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Alejo Rodriguez-Vida, Joaquim Bellmunt
Metastatic urothelial carcinoma (UC) remains an aggressive disease associated with limited treatment options and a reduced survival. In spite of this, the first-line treatment based on platinum-based combinations has remained virtually unchanged for the last 20-30 years. Similarly, before the advent of the immune checkpoint inhibitors, there were no FDA-approved drugs for second-line therapy. In the last few years, impressive signs of anti-tumor activity have been reported with several immunotherapy agents targeting the programmed cell death-1 (PD-1) pathway...
March 14, 2018: Expert Review of Anticancer Therapy
Naghmehossadat Eshghi, Tamara F Lundeen, Lea MacKinnon, Ryan Avery, Phillip H Kuo
An 85-year-old man with stage IIIA Merkel cell carcinoma of the left arm was initially treated with local excision and axillary node dissection followed by radiation therapy. Eight months after surgery, whole-body FDG PET/CT demonstrated intensely hypermetabolic hepatic metastases and abdominal lymphadenopathy. Given his age and comorbidities, he was considered a poor candidate for chemotherapy, and therefore the novel programmed cell death ligand 1 inhibitor avelumab was initiated. FDG PET/CT after 4 cycles showed complete resolution of hepatic and nodal metastases...
March 13, 2018: Clinical Nuclear Medicine
Amruth R Palla, Donald Doll
Merkel cell carcinoma (MCC), a rare skin cancer, is associated with high mortality, especially in a metastatic setting. Though conventional chemotherapy with platinum and etoposide has had high response rates, many of the patients have had early relapse without any effective therapy thereafter. Recently, immune check point inhibitors have shown very good durable responses, leading to the approval of a programmed death-ligand 1 inhibitor Avelumab for these patients. We briefly review the epidemiology and immune basis of the pathogenesis of MCC, which therefore explains the excellent response to check point inhibitors, and throw light on future directions of immunotherapy for this cancer...
2018: ImmunoTargets and Therapy
Toni K Choueiri, James Larkin, Mototsugu Oya, Fiona Thistlethwaite, Marcella Martignoni, Paul Nathan, Thomas Powles, David McDermott, Paul B Robbins, David D Chism, Daniel Cho, Michael B Atkins, Michael S Gordon, Sumati Gupta, Hirotsugu Uemura, Yoshihiko Tomita, Anna Compagnoni, Camilla Fowst, Alessandra di Pietro, Brian I Rini
BACKGROUND: The combination of an immune checkpoint inhibitor and a VEGF pathway inhibitor to treat patients with advanced renal-cell carcinoma might increase the clinical benefit of these drugs compared with their use alone. Here, we report preliminary results for the combination of avelumab, an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF receptor inhibitor approved for second-line treatment of advanced renal-cell carcinoma, in treatment-naive patients with advanced renal-cell carcinoma...
March 9, 2018: Lancet Oncology
Ludovica De Panfilis, Roberto Satolli, Massimo Costantini
BACKGROUND: This article proposes a retrospective analysis of a compassionate use (CU), using a case study of request for Avelumab for a patient suffering from Merkel Cell Carcinoma. The study is the result of a discussion within a Provincial Ethics Committee (EC) following the finding of a high number of requests for CU program. The primary objective of the study is to illustrate the specific ethical and clinical profiles that emerge from the compassionate use program (CUP) issue. The secondary goals are: a) to promote a moral reflection among physicians who require approval for the CUP and b) provide the basis for recommendations on how to request CUP...
March 9, 2018: BMC Medical Ethics
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
Howard L Kaufman, Carla Dias Barbosa, Isabelle Guillemin, Jérémy Lambert, Lisa Mahnke, Murtuza Bharmal
BACKGROUND: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with limited treatment options at advanced stages. There is a paucity of data available regarding the impact of MCC and its management on patients' lives. This study aimed to address this gap by interviewing patients with metastatic MCC entering a trial of an immunotherapy (avelumab). METHODS: In a single-arm, open-label, international, phase 2 trial in patients with stage IV, chemotherapy-refractory, histologically confirmed MCC, patients were invited to participate in semi-structured phone interviews...
March 6, 2018: Patient
Mairead Baker, Lisa Cordes, Isaac Brownell
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Although MCC is chemosensitive, responses to traditional chemotherapeutic agents are not durable. Avelumab, a novel anti-PD-L1 immune checkpoint inhibitor, recently became the first FDA-approved agent for the treatment of metastatic MCC and represents a new option to improve patient survival. Areas covered: This article presents an overview of MCC and summarizes the development of avelumab in the treatment of metastatic MCC. Preclinical studies, phase 1 and phase 2 clinical trials, and the safety profile of avelumab are reviewed...
February 28, 2018: Expert Review of Anticancer Therapy
Maria Rita Gaiser, Michelle Bongiorno, Isaac Brownell
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer that lacks durable responses to traditional chemotherapy. Areas covered: After MCC was shown to be an immunogenic tumor, small trials revealed high objective response rates to PD-1/PD-L1 checkpoint inhibitors. The JAVELIN Merkel 200 (NCT02155647) trial tested the use of avelumab, a human IgG1 monoclonal antibody against PD-L1, in metastatic MCC. Avelumab recently became the first approved drug for metastatic MCC. Expert commentary: By conducting broad phase I studies assessing the safety of avelumab and a small phase II study demonstrating efficacy in this rare orphan tumor type, avelumab gained accelerated approval for the treatment of metastatic MCC...
February 26, 2018: Expert Review of Clinical Pharmacology
Karen Kelly, Jeffrey R Infante, Matthew H Taylor, Manish R Patel, Deborah J Wong, Nicholas Iannotti, Janice M Mehnert, Anja H Loos, Helga Koch, Isabell Speit, James L Gulley
BACKGROUND: Antibodies targeting the programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) checkpoint may cause adverse events (AEs) that are linked to the mechanism of action of this therapeutic class and unique from those observed with conventional chemotherapy. METHODS: Patients with advanced solid tumors who were enrolled in the phase 1 JAVELIN Solid Tumor (1650 patients) and phase 2 JAVELIN Merkel 200 (88 patients) trials received avelumab, a human anti-PD-L1 IgG1 antibody at a dose of 10 mg/kg every 2 weeks...
February 22, 2018: Cancer
Rajani Ravi, Kimberly A Noonan, Vui Pham, Rishi Bedi, Alex Zhavoronkov, Ivan V Ozerov, Eugene Makarev, Artem V Artemov, Piotr T Wysocki, Ranee Mehra, Sridhar Nimmagadda, Luigi Marchionni, David Sidransky, Ivan M Borrello, Evgeny Izumchenko, Atul Bedi
A majority of cancers fail to respond to immunotherapy with antibodies targeting immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1)/PD-1 ligand (PD-L1). Cancers frequently express transforming growth factor-β (TGFβ), which drives immune dysfunction in the tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting CD8+ and TH 1 cells. To address this therapeutic challenge, we invent bifunctional antibody-ligand traps (Y-traps) comprising an antibody targeting CTLA-4 or PD-L1 fused to a TGFβ receptor II ectodomain sequence that simultaneously disables autocrine/paracrine TGFβ in the target cell microenvironment (a-CTLA4-TGFβRIIecd and a-PDL1-TGFβRIIecd)...
February 21, 2018: Nature Communications
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
John Shen, Jason Chang, Melody Mendenhall, Grace Cherry, Jonathan W Goldman, Rajan P Kulkarni
Background: The anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) immunotherapies have shown exceptional activity in many cancers. However, these immunotherapies can also result in diverse adverse cutaneous eruptions that need to be better characterized for ongoing management. The objective was to provide clinical and histopathologic descriptions of the variety of cutaneous adverse events seen in patients who received anti-PD-1/PD-L1 treatment and discuss their management...
2018: Therapeutic Advances in Medical Oncology
Shifaa M Abdin, Dana M Zaher, El-Shaimaa A Arafa, Hany A Omar
Cancer therapy has been constantly evolving with the hope of finding the most effective agents with the least toxic effects to eradicate tumors. Cancer immunotherapy is currently among the most promising options, fulfilling this hope in a wide range of tumors. Immunotherapy aims to activate immunity to fight cancer in a very specific and targeted manner; however, some abnormal immune reactions known as immune-related adverse events (IRAEs) might occur. Therefore, many researchers are aiming to define the most proper protocols for managing these complications without interfering with the anticancer effect...
January 25, 2018: Cancers
Howard L Kaufman, Jeffery S Russell, Omid Hamid, Shailender Bhatia, Patrick Terheyden, Sandra P D'Angelo, Kent C Shih, Céleste Lebbé, Michele Milella, Isaac Brownell, Karl D Lewis, Jochen H Lorch, Anja von Heydebreck, Meliessa Hennessy, Paul Nghiem
BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with poor survival outcomes in patients with distant metastatic disease (mMCC). In an initial analysis from JAVELIN Merkel 200, a phase 2, prospective, open-label, single-arm trial in mMCC, avelumab-a human anti-programmed death-ligand 1 (PD-L1) monoclonal antibody-showed promising efficacy and a safety profile that was generally manageable and tolerable. Here, we report the efficacy of avelumab after ≥1 year of follow-up in patients with distant mMCC that had progressed following prior chemotherapy for metastatic disease...
January 19, 2018: Journal for Immunotherapy of Cancer
Gil Awada, Jean Klastersky
PURPOSE OF REVIEW: The therapeutic armamentarium for advanced non-small-cell lung cancer has evolved considerably over the past years. Immune checkpoint inhibitors targeting programmed cell death-1 such as pembrolizumab and nivolumab or programmed cell death ligand 1 such as atezolizumab, durvalumab and avelumab have shown favorable efficacy results in this patient population in the first-line and second-line setting. These immunotherapies are associated with a distinct toxicity profile based on autoimmune organ toxicity which is a new challenge for supportive care during treatment with these drugs...
January 4, 2018: Current Opinion in Oncology
Hélène Kaplon, Janice M Reichert
The pace of antibody therapeutics development accelerated in 2017, and this faster pace is projected to continue through 2018. Notably, the annual number of antibody therapeutics granted a first approval in either the European Union (EU) or United States (US) reached double-digits (total of 10) for the first time in 2017. The 10 antibodies granted approvals are: brodalumab, dupilumab, sarilumab, guselkumab, benralizumab, ocrelizumab, inotuzumab ozogamicin, avelumab, duvalumab, and emicizumab. Brodalumab, however, had already been approved in Japan in 2016...
January 4, 2018: MAbs
Hao Xie, Alex A Adjei
No abstract text is available yet for this article.
December 2017: Translational Lung Cancer Research
Ignacio Gil-Bazo
No abstract text is available yet for this article.
December 2017: Translational Lung Cancer Research
Yang-Bo Hu, Qun Zhang, Hui-Juan Li, Jean Maire Michot, Hong-Bing Liu, Ping Zhan, Tang-Feng Lv, Yong Song
Background: Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitor therapy is showing marked efficacy in advanced non-small cell lung cancer (NSCLC). Meanwhile, it is concomitant with distinctive immune-related adverse effects. We aim to describe the incidence of pneumonitis and other rare but severe immune-related adverse effects (IRAEs), as well as treatment related deaths. In addition, we analyze the differences in incidence of pneumonitis between PD-1 and PD-L1 inhibitors and standard-of-care chemotherapy...
December 2017: Translational Lung Cancer Research
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