598 Background: Follow-up of patients with germ-cell tumours (GCT) relies on monitoring serum markers (SM) including alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), and lactate dehydrogenase (LDH). Instances of benign, non-GCT related elevation of AFP have been reported as case reports. Identifying such occurrences is crucial to prevent misdiagnosis of residual disease and subsequent overtreatment, which may lead to increased morbidity. Methods: We conducted a national retrospective study in nine GETUG institutions. Patients with isolated persistent elevation of AFP levels above the normal range after receiving curative treatment for GCT without detectable disease on CT scan imaging were identified. Data on patient characteristics, treatment response, changes in SM values over time, and serum AFP levels from first- and second-degree relatives were collected. Familial AFP elevation was defined as AFP levels above the normal range in at least one first- or second-degree relative. Results: From June 1990 to April 2024, 31 patients were identified. Median age was 35 years (range, 19 to 49 years). 15 patients (48%) had pure seminoma, and 16 (52%) had non-seminomatous GCT. Overall, 19 patients (61%) had a clinical stage I disease, 17 (23%) had stage II, and 5 (16%) had stage III. No patient had a history of chronic alcoholism or consumption of medications with hepatic toxicity. Median AFP level after curative treatment was 12 ng/mL (range, 8.8 to 36 ng/mL). No evidence of disease was found on CT scan. An ultrasound examination of the contralateral testis and an FDG-PET/CT were performed in 15 (48%) and 7 patients (23%), respectively, also showing no evidence of disease. Serum AFP levels from family relatives were obtained for 14 patients (45%), with a family elevation identified for 10/14 patients (71%). After a median follow-up of 35 months (range: 7-253 months), AFP levels remained elevated in all 31 patients without documented disease relapse. Conclusions: Benign and often familial elevations of serum AFP levels are rare occurrences, which can be a chance finding following curative treatment for GCT. Ultrasound examination of the contralateral testis and AFP measurement in family members are recommended. Surveillance alone is appropriate.

BACKGROUND:Glioblastoma (GBM) is the most common and aggressive primary CNS tumor in adults and carries a poor prognosis. Although molecular classification has advanced, patient outcomes remain variable. Next-generation sequencing (NGS) can reveal genomic alterations that, while not yet treatment-guiding, offer prognostic and biological insight. The study aimed to investigate the association between molecular alterations in primary GBM tumors and patient survival outcomes. METHODS:This study analyzed medical records of consecutive GBM patients treated between November 1, 2018 and December 31, 2021 at a comprehensive cancer center, for whom NGS data from the tumor was available. Survival analyses were performed according to clinical, radiological, therapeutic, and molecular data. RESULTS:Of 199 patients, 38 were excluded: 15 for recurrence-only data and 23 for incomplete molecular data after first progression. In the survival analysis of the cohort (n = 161) adjusted on surgical resection, MGMT promoter methylation status, number of alterations, age, tumor localization, MIB1 and performance status, EGFR substitutions were significantly associated with increased overall survival (OS) (HR = 0.43 [0.26; 0.72], P = .001), while CDKN2A/B loss and TP53 substitutions were associated with decreased OS (HR = 1.75 [1.08; 2.84], P = .023 and HR = 1.69 [1.04; 2.74], P = .034 respectively). NOTCH1 substitutions showed a trend towards improved progression-free survival (PFS) (HR = 0.55 [0.30; 1.01], P = .054). CONCLUSION:We identified new prognostic markers in GBM, showing for the first time that EGFR substitutions improve OS. Validation in external cohorts and preclinical studies is needed.

PURPOSE:To evaluate the efficacy and safety of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) combined with durvalumab ± tremelimumab in patients with muscle-invasive bladder cancer (MIBC). METHODS:NEMIO (ClinicalTrials.gov identifier: NCT03549715) is a multicenter, randomized, noncomparative phase II trial in cT2-T4a N0-1 cisplatin-eligible MIBC planned for radical cystectomy (RC). Patients received ddMVAC (cisplatin 70 mg/m2, methotrexate 30 mg/m2, doxorubicin 30 mg/m2, and vinblastine 3 mg/m2 on days 1, and pegfilgrastim 6 mg on days 2) once every 2 weeks × four cycles plus durvalumab ± tremelimumab (durvalumab 1,500 mg and tremelimumab 75 mg) once every 4 weeks × two doses (C1D1 and C3D1) before RC. Coprimary end points (local assessment) were pathologic complete response (pCR; ypT0N0) and grade ≥3 treatment-related adverse events (TRAEs). The study was considered positive if the pCR rate was ≥45% and the rate of grade ≥3 TRAEs was ≤30%. RESULTS:From 2018 to 2022, 119 patients received ddMVAC + durvalumab (n = 60) or ddMVAC + durvalumab + tremelimumab (n = 59); 113 underwent RC. The overall Bayesian posterior mean pCR rate was 48.70% (95% CI, 35.93 to 61.56) with doublet and 46.27% (95% CI, 33.92 to 58.85) with triplet. Among 103 patients with PD-L1 data (exploratory), Bayesian posterior mean pCR was 68.25% (95% CI, 54.57 to 80.49) in PD-L1-high tumors versus 33.49% (95% CI, 22.13 to 45.91) in PD-L1-low/negative tumors. Bayesian posterior mean grade ≥3 TRAEs occurred in 40.95% (95% CI, 32.50 to 49.69) overall (30.48% [95% CI, 20.00 to 42.08] doublet; 49.63% [95% CI, 37.55 to 61.73] triplet); immune-related adverse events occurred in 26.9% (grade ≥3 4.2%). Two-year event-free survival and overall survival rates were 75% and 85% in the doublet arm, and 77% and 88% in the triplet arm, respectively. CONCLUSION:Neoadjuvant ddMVAC plus durvalumab demonstrated encouraging pCR rates, favorable early survival outcomes, and manageable safety profile. Adding tremelimumab provides similar pCR but worse toxicity. These results support further study of ddMVAC plus durvalumab as a neoadjuvant chemoimmunotherapy strategy for localized MIBC, to be evaluated in comparative trials within an evolving perioperative treatment landscape.

Histologic variants (HV) of urothelial carcinoma (UC-V) and non-urothelial carcinomas (NUC) of the bladder and urinary tract are aggressive malignancies with poor prognosis and limited response to platinum-based chemotherapy. Despite their biological particularities and distinct immune microenvironments, these HV subtypes are under-represented in immune checkpoint blockade (ICB) trials. PEMBROBLAD is a French national multicenter retrospective study conducted across 24 centers. We included patients with advanced UC-V or NUC who received second-line anti–PD-(L)1 monotherapy after progression on platinum-based chemotherapy between 2016 and 2022. Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. We included 129 UC-V and 34 NUC. With a median follow-up was 21.9 months, the median OS was 8.6 [95

Squamous cell carcinoma (SCC) of the bladder is a rare subtype accounting for 2-5% of bladder cancers in Western countries. Its epidemiology, biological drivers, and clinical behavior differ substantially from urothelial carcinoma (UC), yet most management strategies remain extrapolated from UC due to the absence of dedicated evidence. Robust data are limited, and therapeutic decision-making is challenged by the rarity of this aggressive variant. Bladder SCC is strongly associated with chronic inflammatory conditions, including schistosomiasis, long-term catheterization, and recurrent urinary infections. Most patients present with muscle-invasive disease, characterized by marked local aggressiveness and a lower incidence of early nodal or distant metastases compared with UC. Molecular profiling indicates a predominant basal/squamous phenotype with frequent EGFR pathway activation and TP53/RB1 alterations, highlighting potential therapeutic vulnerabilities. However, the efficacy of perioperative chemotherapy, immunotherapy, or antibody-drug conjugates remains uncertain, as SCC patients are consistently underrepresented in clinical trials and outcomes are rarely reported separately. Emerging targeted strategies, such as Nectin-4 and Trop-2-directed agents, show promise but require prospective, SCC-specific evaluation. Bladder SCC remains an orphan malignancy with significant unmet clinical needs. Dedicated multicenter efforts are crucial to refine diagnostic pathways, integrate molecular characterization, and develop tailored therapeutic approaches. The French AVENTUR Group aims to address these gaps by coordinating national collaboration across institutions and promoting prospective clinical and translational research to improve outcomes in this rare and aggressive bladder cancer subtype.

The prognostic value of histopathological grade in muscle-invasive urothelial carcinoma (MIBC) to predict disease-specific survival (DSS) is understudied. While grading systems like WHO1973 and WHO2004 are established in non-muscle-invasive bladder cancer (NMIBC), their relevance in MIBC remains controversial. This study assessed the prognostic impact of histopathological grade on DSS in a multicenter cohort. We included 1,123 cN0M0 MIBC patients treated with upfront radical cystectomy (1987–2020) at nine centers. Tumors were graded using WHO1973 (G1 + G2 combined as G1/2 due to low numbers vs. G3), WHO2004 (low-grade [LG] vs. high-grade [HG]), and a hybrid three-tier system. Slides were locally reviewed by uro-pathologists. DSS was analyzed using Kaplan-Meier and Cox models, adjusting for age, stage, lympho-vascular invasion, surgical margins, lymph-node status, adjuvant chemotherapy, treatment center, and era of cystectomy. Among all cases, 74 (6.6

Introducción: Hasta hace poco tiempo no existía una terapia adyuvante recomendada para pacientes con metástasis en los ganglios linfáticos (ypN+) después de la quimioterapia neoadyuvante (QNA) y la cistectomía radical (CR) para el cáncer de vejiga músculo invasor (CVMI). El objetivo del estudio fue describir los resultados oncológicos de los pacientes ypN+ tras QNA y CR para CVMI.Métodos: Este estudio retrospectivo colaborativo incluyó a 195 pacientes con enfermedad ypN+ después de QNA seguida de CR y disección bilateral de ganglios linfáticos pélvicos para el CVMI en 7 centros entre 2000 y 2019. Se recopilaron los datos demográficos y las características clínicas y patológicas de los pacientes. Se realizaron análisis de supervivencia con estimaciones de Kaplan-Meier y se generó un modelo de Cox.Resultados: En total, 120 (62%) pacientes fueron pN1, 51 (26%) pN2 y 24 (12%) pN3. Se realizó radioterapia adyuvante en 18 (9%), quimioterapia adyuvante en 40 (21%), y los 137 pacientes restantes (70%) fueron sometidos a observación. La mediana del tiempo de seguimiento fue de 51 meses (IC 95%: 44-62). La mediana de la supervivencia libre de recurrencia, la supervivencia específica al cáncer y la supervivencia global (SG) fue de 18 meses (IC del 95%: 16-21), 47 meses (IC del 95%: 31-70) y 28 meses (IC del 95%: 22-34), respectivamente. En el análisis multivariable, el sexo femenino (HR=1,5; IC 95%: 1,002-2,21; p=0,049) y los márgenes quirúrgicos positivos (HR=1,6; IC 95%: 1,06-2,38; p=0,026) fueron los únicos factores predictivos independientes de la SG. El tipo de tratamiento adyuvante no influyó en la SG (quimioterapia adyuvante, p=0,44; radioterapia adyuvante, p=0,40).Conclusión: Los resultados de supervivencia de los pacientes con CVMI y afectación ganglionar residual tras la QNA y la CR son desfavorecedores. El sexo femenino y los márgenes positivos en la CR se asocian a un pronóstico peor. Estos resultados pueden ser útiles para el diseño de ensayos clínicos a futuro.

735 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) and radical cystectomy is the gold standard in localized muscle-invasive bladder cancer (MIBC), for fit patients. However, NAC is less prescribed in older patients, mainly due to safety concerns. This study aimed to evaluate the feasibility and efficacy of NAC for patients aged ≥ 75. Methods: We retrospectively included older patients, from 14 French GETUG centers. All patients had received at least one cycle of cisplatin-based NAC for localized MIBC, between 2010 and 2022. Primary outcome was NAC feasibility evaluated as the rate of patients that underwent optimal treatment, defined as at least 4 cycles of chemotherapy followed with local treatment (surgery or chemoradiotherapy). Secondary outcomes were NAC safety and efficacy. Results: 156 pts were included. Median age was 77 (from 75 to 96), with 20% aged ≥ 80. Patients were in good general condition: 54% were PS 0, with a median serum albumin level of 39 g/L, and 86% had a creatinine clearance ≥ 60 ml/min. 108 (69%) had a cT2N0 MIBC. 75 (48%) received dose dense MVAC (ddMVAC), 80 (51%) received gemcitabine-cisplatin (GC) and one patient received MVAC. 96 (62%) received an optimal treatment. 50 patients (32%) prematurely stopped NAC, due to death (3 pts, 2 from unknown causes), progressive disease (4), infection (3), toxicity (34 patients) mainly renal and hematological ones. Among them, 38 (76%) underwent local treatment. Among the 112 patients that underwent cystectomy, pathological complete response (pCR) was significantly more frequent when they received ≥ 4 cycles (36/78 = 46% versus 5/34 = 15%, p = 0.002). Median follow up from diagnosis was 28 months, with 97 patients (62%) that were still alive at the end of follow-up. Median disease-free survival was 3 years and 3 months. 2-years overall survival (OS) was 72%; 5-years OS was 56%. Conclusions: These data suggest that NAC for MIBC is feasible in selected older patients, even if toxicity was the main reason for cisplatin-based regimen discontinuation. Older patients who received optimal treatment were more often in pCR. OS in the this cohort of older patients was very similar to the results published in younger patients.

INTRODUCTION:Until recently there was no recommended adjuvant therapy for patients with lymph nodes metastasis (ypN+) following neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). The aim of the study was to describe the oncological outcomes of ypN+ patients following NAC and RC for MIBC. METHODS:This collaborative retrospective study included 195 patients with ypN+ disease after NAC followed by RC and bilateral pelvic lymph node dissection for MIBC between 2000 and 2019 in seven centers. Patients' demographics, clinical and pathological features were collected. Survival analyses were carried out with Kaplan-Meier estimates and a Cox model was generated. RESULTS:A total of 120 patients (62%) were pN1, 51 pN2 (26%) and 24 pN3 (12%). Adjuvant radiation therapy was performed in 18 (9%), adjuvant chemotherapy in 40 (21%) and the remaining 137 (70%) patients were observed. The median follow-up time was 51 months (95%CI 44-62). Median times for recurrence-free survival, cancer-specific survival and overall survival (OS) were 18 months (95%CI 16-21), 47 months (95%CI 31-70) and 28 months (95%CI 22-34) respectively. On multivariable analysis, female gender (HR = 1.5, 95%CI 1.002-2.21, p = 0.049) and positive surgical margins (HR = 1.6, 95%CI 1.06-2.38, p = 0.026) were the only independent predictor of OS. The type of adjuvant therapy did not impact OS (adjuvant chemotherapy, p = 0.44; adjuvant radiotherapy p = 0.40). CONCLUSION:MIBC patients with residual node positive disease following NAC and RC have poor survival outcomes. Females and patients with positive margin status at RC carry a poorer prognosis. These results may be beneficial for clinical trial design.

5034 Background: Since 2014, adaptation of chemotherapy based on tumor marker decline after the cycle of BEP (Bleomycin, Etoposide, Cisplatin) is a standard for patients with IGCCCG poor-risk NSGCT based on data from the GETUG-13 phase 3 trial (Fizazi et al, Lancet Oncol 2014; J Clin Oncol 2024). The aim of this multicenter study was to evaluate the GETUG-13 algorithm when used in routine practice. Methods: We collected data from all poor-risk NSGCT patients treated consecutively in 13 expert centers from 2013 to 2019. After one cycle of BEP, tumor marker levels were assessed at day 18-21. Pts with a favorable decline continued with BEP for 3 additional cycles (Fav group), whereas those with an unfavorable decline received up to 4 cycles of dose-dense chemotherapy (Unfav group). Data was analysed descriptively, and the Kaplan-Meier method was used to estimate progression-free (PFS) and overall survival (OS). Results: Data from 146 patients were collected (46 with PS ≥ 2, 35 with mediastinal NSGCT): 111 (76%) had an Unfav decline and 35 (24%) had a Fav decline. More pts with hCG > 50 000 UI/L and AFP > 10 000 were in the Unfav group (44.9% vs 17.6%, p=0.0045, and 26.9% vs 8.8%, p=0.0282). Surgery of residual masses was performed in 85.7% and 74.3% in the Fav and Unfav groups, and the procedure was complete in 83.3% and 59%, respectively. With a median follow-up of 5.8 years (95% CI,63.2-77.2), 5-year PFS rates were 68.6% (95% CI, 50.5-81.2) and 61.1% (95% CI, 51.2-69.6) in the Fav and Unfav groups, respectively. Five-year OS rates were 73.8% (95% CI, 55.6-85.4) and 64.6% (95% CI, 54.6; 73.0), respectively. In the short term, neuropathy, anemia and thrombopenia were more frequent in the Unfav group. Treatment-related deaths were reported in 2 (5.7%) and 5 (4.5%) (including 2 post-surgery deaths) pts in the Fav and Unfav groups, respectively. Peripheral neuropathy evolved favorably, with 4 (5.9%), 2 (3.8%) and no pts in the Unfav group reporting grade 3 toxicity at 6 months, 1 year and at last follow-up, respectively. Long-term side effects were infrequent with only one pt with grade 3 cardiovascular toxicity in the Unfav group. Late grade 2 toxicities included cardiovascular toxicity (1.4%), hypoacousia (1.4%), peripheral neuropathy (4.2%), chronic renal failure (CRF) (9.9%) in the Unfav group, and grade 2 CRF (8.3%) in the Fav group. In both groups, almost 80% pts had returned to work. Among pts with progression or relapse, salvage high-dose chemotherapy with stem-cell transplant was used in 4/11 (36.4%) and 13/33 (43.3%) in the Fav and Unfav groups, respectively. Conclusions: The GETUG-13 algorithm can be safely used in routine practice by expert centers, with a high cure rate similar to that reported in the original phase 3 trial and rare long-term toxicity. This data confirms that this algorithm is standard for poor-risk NSGCT.

Large genomic programs have contributed to improving drug development in cancer. To assess the potential benefit of using larger gene panels to guide molecular-based treatments, we conducted a multicenter randomized trial in patients with advanced and/or metastatic solid cancer. Molecular alterations were determined using either a panel of 324 cancer-related genes (Foundation OneCDX (F1CDX)) or a limited panel of 87 single-nucleotide/indel genes and genome-wide copy number variations (CTL) and reviewed by a molecular tumor board to identify molecular-based recommended therapies (MBRTs). Using paired data from both panels for each patient, the primary endpoint was the proportion of patients with an MBRT identified. Main secondary endpoints included the number of patients with at least one actionable alteration leading to MBRT identification, the number of patients with and without MBRTs initiated, progression-free survival, best overall response, duration of response and safety. Among the 741 patients screened, 45.7% had quality-checked tumor samples. MBRTs were identified with F1CDX in 175 (51.6%) patients and with CTL in 125 (36.9%) patients, translating to a significant increase of 14.8 percentage points (P < 0.001) with the more comprehensive gene panel versus the more limited panel, meeting the primary endpoint. However, no differences in clinical outcomes were observed in these patients with advanced and/or metastatic cancer in need of treatment beyond standard genomic alterations. These findings illustrate the potential for larger gene panels to increase the number of molecularly matched therapies. Larger studies are needed to assess the clinical benefit of expanded MBRTs. ClinicalTrials.gov registration: NCT03163732 .

ABSTRACT Background Immune checkpoint inhibitors (ICIs) improved survival in patients with locally advanced or metastatic urothelial carcinoma (la/mUC). Patient‐reported symptoms in this context were poorly studied. The study aimed to compare symptom severity between patients and clinicians. Methodology The secondary analysis of the AMI clinical trial comparing changes in the gut microbiota in patients with la/mUC treated with pembrolizumab was conducted in nine French centers. Secondary endpoints were expected in this prospective study. Patient‐Reported Outcome‐Common Terminology Criteria for Adverse Events (PRO‐CTCAE) and CTCAE were assessed respectively by patients and clinicians before pembrolizumab initiation, and at each treatment visit until treatment cycle 12. Agreement in severity between clinicians and patients for grade ≥ 3 symptoms was calculated with Cohen's kappa coefficient. The toxicity index was generated for CTCAE and PRO‐CTCAE to assess discordance in a longitudinal manner. The Wilcoxon test was used to compare clinicians' and patients' toxicity index and symptom severity frequencies. Results Thirty‐nine patients were included (M/F sex ratio: 2.5) from December 2020 to March 2022. PRO‐CTCAE baseline completion rate was 77.5%. Cohen's kappa coefficient ranged from −0.017 (95% confidence interval (CI), [−0.039, 0.005]) for numbness/tingling to 0.161 (95% CI, [0.045, 0.276]) for fatigue. The patient self‐rated symptom toxicity index was > 2 for all symptoms compared to ≤ 0.62 (fatigue) when assessed by clinicians in longitudinal reporting of symptom frequency and severity with a p value < 0.001. The three most commonly reported symptoms by patients and clinicians, respectively, were: Fatigue 53.3% versus 23.4%, generalized pain 42.4% versus 16.5%, and insomnia 41.1% versus 9.5%. Symptom frequency reports between clinicians and patients were statistically different (p < 0.009). Conclusions Symptom severity assessment showed discordance between patients and physicians. Clinicians reported fewer symptoms and graded them less severely than patients. PROs should be used to accurately reflect patient experience. Trial Registration ClinicalTrials.gov identifier: NCT04566029

TPS904 Background: Activating FGFR3 gene alterations have been identified in up to 20% of advanced/metastatic urothelial cancers (mUC). The pan-FGFR inhibitor erdafitinib (erda) is approved for the treatment of mUC with susceptible FGFR3 genetic alterations whose disease has progressed on or after at least one line of prior systemic therapy. Since pan-FGFR inhibitors target all four isoforms of FGFR (1-4), their lack of FGFR isoform specificity can lead to off-target toxicity (e.g., hyperphosphatemia, stomatitis, ocular toxicity, skin and nail toxicity) and loss of activity due to development of on-target resistance mutations (e.g., V555M/L gatekeeper). TYRA-300 has been designed to be more selective for FGFR3 over FGFR1/2/4 to minimize off-target toxicity and to avoid interactions with known FGFR3 gatekeeper mutations. TYRA-300 is in development for the treatment of FGFR3 + mUC and other solid tumors (SURF301 - NCT05544552). Methods: SURF301 is a first-in-human, open-label, Phase 1/2 global study in several parts: dose escalation in participants with advanced malignancies, with/without FGFR3 alterations (Phase 1, Part A); dose expansion in participants with FGFR3 -activating mutations or fusions (Phase 1, Part B); and select tumor expansion cohorts with FGFR3 activating mutations or fusions (Phase 2). The purpose of Phase 1 is to evaluate the safety, tolerability, pharmacokinetics (PK), preliminary antitumor activity of TYRA-300, and identify the recommended Phase 2 dose (RP2D). Phase 2 will enroll participants in FGFR3 + mUC and other tumor types to further explore the anti-tumor activity and safety of TYRA-300. SURF301 study began enrolling patients in November 2022 and is ongoing in Australia, the United States, France, and Spain. Clinical trial information: NCT05544552 .

PURPOSE After radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC), prognosis is poor for high-risk patients. This study evaluated safety and efficacy of neoadjuvant chemotherapy (cisplatin or carboplatin + gemcitabine) in combination with durvalumab in these patients. PATIENTS AND METHODS This phase II trial (ClinicalTrials.gov identifier: NCT04617756 ) included patients with nonmetastatic, high-grade UTUC, on the basis of the ureteroscopic biopsy or urine cytology, and/or infiltrative aspect of the renal pelvis/ureteral wall by computed tomography imaging. Before RNU, patients received durvalumab plus gemcitabine/cisplatin (cohort 1) or durvalumab plus gemcitabine/carboplatin (cohort 2) once every 3 weeks for a total of four cycles (cohort choice on the basis of the glomerular filtration rate). The primary objective was the pathologic complete response (ypT0) rate in each cohort. RESULTS Fifty patients were enrolled between 2021 and 2024 (31 in cohort 1; 19 in cohort 2). Median age was 68 years (range, 38-79), and 59% were men. Forty-five patients received four cycles of treatment, three patients three cycles, and one patient two cycles. Five patients switched to carboplatin during treatment. At surgery (N = 45 patients), rates of pT0 were 13% (4/29) in cohort 1 and 5% (1/19) in cohort 2. Fifty percent (15/29) of patients were pTa/pT1 in cohort 1, and 42% (8/19) in cohort 2. No severe immunotherapy-mediated toxicity was observed. Four patients had chemotherapy-related grade 3 neutropenia, one grade 4; one patient had grade 3 thrombopenia, one grade 4; and four patients had grade 3 anemia. CONCLUSION Although our negative study did not meet its primary end point in either cohort, the combination of durvalumab and platin-based chemotherapy, especially cisplatin, showed promising results in terms of downstaging. The safety profile was good and the surgical risk was not increased.

Introduction:Primary urethral cancer (PUC) is rare, and limited data exist on optimal treatment and survival, particularly in metastatic cases. The objective of this study was to describe treatment patterns, responses and survival in a contemporary cohort. Patients and Methods:Data from patients diagnosed with PUC between January 1, 2000 and December 31, 2018, were retrospectively collected from nine French tertiary centres. To enhance the statistical power of survival analysis in the metastatic stage, patients with synchronous and metachronous metastatic disease were pooled. Results:We identified 71 patients (62% males, 38% females). The most common histological types were urothelial (40.0%), squamous cell (34.3%) and adenocarcinomas (14.3%). At diagnosis, 35.2% had localized disease, 49.3% had locally advanced disease and 15.5% had distant metastases. Twenty-seven patients had a metachronous metastatic cancer. Multimodal therapy was used in 24% of localized and 57.1% of locally advanced disease. Among the 60 patients with non-metastatic disease, median disease-free survival (DFS) was 21.2 months. Nodal involvement was associated with worse DFS (HR: 2.03, p = 0.039), while multimodal treatment did not improve DFS (HR: 1.22, p = 0.5419). For metastatic patients, median overall survival was 15.2 months, and progression-free survival was 6.4 months. Main study limitations were an overrepresentation of locally advanced disease and the small cohort size. Conclusions:This retrospective study highlights the significant heterogeneity in terms of histology, stage at diagnosis and treatment of PUC. This study is one of the few to describe treatments and survival in metastatic PUC patients. Efforts must be made to improve survival in these patients.

127 Background: VEGFR tyrosine kinase inhibitors (TKIs) in combination with immune checkpoint inhibitors (ICIs) have demonstrated clinical activity in pts with previously treated mCRC, particularly in pts without liver metastases (LM). Zanzalintinib (zanza) is a novel, oral, multitargeted TKI with activity against VEGFR, MET, and TAM kinases. Here, we present results from the randomized expansion cohort of pts with previously treated non-MSI-H/dMMR mCRC receiving zanza ± atezolizumab (atezo) in the phase 1 STELLAR-001 study (NCT03845166). Methods: Adults (aged ≥18 y) with locally advanced or metastatic CRC that was RAS -wildtype, who were refractory/intolerant to prior standard of care (5-FU–based treatment ± targeted therapies) and had an ECOG PS of 0/1, were enrolled. Pts with MSI-high or dMMR CRC, or who had received prior treatment with a PD-L1/PD-1 targeting ICI, regorafenib, and/or TAS-102, were excluded. Pts were randomized 1:1 to receive zanza+atezo (100 mg QD + 1200 mg Q3W) or single-agent zanza (100 mg QD). Objectives were to evaluate median (m)OS, investigator-assessed ORR, and mPFS per RECIST 1.1, and safety. Results: As of May 6, 2024, 107 pts were enrolled (zanza+atezo, n=54; zanza, n=53). In the zanza+atezo/zanza groups, median age was 61/60 years, 39%/51% had an ECOG PS of 1, pts had a median 2.5/3.0 (range, 1–5) prior lines of therapy, and 31%/32% did not have LM. With a median follow-up of 15 months across both arms, the mOS was 14.3 and 11.1 months for zanza+atezo and zanza, respectively (HR 0.75, 95% CI 0.45–1.26), confirmed ORR was 7.4% and 1.9% (all partial responses), mPFS was 4.0 and 3.0 months (HR 0.68, 0.44–1.04), and DCR was 59% and 55%. In pts without LM, mOS was not reached and 12.5 months (HR 0.46, 0.15–1.36) with 6-month survival rates of 88% and 65%, confirmed ORR was 18.0% and 5.9%, mPFS was 8.2 and 3.3 months (HR 0.40, 0.16–1.0), and DCR was 76% and 59%. The most common treatment-related adverse events (TRAEs) were diarrhea (zanza+atezo, 52%; zanza, 49%), nausea (54%, 36%), and decreased appetite (41%, 36%). Grade 3/4 TRAEs occurred in 48% of pts with zanza+atezo and 40% with zanza (Grade 4 in 3.7% and 0); a Grade 5 TRAE occurred in 1 pt (2%) in each group. 89% and 94% of pts had discontinued study treatment. Zanza was discontinued due to TRAEs in 11% and 8% of pts; atezo was discontinued due to TRAEs in 9% (zanza+atezo). Biomarker analysis is ongoing and results will be presented. Conclusions: Clinical activity was observed with zanza both as a single agent and in combination with atezo in this cohort of heavily pretreated pts with mCRC. Greater activity was seen with zanza+atezo versus zanza alone, particularly in pts without LM. Both treatments were generally well tolerated. Evaluation of zanza+atezo versus regorafenib is ongoing in the phase 3 STELLAR-303 study in non-MSI-H/dMMR mCRC (NCT05425940). Clinical trial information: NCT03845166 .

Background This Phase 1b/2 study assessed the efficacy in terms of objective response rate (ORR) of the FGFR1/2/3 kinase inhibitor derazantinib as monotherapy or in combination with atezolizumab in patients with metastatic urothelial cancer (mUC) and FGFR1-3 genetic aberrations (FGFR1-3GA).Methods This multicenter, open-label study comprised 5 substudies. In Substudies 1 and 5, patients with mUC with FGFR1-3GA received derazantinib monotherapy (300 mg QD in Substudy 1, 200 mg BID in Substudy 5). In Substudy 2, patients with any solid tumor received atezolizumab 1200 mg every 3 weeks plus derazantinib 200 or 300 mg QD. In Substudy 3, patients with mUC harboring FGFR1-3GA received derazantinib 200 mg BID plus atezolizumab 1200 mg every 3 weeks. In Substudy 4, patients with FGFR inhibitor-resistant mUC harboring FGFR1-3GA received derazantinib 300 mg QD monotherapy or derazantinib 300 mg QD plus atezolizumab 1200 mg every 3 weeks.Results The ORR for Substudies 1 and 5 combined was 4/49 (8.2%, 95% confidence interval = 2.3% to 19.6%), which was based on 4 partial responses. The ORR in Substudy 4 was 1/7 (14.3%, 95% confidence interval = 0.4% to 57.9%; 1 partial response for derazantinib 300 mg monotherapy, zero for derazantinib 300 mg plus atezolizumab 1200 mg). In Substudy 2, derazantinib 300 mg plus atezolizumab 1200 mg was identified as a recommended dose for Phase 2. Only 2 patients entered Substudy 3.Conclusions Derazantinib as monotherapy or in combination with atezolizumab was well-tolerated but did not show sufficient efficacy to warrant further development in mUC. Clinicaltrials.gov NCT04045613, EudraCT 2019-000359-15Conclusions Derazantinib as monotherapy or in combination with atezolizumab was well-tolerated but did not show sufficient efficacy to warrant further development in mUC. Clinicaltrials.gov NCT04045613, EudraCT 2019-000359-15