer (MIBC), and to determine whether trial-derived evidence can inform response evaluation in contemporary practice. SUBJECTS/PATIENTS AND METHODS:We searched PubMed, Embase and ClinicalTrials.gov through August 2025 for randomised controlled trials (RCTs) of neoadjuvant chemotherapy, chemo-immunotherapy or immunotherapy in non-metastatic MIBC (cT2-T4a N0-1 M0), and for prospective single-arm chemo-immunotherapy or immunotherapy trials. We extracted data on imaging modality and coverage, endoscopic and biomarker-based assessment, timing, correlation with final pathology and diagnostic accuracy. Given heterogeneity in definitions and reporting, no meta-analysis was performed. RESULTS:We identified 22 studies, including 14 RCTs. Most incorporated response evaluation, yet methods differed widely. Computed tomography (CT) was the most frequent modality in RCTs, whereas bladder magnetic resonance imaging (MRI) predominated in recent single-arm immunotherapy trials. Timing was inconsistent and usually post-treatment; only two trials performed interim assessment. Endoscopic evaluation was concentrated in bladder-preservation trials, and circulating tumour DNA (ctDNA) was used selectively. Only five studies correlated restaging with final pathology; multiparametric MRI scored with nacVI-RADS predicted pathological complete response with 72%-83% accuracy. No trial reported imaging accuracy for distant metastases after NAT. CONCLUSION:Response assessment after NAT in MIBC remains insufficiently standardised. Trial-derived evidence supports cross-sectional imaging before radical local treatment, with CT the most established modality, largely reflecting trial-design conventions and availability rather than demonstrated diagnostic superiority; bladder MRI is more accurate for local restaging. Emerging biomarkers such as ctDNA require validation. Harmonising timing, modalities and response definitions is needed to enable evidence-based treatment adaptation.

Background Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy is the leading theranostic strategy for metastatic castration-resistant prostate cancer (mCRPC). Randomised trials have shown survival benefit with [177Lu]Lu-PSMA-617, but prospective multicentre real-world data for the widely used alternative ligand [177Lu]Lu-PSMA-I&T remain scarce. In this study, we evaluated the safety and clinical activity of [177Lu]Lu-PSMA-I&T in routine practice. Methods This prospective, multicentre, Swiss registry enrolled consecutive men older than 18 years with histologically confirmed prostate adenocarcinoma undergoing intravenous [177Lu]Lu-PSMA-I&T therapy (7 GBq every 6 weeks for up to six cycles). Eligible patients had Eastern Cooperative Oncology Group performance status of 2 or less and PSMA-positive mCRPC with progressive disease after androgen receptor pathway inhibitor therapy or chemotherapy, or both, unless deemed unfit. The primary outcome was safety, assessed by treatment-emergent adverse events graded according to Common Terminology Criteria for Adverse Events (version 5.0). Assessments were performed at predefined timepoints before each treatment cycle and during the post-therapy follow-up. Secondary outcomes included the best prostate-specific antigen (PSA) response and PSA decline of 50% or more (PSA50) response according to the Prostate Cancer Working Group 3 criteria. All patients who underwent at least one treatment cycle were included in the final analysis of the observational registry. This study is registered at ClinicalTrials.gov, NCT06830408. Findings Between May 25, 2020, and June 4, 2024, 333 patients with mCRPC received [177Lu]Lu-PSMA-I&T therapy and were included in the analysis. The median follow-up was 12·0 months (IQR 6·5–20·0). Grade 3 treatment-emergent haematological toxicities included anaemia in 26 (8·8%; 95% CI 5·8–12·6) of 295, thrombocytopenia in nine (3·1%; 1·4–5·7) of 295, leukopenia in five (1·7%; 0·6–3·9) of 295, lymphopenia in 54 (21·1%; 16·3–26·6) of 256, and neutropenia in one (0·4%; 0·0–2·2) of 256. No grade 3 or worse renal toxicity or grade 4–5 treatment-emergent adverse events were observed. Best PSA response was achieved in 198 (64·3%; 95% CI 58·7–69·6) of 308 patients and PSA50 in 137 (44·5%; 38·8–50·2). Interpretation [177Lu]Lu-PSMA-I&T showed clinically meaningful activity with a favourable safety profile in heavily pretreated mCRPC. These findings provide prospective evidence supporting the safety and activity of PSMA-targeted radioligand therapy with [177Lu]Lu-PSMA-I&T in routine clinical practice. Funding Swiss Hadron Foundation.

Despite excellent cure rates in first-line and salvage treatment, some patients with germ cell tumors (GST) develop progressive disease even after intensified treatment with high-dose chemotherapy (HDCT). No established standard exists for this treatment-refractory disease situation, the prognosis of patients is generally poor, sustained remission is very rare, and the therapeutic concept is normally palliative. Gemcitabine-based combinations continue to represent the most important systemic option. Immune checkpoint inhibitors have failed to show relevant efficacy in various studies. Classical targeted therapies such as multi-tyrosine kinase or mTOR inhibitors are ineffective in most cases. Some new approaches, including CD30-targeted antibody-drug conjugates as well as claudin-6-targeted chimeric antigen receptor (CAR) T-cell therapies in particular have delivered first indications of clinical activity and new perspectives. The clinical relevance of these novel approaches is currently being assessed in trials.

Salivary gland carcinomas (SGC) are rare, heterogenous malignancies with limited treatment options in recurrent or metastatic (r/m) disease. We investigated the impact of immunohistochemical and molecular markers on treatment choice and patient outcomes. We retrospectively investigated clinical, pathological and molecular characteristics of 51 patients (pts) with r/m SGC treated at the University Hospital Zurich between 2010 and 2024. Immunohistochemical and molecular profiles were evaluated in respect to treatment selection, response and survival. Salivary duct carcinoma (SDC) and adenoid-cystic carcinoma (AdCC) were the most common subtypes. In the SDC group, in 15/20 pts personalized first-line treatment based on immunohistochemical or molecular findings resulted in higher response rates and longer duration of response compared to chemotherapy. In 20 pts of the AdCC group, no actionable alterations were identified. Yet, pts in this group demonstrated the longest overall survival despite low response rates. Among 11 pts with other subtypes, one pt with secretory carcinoma and ETV6::NTRK3 fusion experienced a sustained response to larotrectinib. HER2 IHC2 + expression without gene amplification was observed in 15 pts. Two pts responded to trastuzumab deruxtecan (TDxd) after progression on first line therapy. The impact of immunohistochemical or molecular markers on treatment selection and response was most pronounced in SDC. HER2 IHC2 + expression was observed across multiple subtypes, indicating that TDxd may represent a potential treatment option for more pts than previously anticipated. The impact of comprehensive genomic profiling on targeted treatment options is currently still modest.

4503 Background: Perioperative chemo-IO is a new standard for MIBC but pathological complete remission (pCR) rates remain modest. Intravesical Bacillus Calmette Guérin (BCG) is very effective in non-muscle invasive bladder cancer, inducing a local immune response and likely activation of adaptive immunity, with evidence of systemic immune modulation that may enhance downstream immune-oncological effects. The use of BCG in MIBC has not yet been explored, primarily due to concerns about systemic complications. The recombinant BCG vaccine VPM1002BC (rBCG) is associated with enhanced immunogenicity and an improved safety profile. We hypothesize that the combination of intravesical rBCG and chemo-IO in MIBC may act synergistically, augmenting systemic immune activation and hereby improve antitumor efficacy without compromising safety. Methods: SAKK 06/19 is an open-label single arm phase II trial for cT2-T4a N0-1 MIBC patients (pts) eligible for cisplatin and radical cystectomy with lymphadenectomy (RC). rBCG was instilled weekly x3 (day 1, 8, 15). Atezolizumab (Atezo) 1200 mg was administered on day 1 and then x4 every 3 weeks (q3w). Cisplatin and gemcitabine started on day 22 and were given for 4 cycles q3w followed by RC. Only in case of ≥ ypT2 or ypN+, Atezo q3w was given after surgery for 13 cycles. pCR defined as ypT0 ypN0 and assessed by central pathological review was the primary endpoint. Based on Simon’s minimax 2-stage design with H0 pCR ≤ 35% and H1 pCR ≥ 55%, accrual of 46 pts was needed (including 15% dropouts). Secondary endpoints included event free survival (EFS), overall survival (OS), pathological response (PaR, ≤ ypT1N0), feasibility and safety. NCT04630730. Results: 47 pts were included between 04/22 and 04/25 at 10 Swiss sites. 7 pts did not undergo RC (6 refused, 1 unfit for surgery). Of the 40 resected pts 53% had cT2, 37% cT3, 10% cT4 and 88% cN0, 12% cN1. rBCG was instilled in 95% of pts, 78% had all 3 doses. 98% received 4 doses of Atezo and 95% had 4 cycles of platinum (20% switched to carboplatin). pCR according to central review was 65% (26/40; one-sided 95% CI lower boundary of 51%) and PaR was 80% (32/40). Overall pCR for all included pts was 55% (26/47). TRAEs overall, G3, G4 were 48%, 9%, 0% to rBCG, 55%, 15%, 2% to Atezo and 98%, 38%, 17% to chemotherapy. No treatment-related deaths occurred. At a median follow-up of 11.8 months 1-year overall EFS was 88% (95% CI 71 - 95) and OS 95% (95% CI 81 - 99). Conclusions: This is the first trial to combine intravesical rBCG with chemo-IO in MIBC. The combination was feasible and safe without unexpected toxicities. The centrally assessed pCR rate of 65% and PaR of 80% are among the highest reported in an unselected MIBC population. Integration of intravesical rBCG into novel MIBC treatment regimens appears highly promising, particularly in the context of bladder-preservation approaches. Clinical trial information: NCT04630730 .

PURPOSE:Intravesical Bacillus Calmette-Guérin (BCG) is highly effective in non-muscle-invasive bladder cancer (MIBC) but has not been evaluated in MIBC. The recombinant BCG vaccine VPM1002BC (rBCG) has potentially enhanced immunogenicity and an improved safety profile. We investigated neoadjuvant intravesical rBCG combined with chemoimmunotherapy in MIBC. PATIENTS AND METHODS:SAKK 06/19 was an open-label single-arm phase II trial for cT2-T4a N0-1 MIBC eligible for cisplatin and radical cystectomy with lymph node dissection (RC-LND). rBCG was instilled once per week three times starting on day 1. Atezolizumab was administered on day 1 for a total of four doses, and cisplatin/gemcitabine was started on day 22 for four cycles followed by RC-LND. Adjuvant atezolizumab was only administered in the case of >yT1 ypN0. The primary end point was centrally reviewed pathologic complete response (pCR, ypT0 ypN0). Based on Simon's minimax two-stage design with H0 pCR ≤35%, H1 pCR ≥55%, one-sided alpha 5%, and power 80%, 46 patients were needed. Secondary end points included pathologic overall response (PaR, ≤ypT1 ypN0), event-free survival (EFS), overall survival (OS), and safety. RESULTS:Forty-seven patients were included between April 2022 and April 2025. Seven patients did not undergo RC-LND (six declined, one unfit for surgery). rBCG was instilled in 95%, and 78% had all three doses. Centrally reviewed pCR was 68% (27 of 40; one-sided 95% CI lower boundary 53%), and PaR was 83% (33 of 40; 95% CI, 67 to 93). Treatment-related adverse events (any grade, grade 3, grade 4) were 42%, 9%, and 0% for rBCG; 55%, 15%, and 2% for atezolizumab; and 96%, 38%, and 17% for chemotherapy. CONCLUSION:To our knowledge, this is the first trial combining intravesical rBCG with chemoimmunotherapy in MIBC, demonstrating high pCR and PaR rates that warrant further investigation in prospective randomized trials.

Trotz exzellenter Heilungsraten in der Erst- und Salvage-Therapie entwickeln einzelne Patienten mit Keimzelltumoren (KZT) eine progrediente Erkrankung selbst nach intensivierter Therapie mittels Hochdosis-Chemotherapie (HDCT). Für die therapierefraktäre Erkrankungssituation existiert kein etablierter Standard, die Prognose der Patienten ist i. d. R. ungünstig und eine dauerhafte Remission sehr selten, das Therapiekonzept palliativ. Gemcitabin-basierte Kombinationen stellen derzeit weiterhin die wichtigste systemische Option dar. Immuncheckpointinhibitoren zeigten in verschiedenen Studien keine relevante Wirksamkeit. Auch klassische Targeted-Therapien wie Multi-Tyrosinkinase- oder mTOR-Inhibitoren sind in den meisten Fällen ineffektiv. Einzelne neue Ansätze, wie CD30-gerichtete Antikörper-Wirkstoff-Konjugate sowie insbesondere Claudin-6-gerichtete Chimeric-Antigen-Receptor(CAR)-T-Zell-Therapien, bieten jedoch erste Hinweise auf klinische Aktivität und neue Perspektiven. Der klinische Stellenwert dieser neuen Ansätze ist derzeit Gegenstand von Studien.

INTRODUCTION:Adherence to clinical guidelines in the management of testicular germ-cell cancer ensures optimal oncological outcomes, minimizes the risk of overtreatment and undertreatment, and reduces unnecessary investigations including radiographic imaging. An interdisciplinary testis cancer clinic (ITCC) in the Department of urology of the University Hospital Zürich was therefore established in 2016 led by a urologist and medical oncologist, who had both specialized in germ-cell cancer. Aside from treatment decision visits, structured follow-up schedules were integrated to guarantee guideline-conformant therapy and follow-up. We aimed to evaluate the impact of the ITCC on guideline adherence and follow-up. MATERIALS AND METHODS:A retrospective analysis was conducted on all testicular germ-cell cancer patients treated from 2012 to 2020 in our hospital. Patients were categorized into 2 groups: those followed prior to the establishment of the ITCC and those thereafter. We compared patient characteristics, follow-up protocols, and the compliance with guideline-recommended follow-up schedules. RESULTS:We included 143 patients, with 77 in the pre-ITCC group and 66 in the ITCC group. Adherence to clinical follow-up guidelines over a 5-year period was significantly higher in the ITCC group, with 89% completeness of the recommended consultations and diagnostics compared to only 21% in the pre-ITCC group. Additionally, the median number of computed tomography scans was significantly lower in the ITCC group during each of the 5 years of follow-up. The time between orchiectomy and start of further therapies was significantly shorter in the ITCC group (median 24 days versus 32 days, P < 0.01) and significantly less patients were lost to follow-up (11% versus 36%, P < 0.001). CONCLUSIONS:A well-structured ITCC can improve the quality of care of testis cancer patients by optimizing adherence to follow-up schedules and therefore expediting further therapies, reducing unnecessary diagnostics and minimizing loss to follow-up.

INTRODUCTION:The landscape of diagnosis and treatment of locally advanced and metastatic prostate cancer has seen an unprecedented evolution in recent years. Incorporation of results from pivotal studies is crucial for state-of-the-art counselling of patients and to inform treatment recommendations. However, in daily practice ambiguous situations may occur or various options may seem adequate. Furthermore, specific national regulations, e.g. availability of diagnostic tools and drug approvals, may influence treatment choices. This paper presents the voting results of a Swiss expert panel that convened in August 2024 and discussed selected questions addressed by an international panel of experts during the Advanced Prostate Cancer Conference held in Lugano in April 2024. The objective is to facilitate national harmonization of diagnosis and treatment of locally advanced and metastatic prostate cancer and thereby providing a basis for discussion with individuals with prostate cancer.

BACKGROUND AND OBJECTIVE:This publication represents a summary of the updated 2025 European Association of Urology (EAU) guidelines for muscle-invasive and metastatic bladder cancer (MMIBC). The aim is to provide practical recommendations on the clinical management of MMIBC with a focus on diagnosis, treatment, and follow-up. METHODS:For the 2025 guidelines, new and relevant evidence was identified, collated, and appraised via a structured assessment of the literature. Databases searched included Medline, EMBASE, and the Cochrane Libraries. Recommendations within the guidelines were developed by the panel to prioritise clinically important care decisions. The strength of each recommendation was determined according to a balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including the certainty of estimates), and the nature and variability of patient values and preferences. KEY FINDINGS AND LIMITATIONS:The key recommendations emphasise the importance of thorough diagnosis, treatment, and follow-up for patients with MMIBC. The guidelines stress the importance of a multidisciplinary approach to the treatment of MMIBC patients and the importance of shared decision-making with patients. The key changes in the 2025 muscle-invasive bladder cancer (MIBC) guidelines include the following: a new recommendation for the use of susceptible FGFR3 alterations to select patients with unresectable or metastatic urothelial carcinoma for treatment with erdafitinib; significant adaption and update of the recommendations for pre- and postoperative radiotherapy and sexual organ-preserving techniques in women; new recommendation related to radical cystectomy and extent of lymph node dissection based on the results of the SWOG trial; recommendation related to hospital volume; new recommendations for salvage cystectomy after trimodality therapy and for the management of all patients who are candidates for trimodality bladder-preserving treatment in a multidisciplinary team setting using a shared decision-making process; significant adaption and update to the recommendation for adjuvant nivolumab in selected patients with pT3/4 and/or pN+ disease not eligible for, or who declined, adjuvant cisplatin-based chemotherapy; and addition of a new recommendation for metastatic disease regarding the antibody-drug conjugate trastuzumab deruxtecan in case of HER2 overexpression; in addition, removal of the recommendations on sacituzumab govitecan as the manufacturer has withdrawn the US Food and Drug Administration approval for this product; update of the follow-up of MIBC; and full update of the management algorithms of MIBC. CONCLUSIONS AND CLINICAL IMPLICATIONS:This overview of the 2025 EAU guidelines offers valuable insights into risk factors, diagnosis, classification, treatment, and follow-up of MIBC patients and is designed for effective integration into clinical practice.

The pathological and patient outcomes after the resection of residual thoracic germ cell tumors following sequential high-dose chemotherapy with autologous stem cell transplantation (HDC + SC) have rarely been investigated. We retrospectively analyzed 79 male patients who underwent resection for residual germ cell tumors after HDC + SC between 1999 and 2017. Patient information, tumor characteristics, and short-term outcomes were analyzed. Long-term outcomes and survival curves were analyzed via the Kaplan‒Meier-method. In the HDC + SC cohort, lung metastases were observed in 88.6

Representativeness of Study Participants

AimsTo resolve the ongoing controversy surrounding the impact of teratoma (TER) in the primary among patients with metastatic testicular non-seminomatous germ-cell tumours (NSGCT).Patients and methodsUsing the International Germ Cell Cancer Collaborative Group (IGCCCG) Update Consortium database, we compared the survival probabilities of patients with metastatic testicular GCT with TER (TER) or without TER (NTER) in their primaries corrected for known prognostic factors. Progression-free survival (5y-PFS) and overall survival at 5 years (5y-OS) were estimated by the Kaplan-Meier method.ResultsAmong 6792 patients with metastatic testicular NSGCT, 3224 (47%) had TER in their primary, and 3568 (53%) did not. In the IGCCCG good prognosis group, the 5y-PFS was 87.8% in TER versus 92.0% in NTER patients (p = 0.0001), the respective 5y-OS were 94.5% versus 96.5% (p = 0.0032). The corresponding figures in the intermediate prognosis group were 5y-PFS 76.9% versus 81.6% (p = 0.0432) in TER and NTER and 5y-OS 90.4% versus 90.9% (p = 0.8514), respectively. In the poor prognosis group, there was no difference, neither in 5y-PFS [54.3% in TER patients versus 55.4% (p = 0.7472) in NTER], nor in 5y-OS [69.4% versus 67.7% (p = 0.3841)]. NSGCT patients with TER had more residual masses (65.3% versus 51.7%, p < 0.0001), and therefore received post-chemotherapy surgery more frequently than NTER patients (46.8% versus 32.0%, p < 0.0001).ConclusionTeratoma in the primary tumour of patients with metastatic NSGCT negatively impacts on survival in the good and intermediate, but not in the poor IGCCCG prognostic groups.

Circulating tumor DNA (ctDNA) is emerging as a potential biomarker in early-stage urothelial cancer, but its utility in metastatic disease remains unknown. In the phase 3 KEYNOTE-361 study, pembrolizumab with and without chemotherapy was compared with chemotherapy alone in patients with metastatic urothelial cancer. The study did not meet prespecified efficacy thresholds for statistical significance. To identify potential biomarkers of response, we retrospectively evaluated the association of pre- and posttreatment ctDNA with clinical outcomes in a subset of patients who received pembrolizumab (n = 130) or chemotherapy (n = 130) in KEYNOTE-361. Baseline ctDNA was associated with best overall response (BOR; P = 0.009), progression-free survival (P < 0.001) and overall survival (OS; P < 0.001) for pembrolizumab but not for chemotherapy (all; P > 0.05). Chemotherapy induced larger ctDNA decreases from baseline to treatment cycle 2 than pembrolizumab; however, change with pembrolizumab (n = 87) was more associated with BOR (P = 4.39 x 10(-5)) and OS (P = 7.07 x 10(-5)) than chemotherapy (n = 102; BOR: P = 1.01 x 10(-4); OS: P = 0.018). Tumor tissue-informed versions of ctDNA change metrics were most associated with clinical outcomes but did not show a statistically significant independent value for explaining OS beyond radiographic change by RECIST v.1.1 when jointly modeled (pembrolizumab P = 0.364; chemotherapy P = 0.823). These results suggest distinct patterns in early ctDNA changes with immunotherapy and chemotherapy and differences in their association with long-term outcomes, which provide preliminary insights into the utility of liquid biopsies for treatment monitoring in metastatic urothelial cancer. Clinical trial registration: NCT02853305.

Purpose MiR-371a-3p represents a novel liquid biomarker that detects all histologies of germ-cell tumors (GCT) except teratoma. However, it is currently unclear whether miR-371a-3p results obtained directly from RT-PCR (raw Cq) or normalized for housekeeper genes and transformed into the relative quantity (RQ) value should be used and at what cut-off level. The purpose of this research was to evaluate, which values should be used, and a potential cut-off level for relapse-detection to inform subsequent studies. Materials and Methods We applied a CE-certified qRT-PCR test to measure miR-371a-3p at each follow-up visit during active surveillance in 34 men with stage I testicular GCT. MiR-371a-3p levels were calculated by the ΔΔ method. Results About 18 Patients had pure seminoma and 16 had mixed or nonseminomatous testicular GCT. Recurrences were detected in 10 patients and were correctly identified by both raw and housekeeper-normalized miR-371a-3p serum levels. The raw Cq, with a cut-off value of <28, resulted in only 1 false positive (3%), whereas RQ, with a cut-off value of >15, produced 6 false positive results (17%). Most of these false positive results normalized in subsequent measurements. The RQ approach detected recurrence in 1 patient 6 months earlier than the raw Cq approach. Conclusion Our preliminary data suggest that this CE-certified assay, using previously suggested cut-off values, is a promising method for detecting disease recurrence, provided a confirmatory second test is conducted to identify false positive results. To avoid unnecessary scans or overtreatment, we are currently validating this assay and cut-offs in a prospective cohort study.

4518 Background: ctDNA is emerging as a potential biomarker of disease in early-stage bladder cancer but is less understood in advanced UC. We present a retrospective analysis of pre-treatment and on-treatment ctDNA data by clinical outcomes with pembro monotherapy versus chemo in pts with advanced UC from the phase 3 KEYNOTE-361 trial (NCT02853305). Methods: Pts with previously untreated advanced UC were randomly assigned 1:1:1 to pembro + chemo, pembro alone, or chemo alone. Tumor tissue mutations were evaluated with whole exome sequencing of tumor and matched normal DNA. Plasma ctDNA was evaluated using the Guardant Health (GH) Guardant 360 LDT assay. ctDNA changes from pre-treatment cycle 1(C1) to on-treatment cycle 2 (C2) were quantified by maximum variant allele frequency (maxVAF) of tumor tissue–specific mutations (tumor-informed [TI] approach) or GH molecular response (MR) score. Association between C2/C1 ratios or baseline TI maxVAF and clinical outcomes (ORR, PFS, and OS) were evaluated. Nominal statistical significance of maxVAF was prespecified at 0.05 (hypothesis, negative). Results: ctDNA samples from 263 pts (n = 131, chemo; n = 132, pembro) were analyzed. Clinical characteristics and baseline ctDNA levels within arms were similar. Lower C1 maxVAF was associated with improved ORR, PFS, and OS in the pembro arm ( P < 0.01) and was robust to adjustment for TMB and PD-L1, but not in the chemo arm ( P > 0.05). Larger C2 reductions in ctDNA levels were observed in the chemo vs pembro arm (median ratio of C2/C1 TI maxVAF, 0.03 vs 0.71, respectively); similar observations were made for MR score. ctDNA reductions were associated with improved ORR, PFS ( P < 0.001), and OS ( P < 0.01) for TI maxVAF in the chemo arm; MR score was significantly associated with ORR and PFS ( P < 0.01). Associations were stronger in the pembro arm ( P < 0.001) and were robust to adjustment for TMB and PD-L1. ctDNA changes from C1 to C2 did not show independent explanatory value for OS when RECIST v1.1 response status was added as a variable. Conclusions: ctDNA levels at baseline appear prognostic for pembro. Reductions in ctDNA during the first treatment cycle were associated with outcome. Distinct patterns of ctDNA response were observed with the different treatments, and stronger associations with long-term clinical outcome were observed with pembro. Association of OS for both pembro and chemo was not retained when adjusting for tumor response. Early ctDNA dynamics did not offer additional benefit in predicting outcome beyond radiographic assessment of tumor size change. Clinical trial information: NCT02853305 .

Immunotherapy with checkpoint inhibitors including atezolizumab, pembrolizumab and nivolumab has become an essential pillar in the management of muscle invasive and metastatic urothelial carcinoma. The field has evolved quickly in the past few years and several early beliefs have recently been upended. One such belief relates to the predictive value of PD-L1 expression based on immunohistochemistry. Nevertheless, requirements for PD-L1 expression from regulatory bodies still restrict the use of checkpoint inhibitors in urothelial carcinoma. This article provides a critical review of the available data from the registration trials on which the current regulations have been based with the conclusion that a review of the current approval status incorporating PD-1 expression is warranted.

Adjuvant immunotherapy has been recently recommended for patients with metastatic clear cell renal cell carcinoma (ccRCC), but there are no tissue biomarkers to predict treatment response in ccRCC. Potential predictive biomarkers are mainly assessed in primary tumor tissue, whereas metastases (METs) remain understudied. To explore potential differences between genomic alterations and immune phenotypes in primary tumors and their matched METs, we analyzed primary tumors (PTs) of 47 ccRCC patients and their matched distant METs by comprehensive targeted parallel sequencing, whole-genome copy number variation analysis, determination of microsatellite instability, and tumor mutational burden. We quantified the spatial distribution of tumor-infiltrating CD8+ T cells and coexpression of the T-cell-exhaustion marker thymocyte selection-associated high mobility group box (TOX) by digital immunoprofiling and quantified tertiary lymphoid structures. Most METs were pathologically "cold." Inflamed, pathologically "hot" PTs were associated with decreased disease-free survival, worst for patients with high levels of CD8+TOX+ T cells. Interestingly, inflamed METs showed a relative increase in exhausted CD8+TOX+ T cells and increased accumulative size of tertiary lymphoid structures compared with PTs. Integrative analysis of molecular and immune phenotypes revealed BAP1 and CDKN2A/B deficiency to be associated with an inflamed immune phenotype. Our results highlight the distinct spatial distribution and differentiation of CD8+ T cells at metastatic sites, and the association of an inflamed microenvironment with specific genomic alterations.

2061 Background: Primary Intracranial Germ Cell Tumors (iGCT) are rare. Previous prospective and retrospective studies mainly included pediatric patients (pts) with a median age of 10-14 years. The aim of this retrospective analysis was to evaluate characteristics, treatment and outcome of adolescents and adults with iGCT. Methods: Data were collected from 10 institutions in Germany and Switzerland. Pts aged >/= 16 years at first diagnosis or at relapse with a primary iGCT were included. Objective responses were evaluated by local investigators. Statistics (Cox proportional hazard model, progression-free survival (PFS) and overall survival (OS) analyzed by Kaplan-Meier method) were performed with SPSS v29. Results: We identified 75 pts (92.0% male) with a median age of 23 years (range 16-60, 94.7% >/= 18 years). At first diagnosis, histology was pure germinoma in 70.7%, pure teratoma in 10.7%, other non-germinomatous GCT (NGGCT) in 13.3%, unknown in 5.3% of pts. Localized, bifocal, and metastatic disease was found in 72.0, 6.7, and 21.3% of pts. As part of their first line (1L) treatment, 69.3%, 80.0%, and 62.7% received surgery, radiotherapy, and chemotherapy, respectively. High dose chemotherapy/ autologous stem cell transplantation (HDCT/ASCT) was part of 1L treatment in n=3 pts with NGGCT. Trimodal and bimodal treatment was performed in 48.0% and 32.0% of pts. Response to 1L therapy was complete remission (CR) in 61.3%, partial remission tumor marker negative (PRm-) in 16.0%, PRm+ in 4.0%, PR with tumor marker status unknown in 4.0%, progressive disease (PD) in 2.7%, and unknown in 12.0%. Relapse occurred in 13/75 pts (17.3%) with unknown histology (n=4), teratoma (n=2), other NGGCT (n=4), and germinoma (n=3). In 2 pts. in whom germinoma was diagnosed at time of first diagnosis, at time of recurrence PNET and Yolk sac tumor were histologically proven. Median time to relapse was 19.0 months (mo.; range 3-223). HDCT/ASCT as salvage treatment was performed in 5 pts with NGGCT and in one pt with germinoma as 2L (n=5) or 3L (n=1). NGGCT histology was associated with increased risk for recurrence or death (p=0.012 and 0.039).3-year PFS was 90.7% (germinoma: 98.1%, NGGCT: 73.9%) and 5-year OS was 92.0% (germinoma: 98.1%; NGGCT: 78.3%). Median follow-up time was 60 mo (range 0-339). Conclusions: Disease characteristics, treatment and outcomes of adolescent/ adult iGCT pts are comparable to those reported in pediatric pts. High cure rates are achieved in pts with pure germinoma and current treatment concepts. In pts with NGGCT further investigation is needed to improve survival outcomes.