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Pembrolizumab and urothelial

Di Maria Jiang, Srikala S Sridhar
BACKGROUND: Metastatic urothelial cancer (UC) is a lethal disease. Until 2016, cytotoxic chemotherapy with substantial toxicity was the only therapeutic option. In the first-line metastatic setting, cisplatin-based combination chemotherapy remains the standard of care. For cisplatin-ineligible patients, carboplatin-based regimens that are less efficacious are often substituted. In platinum-refractory patients, taxanes and vinflunine are the most commonly used. Recently, treatment options have largely expanded with the development of the immune checkpoint inhibitors (ICIs)...
November 2018: Asia-Pacific Journal of Clinical Oncology
Abhishek Tripathi, Elizabeth R Plimack
PURPOSE OF REVIEW: Until recently, effective treatment options for patients with advanced urothelial carcinoma were limited to platinum-based chemotherapy. In the post-platinum setting and for patients ineligible for cisplatin, minimally effective second-line chemotherapy was used and outcomes were poor. The approval of immune checkpoint inhibitors has significantly changed the treatment landscape of urothelial carcinoma. Here, we review current data demonstrating their efficacy in advanced disease and ongoing trials investigating novel combination strategies...
November 7, 2018: Current Urology Reports
J Bedke, V Stühler, T Todenhöfer, A Stenzl
Immune checkpoint inhibitors (ICI) have significantly improved the systemic therapy of metastatic disease in genitourinary malignancies. With the European Medicines Agency (EMA) approval of the antibodies nivolumab and pembrolizumab directed against programmed cell death 1 (PD-1) as well as the PD-L1 antibody atezolizumab, three agents are available for the treatment of metastatic urothelial carcinoma and renal cell carcinoma. This article describes the underlying mode of action of PD-1/PD-L1 blockade and other ICIs to activate the immune system for effective tumor rejection...
November 2018: Der Urologe. Ausg. A
Jun Lu, Roberto J Firpi-Morell, Long H Dang, Jinping Lai, Xiuli Liu
The programmed death 1 (PD-1), programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) immune checkpoints are negative regulators of T-cell immune function. Inhibition of these targets by antibodies (PD-1 blocking therapy) has been explored to treat solid malignancies such as melanoma, non-small cell lung cancer and other cancers. PD-1 blocking therapy is known to cause gastrointestinal tract adverse events in some patients and some of the adverse events are thought to be immune-mediated...
October 2018: Gastroenterology Research
Andrea Necchi, Andrea Anichini, Daniele Raggi, Alberto Briganti, Simona Massa, Roberta Lucianò, Maurizio Colecchia, Patrizia Giannatempo, Roberta Mortarini, Marco Bianchi, Elena Farè, Francesco Monopoli, Renzo Colombo, Andrea Gallina, Andrea Salonia, Antonella Messina, Siraj M Ali, Russell Madison, Jeffrey S Ross, Jon H Chung, Roberto Salvioni, Luigi Mariani, Francesco Montorsi
PURPOSE: To determine the activity of pembrolizumab as neoadjuvant immunotherapy before radical cystectomy (RC) for muscle-invasive bladder carcinoma (MIBC) for which standard cisplatin-based chemotherapy is poorly used. PATIENTS AND METHODS: In the PURE-01 study, patients had a predominant urothelial carcinoma histology and clinical (c)T≤3bN0 stage tumor. They received three cycles of pembrolizumab 200 mg every 3 weeks before RC. The primary end point in the intention-to-treat population was pathologic complete response (pT0)...
October 20, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Kirollos S Hanna
Urothelial Carcinoma (UC) is the second most common malignancy of the genitourinary system and is the sixth most common cancer in the USA. Over a decade prior to 2016, the standard of care for early disease consisted of transuretheral resection of the bladder tumor with or without intravesicular chemotherapy or immunotherapy. Systemic chemotherapies such as gemcitabine and cisplatin combinations or dose-dense methotrexate, vinblastine, doxorubicin, cisplatin were reserved for recurrent, muscle-invasive, advanced or metastatic disease...
October 10, 2018: Journal of Oncology Pharmacy Practice
Fabian Finkelmeier, Oliver Waidmann, Joerg Trojan
T-cell checkpoint inhibition as a cancer treatment approach has been the main breakthrough in cancer treatment during the last years. Since the approval of the first commercial CTLA-4 antibody ipilimumab in 2011 for the treatment of melanoma, research and drug development in this field has accelerated massively. In 2014, the US Food and Drug Administration (FDA) approved the first PD-1 targeting agent, namely pembrolizumab, shortly followed by nivolumab. Areas covered: Nivolumab is a fully human immunoglobulin G4 anti-PD-1 monoclonal antibody which is approved for multiple advanced malignancies, including melanoma, non-small cell lung cancer, renal cell cancer, Hodgkin's lymphoma, squamous head and neck cancer, and urothelial carcinoma...
October 10, 2018: Expert Review of Anticancer Therapy
David D Stenehjem, Dao Tran, Michael A Nkrumah, Shilpa Gupta
Introduction: Until recently, systemic chemotherapy was the only option for treating bladder cancer and outcomes remained dismal. After a long gap of no progress for 40 years, immuno-therapy with checkpoint inhibitors (PDL1 and PD1) has revolutionized the treatment paradigm of bladder cancer, with five approved agents to treat platinum-refractory bladder cancer since the first approval of atezolizumab in May 2016. Methods: This review summarizes the most recent data on approved checkpoint inhibitors currently used in management of advanced bladder cancer...
2018: OncoTargets and Therapy
Alice Tzeng, C Marcela Diaz-Montero, Patricia A Rayman, Jin S Kim, Paul G Pavicic, James H Finke, Pedro C Barata, Marcelo Lamenza, Sarah Devonshire, Kim Schach, Hamid Emamekhoo, Marc S Ernstoff, Christopher J Hoimes, Brian I Rini, Jorge A Garcia, Timothy D Gilligan, Moshe C Ornstein, Petros Grivas
BACKGROUND: The identification of prognostic and/or predictive biomarkers for response to immune checkpoint inhibitors (ICI) could help guide treatment decisions. OBJECTIVE: We assessed changes in programmed cell death-1 (PD1)/PD1 ligand (PDL1) expression in key immunomodulatory cell subsets (myeloid-derived suppressor cells [MDSC]; cytotoxic T lymphocytes [CTL]) following ICI therapy and investigated whether these changes correlated with outcomes in patients with metastatic urothelial carcinoma (mUC)...
October 2018: Targeted Oncology
Tara C Mitchell, Omid Hamid, David C Smith, Todd M Bauer, Jeffrey S Wasser, Anthony J Olszanski, Jason J Luke, Ani S Balmanoukian, Emmett V Schmidt, Yufan Zhao, Xiaohua Gong, Janet Maleski, Lance Leopold, Thomas F Gajewski
PURPOSE: Tumors may evade immunosurveillance through upregulation of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Epacadostat is a potent and highly selective IDO1 enzyme inhibitor. The open-label phase I/II ECHO-202/KEYNOTE-037 trial evaluated epacadostat plus pembrolizumab, a programmed death protein 1 inhibitor, in patients with advanced solid tumors. Phase I results on maximum tolerated dose, safety, tolerability, preliminary antitumor activity, and pharmacokinetics are reported...
September 28, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Omar Abdel-Rahman, Hani Oweira, Anwar Giryes
A systematic review was performed to explore the health-related quality of life (HRQoL) outcomes among cancer patients receiving PD-(L)1 inhibitors compared to those receiving traditional cytotoxic therapy. Areas covered: Citations from PubMed and the American Society of Clinical Oncology meeting library were examined. Cross-references from original studies and review articles were also reviewed. Eligible trials included randomized controlled trials of cancer patients treated with one of the PD-(L)1 inhibitors and reporting HRQoL outcomes...
September 26, 2018: Expert Review of Anticancer Therapy
Johannes C Melms, Rohit Thummalapalli, Kristin Shaw, Huihui Ye, Leo Tsai, Rupal S Bhatt, Benjamin Izar
The development of a new lesion in a patient with a complete remission to anti-PD-1 therapy is highly concerning for a drug resistant escape lesion. Here, we present a case of a 62-year-old patient with chemotherapy-resistant metastatic urothelial cancer who had a complete remission to pembrolizumab. The patient's disease burden tracked closely to serum levels of alpha-fetoprotein (AFP) expressed by the tumor and served as an accurate tumor marker. Surveillance imaging revealed a solitary growing pulmonary nodule mimicking an escape lesion in the absence of an increase in AFP levels...
September 12, 2018: Journal for Immunotherapy of Cancer
Hyung Suk Kim, Ho Kyung Seo
Urothelial carcinoma (UC), originating in the bladder or upper urinary tract, is the most common histological type of cancer. Currently, platinum-based cytotoxic chemotherapy is the standard treatment for metastatic UC (mUC) and the preferred treatment option in the perioperative (neoadjuvant and/or adjuvant) setting of muscle invasive bladder cancer (MIBC). In addition, intravesical bacillus Calmette-Guerin immunotherapy or chemotherapy is applied as the adjuvant therapeutic option in non-muscle invasive bladder cancer (NMIBC) after transurethral resection, to prevent recurrence and progression...
September 2018: Investigative and Clinical Urology
Mamta Parikh, Chong-Xian Pan, Laurel A Beckett, Yueju Li, Daniel A Robles, Pawandeep K Aujla, Primo N Lara
INTRODUCTION: Cytotoxic chemotherapy might prime urothelial cancer (UC) to checkpoint inhibition, prompting a trial of chemotherapy with the programmed death receptor-1 inhibitor pembrolizumab. PATIENTS AND METHODS: Patients with advanced, platinum-refractory UC received pembrolizumab and either docetaxel (arm A) or gemcitabine (arm B). Primary end points were assessments of maximum tolerated dose and dose-limiting toxicity (DLT). Secondary end points were overall response rate (ORR) and progression-free survival (PFS)...
July 12, 2018: Clinical Genitourinary Cancer
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
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