Treatment-free Survival After First-line Therapies for Metastatic Renal Cell Carcinoma: An International Metastatic Renal Cell Carcinoma Database Consortium Analysis.

Background And Objective: Patients receiving immune checkpoint blockade (ICB) therapy may experience periods of prolonged disease control without a need for systemic therapy. Treatment-free survival (TFS) is an important measure for this period, but no data are available for patients with metastatic renal cell carcinoma (mRCC) starting first-line agents. Our aim was to analyze TFS outcomes for patients with mRCC starting first-line therapy.

Impact of Prior Chemotherapy on Response to Second-line Pembrolizumab in Urothelial Cancer: Exploratory Analysis of the Phase 3 KEYNOTE-045 Trial.

Background And Objective: Until recently, the standard first-line treatment for advanced urothelial carcinoma (UC) was platinum-based combination chemotherapy followed by avelumab maintenance therapy for patients without progressive disease (PD). For patients with advanced UC who experience PD or recurrence, standard-of-care treatment is pembrolizumab monotherapy based on the phase 3 KEYNOTE-045 study. This post hoc analysis of the KEYNOTE-045 study evaluated the efficacy of pembrolizumab compared with chemotherapy by the best response to prior platinum-based chemotherapy.

Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma.

Background: Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain.

Methods: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent.

Effectiveness of Adjuvant Chemotherapy in Variant Histology Upper Tract Urothelial Carcinoma Following Radical Nephroureterectomy: Stabilized Inverse Probability Treatment Weighting Analysis of Single Center Experience.

Purpose: The study aimed to investigate the impact of adjuvant chemotherapy on time to recurrence (TTR) and overall survival (OS) in patients with histologic variants of upper tract urothelial carcinoma (VUTUC) following radical nephroureterectomy (RNU).

Materials And Methods: A retrospective review of 131 VUTUC patients' medical records, from a pool of 368 non-metastatic localized or locally advanced UTUC cases, treated at a single tertiary referral center between January 2011 and January 2021. The intervention was adjuvant chemotherapy administration post-RNU.

Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy.

Background And Objective: In comparison to chemotherapy, enfortumab vedotin (EV) prolonged overall survival in patients with previously treated advanced urothelial carcinoma in EV-301. The objective of the present study was to assess patient experiences of EV versus chemotherapy using patient-reported outcome (PRO) analysis of health-related quality of life (HRQoL).

Methods: For patients in the phase 3 EV-301 trial randomized to EV or chemotherapy we assessed responses to the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline, weekly for the first 12 wk, and then every 12 wk until discontinuation.

Outcomes of Patients with Brain Metastases from Renal Cell Carcinoma Receiving First-line Therapies: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

Patients with brain metastases (BrM) from renal cell carcinoma and their outcomes are not well characterized owing to frequent exclusion of this population from clinical trials. We analyzed data for patients with or without BrM using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). A total of 389/4799 patients (8.

IFITM3-mediated activation of TRAF6/MAPK/AP-1 pathways induces acquired TKI resistance in clear cell renal cell carcinoma.

Purpose: Vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been the standard of care for advanced and metastatic clear cell renal cell carcinoma (ccRCC). However, the therapeutic effect of TKI monotherapy remains unsatisfactory given the high rates of acquired resistance to TKI therapy despite favorable initial tumor response.

Materials And Methods: To define the TKI-resistance mechanism and identify new therapeutic target for TKI-resistant ccRCC, an integrative differential gene expression analysis was performed using acquired resistant cohort and a public dataset.

Xaluritamig, a STEAP1 × CD3 XmAb 2+1 Immune Therapy for Metastatic Castration-Resistant Prostate Cancer: Results from Dose Exploration in a First-in-Human Study.

Unlabelled: Xaluritamig (AMG 509) is a six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeted T-cell engager designed to facilitate lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. This first-in-human study reports monotherapy dose exploration for patients with metastatic castration-resistant prostate cancer (mCRPC), primarily taxane pretreated. Ninety-seven patients received ≥1 intravenous dose ranging from 0.

AMG 509 (Xaluritamig), an Anti-STEAP1 XmAb 2+1 T-cell Redirecting Immune Therapy with Avidity-Dependent Activity against Prostate Cancer.

Unlabelled: The tumor-associated antigen STEAP1 is a potential therapeutic target that is expressed in most prostate tumors and at increased levels in metastatic castration-resistant prostate cancer (mCRPC). We developed a STEAP1-targeted XmAb 2+1 T-cell engager (TCE) molecule, AMG 509 (also designated xaluritamig), that is designed to redirect T cells to kill prostate cancer cells that express STEAP1. AMG 509 mediates potent T cell-dependent cytotoxicity of prostate cancer cell lines in vitro and promotes tumor regression in xenograft and syngeneic mouse models of prostate cancer in vivo.

Avelumab first-line maintenance plus best supportive care (BSC) vs. BSC alone for advanced urothelial carcinoma: JAVELIN Bladder 100 Asian subgroup analysis.

Background: The phase 3 JAVELIN Bladder 100 trial showed significantly prolonged overall survival (OS) with avelumab first-line maintenance + best supportive care (BSC) vs. BSC alone in patients with advanced urothelial carcinoma (UC) that had not progressed with first-line platinum-containing chemotherapy. Here, efficacy and safety were assessed from the initial analysis of the JAVELIN Bladder 100 trial (data cutoff October 21, 2019) in patients enrolled in Asian countries.

Characterization of Patients With Metastatic Renal Cell Carcinoma Experiencing Complete Response to First-line Therapies: Results From the International Metastatic Renal Cell Carcinoma Database Consortium.

Purpose: Clinical trials have demonstrated higher complete response rates in the immuno-oncology-based combination arms than in the tyrosine kinase inhibitor arms in patients with metastatic renal cell carcinoma. We aimed to characterize real-world patients who experienced complete response to the contemporary first-line therapies.

Materials And Methods: Using the International Metastatic Renal Cell Carcinoma Database Consortium, response-evaluable patients who received frontline immuno-oncology-based combination therapy or tyrosine kinase inhibitor monotherapy were analyzed.

FORT-1: Phase II/III Study of Rogaratinib Versus Chemotherapy in Patients With Locally Advanced or Metastatic Urothelial Carcinoma Selected Based on / mRNA Expression.

Purpose: Rogaratinib, an oral pan-fibroblast growth factor receptor (FGFR1-4) inhibitor, showed promising phase I efficacy and safety in patients with advanced urothelial carcinoma (UC) with mRNA overexpression. We assessed rogaratinib efficacy and safety versus chemotherapy in patients with mRNA-positive advanced/metastatic UC previously treated with platinum chemotherapy.

Methods: FORT-1 (ClinicalTrials.

Outcomes of patients with advanced non-clear cell renal cell carcinoma treated with first-line immune checkpoint inhibitor therapy.

Background: Immune checkpoint inhibitors (ICI) have demonstrated impressive activity in metastatic clear-cell renal cell carcinoma (ccRCC) and have become standard treatment options for patients with advanced disease. Data supporting the effectiveness of ICI-based therapy in advanced non-clear cell RCC (nccRCC) is more limited.

Methods: We performed a retrospective analysis using the International Metastatic RCC Database Consortium (IMDC) to evaluate the outcomes of patients with advanced nccRCC.

Predictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial.

The RANGE study (NCT02426125) evaluated ramucirumab (an anti-VEGFR2 monoclonal antibody) in patients with platinum-refractory advanced urothelial carcinoma (UC). Here, we use programmed cell death-ligand 1 (PD-L1) immunohistochemistry (IHC) and transcriptome analysis to evaluate the association of immune and angiogenesis pathways, and molecular subtypes, with overall survival (OS) in UC. Higher PD-L1 IHC and immune pathway scores, but not angiogenesis scores, are associated with greater ramucirumab OS benefit.

Putative Biomarkers of Clinical Benefit With Pembrolizumab in Advanced Urothelial Cancer: Results from the KEYNOTE-045 and KEYNOTE-052 Landmark Trials.

Purpose: In an exploratory analysis, we investigated the association between programmed death ligand 1 (PD-L1), tumor mutational burden (TMB), T-cell-inflamed gene expression profile (TcellinfGEP), and stromal signature with outcomes of pembrolizumab in urothelial carcinoma (UC).

Patients And Methods: Patients with advanced UC received first-line pembrolizumab 200 mg every 3 weeks in the single-arm phase II KEYNOTE-052 trial (NCT02335424) and salvage pembrolizumab 200 mg every 3 weeks or chemotherapy (paclitaxel/docetaxel/vinflunine) in the randomized phase III KEYNOTE-045 trial (NCT02256436). The association of each biomarker (continuous variable) with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was evaluated using logistic regression (ORR) and Cox PH (PFS, OS), adjusted for ECOG PS; nominal P values were calculated without multiplicity adjustment (one-sided, pembrolizumab; two-sided, chemotherapy).

PD-L1 Upregulation by the mTOR Pathway in VEGFR-TKI-Resistant Metastatic Clear Cell Renal Cell Carcinoma.

Purpose: Tyrosine kinase inhibitors (TKI) targeting vascular endothelial growth factor receptor (VEGFR) signaling pathways have been used for metastatic clear cell renal cell carcinoma (mCCRCC), but resistance to the drug develops in most patients. We aimed to explore the underlying mechanism of the TKI resistance with regard to programmed death-ligand 1 (PD-L1) and to investigate signaling pathway associated with the resistant mechanism.

Materials And Methods: To determine the mechanism of resistance, 10 mCCRCC patients from whom tumor tissues were harvested at both the pretreatment and the TKI-resistant post-treatment period were included as the discovery cohort, and their global gene expression profiles were compared.

Clinical evidence and insights supporting the use of avelumab first-line maintenance treatment in patients with advanced urothelial carcinoma in the Asia-Pacific region.

Until recently, international and Asia-specific guidelines for advanced urothelial carcinoma (UC) recommended first-line (1L) platinum-based chemotherapy, followed by second-line (2L) anti-PD-1 or anti-PD-L1 immune checkpoint inhibitor (ICI) therapy where possible, or 1L ICI therapy in cisplatin-ineligible patients with PD-L1+ tumors. However, long-term outcomes remain poor and only a minority of patients receive 2L therapy. The JAVELIN Bladder 100 trial-which assessed avelumab (anti-PD-L1 antibody) as 1L maintenance therapy plus best supportive care (BSC) versus BSC alone in patients with advanced UC that had not progressed with 1L platinum-based chemotherapy-is the only phase 3 trial of ICI-based treatment in the 1L setting to show significantly improved overall survival, and this treatment approach is now recommended in updated treatment guidelines.

Clinical features and oncological outcomes of primary female urethral cancer.

Purpose: Investigation of the clinical features and treatment outcomes of primary female urethral cancer (FUC) at a single institution.

Materials And Methods: We retrospectively reviewed 32 FUC patients during 1997-2017. We investigated preoperative risk factors predicting overall (overall survival [OS]) and recurrence-free survival (RFS) and reviewed clinical features, treatment modality, and oncologic outcomes according to pathology.

Exposure-response relationship of ramucirumab in RANGE, a randomized phase III trial in advanced urothelial carcinoma refractory to platinum therapy.

Aims: Patients with advanced urothelial carcinoma (UC) who progress after platinum-based chemotherapy have a poor prognosis, and there is a medical need to improve current treatment options. Ramucirumab plus docetaxel significantly improved progression-free survival but not overall survival (OS) in platinum-refractory advanced UC (RANGE trial; NCT02426125). Here, we report the exposure-response (ER) of ramucirumab plus docetaxel using data from the RANGE trial.

Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma.

Importance: Interim analyses of the IMmotion151 trial (A Study of Atezolizumab in Combination With Bevacizumab Versus Sunitinib in Participants With Untreated Advanced Renal Cell Carcinoma) reported improved progression-free survival (PFS) for patients with programmed death ligand 1-positive (PD-L1+) metastatic renal cell carcinoma (mRCC) receiving the PD-L1 inhibitor atezolizumab plus the vascular endothelial growth factor (VEGF) inhibitor bevacizumab vs the receptor tyrosine kinase inhibitor sunitinib. Overall survival (OS) results were immature at interim analyses.

Objective: To report the final OS results, safety, and exploratory biomarker analyses of the association of transcriptomic subgroups with OS in the IMmotion151 trial.

Clinical Outcomes of Platinum-ineligible Patients with Advanced Urothelial Carcinoma Treated With First-line PD1/L1 Inhibitors.

Background: PD1/L1 inhibitors are approved by FDA as first-line therapy for patients with advanced urothelial carcinoma (aUC) who are cisplatin-ineligible with high tumor PD-L1 expression or are platinum-ineligible regardless of PD-L1 expression. However, the outcomes when employing PD1/L1 inhibitors for platinum-ineligible patients are unclear. This retrospective analysis evaluates the clinical outcomes of first-line PD1/L1 inhibitors in patients with aUC deemed to be platinum-ineligible.