Publications by authors named "T Powles"

666 Publications

Checkpoint inhibitors in metastatic papillary renal cell carcinoma.

Cancer Treat Rev 2021 May 20;99:102228. Epub 2021 May 20.

Medical Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France. Electronic address:

Papillary Renal Cell Carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC) and a distinct entity, although heterogenous, associated with poor outcomes. The treatment landscape of metastatic pRCC (mpRCC) relied so far on targeted therapies, mimicking previous developments in metastatic clear-cell renal cell carcinoma. However, antiangiogenics as well as mTOR inhibitors retain only limited activity in mpRCC. As development of immune checkpoint inhibitors (ICI) is now underway in patients with mpRCC, we aimed at discussing early activity data and potential for future therapeutic strategies in monotherapy or combination. Expression of immune checkpoints such as PD-L1 and infiltrative immune cells in pRCC could provide insights into their potential immunogenicity, although this is currently poorly described. Based on retrospective and prospective data, efficacy of ICI as single agent remains limited. Combinations with tyrosine-kinase inhibitors, notably with anti-MET inhibitors, harbor promising response rates and may enter the standard of care in untreated patients. Collaborative work is needed to refine the molecular and immune landscape of pRCC, and pursue efforts to set up predictive biomarker-driven clinical trials in these rare tumors.
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http://dx.doi.org/10.1016/j.ctrv.2021.102228DOI Listing
May 2021

The 2021 Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibitor-based Combination Therapies for Treatment-naive Metastatic Clear-cell Renal Cell Carcinoma Are Standard of Care.

Eur Urol 2021 May 29. Epub 2021 May 29.

The Royal Free London NHS Foundation Trust, London, UK; UCL Division of Surgery and Interventional Science, London, UK; Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Electronic address:

The recent randomized controlled phase III CLEAR trial results are the last to complement immune checkpoint inhibitor (ICI)-based doublet combination therapies for treatment-naïve metastatic clear-cell renal cell carcinoma. The CLEAR trial demonstrated an improved progression-free survival (PFS), overall survival (OS), and an objective response rate (ORR) benefit for the combination of lenvatinib plus pembrolizumab over sunitinib. The CheckMate-9ER trial update demonstrated an ongoing PFS, OS, and quality-of-life benefit for cabozantinib plus nivolumab over sunitinib as did the update of Keynote-426 for axitinib plus pembrolizumab in the intention-to-treat population, with a PFS benefit seen across all International Metastatic Database Consortium (IMDC) subgroups. In the IMDC intermediate- and poor-risk groups, the CheckMate-214 trial of ipilimumab plus nivolumab confirmed the OS benefit with a PFS plateauing after 30 months. The RCC Guidelines Panel recommends three tyrosine kinase inhibitors + ICI combinations of axitinib plus pembrolizumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab across all IMDC risk groups in advanced first-line RCC, and dual immunotherapy of ipilimumab and nivolumab in IMDC intermediate- and poor-risk groups. PATIENT SUMMARY: New data from combination trials with immune checkpoint inhibitors for advanced kidney cancer confirm a survival benefit for lenvatinib plus pembrolizumab, cabozantinib plus nivolumab (with improved quality-of-life), axitinib plus pembrolizumab, and ipilimumab plus nivolumab. These combination therapies are recommended as first-line treatment for advanced kidney cancer.
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http://dx.doi.org/10.1016/j.eururo.2021.04.042DOI Listing
May 2021

Immune Checkpoint Inhibition in Advanced Bladder and Kidney Cancer: Responses and Further Management.

Am Soc Clin Oncol Educ Book 2021 Jun;41:e182-e189

Barts Health NHS Trust and the Royal Free NHS Foundation Trust, Barts Cancer Institute, and Queen Mary University of London, London, United Kingdom.

Immune checkpoint inhibitors have an established role in the treatment of newly diagnosed metastatic kidney cancer. Treatment regimens combining nivolumab plus ipilimumab, pembrolizumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib have demonstrated superior overall survival compared with sunitinib in randomized studies. Response rates vary from 42% to 71.1% with these combinations. Atezolizumab and pembrolizumab have been approved for the treatment of cisplatin-ineligible patients with metastatic bladder cancer. These and other checkpoint inhibitors have been studied in metastatic bladder cancer and are routinely used after progression on platinum-based chemotherapy. Durable responses are observed in bladder and kidney cancer. Although some patients may experience immune-related adverse events requiring treatment discontinuation, a portion of these patients will continue to experience a response off-therapy. At the time of progression, patients with metastatic kidney cancer may be treated with antiangiogenesis agents, and there are data suggesting that they may also be treated with a rechallenge of immunotherapy. In patients with metastatic bladder cancer who have progression after immune checkpoint inhibition, there are considerable data supporting the use of enfortumab vedotin. Ongoing studies are evaluating novel combinations of immune checkpoint inhibitors with other agents; thus, the treatment landscape of metastatic bladder and kidney cancer is expected to continue to evolve rapidly.
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http://dx.doi.org/10.1200/EDBK_323835DOI Listing
June 2021

Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial.

Lancet Oncol 2021 May 26. Epub 2021 May 26.

University of Michigan Health System, Ann Arbor, MI, USA.

Background: PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma.

Methods: KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305.

Findings: Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7-36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5-8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4-7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65-0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5-19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3-16·7) in the chemotherapy group (0·86, 0·72-1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1-17·9] with pembrolizumab vs 14·3 months [12·3-16·7] with chemotherapy; HR 0·92, 95% CI 0·77-1·11) and the population with CPS of at least 10 (16·1 months [13·6-19·9] with pembrolizumab vs 15·2 months [11·6-23·3] with chemotherapy; 1·01, 0·77-1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group.

Interpretation: The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma.

Funding: Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.
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http://dx.doi.org/10.1016/S1470-2045(21)00152-2DOI Listing
May 2021

Radiomics for Renal Cell Carcinoma: Predicting Outcomes from Immunotherapy and Targeted Therapies-A Narrative Review.

Eur Urol Focus 2021 May 11. Epub 2021 May 11.

Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, UK.

T-cell immunotherapy and molecular targeted therapies have become standard-of-care treatments for renal cell carcinoma (RCC). There is a need to develop robust biomarkers that predict patient outcomes to targeted therapies to personalise treatment. In recent years, quantitative analysis of imaging features, termed radiomics, has been used to extract tumour features. This narrative mini review summarises the evidence for radiomics prediction of immunotherapy and molecular targeted therapy outcomes in RCC. Radiomics may predict survival, treatment response, and disease progression in RCC treated with tyrosine kinase inhibitors (eg, sunitinib) and immune checkpoint inhibitors (eg, nivolumab). Further validation is necessary in large-scale studies. PATIENT SUMMARY: We summarise evidence on the ability of features extracted from CT (computed tomography) scans to predict patient outcomes from new treatments for kidney cancer. Although these features can predict treatment outcomes for patients, including survival, treatment response, and cancer progression, further research is necessary before this technology can be applied clinically.
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http://dx.doi.org/10.1016/j.euf.2021.04.024DOI Listing
May 2021