Publications by authors named "Powles T"

Treatment options for recurrent high-risk non-muscle-invasive bladder cancer (HR NMIBC) and muscle-invasive bladder cancer (MIBC) are limited, highlighting a need for clinically effective, accessible, and better-tolerated alternatives. In this review we examine the clinical development program of TAR-200, a novel targeted releasing system designed to provide sustained intravesical delivery of gemcitabine to address the needs of patients with NMIBC and of those with MIBC. We describe the concept and design of TAR-200 and the clinical development of this gemcitabine intravesical system in the SunRISe portfolio of studies.

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Background: The phase 3 open-label KEYNOTE-426 study demonstrated that first-line pembrolizumab plus axitinib improved overall survival (OS) and progression-free survival (PFS) versus sunitinib for metastatic renal cell carcinoma (mRCC) in a global population. This subgroup analysis investigated the efficacy and safety of pembrolizumab-axitinib versus sunitinib in patients enrolled in KEYNOTE-426 in East Asia (Japan, South Korea, and Taiwan).

Methods: Adults with clear cell mRCC were randomly assigned 1:1 to receive intravenous pembrolizumab 200 mg every 3 weeks with oral axitinib 5 mg twice daily or oral sunitinib 50 mg once daily (4 weeks on/2 weeks off).

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Effective targeting of somatic cancer mutations to enhance the efficacy of cancer immunotherapy requires an individualized approach. Autogene cevumeran is a uridine messenger RNA lipoplex-based individualized neoantigen-specific immunotherapy designed from tumor-specific somatic mutation data obtained from tumor tissue of each individual patient to stimulate T cell responses against up to 20 neoantigens. This ongoing phase 1 study evaluated autogene cevumeran as monotherapy (n = 30) and in combination with atezolizumab (n = 183) in pretreated patients with advanced solid tumors.

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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.

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Lenvatinib plus pembrolizumab significantly improved efficacy versus sunitinib in treatment of advanced renal cell carcinoma (aRCC) in the phase 3 CLEAR study. We report results of an exploratory post hoc analysis of tumor response data based on baseline metastatic characteristics of patients who received lenvatinib plus pembrolizumab versus sunitinib, at the final overall survival analysis time point of CLEAR (cutoff: July 31, 2022). Treatment-naïve adults with aRCC were randomized to: lenvatinib (20 mg PO QD in 21-day cycles) plus pembrolizumab (n = 355; 200 mg IV Q3W); lenvatinib plus everolimus (not reported here); or sunitinib (n = 357; 50 mg PO QD; 4 weeks on/2 weeks off).

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Introduction: 1L PBC has historically been recommended for patients with la/mUC. Maintenance avelumab is recommended for patients without disease progression following 1L PBC. Real-world data on the proportion of patients eligible for maintenance avelumab are limited, and outcomes among patients ineligible for maintenance avelumab are uncertain.

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Introduction: KEYNOTE-361 evaluated first-line pembrolizumab with and without platinum-based chemotherapy versus chemotherapy alone in advanced or metastatic urothelial carcinoma. The primary end points of progression-free survival (PFS) or overall survival (OS) were not met. Exploratory analysis of efficacy by platinum agent (cisplatin or carboplatin) is reported.

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Article Synopsis
  • The IMvigor210 trial assessed the long-term efficacy and safety of atezolizumab, an anti-PD-L1 therapy, in patients with advanced metastatic urothelial carcinoma (UC), showing manageable toxicity.
  • The trial involved two cohorts: untreated UC patients ineligible for cisplatin-based chemotherapy and those previously treated with platinum-based chemotherapy, with a median follow-up of up to 96.4 months.
  • Results indicated objective response rates of 23.5% in untreated patients and 16.5% in previously treated patients, with median overall survival of 16.3 months and 7.9 months, respectively, along with a notable percentage of patients experiencing grade 3/4 adverse events. *
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Article Synopsis
  • Advances in molecular diagnostics are transforming how prostate, renal, and urothelial cancers are assessed, offering more accurate detection methods for disease burden and minimal residual disease (MRD).
  • A literature review from 1980-2024 highlights emerging radiographic and molecular tools aimed at improving disease quantification and monitoring through innovative technologies and biomarker-informed trials.
  • New developments, like novel radiotracers and molecular detection methods (e.g., circulating tumor DNA), provide insights into disease mechanisms and have the potential to enhance clinical management, although full MRD application is still in progress.
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Introduction: The phase 3 KEYNOTE-361 trial of first-line pembrolizumab with or without chemotherapy versus chemotherapy alone in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) completed enrollment before the approval of postchemotherapy maintenance avelumab for patients without progressive disease. This post hoc analysis evaluated the outcomes of patients who received chemotherapy alone in KEYNOTE-361 by retrospective eligibility for subsequent maintenance therapy.

Patients And Methods: Patients in the chemotherapy alone arm were retrospectively categorized as maintenance eligible (received ≥4 cycles of chemotherapy and did not die or experience disease progression within 10 weeks of chemotherapy completion), maintenance ineligible (received <4 cycles of chemotherapy or had progressive disease or died within 0-10 weeks after completion of ≥4 cycles of chemotherapy), and indeterminate eligibility for maintenance therapy (if neither maintenance eligible or ineligible).

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Checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have revolutionized cancer therapy across many indications including urothelial carcinoma (UC). Because many patients do not benefit, a better understanding of the molecular mechanisms underlying response and resistance is needed to improve outcomes. We profiled tumors from 2,803 UC patients from four late-stage randomized clinical trials evaluating the PD-L1 inhibitor atezolizumab by RNA sequencing (RNA-seq), a targeted DNA panel, immunohistochemistry, and digital pathology.

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Clinical trials to establish the efficacy of new agents in the adjuvant cancer setting typically take many years to complete. During that time, external factors can impact recruitment and reporting plans. An example is a new standard of care becoming available during the recruitment period.

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Article Synopsis
  • The review focuses on the recent advancements in treatment options for metastatic renal cell carcinoma (mRCC), highlighting the importance of selecting appropriate first- and second-line therapies based on the latest evidence.
  • First-line treatments include immune checkpoint inhibitor combinations and tyrosine kinase inhibitors, with four regimens approved internationally; however, treatment decisions are complicated by the absence of head-to-head trials and standardized biomarkers.
  • Clinicians must consider various factors, such as the IMDC risk score and patient preferences, when transitioning between treatment lines to ensure personalized and effective care for mRCC patients.
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Purpose: The three-arm, phase III KEYNOTE-361 study did not meet its dual primary endpoints of progression-free survival (PFS) or overall survival (OS) with first-line pembrolizumab plus chemotherapy versus chemotherapy in advanced urothelial carcinoma. This prespecified exploratory analysis assessed the association of tumor mutational burden (TMB) and PD-L1 combined positive score (CPS) with clinical outcomes.

Patients And Methods: TMB and PD-L1 CPS were determined via whole-exome sequencing and PD-L1 IHC 22C3 pharmDx, respectively.

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Background: First-line pembrolizumab monotherapy is a standard of care for platinum-ineligible patients with advanced urothelial carcinoma (UC). No global standardized definition of platinum ineligibility exists. This study aimed to evaluate the efficacy and safety of pembrolizumab monotherapy in patients with UC who met various criteria for platinum ineligibility.

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Article Synopsis
  • Immune-oncology strategies are improving treatment for renal cell carcinoma (RCC), especially with the introduction of immunotherapy in the perioperative setting.
  • Adjuvant therapy with pembrolizumab has shown benefits in disease-free survival post-surgery but there's limited support for neoadjuvant therapies outside trials; both strategies have their risks and challenges.
  • While adjuvant immunotherapy is now a standard treatment, understanding the optimal use of neoadjuvant approaches is still unclear and requires further research in biomarker development and clinical trials.
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Article Synopsis
  • Clinical trials in genitourinary oncology are primarily classified as industry-sponsored trials (ISTs) led by pharmaceutical companies, or investigator-initiated trials (IITs) spearheaded by academic researchers, with both playing critical roles in advancing cancer treatment.
  • A study analyzing data from the US, Canada, France, and the UK found a total of 5,834 GU trials from 2007 to 2021, with a near-equal distribution of ISTs and IITs, though post-2017 saw a notable increase in ISTs, particularly in Canada and the UK.
  • The widening gap between ISTs and IITs is likely due to funding and resource constraints for researchers
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Background: Neoadjuvant chemotherapy followed by radical cystectomy is the standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer. Adding perioperative immunotherapy may improve outcomes.

Methods: In this phase 3, open-label, randomized trial, we assigned, in a 1:1 ratio, cisplatin-eligible patients with muscle-invasive bladder cancer to receive neoadjuvant durvalumab plus gemcitabine-cisplatin every 3 weeks for four cycles, followed by radical cystectomy and adjuvant durvalumab every 4 weeks for eight cycles (durvalumab group), or to receive neoadjuvant gemcitabine-cisplatin followed by radical cystectomy alone (comparison group).

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Background: Belzutifan, a hypoxia-inducible factor 2α inhibitor, showed clinical activity in clear-cell renal-cell carcinoma in early-phase studies.

Methods: In a phase 3, multicenter, open-label, active-controlled trial, we enrolled participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies and randomly assigned them, in a 1:1 ratio, to receive 120 mg of belzutifan or 10 mg of everolimus orally once daily until disease progression or unacceptable toxic effects occurred. The dual primary end points were progression-free survival and overall survival.

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• This ESMO CPG provides recommendations for diagnosis, staging, pathology, treatment and follow-up of penile cancer. • Algorithms for the management of primary penile tumours and inguinal lymph nodes are provided. • The author group encompasses a multidisciplinary group of experts from different institutions and countries in Europe.

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