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Pembrolizumab and urothelial

Pooja Ghatalia, Matthew Zibelman, Daniel M Geynisman, Elizabeth Plimack
The treatment of advanced metastatic urothelial carcinoma has recently evolved with the approval of five checkpoint inhibitors. In the second-line setting, in patients who have progressed on cisplatin-based chemotherapy, pembrolizumab, atezolizumab, durvalumab, nivolumab and avelumab are United States Food and Drug Administration (FDA) approved. In cisplatin-ineligible patients, atezolizumab and pembrolizumab are the FDA-approved checkpoint inhibitors. Here we describe the updated clinical efficacy of these checkpoint inhibitors in the treatment of advanced urothelial carcinoma and then suggest how they can be sequenced in the context of available chemotherapeutic options...
2018: Therapeutic Advances in Medical Oncology
Vikram Narayan, Andreas Kahlmeyer, Philipp Dahm, Nicole Skoetz, Michael C Risk, Connie Bongiorno, Neil Patel, Eu Chang Hwang, Jae Hung Jung, Gerald Gartlehner, Frank Kunath
BACKGROUND: The use of systemic immunotherapy targets is emerging as an important treatment option for metastatic urothelial carcinoma, particularly for patients who cannot tolerate or who fail cisplatin-based chemotherapy. One such target is the inhibition of the checkpoint protein programmed cell death-1 (PD-1) receptor and its ligand (PD-L1) by monoclonal antibodies. OBJECTIVES: To assess the effects of pembrolizumab monotherapy versus chemotherapy for treatment of advanced urothelial carcinoma with disease progression during or following platinum-containing chemotherapy...
July 23, 2018: Cochrane Database of Systematic Reviews
Daniel Gallacher, Xavier Armoiry, Peter Auguste, Rachel Court, Theodoros Mantopoulos, Jacoby Patterson, Maria De Santis, Joanne Cresswell, Hema Mistry
Pembrolizumab is an intravenously administered monoclonal antibody licensed for locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy. This summary presents the perspective of Warwick Evidence, the Evidence Review Group (ERG) appointed by the National Institute of Health and Care Excellence (NICE) for the single technology appraisal of pembrolizumab for this indication. Pembrolizumab is manufactured by Merck, Sharp and Dohme (MSD). The major source of clinical effectiveness was the KEYNOTE-045 trial, where 542 patients received either pembrolizumab or clinician's choice of docetaxel, paclitaxel or vinflunine as a second-line treatment...
July 21, 2018: PharmacoEconomics
Nikita D Nabar, Maximilian P Brandt, Christian Thomas, Igor Tsaur, Georg Bartsch, Wolfgang Jaeger, Axel Haferkamp, Thomas Höfner
INTRODUCTION: Treatment strategy for inoperable and metastatic urothelial carcinoma (mUC) has been revolutionized by the introduction of programmed cell death protein 1 (PD-1) and programmed cell death protein ligand (PD-L1) antibodies. During the last 3 decades treatment options were limited to chemotherapy, making further treatment of patients whose disease progressed under ongoing therapy or who were ineligible to receive cytotoxic therapy in the first place, nearly impossible. EVIDENCE ACQUISITION: Five antibodies including pembrolizumab (PD-L1 antibody), atezolizumab (PD-1 antibody), nivolumab (PD-1 antibody), avelumab and durvalumab (PDL1 antibodies) have been approved in the treatment of advanced urothelial carcinoma in firstand second-line treatment setting...
July 18, 2018: Minerva Urologica e Nefrologica, the Italian Journal of Urology and Nephrology
Alison Claire Tree, Kelly Jones, Shaista Hafeez, Mansour Taghavi Azar Sharabiani, Kevin Joseph Harrington, Susan Lalondrelle, Merina Ahmed, Robert Anthony Huddart
There is currently significant interest in the potential benefits of combining radiation and immune checkpoint blockade (ICB) to stimulate both regional and distant abscopal immune responses. In melanoma and lung cancer, patients who have received radiation therapy during ICB appear to have prolonged survival. The PLUMMB trial (Pembrolizumab in Muscle-invasive/Metastatic Bladder cancer) (NCT02560636) is a phase I study to test the tolerability of a combination of weekly radiation therapy with pembrolizumab in patients with metastatic or locally advanced urothelial cancer of the bladder...
August 1, 2018: International Journal of Radiation Oncology, Biology, Physics
Kristina Buder-Bakhaya, Jessica C Hassel
Background: Immune checkpoint inhibition (ICI) with anti-CTLA-4 and/or anti-PD-1 antibodies is standard treatment for metastatic melanoma. Anti-PD-1 (pembrolizumab, nivolumab) and anti-PD-L1 antibodies (atezolizumab, durvalumab, and avelumab) have been approved for treatment of several other advanced malignancies, including non-small-cell lung cancer (NSCLC); renal cell, and urothelial carcinoma; head and neck cancer; gastric, hepatocellular, and Merkel-cell carcinoma; and classical Hodgkin lymphoma...
2018: Frontiers in Immunology
Justin B Hellman, Ilana Traynis, Lily Koo Lin
We report the first case of fatal myocarditis presenting as bilateral ptosis in a patient on combination therapy with pembrolizumab and epacadostat. An 83 year-old man with stage III high-grade urothelial carcinoma presented with acute onset droopy eyelids one month after starting pembrolizumab and epacadostat. Exam showed myogenic ptosis and ophthalmoplegia. He was later found to have acute myocarditis with complete heart block and subsequently passed away. Pembrolizumab in combination with epacadostat can induce a potentially fatal myocarditis...
July 9, 2018: Orbit
F Gómez-Veiga, A Alcaraz-Asensio, J Burgos-Revilla, J Cózar-Olmo
OBJECTIVE: To put forth new findings of urologic oncology with impact on clinical practice presented during 2017 in the main annual meetings. METHODS: This document reviews abstracts on prostate, kidney and bladder cancer presented at the congresses of 2016 (EAU, AUA, ASCO, ESMO and ASTRO) and publications with the highest impact in this period valued with the highest scores by the OncoForum committee. RESULTS: Among patients at high risk of recurrent renal cell carcinoma after nephrectomy, adjuvant sunitinib compared to placebo showed a benefit in patients at higher risk of recurrence...
June 20, 2018: Actas Urologicas Españolas
Mohsin Shah, Jean H Tayar, Noha Abdel-Wahab, Maria E Suarez-Almazor
OBJECTIVES: Immune checkpoint inhibitors (ICIs) can successfully treat cancer, but their use can be hindered by serious immune-related adverse events. We report six patients receiving ICIs who presented with de novo myositis. METHODS: We identified patients with myositis who were receiving ICIs between January 2004 and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS: Six patients developed de novo myositis. The mean age was 64...
May 18, 2018: Seminars in Arthritis and Rheumatism
Thomas W Flaig
Urothelial carcinoma is the predominant histologic type of bladder cancer. After 30 years of minimal progress in the treatment of advanced-stage disease, recent advances in the genomic characterization of urothelial cancer and breakthroughs in bladder cancer therapeutics have rejuvenated the field. Nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab are among the exciting recent novel therapeutic advances gaining approvals by the FDA for treatment of advanced-stage urothelial carcinoma. Yet the challenge for clinicians is to determine the optimal choice of agents as first-line or second-line therapy and which offers the best chance for overall survival for the individual patient in this rapidly changing field...
May 2018: Journal of the National Comprehensive Cancer Network: JNCCN
M-O Grimm, H Oppel-Heuchel, S Foller
Immune checkpoint inhibitors are a new standard therapy for advanced or metastatic urothelial as well as renal cell carcinoma. Atezolizumab and Pembrolizumab have been approved for the treatment of cisplatin-ineligible patients with transitional call cancer in the 1st line setting; both antibodies and Nivolumab may also be used after platinum based prior therapy. Regarding renal cell carcinoma approval for 1st line treatment with the combination of Nivolumab and Ipilimumab for patients at intermediate or high risk (IMDC) is currently expected...
May 2018: Der Urologe. Ausg. A
Vadim S Koshkin, Petros Grivas
PURPOSE OF REVIEW: Advanced urothelial carcinoma (aUC) has long been treated preferably with cisplatin-based chemotherapy, but many patients are cisplatin-ineligible whereas for those who progress on a platinum-based regimen treatment options are limited. We review key recent data regarding immune checkpoint inhibitors that are changing this treatment landscape. RECENT FINDINGS: Since May 2016, five different agents targeting the PD-1/PD-L1 pathway (atezolizumab, pembrolizumab, nivolumab, avelumab, durvalumab) have received FDA approval for the treatment of aUC in the platinum-refractory setting, while pembrolizumab and atezolizumab are FDA-approved for cisplatin-ineligible patients in the first-line setting...
April 11, 2018: Current Oncology Reports
Irene Resch, Shahrokh F Shariat, Kilian M Gust
Until recently, there were no true innovations in the management of locally advanced (aUC) and metastatic urothelial cancer (mUC) in the last three decades. Vinflunine has been approved by the EMA (European Medicines Agency) with only limited improvement compared to best supportive care in second line treatment. In addition, gemcitabine/cisplatin has been established as an alternative to methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). The advent of checkpoint inhibitors (CPI) revolutionized the care of these patients, transforming a unanimously deadly disease into one with hope through sustained disease control...
2018: Memo
David J Vaughn, Joaquim Bellmunt, Yves Fradet, Jae Lyun Lee, Lawrence Fong, Nicholas J Vogelzang, Miguel A Climent, Daniel P Petrylak, Toni K Choueiri, Andrea Necchi, Winald Gerritsen, Howard Gurney, David I Quinn, Stephane Culine, Cora N Sternberg, Yabing Mai, Haojie Li, Rodolfo F Perini, Dean F Bajorin, Ronald de Wit
Purpose In the phase III KEYNOTE-045 study ( identifier: NCT02256436), pembrolizumab significantly prolonged overall survival compared with investigator's choice of chemotherapy in patients with previously treated advanced urothelial cancer. Here, we report the results of health-related quality-of-life (HRQoL) analyses from the KEYNOTE-045 trial. Patients and Methods Patients were randomly assigned 1:1 to pembrolizumab 200 mg or investigator's choice of docetaxel 75 mg/m2 , paclitaxel 175 mg/m2 , or vinflunine 320 mg/m2 administered intravenously every 3 weeks...
June 1, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Jens Bedke, Tilman Todenhöfer, Arnulf Stenzl
The treatment of metastatic urothelial carcinoma is characterized by the administration of combinatory regimes of chemotherapy. In the first-line treatment theses regimes demonstrate relatively good objective response rates and prolongation of overall survival. The prognosis declines if the patient is refractory to platin in the second- or third-line treatment or if the patient is ineligible for cisplatin in the first-line setting. Cisplatin ineligibility is defined by a poor renal function or subsequent comorbidities...
April 2018: Aktuelle Urologie
Elie El Rassy, Ziad Bakouny, Fouad Aoun, Fadi G Haddad, Ghassan Sleilaty, Tarek Assi, Joseph Kattan
AIM: To determine which of the approved immune checkpoint inhibitors is the optimal treatment in metastatic urothelial bladder cancer. METHODS & MATERIALS: Only the pivotal Phase III trials of second-line metastatic urothelial bladder cancer were included in this network meta-analysis. RESULTS: This NMA included three pooled trials (NCT00315237, NCT02256436 and NCT02302807) of 1125 participants. Pembrolizumab was the only treatment with positive effect on overall survival compared with the best supportive care...
June 2018: Immunotherapy
Takeshi Yuasa, Shinji Urakami, Junji Yonese
Cytotoxic chemotherapy has been the mainstay of medical therapy for metastatic urothelial cancer. Currently, the gemcitabine/cisplatin regimen is widely used worldwide as the standard first-line medical treatment. Very recently, in 2017, pembrolizumab, a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1, was approved as a second-line treatment to be used after platina-based chemotherapy for metastatic urothelial cancer in Japan. Based on its promising anti-tumor efficacy and manageable safety profile as demonstrated in the phase III KEYNOTE-045 trial, pembrolizumab therapy is expected to be rapidly introduced for treating metastatic urothelial cancer in clinical practice...
March 20, 2018: International Journal of Clinical Oncology
M Alsharedi, R Srivastava, N Elmsherghi
Immunotherapy has revolutionized cancer care in the modern era of oncology. Research in immunotherapy has led to important advances in the treatment of melanoma, non-small cell lung cancer and other malignancies using checkpoint inhibition. Multiple systemic immunotherapies have been approved or are currently being investigated for the management of urothelial malignancies (1). Five antibodies targeting the programmed cell death protein 1--programmed cell death 1 ligand 1 (PD-1--PD-L1) pathway have been approved by the U...
December 2017: Drugs of Today
Izak Faiena, Amy L Cummings, Anna M Crosetti, Allan J Pantuck, Karim Chamie, Alexandra Drakaki
Our expanding knowledge of immunotherapy for solid tumors has led to an explosion of clinical trials aimed at urothelial carcinoma. The primary strategy is centered on unleashing the immune system by releasing the inhibitory signals propagated by programmed cell death-1 (PD-1) and its ligand programmed cell death ligand-1 (PD-L1). Many antibody constructs have been developed to block these interactions and are used in clinical trials. The Food and Drug Administration has already approved a number of checkpoint inhibitors such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibodies including ipilimumab; anti-PD-1 monoclonal antibodies including nivolumab and pembrolizumab; anti-PD-L1 antibodies including atezolizumab, avelumab, and durvalumab...
2018: Drug Design, Development and Therapy
Nora Sundahl, Sylvie Rottey, Daan De Maeseneer, Piet Ost
Until recently, patients with locally advanced or metastatic urothelial carcinoma after progression on cisplatin-containing chemotherapy had limited systemic treatment options with no significant survival benefit and poor tolerability. Advances in the field of immunotherapy with the introduction of checkpoint inhibitors have led to paradigm shifts in the treatment of various malignancies. Areas covered: The current review will summarize the clinical evidence of checkpoint inhibitors in bladder cancer, with a focus on pembrolizumab...
February 2018: Expert Review of Anticancer Therapy
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