Muscle-invasive Urothelial Carcinoma Research Articles

Adjuvant Nivolumab in High-Risk Muscle-Invasive Urothelial Carcinoma: Expanded Efficacy From CheckMate 274.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.CheckMate 274 is a phase III, randomized, double-blind trial of adjuvant nivolumab versus placebo for muscle-invasive urothelial carcinoma (MIUC) at high risk of recurrence after radical resection. The primary end points of disease-free survival (DFS) in intent-to-treat (ITT) and tumor PD-L1 expression ≥1% populations were met. We report results at an extended median follow-up of 36.1 months in the ITT population. In addition, we report interim overall survival (OS) data for the first time and an exploratory analysis among patients with bladder primary tumors (muscle-invasive bladder cancer [MIBC]). Consistent DFS benefit with nivolumab versus placebo was observed in both the ITT (hazard ratio [HR], 0.71 [95% CI, 0.58 to 0.86]) and PD-L1 ≥1% (HR, 0.52 [95% CI, 0.37 to 0.72]) patients. The HR for OS with nivolumab versus placebo was 0.76 (95% CI, 0.61 to 0.96) in the ITT population and 0.56 (95% CI, 0.36 to 0.86) in the PD-L1 ≥1 population. Continuous benefit in nonurothelial tract recurrence-free survival and distant metastasis-free survival was also observed in both patient populations. The exploratory analysis of patients with MIBC also showed continued efficacy benefits, irrespective of PD-L1 status. No new safety signals were reported. Overall, these results further support adjuvant nivolumab as a standard of care for high-risk MIUC after radical resection.

Prognostic Value of Tumour Infiltrating T-Lymphocytes (Tils) with Special Preference to CD8 Positive T-Lymphocyte in Muscle Invasive Urothelial Bladder Cancer

Prognostic Value of Tumour Infiltrating T-Lymphocytes (Tils) with Special Preference to CD8 Positive T-Lymphocyte in Muscle Invasive Urothelial Bladder Cancer

Real-world evaluation of nivolumab utilization in adjuvant treatment of localized muscle-invasive urothelial carcinoma

IntroductionIn 2022, nivolumab was granted marketing authorization for adjuvant treatment in patients at high-risk of recurrence following surgery for localized invasive muscle urothelial carcinoma, who express PD-L1 on the operative specimen. We aimed to investigate its real-world utilization. Materials and methodsOur bicentric real-world study, conducted at Foch Hospital and Georges-Pompidou European Hospital between July 2022 and January 2024, included patients who underwent surgery for urothelial carcinoma or were referred for adjuvant nivolumab treatment at these centers. ResultsA total of 200 patients underwent surgery during the study period, of whom 70 met the high-risk criteria, with 46% of these patients not receiving adjuvant treatment due to ineligibility. Our survival outcomes among patients treated by nivolumab are consistent with the results of the CheckMate 274 study (Bajorin et al. N Engl J Med. 2021). Our study population was older and frailer than that of the study cohort, with a mean age of 69years. Significant PD-L1 expression was observed in 66% of the tested patients. The median disease-free survival was 11.34months in patients who received neoadjuvant chemotherapy followed by surgery and adjuvant nivolumab. Nivolumab was generally well-tolerated, but 25% of patients discontinued it due to toxicity. Our initial data on treatments for recurrence after adjuvant nivolumab highlighted the effectiveness of conventional chemotherapy (cisplatin or carboplatin combined with gemcitabine) and targeted chemotherapy (enfortumab vedotin). ConclusionOur real-world data align with existing literature regarding adjuvant nivolumab in localized invasive muscle urothelial carcinoma. Level of evidence3.

Classical chemotherapy, immunotherapy, or adjuvant radiotherapy-how to improve the oncologic outcome of radical cystectomy?

According to current guidelines, patients with muscle-invasive urothelial carcinoma (pT2-pt4a pN0) should be offered neoadjuvant cisplatin-containing chemotherapy before radical cystectomy. If not used neoadjuvantly, chemotherapy can be administered in the adjuvant setting (for > pT3 or pN+ disease). Both neoadjuvant and adjuvant therapy lead to improved overall survival. In the adjuvant setting, the checkpoint inhibitor nivolumab has also been approved for treatment of PD-L1-positive tumors (tumor proportion score [TPS] ≥ 1%). On the one hand, real-world evidence shows that cisplatin-fit patients often do not receive chemotherapy and, on the other hand, that arelevant proportion of patients are also not suitable for cisplatin-based chemotherapy. Further multimodal therapeutic strategies are hence urgently needed to improve the prognosis of affected patients. In particular, the use of antibody-drug conjugates and combination strategies involving checkpoint inhibitors are currently being intensively researched.

Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma.

Muscle-invasive urothelial carcinoma is an aggressive disease with high rates of relapse. Whether pembrolizumab as adjuvant therapy would be effective in patients with high-risk muscle-invasive urothelial carcinoma after radical surgery is unknown. In this phase 3 trial, we randomly assigned patients, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks for 1 year or to undergo observation. Randomization was stratified according to pathological stage, centrally tested programmed death ligand 1 (PD-L1) status, and previous neoadjuvant chemotherapy. The coprimary end points were disease-free survival and overall survival in the intention-to-treat population. We considered the trial to be successful if either disease-free survival or overall survival was significantly longer with pembrolizumab than with observation. A total of 702 patients underwent randomization; 354 were assigned to receive pembrolizumab, and 348 were assigned to observation. As of July 5, 2024, the median duration of follow-up for disease-free survival was 44.8 months. The median disease-free survival was 29.6 months (95% confidence interval [CI], 20.0 to 40.7) with pembrolizumab and 14.2 months (95% CI, 11.0 to 20.2) with observation (hazard ratio for disease progression or death, 0.73; 95% CI, 0.59 to 0.90; two-sided P = 0.003). Grade 3 or higher adverse events (regardless of attribution) occurred in 50.7% of the patients in the pembrolizumab group and in 31.6% of the patients in the observation group. Among patients with high-risk muscle-invasive urothelial carcinoma after radical surgery, disease-free survival was significantly longer with adjuvant pembrolizumab than with observation. (Funded by the National Cancer Institute of the National Institutes of Health and others; Alliance A031501 AMBASSADOR ClinicalTrials.gov number, NCT03244384.).

Bladder Adjuvant RadioTherapy (BART): Acute and Late Toxicity from a Phase III Multicentre Randomized Controlled Trial: Acute and late toxicity in BART RCT.

To report toxicity from the multicentre phase III randomized trial of Bladder Adjuvant Radiotherapy (BART) after radical cystectomy (RC) and chemotherapy in high-risk muscle-invasive bladder cancer (MIBC). Patients with non-metastatic urothelial MIBC with ≥1 high-risk feature after RC: pT3-4, pN1-3, nodal yield <10, positive margin, or ≥cT3 downstaged with neoadjuvant chemotherapy; were randomized 1:1 to observation (Obs) or adjuvant radiotherapy (RT) at 4 centres, stratified by pN stage (N0, N+) and chemotherapy (neoadjuvant, adjuvant, none). Stoma-sparing IG-IMRT 50.4Gy/28# was prescribed to the cystectomy bed and pelvic nodes. Acute toxicity (≤3 months of RT/randomization) and late toxicity were assessed per protocol using CTCAE v5.0. Patients progressing within 3 or 6 months of randomization were excluded from acute or late toxicity analysis respectively. BART trial enrolled 153 patients (Obs=76, RT=77). About half (49%) had pN+. Nearly 90% received chemotherapy (70% neoadjuvant; most commonly gemcitabine plus cisplatin). In the RT arm, 63/77 completed radiotherapy per protocol with no toxicity-related RT termination. Of the 134 patients analyzable for acute toxicity, no difference was observed in grade 3 (Obs 4.2% vs RT 1.6%, p=0.34). Grade 2 effects were higher with RT (17.5% vs 1.1%, p<0.001), mainly diarrhea/enteritis or proctitis. Late toxicity was analyzable for 104 patients (Obs=57, RT=47) with median follow up of 27 months. Grade 3-4 toxicity were about 10% (Obs 10.5% vs RT 8.4%, p=0.62), and cumulative late grade 2+ toxicity was similar in both the groups (17.5% vs 23.3%, p=0.27). In the largest trial of adjuvant radiotherapy for high-risk urothelial MIBC, severe acute and late toxicity were low and similar with observation or radiotherapy. The oncological outcomes are awaited.

1992P Real-world (RW) characteristics and outcomes in patients (pts) with muscle-invasive urothelial carcinoma (MIUC) treated with adjuvant nivolumab (NIVO) with or without neoadjuvant chemotherapy (NAC)

1992P Real-world (RW) characteristics and outcomes in patients (pts) with muscle-invasive urothelial carcinoma (MIUC) treated with adjuvant nivolumab (NIVO) with or without neoadjuvant chemotherapy (NAC)

1964MO Alliance A031501: AMBASSADOR study of adjuvant pembrolizumab (Pembro) in muscle-invasive urothelial carcinoma (MIUC) vs observation (Obs): Extended follow-up disease-free survival (DFS) results and metastatic (met) disease recurrence distribution

1964MO Alliance A031501: AMBASSADOR study of adjuvant pembrolizumab (Pembro) in muscle-invasive urothelial carcinoma (MIUC) vs observation (Obs): Extended follow-up disease-free survival (DFS) results and metastatic (met) disease recurrence distribution

2021TiP INTerpath-005: Phase II study of pembrolizumab (pembro) with V940 (mRNA-4157) versus pembro with placebo (pbo) for adjuvant treatment of resected high-risk muscle-invasive urothelial carcinoma (MIUC)

2021TiP INTerpath-005: Phase II study of pembrolizumab (pembro) with V940 (mRNA-4157) versus pembro with placebo (pbo) for adjuvant treatment of resected high-risk muscle-invasive urothelial carcinoma (MIUC)

2024TiP NETOS: A personalized approach of neoadjuvant therapy, including INCB099280 monotherapy and bladder preservation, for muscle-invasive urothelial bladder carcinoma (MIBC) with ctDNA monitoring

2024TiP NETOS: A personalized approach of neoadjuvant therapy, including INCB099280 monotherapy and bladder preservation, for muscle-invasive urothelial bladder carcinoma (MIBC) with ctDNA monitoring

Muscle-invasive and metastatic urothelial carcinoma of the urinary bladder : Current state of histopathologic, molecular, and immunologic prognostic and predictive factors

Muscle-invasive and metastatic urothelial carcinoma (UC) represents aheterogeneous disease entity with numerous morphological, molecular, and immunological phenotypes. This article aims to provide an overview of current histopathological, molecular, and immunological prognostic and predictive factors in muscle-invasive and metastatic UC. Muscle-invasive and metastatic UC exhibits awide range of divergent differentiations and histological subtypes. The correct diagnosis of these morphological variants is essential, as they may determine the clinical course and may also present specific and potentially therapeutically targetable molecular alterations (e.g., HER2 alterations in micropapillary UC). The morphological subtypes largely correlate with the six molecular consensus subtypes. Furthermore, morphological and molecular subtypes are associated with immunological properties that are relevant for modern immunotherapies, such as the PD-L1 status. Numerous immunotherapy studies in the setting of curatively treatable muscle-invasive UC will be reported in 2024 and 2025, likely leading to an increasing number of PD-L1 testing indications.

PD-L1 expression and its correlation with tumor biomarkers in Chinese urothelial bladder cancer

Data on prevalence of programmed death ligand-1 (PD-L1) expression and its correlation with tumor biomarkers in Chinese patients with muscle-invasive urothelial bladder cancer (MIUBC) are scarce. We investigated the prevalence of PD-L1 expression, PD-L1 expression in tumor cells (TC) and immune cells (IC), and its correlation with tumor biomarkers (CD8+ T cells and tumor mutation burden [TMB]) in Chinese patients with newly diagnosed MIUBC (NCT03433924). Of 248 patients enrolled, 229 with PD-L1 data available were analysed. High PD-L1 expression (≥ 25% of TC or IC with PD-L1 expression) was observed in 120 (52.4%) patients. 59 cases showed positive staining in ≥ 25% of TC, and 82 cases had positive staining in ≥ 25% of IC. High expression of CD8+ T cell and TMB (> 10 mutations/megabase) was observed in 44.5% and 54.1% patients, respectively. A positive correlation was observed between percentage of TC with membrane PD-L1 positivity and CD8+ T cells (0.34; P < 0.001) and between IC with membrane PD-L1 positivity and CD8+ T cells (0.44; P < 0.001). There is high prevalence of PD-L1 expression in Chinese patients with MIUBC, suggesting that a sizable subset of patients could benefit from immunotherapy. The correlation of PD-L1 expression with tumor biomarkers provide clues for mechanisms underlying the effects of biomarkers for predicting efficacy.

Digital volumetric assessment of CIS and tumor mass compliments conventional histopathological assessment in muscle-invasive urothelial bladder cancer.

Carcinoma in situ (CIS) of the bladder is a known parameter regarding the prognosis and recurrence tendency of urothelial carcinomas. Nevertheless, there is little evidence whether the amount of CIS or other precursor lesions, as well as the quantified tumor mass of muscle-invasive urothelial carcinoma, has an influence on the survival or recurrence rate of affected patients. From 80 patients with muscle invasive urothelial bladder cancer and radical cystectomy, 23 samples each were obtained as part of a whole organ mapping in a single institution study, in which the precursor lesions and tumor area were digitally measured and further correlated to pathological standard parameters, patient survival, molecular luminal and basal subtypes, and immune infiltration. Significant correlations were found between tumor mass and surface lining CIS amount for pT-stage, lymphovascular invasion, and perineural infiltration. Furthermore, an increased tumor mass as well as an increased amount of CIS combined with an increased tumor mass showed a significantly reduced survival rate in multivariable analysis (HR = 2.75; P = 0.019 vs. HR = 3.54; P = 0.002) as well as a significantly increased recurrence. No correlations could be found with molecular subtypes and immune infiltration. The exact measurement of the tumor mass with and without the CIS surface area, whether manually or, more specifically, digitally, could be incorporated into routine diagnostics and implemented as an independent predictor for patient post-surgical outcomes. It can therefore serve as an additional predictor for risk stratification and, if necessary, intensified follow-up care or therapy.

Bladder Tumor-Focused Adaptive Radiation Therapy: Clinical Outcomes of a Phase I Dose Escalation Study

Purpose/ObjectivesWe determine the maximum tolerated tumour focused dose (MTD) for the radical treatment of muscle invasive bladder cancer (MIBC) enabled by image guided adaptive radiotherapy (IGART) and long-term clinical outcomes. Materials/Methods: Fifty-nine patients with T2-T4aN0M0 unifocal urothelial MIBC suitable for daily radical radiotherapy were recruited prospectively to an ethics approved protocol (XX). The uninvolved bladder (PTVbladder) was planned to 52Gy in 32 fractions (f). The bladder tumour (PTVtumour) was planned to an assigned dose level of 68, 70, 72, or 74Gy. If organ at risk (OAR) dose constraints were violated, then PTVtumour was planned to 64Gy. Dose level allocation was determined by concurrent toxicity assessment of all previous patients recruited. Acute toxicity was evaluated using CTCAE v3.0; late toxicity was evaluated using RTOG criteria. The MTD was predefined as the highest dose level with estimated probability of ≤ 15% ≥G3 late toxicity and observed rate <50% acute G3 and <10% acute G4 toxicity. ResultsTwenty-six patients were assigned to 68Gy, of whom 6 were planned to 64Gy; 29 patients were assigned to 70Gy of whom 1 was planned to 68Gy, 2 patients were assigned and planned to 72Gy; no patients were assigned to 74Gy. Three patients did not complete treatment as planned, of whom only 1 patient stopped treatment because dose limiting toxicity occurred. The MTD was 70Gy. Acute genitourinary (GU) and gastrointestinal (GI) G3 acute toxicity was seen in 19% and 7% patients respectively. No grade 4 GU or GI toxicity was seen. Late toxicity (any) G3 and G4 was seen in 14% and 2% patients respectively. The 5-year overall survival was 58% (95% CI 44-71%). The bladder preservation rate was 89% (95% CI, 88 to 96%) with 6 patients not retaining native bladder function. ConclusionBladder tumour focused dose escalation to 70Gy using IGART is feasible with acceptable toxicity. This dose level has been evaluated in a phase II randomised control trial (XXXXX).

Perioperative sacituzumab govitecan (SG) alone or in combination with pembrolizumab (Pembro) for patients with muscle-invasive urothelial bladder cancer (MIBC): SURE-01/02 interim results.

LBA4517 Background: SG is an antibody-drug conjugate composed of an anti-trophoblast cell surface antigen 2 (Trop-2) antibody coupled to SN-38 (a topoisomerase-I inhibitor) with US FDA-accelerated approval for locally advanced or metastatic urothelial carcinoma (mUC). A multi-cohort, open-label, phase 2 SURE study is evaluating neoadjuvant SG (SURE-01, NCT05226117) or neoadjuvant SG+pembrolizumab followed by adjuvant pembrolizumab (SURE-02, NCT05535218) in MIBC in a flexible design allowing a bladder-sparing approach. We report interim results from SURE-01. Methods: Pts with cT2-4N0M0 MIBC who were ineligible for or refused cisplatin-based neoadjuvant chemotherapy were planned to receive 4 cycles of neoadjuvant SG 10 mg/kg intravenously (IV) on days 1 and 8, Q3W, followed by radical cystectomy (RC). The trial included pre-post MRI imaging of the pelvis and ctDNA analysis. Pts with clinical complete response (cCR, defined with negative MRI, cystoscopy and ctDNA assays) refusing RC were offered redo transurethral resection of the bladder tumor (reTURBT) followed by observation in case no viable high-grade tumor in the bladder was found. The primary endpoint of the study is to assess the proportion of ypT0N0. The assumptions include a ypT0N0≤20% as H0 and ≥45% as H1 in a single-stage A’Hern’s design. Secondary end points include event-free survival (EFS), cCR rate and OS. Treatment-related adverse events (TRAEs) and safety are assessed using standard criteria (CTCAE v5). Tumor samples underwent comprehensive genomic profiling assay. Results: From 03/22 to 11/23, 21 pts were enrolled. After the initial 8 pts the study was amended with SG at 7.5 mg/Kg dose due to a Grade 5 TRAE. Median age was 71y, 7 pts (33.3%) had a cT3-4N0. Ten pts (47.6%) had a mixed variant histology. All pts received at least 1 cycle of SG: Grade ≥3 TRAE occurred in 9 pts (42.5%), including one Grade 5 event (at 10mg/Kg dose). Toxicity was unrelated to UGT1A1 polymorphism. Ten pts (47.6%) achieved a cCR. Sixteen pts are evaluable for final response at treatment completion: one pt had a disease progression and started palliative therapy, two did not undergo RC due to TRAE. Thirteen pts have undergone surgery (RC: N=10; reTURBT: N=3). ypT0N0-x response was achieved in 6/16 pts (37.5%), 7 (43.7%) an ypT≤1N0-x response. All pts with a residual disease revealed a ctDNA-negative test post-RC. Tumor samples from pts with cCR were enriched in ARID1A and BRCA1/2 mutations vs nonCR: 40 vs 9%, 30 vs 18%; nonCR were enriched in ERBB2 mutations vs cCR: 44 vs 10%. Conclusions: Observed ypT0N0-x responses after neoadjuvant SG showed promising activity in MIBC who have a high unmet need, with a potential to avoid RC. Reduced dose of SG was feasible and the data support the ongoing SURE studies in MIBC. Clinical trial information: NCT05226117 ; NCT05535218 .

Comparison of clinical outcomes of bladder preservation and surgery in a real-world study of patients with muscle invasive urothelial carcinoma using urine and plasma based MRD (minimal residual disease) assays.

Comparison of clinical outcomes of bladder preservation and surgery in a real-world study of patients with muscle invasive urothelial carcinoma using urine and plasma based MRD (minimal residual disease) assays.

Avelumab (A) as neoadjuvant therapy in patients (pts) with muscle-invasive urothelial carcinoma (MIUC): Survival data of AURA trial, Oncodistinct 004.

4516 Background: Immunotherapy in the perioperative setting of MIUC appears promising. The AURA trial (NCT03674424) investigated the addition of avelumab to neoadjuvant dose-dense MVAC (ddMVAC) or cisplatin-gemcitabine (CG) respectively, followed by surgery in the cisplatin-eligible cohort. The primary endpoint was previously reported with high pathological complete response (pCR) rates with each cisplatin-based regimen. In the cisplatin-ineligible cohort, pts were randomized to neoadjuvant A alone or in combination with paclitaxel-gemcitabine (PG) followed by surgery. Avelumab monotherapy showed encouraging pCR but the addition of PG did not provide any benefit. Here, we report the survival data from cisplatin-eligible and ineligible cohorts of the AURA trial. Methods: In the cisplatin-eligible cohort, 79 pts were randomly assigned to the ddMVAC-A (n=39) or CG-A (n=40) groups. In the cisplatin-ineligible cohort, 58 pts were randomly assigned to the PG-A (n=29) or A (n=29) groups. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method at 12 months and 36 months for the overall cohort and by subgroups. Results: Median follow-up was 33 months and 45 deaths were reported. In the cisplatin-eligible cohort, 12-month DFS was 92% (95% CI, 83-96%) and 36-month DFS was 72% (95% CI, 57-83%). For ddMVAC-A group: 97% and 77%, respectively. For CG-A group: 86% and 68%. Overall, 12-month OS was 89% (95% CI, 80-95%) and 36-month OS was 73% (95% CI, 61-83%). For ddMVAC-A: 95% and 87%. For CG-A: 84% and 61%. Among the ypT0N0 pts, no events were registered within 12 months of follow-up showing a DFS rate of 100% for both arms. At 36 months no events were reported for pts treated with ddMVAC-A and two for CG-A showing DFS rates of 100% and 78% respectively. In the cisplatin-ineligible cohort, 12-month DFS was 60% (95% CI, 46-72%) and 12-month OS was 71% (95% CI, 57-81%). For PG-A: 52% and 67%. For A: 68% and 75%. Among the ypT0N0 pts, no DFS events occurred within 12 months. Data for 36-month are not yet mature. Overall, the main cause of death was disease progression (73%). Conclusions: The addition of neoadjuvant avelumab to cisplatin-based chemotherapy results in a high DFS and OS at 12 and 36 months respectively, especially in pts with complete response to neoadjuvant treatment. Combination with ddMVAC regimen offers robust activity. Cisplatin-ineligible pts had lower survival outcomes with no benefit of PG addition. Clinical trial information: NCT03674424 . [Table: see text]

NETOS: A personalized approach of neoadjuvant therapy, including INCB099280 monotherapy and bladder preservation, for muscle-invasive urothelial bladder carcinoma (MIBC) with ctDNA monitoring.

TPS4624 Background: MIBC is a systemic disease as &gt;40% of patients (pts) ultimately develop recurrence after radical cystectomy (RC). For pts who cannot receive or refuse cisplatin-based chemotherapy there is no standard-of-care neoadjuvant therapy. Single-agent pembrolizumab, given neoadjuvantly in patients with T2-4N0M0 MIBC, was effective in PURE-01 trial. A proportion of these pts refused RC and were cured with pembro and redo transurethral resection of the bladder tumor (reTURBT; Bandini et al. PMID: 32979511). There are increasing concerns by the pts related to the need to undergo RC whenever they achieve a clinical complete response (cCR) with TURBT and systemic therapy. INCB099280 is a potent, orally bioavailable, selective, small molecule that targets PD-L1 that is being developed for the treatment of advanced malignant diseases. A phase 1, dose-escalation and expansion study is ongoing in pts with select advanced solid tumors (NCT04242199); safety and preliminary efficacy results have been reported (Prenen et al. ESMO-IO 2023). Our hypothesis is that INCB099280 can be offered in biomarker-selected pts as a maintenance therapy instead of any additional treatment, provided that a cCR after the induction phase is obtained. Methods: Pts should have a predominant urothelial carcinoma (UC) histology, have a clinical stage T2-T4N0M0 MIBC, be ineligible for or refuse to receive cisplatin-based chemotherapy. The study will also select pts with a circulating tumor DNA (ctDNA)-positive test (Signatera ctDNA assay) and will be staged with pelvic MRI. Pts will receive 12 weeks of INCB099280 at the dose of 400 mg twice daily (BID), continuously. Restaging will be planned with ctDNA, imaging and reTURBT. Pts who will achieve a cCR (i.e., no evidence of residual disease at the histological examination, clearance of ctDNA and the evidence of no residual detectable disease at cross-sectional imaging, evaluated locally) will receive additional INCB099280 400 mg BID for a maintenance period of 12 months. Pts with evidence of high grade or infiltrating residual disease will be discontinued from the study. Those with a Ta/T1-low grade disease will be managed according to physician’s preference: they may be eligible to continue within the study protocol and receive maintenance INCB099280 400 mg BID for a total period of 12 months. The primary endpoint is the proportion of cCR and the study is planned according to A'Hern one-stage binomial design, with H0 ≤5% and H1 ≥20%, 5% one-sided Alpha, 80% power and 10% drop-out rate. The overall sample size Will be of 30 pts. Secondary endpoints will include safety (CTCAE v.5.0), event-free survival, bladder-intact overall survival (OS) and OS (EUCT number: 2024-511029-73-00). Clinical trial information: 2024-511029-73-00.

Preliminary results from a multi-center phase Ib/II study of RC48-ADC combined with tislelizumab as neoadjuvant treatment in patients with HER2 positive locally advanced muscle-invasive urothelial bladder cancer (Hope-03).

e16595 Background: To evaluate the safety and efficacy of RC48-ADC, a humanized anti-HER2 antibody conjugated with monomethyl auristatin E, and tislelizumab, a PD-1 antibody, as a novel neoadjuvant treatment combination in patients with HER2 positive locally advanced muscle-invasive bladder cancer (MIBC). The study design has been presented at 2022 ESMO Asia meeting. The preliminary results would be reported this time. Methods: This is a Ib/II, multi-center, open-label, single-arm study (ChiECRCT20210564). 51 patients with pathological and imaging diagnosed cT2-4bN0-3M0-1a HER2 positive MIBC will be included. RC48-ADC is given every 2 weeks with a maximum dose of 120mg intravenously, and tislelizumab is given every three weeks at the dose of 200mg intravenously. Treatment efficacy will be performed by imaging and transurethral resection of tumors after the neoadjuvant treatment. Patients without disease progression will receive radical cystectomy or bladder-sparing therapies based on individual risk profiles and preferences. The primary endpoints are clinical complete remission rate (cCR, T0/Ta/Tis), pathological complete remission rate (pCR) and safety. The secondary endpoints are disease control rate (DCR), overall survival (OS), local recurrence free survival (LRFS), distant metastasis free survival (DMFS) and quality of life. Results: Until now, 18 patients were included successfully, with 3 female patients and 15 male patients. And the median age was 64.47 years old. Of them, 7 patients were HER2(2+), and 11 patients were HER2(3+). The clinical stages were T2-4aN0-3M1a. Sixteen patients had the primary efficacy evaluation by now. After the neoadjuvant treatment, 7 patients were T0, 4 patients Tis, 2 patients partial response (PR), 2 patients stable disease (SD) and 1 patient suffered from progress of local disease. Hence the cCR rate was 68.75%, and the DCR was 90.91%. Fourteen patients chose radiotherapy as bladder-sparing therapy and no evidence of tumor in 6 patients who received treatment efficacy after radiotherapy. Two patients received radical cystectomy and pT3N0M0 was achieved for both. No patient died so far. For safety analysis, 4 patients suffered from immune-related adverse event, namely, grade 2 myositis, grade 1 elevated transaminase and grade 1 hyperthyroidism which led to treatment interruption of tislelizumab. And 10 patients experienced RC48-ADC related toxicities, including grade 1 elevated transaminase, grade 1 erythra and grade 1 paresthesia. No treatment related dose reduction happened. Conclusions: The novel neoadjuvant combination of RC48-ADC and tislelizumab showed promising down stage efficacy in patients with HER2 positive locally advanced MIBC and the toxicities were manageable, which would be verified by the final analysis. Clinical trial information: ChiECRCT20210564.

Neoadjuvant cisplatin-based chemotherapy followed by selective bladder preservation chemoradiotherapy in muscle-invasive urothelial carcinoma of the bladder: Post hoc analysis of two prospective studies.

Neoadjuvant cisplatin-based chemotherapy followed by selective bladder preservation chemoradiotherapy in muscle-invasive urothelial carcinoma of the bladder: Post hoc analysis of two prospective studies.