DOCSLIB.ORG

REGN910), a Fully Human Anti–Angiopoietin-2 (Ang2) Monoclonal Antibody, in Patients with Advanced Solid Tumors Kyriakos P

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
REGN910), a Fully Human Anti–Angiopoietin-2 (Ang2) Monoclonal Antibody, in Patients with Advanced Solid Tumors Kyriakos P Published OnlineFirst October 21, 2015; DOI: 10.1158/1078-0432.CCR-15-1221 Cancer Therapy: Clinical Clinical Cancer Research A Phase I First-in-Human Study of Nesvacumab (REGN910), a Fully Human Anti–Angiopoietin-2 (Ang2) Monoclonal Antibody, in Patients with Advanced Solid Tumors Kyriakos P. Papadopoulos1, Robin Kate Kelley2, Anthony W. Tolcher1, Albiruni R. Abdul Razak3, Katherine Van Loon2, Amita Patnaik1, Philippe L. Bedard3, Ariceli A. Alfaro2, Muralidhar Beeram1, Lieve Adriaens4, Carrie M. Brownstein4, Israel Lowy4, Ana Kostic4, Pamela A. Trail4,BoGao4, A. Thomas DiCioccio4, and Lillian L. Siu3 Abstract Purpose: Nesvacumab (REGN910) is a fully human immu- and diarrhea (each 10.6%; all grade 2). Nesvacumab was noglobulin G1 (IgG1) monoclonal antibody that specifically characterized by linear kinetics and had a terminal half-life of binds and inactivates the Tie2 receptor ligand Ang2 with high 6.35 to 9.66 days in a dose-independent manner. Best response by affinity, but shows no binding to Ang1. The main objectives of RECIST 1.1 in 43 evaluable patients included 1 partial response this trial were to determine the safety, tolerability, dose-limit- (adrenocortical carcinoma) of 24 weeks duration. Two patients ing toxicities (DLT), and recommended phase II dose (RP2D) with hepatocellular carcinoma had stable disease (SD) > 16 of nesvacumab. weeks, with tumor regression and >50% decrease in a-fetopro- Experimental Design: Nesvacumab was administered intrave- tein. Analyses of putative angiogenesis biomarkers in serum and nously every two weeks with dose escalations from 1 to 20 mg/kg tumor biopsies were uninformative for treatment duration. in patients with advanced solid tumors. Conclusions: Nesvacumab safety profile was acceptable at all Results: A total of 47 patients were treated with nesvacumab. dose levels tested. Preliminary antitumor activity was observed in No patients in the dose escalation phase experienced DLTs, patients with treatment-refractory advanced solid tumors. On the therefore a maximum tolerated dose (MTD) was not reached. basis of cumulative safety, antitumor activity, pharmacokinetic The most common nesvacumab-related adverse events were and pharmacodynamic data, the 20 mg/kg dose was determined fatigue (23.4%), peripheral edema (21.3%), decreased appetite, to be the RP2D. Clin Cancer Res; 22(6); 1348–55. Ó2015 AACR. Introduction maturation and control of peripheral capillary permeability (9– 11), while preclinical tumor models confirm that Ang2 is an Inhibition of tumor angiogenesis, particularly with VEGF/ important regulator of tumor angiogenesis and growth (12– VEGF receptor antagonists, is a validated therapeutic approach 16). Ang2 expression is upregulated in a range of human cancers for select oncologic indications (1–4). Angiopoietin-1 (Ang1) and (17–21), and high levels of circulating Ang2 are associated with a angiopoietin-2 (Ang2), ligands for the vascular endothelial cell poor prognosis (22, 23). receptor tyrosine kinase Tie2 (5, 6) are proangiogenic factors Nesvacumab is a fully human immunoglobulin G1 (IgG1) selectively expressed during the angiogenesis process involved in VelocImmune monoclonal antibody that selectively binds Ang2 tumor neovascularization (7, 8). Ang1 appears to play a role in with high affinity (24 pmol), blocks Ang2 binding to the Tie2 receptor; but does not bind to Ang1. In human tumor cell line 1South Texas Accelerated Research Therapeutics (START), San Anto- xenograft models, nesvacumab as a single agent demonstrated nio, Texas. 2Helen Diller Family Comprehensive Cancer Center, Uni- significant tumor growth inhibition in prostate adenocarcinoma versity of California San Francisco, San Francisco, California. 3Princess (PC3), colorectal adenocarcinoma (Colo205), and epidermoid Margaret Cancer Centre, Toronto, Ontario. 4Regeneron Pharmaceuti- cals, Inc., Tarrytown, New York. carcinoma (A431; ref. 13). Non-human toxicology studies in Sprague Dawley rats and cynomolgus monkeys showed no direct, Note: Supplementary data for this article are available at Clinical Cancer definitive adverse toxic insult to any organ of either species (data Research Online (http://clincancerres.aacrjournals.org/). on file, Regeneron). The no-observed-adverse-effect levels Prior presentation: Presented in part at the annual meeting of the American (NOAEL) in rat and monkey dosed every other week were 50 Society of Clinical Oncology (ASCO), June 2013, Chicago, IL. mg/kg by the intravenous route and 10 mg/kg by the subcuta- Corresponding Author: Kyriakos P. Papadopoulos, South Texas Accelerated neous route, the highest nesvacumab doses evaluated for each Research Therapeutics, 4383 Medical Drive, San Antonio, TX 78229. Phone: 210- route of administration in these studies. 593-5250; Fax: 210-615-1121; E-mail: [email protected] On the basis of these data, the selected starting dose of nesva- doi: 10.1158/1078-0432.CCR-15-1221 cumab for this phase I study was conservatively chosen as 1 mg/kg Ó2015 American Association for Cancer Research. administered by intravenous infusion every 2 weeks. This first-in- 1348 Clin Cancer Res; 22(6) March 15, 2016 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst October 21, 2015; DOI: 10.1158/1078-0432.CCR-15-1221 Nesvacumab for Advanced Solid Tumors determine the MTD, enrollment was sequential and in a standard Translational Relevance 3þ3 design. Dose escalation was allowed if dose-limiting toxicity Angiopoietin-2 (Ang2) expression is a key regulator of (DLT) occurred in 0/3 or 1/6 patient in each cohort during cycle tumor angiogenesis and growth. Ang2, which functions as a 1 (28 days). Patients not completing the first cycle for reasons ligand for vascular endothelial cell receptor tyrosine kinase other than DLT were considered nonevaluable and replaced. Tie2, is upregulated in various cancers and associated with Expansion cohorts at candidate recommended phase II dose poor prognosis. Preclinically, Ang-2 inhibition results in (RP2D) levels enrolled patients with advanced solid tumors decreased tumor vascularity and significant inhibition of (safety expansion cohorts) enriched for patients with HCC to human xenograft tumor growth. Furthermore, Ang2 inhibi- further characterize safety and tolerability and assess preliminary tion potentiates the antitumor effects of anti-VEGF agents. antitumor activity. Enrichment for HCC in the expansion cohorts Nesvacumab (REGN910) is a novel IgG1 fully human anti- was a protocol amendment based on the observation of signif- Ang2 monoclonal antibody. This article reports the first-in- icant a-fetoprotein (AFP) decline and tumor regression in a human study of nesvacumab in patients with advanced patient with HCC treated in the dose escalation phase. Study tumors. The majority of analyzed tumors expressed Ang2, but treatment continued until disease progression, unacceptable tox- none of several putative angiogenic biomarkers was informa- icity (including DLT), or withdrawal of consent. tive for clinical efficacy. The manageable toxicity profile and DLTs were defined during cycle 1, as any treatment-related preliminary evidence of antitumor activity support the further grade 4 anorexia, nausea, vomiting, or diarrhea, or grade 3 development of nesvacumab, particularly in combination nonhematologic toxicities except inadequately treated grade 3 with other targeted antiangiogenic and cytotoxic therapies. anorexia, nausea, vomiting, or diarrhea. Hematologic toxicities defined as DLT were grade 3 or 4 neutropenia complicated by fever 101.3F (38.5C) or infection, grade 4 neutropenia 7 days duration, grade 3 thrombocytopenia complicated by hemor- human phase I study (NCT01271972) reports the safety, tolera- rhage, or grade 4 thrombocytopenia. bility, pharmacokinetic, pharmacodynamic markers, preliminary antitumor efficacy, and recommended phase II dose for nesva- Study assessments cumab administered every 2 weeks in patients with advanced Safety assessments were performed weekly during the first cycle solid tumors. and every two weeks throughout the study treatment period, followed by a posttreatment study visit 30 days (Æ5 days) after Patients and Methods the last dose. Assessments included vital sign measurements, This multicenter, phase I, nonrandomized, open-label study physical examinations, clinical laboratory tests, urinalysis, brain was conducted at two centers in the United States and one MRIs (every 2 cycles, instituted following an index patient with fi center in Canada. All patients provided written informed con- neurologic symptoms, found to have an atypical brain nding), sent, and the study was conducted in accordance with the and collection of adverse event (AE) information. The severity of International Conference on Harmonization Good Clinical an AE was graded by the investigator using the National Cancer Practice guidelines and all applicable local regulatory require- Institute-Common Terminology Criteria for Adverse Events (NCI- ments and laws. CTCAE), version 4.0. Tumor response radiologic assessments were performed at baseline and approximately every 8 weeks according to the Patient eligibility Response Evaluation Criteria in Solid Tumors (RECIST), version Eligible patients were 18 years, with histologically proven 1.1. Serum tumor markers as appropriate for tumor type were advanced solid malignancies, Eastern Cooperative Oncology used to assess the effect of nesvascumab therapy. Group (ECOG) performance status 1, and adequate
Load more

Recommended publications
  • Predictive QSAR Tools to Aid in Early Process Development of Monoclonal Antibodies
    Predictive QSAR tools to aid in early process development of monoclonal antibodies John Micael Andreas Karlberg Published work submitted to Newcastle University for the degree of Doctor of Philosophy in the School of Engineering November 2019 Abstract Monoclonal antibodies (mAbs) have become one of the fastest growing markets for diagnostic and therapeutic treatments over the last 30 years with a global sales revenue around $89 billion reported in 2017. A popular framework widely used in pharmaceutical industries for designing manufacturing processes for mAbs is Quality by Design (QbD) due to providing a structured and systematic approach in investigation and screening process parameters that might influence the product quality. However, due to the large number of product quality attributes (CQAs) and process parameters that exist in an mAb process platform, extensive investigation is needed to characterise their impact on the product quality which makes the process development costly and time consuming. There is thus an urgent need for methods and tools that can be used for early risk-based selection of critical product properties and process factors to reduce the number of potential factors that have to be investigated, thereby aiding in speeding up the process development and reduce costs. In this study, a framework for predictive model development based on Quantitative Structure- Activity Relationship (QSAR) modelling was developed to link structural features and properties of mAbs to Hydrophobic Interaction Chromatography (HIC) retention times and expressed mAb yield from HEK cells. Model development was based on a structured approach for incremental model refinement and evaluation that aided in increasing model performance until becoming acceptable in accordance to the OECD guidelines for QSAR models.
    [Show full text]
  • USAN Naming Guidelines for Monoclonal Antibodies |
    Monoclonal Antibodies In October 2008, the International Nonproprietary Name (INN) Working Group Meeting on Nomenclature for Monoclonal Antibodies (mAb) met to review and streamline the monoclonal antibody nomenclature scheme. Based on the group's recommendations and further discussions, the INN Experts published changes to the monoclonal antibody nomenclature scheme. In 2011, the INN Experts published an updated "International Nonproprietary Names (INN) for Biological and Biotechnological Substances—A Review" (PDF) with revisions to the monoclonal antibody nomenclature scheme language. The USAN Council has modified its own scheme to facilitate international harmonization. This page outlines the updated scheme and supersedes previous schemes. It also explains policies regarding post-translational modifications and the use of 2-word names. The council has no plans to retroactively change names already coined. They believe that changing names of monoclonal antibodies would confuse physicians, other health care professionals and patients. Manufacturers should be aware that nomenclature practices are continually evolving. Consequently, further updates may occur any time the council believes changes are necessary. Changes to the monoclonal antibody nomenclature scheme, however, should be carefully considered and implemented only when necessary. Elements of a Name The suffix "-mab" is used for monoclonal antibodies, antibody fragments and radiolabeled antibodies. For polyclonal mixtures of antibodies, "-pab" is used. The -pab suffix applies to polyclonal pools of recombinant monoclonal antibodies, as opposed to polyclonal antibody preparations isolated from blood. It differentiates polyclonal antibodies from individual monoclonal antibodies named with -mab. Sequence of Stems and Infixes The order for combining the key elements of a monoclonal antibody name is as follows: 1.
    [Show full text]
  • Monoclonal Antibody Playbook
    Federal Response to COVID-19: Monoclonal Antibody Clinical Implementation Guide Outpatient administration guide for healthcare providers 2 SEPTEMBER 2021 1 Introduction to COVID-19 Monoclonal Antibody Therapy 2 Overview of Emergency Use Authorizations 3 Site and Patient Logistics Site preparation Patient pathways to monoclonal administration 4 Team Roles and Responsibilities Leadership Administrative Clinical Table of 5 Monoclonal Antibody Indications and Administration Indications Contents Preparation Administration Response to adverse events 6 Supplies and Resources Infrastructure Administrative Patient Intake Administration 7 Examples: Sites of Administration and Staffing Patterns 8 Additional Resources 1 1. Introduction to Monoclonal Therapy 2 As of 08/13/21 Summary of COVID-19 Therapeutics 1 • No Illness . Health, no infections • Exposed Asymptomatic Infected . Scope of this Implementation Guide . Not hospitalized, no limitations . Monoclonal Antibodies for post-exposure prophylaxis (Casirivimab + Imdevimab (RGN)) – EUA Issued. • Early Symptomatic . Scope of this Implementation Guide . Not hospitalized, with limitations . Monoclonal Antibodies for treatment (EUA issued): Bamlanivimab + Etesevimab1 (Lilly) Casirivimab + Imdevimab (RGN) Sotrovimab (GSK/Vir) • Hospital Adminission. Treated with Remdesivir (FDA Approved) or Tocilizumab (EUA Issued) . Hospitalized, no acute medical problems . Hospitalized, not on oxygen . Hospitlaized, on oxygen • ICU Admission . Hospitalized, high flow oxygen, non-invasive ventilation
    [Show full text]
  • REGENERON PHARMACEUTICALS, INC. (Exact Name of Registrant As Specified in Charter)
    UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, DC 20549 FORM 8-K CURRENT REPORT Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934 Date of Report (Date of earliest event reported): February 9, 2017 (February 9, 2017) REGENERON PHARMACEUTICALS, INC. (Exact Name of Registrant as Specified in Charter) New York 000-19034 13-3444607 (State or other jurisdiction (Commission (IRS Employer of Incorporation) File No.) Identification No.) 777 Old Saw Mill River Road, Tarrytown, New York 10591-6707 (Address of principal executive offices, including zip code) (914) 847-7000 (Registrant's telephone number, including area code) Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions: ☐ Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) ☐ Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) ☐ Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) ☐ Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) Item 2.02 Results of Operations and Financial Condition. On February 9, 2017, Regeneron Pharmaceuticals, Inc. issued a press release announcing its financial and operating results for the quarter and year ended December 31, 2016. A copy of the press release is being furnished to the Securities and Exchange Commission as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated by reference to this Item 2.02.
    [Show full text]
  • The Future of Antibodies As Cancer Drugs
    REVIEWS Drug Discovery Today Volume 17, Numbers 17/18 September 2012 The biopharmaceutical industry’s pipeline of anticancer antibodies includes 165 candidates with substantial diversity in composition, targets and mechanisms of action that hold promise to be the cancer drugs of the future. Reviews FOUNDATION REVIEW Foundation review: The future of antibodies as cancer drugs 1 2 Dr Janice Reichert Janice M. Reichert and Eugen Dhimolea is Research Assistant Professor at Tufts 1 Center for the Study of Drug Development, Tufts University School of Medicine, 75 Kneeland Street, University’s Center for the Study of Drug Development Suite 1100, Boston, MA 02111, USA 2 (CSDD). She is also Founder Department of Medical Oncology, Dana-Farber Cancer Institute/Harvard Medical School, 77 Louis Pasteur Ave., and Editor-in-Chief of mAbs, Harvard Institutes of Medicine, Room 309, Boston, MA 02215, USA a peer-reviewed, PubMed- indexed biomedical journal that focuses on topics relevant to antibody research Targeted therapeutics such as monoclonal antibodies (mAbs) have proven and development; President of the board of directors of The Antibody Society; and a member of the board successful as cancer drugs. To profile products that could be marketed in of the Peptide Therapeutics Foundation. At CSDD, the future, we examined the current commercial clinical pipeline of mAb Dr Reichert studies innovation in the pharmaceutical and biotechnology industries. Her work focuses on candidates for cancer. Our analysis revealed trends toward development of strategic analyses of investigational candidates and marketed products, with an emphasis on the clinical a variety of noncanonical mAbs, including antibody–drug conjugates development and approval of new therapeutics and (ADCs), bispecific antibodies, engineered antibodies and antibody vaccines.
    [Show full text]
  • CYRAMZA (Ramucirumab) Injection Label
    1 HIGHLIGHTS OF PRESCRIBING INFORMATION • 500 mg/50 mL (10 mg per mL) solution, single-dose vial (3) These highlights do not include all the information needed to use CYRAMZA safely and effectively. See full prescribing information ------------------------------- CONTRAINDICATIONS ------------------------------ for CYRAMZA. None CYRAMZA (ramucirumab) injection, for intravenous infusion ------------------------ WARNINGS AND PRECAUTIONS ----------------------- Initial U.S. Approval: 2014 • Arterial Thromboembolic Events (ATEs): Serious, sometimes fatal WARNING: HEMORRHAGE ATEs have been reported in clinical trials. Discontinue CYRAMZA for severe ATEs. (5.2) See full prescribing information for complete boxed warning. • Hypertension: Monitor blood pressure and treat hypertension. CYRAMZA increased the risk of hemorrhage, including severe Temporarily suspend CYRAMZA for severe hypertension. and sometimes fatal hemorrhagic events. Permanently Discontinue CYRAMZA for hypertension that cannot be medically discontinue CYRAMZA in patients who experience severe controlled. (5.3) bleeding [see Dosage and Administration (2.3), Warnings and • Infusion-Related Reactions: Monitor for signs and symptoms Precautions (5.1)]. during infusion. (5.4) • Gastrointestinal Perforation: Discontinue CYRAMZA. (5.5) --------------------------- RECENT MAJOR CHANGES -------------------------- • Impaired Wound Healing: Withhold CYRAMZA prior to surgery. Indications and Usage 11/2014 (5.6) • Clinical Deterioration in Patients with Cirrhosis: New onset or Dosage and Administration:
    [Show full text]
  • COVID-19 Immunotherapy: Novel Humanized 47D11 Monoclonal Antibody
    Review Article ISSN: 2574 -1241 DOI: 10.26717/BJSTR.2020.29.004828 COVID-19 Immunotherapy: Novel Humanized 47D11 Monoclonal Antibody Basma H Marghani* Department of Physiology, Faculty of Veterinary Medicine, Mansoura University, Egypt *Corresponding author: Basma H Marghani, Department of Physiology, Faculty of Veterinary Medicine, Mansoura University, Egypt ARTICLE INFO ABSTRACT Received: August 10, 2020 Published: August 18, 2020 rapidly to the other countries all over the world, caused a novel Coronavirus-2019 (COV- SARS-CoV-2 was appeared firstly in Wuhan, China in December 2019, then spread- gency. After infection, virus entry the host cell through spike proteins (S)- angiotensin Citation: Basma H Marghani. COVID-19 ID-19). The World Health Organization was branded COVID-19 as a global health emer Immunotherapy: Novel Humanized 47D11 converting enzyme 2 (ACE2) cell membrane receptor via their S-Binding domain, then Monoclonal Antibody. Biomed J Sci & Tech virus replication caused acute respiratory disease syndrome (ARDS). Till now there was Res 29(4)-2020. BJSTR. MS.ID.004828. no vaccines or anti-viral drugs for coronavirus infection. One effective treatment is the use of human monoclonal antibodies (mAbs) which are engineered to target and block Keywords: COVID-19; Immunotherapy; cell surface receptor. mAbs could be given to people in the early stages of COVID-19 as a Full-Length Humanized Monoclonal Anti- therapeutic, or used prophylactically to give immediate, long-term immunity to vulnera- bodies; ACE Inhibitor ble people such as healthcare workers. The neutralizing humanized 47D11 monoclonal antibody targets a common epitope on SARS-CoV2 virus and may offer potential for pre- Abbreviations: ACE2: Angiotensin-Con- vention and treatment of COVID-19.89U (Graphical Abstract 1).
    [Show full text]
  • Erbitux® (Cetuximab)
    Erbitux® (cetuximab) (Intravenous) -E- Document Number: MODA-0494 Last Review Date: 06/01/2021 Date of Origin: 09/03/2019 Dates Reviewed: 09/2019, 01/2020, 04/2020, 07/2020, 10/2020, 01/2021, 04/2021, 06/2021 I. Length of Authorization 1 Coverage will be provided for six months and may be renewed unless otherwise specified. • SCCHN in combination with radiation therapy: Coverage will be provided for the duration of radiation therapy (6-7 weeks). II. Dosing Limits A. Quantity Limit (max daily dose) [NDC Unit]: Weekly Every two weeks Erbitux 100 mg/50 mL solution for injection 1 vial every 7 days 1 vial every 14 days 3 vials every 7 days Erbitux 200 mg/100 mL solution for injection 6 vials every 14 days (5 vials for first dose only) B. Max Units (per dose and over time) [HCPCS Unit]: Weekly Every two weeks − Load: 100 billable units x 1 dose 120 billable units every 14 days − Maintenance Dose: 60 billable units every 7 days III. Initial Approval Criteria 1 Coverage is provided in the following conditions: • Patient is at least 18 years of age; AND Colorectal Cancer (CRC) † ‡ 1,2,12,13,17,19,2e,5e-8e,10e-12e,15e • Patient is both KRAS and NRAS mutation negative (wild-type) as determined by FDA- approved or CLIA-compliant test*; AND • Will not be used as part of an adjuvant treatment regimen; AND • Patient has not been previously treated with cetuximab or panitumumab; AND • Will not be used in combination with an anti-VEGF agent (e.g., bevacizumab, ramucirumab); AND Moda Health Plan, Inc.
    [Show full text]
  • Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy
    cancers Review Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy Laura Boyero 1 , Amparo Sánchez-Gastaldo 2, Miriam Alonso 2, 1 1,2,3, , 1,2, , José Francisco Noguera-Uclés , Sonia Molina-Pinelo * y and Reyes Bernabé-Caro * y 1 Institute of Biomedicine of Seville (IBiS) (HUVR, CSIC, Universidad de Sevilla), 41013 Seville, Spain; [email protected] (L.B.); [email protected] (J.F.N.-U.) 2 Medical Oncology Department, Hospital Universitario Virgen del Rocio, 41013 Seville, Spain; [email protected] (A.S.-G.); [email protected] (M.A.) 3 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain * Correspondence: [email protected] (S.M.-P.); [email protected] (R.B.-C.) These authors contributed equally to this work. y Received: 16 November 2020; Accepted: 9 December 2020; Published: 11 December 2020 Simple Summary: Immuno-oncology has redefined the treatment of lung cancer, with the ultimate goal being the reactivation of the anti-tumor immune response. This has led to the development of several therapeutic strategies focused in this direction. However, a high percentage of lung cancer patients do not respond to these therapies or their responses are transient. Here, we summarized the impact of immunotherapy on lung cancer patients in the latest clinical trials conducted on this disease. As well as the mechanisms of primary and acquired resistance to immunotherapy in this disease. Abstract: After several decades without maintained responses or long-term survival of patients with lung cancer, novel therapies have emerged as a hopeful milestone in this research field.
    [Show full text]
  • The Angiopoietin-2 and TIE Pathway As a Therapeutic Target for Enhancing Antiangiogenic Therapy and Immunotherapy in Patients with Advanced Cancer
    International Journal of Molecular Sciences Review The Angiopoietin-2 and TIE Pathway as a Therapeutic Target for Enhancing Antiangiogenic Therapy and Immunotherapy in Patients with Advanced Cancer Alessandra Leong and Minah Kim * Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; afl[email protected] * Correspondence: [email protected] Received: 26 September 2020; Accepted: 13 November 2020; Published: 18 November 2020 Abstract: Despite significant advances made in cancer treatment, the development of therapeutic resistance to anticancer drugs represents a major clinical problem that limits treatment efficacy for cancer patients. Herein, we focus on the response and resistance to current antiangiogenic drugs and immunotherapies and describe potential strategies for improved treatment outcomes. Antiangiogenic treatments that mainly target vascular endothelial growth factor (VEGF) signaling have shown efficacy in many types of cancer. However, drug resistance, characterized by disease recurrence, has limited therapeutic success and thus increased our urgency to better understand the mechanism of resistance to inhibitors of VEGF signaling. Moreover, cancer immunotherapies including immune checkpoint inhibitors (ICIs), which stimulate antitumor immunity, have also demonstrated a remarkable clinical benefit in the treatment of many aggressive malignancies. Nevertheless, the emergence of resistance to immunotherapies associated with an immunosuppressive tumor microenvironment has restricted therapeutic response, necessitating the development of better therapeutic strategies to increase treatment efficacy in patients. Angiopoietin-2 (ANG2), which binds to the receptor tyrosine kinase TIE2 in endothelial cells, is a cooperative driver of angiogenesis and vascular destabilization along with VEGF. It has been suggested in multiple preclinical studies that ANG2-mediated vascular changes contribute to the development and persistence of resistance to anti-VEGF therapy.
    [Show full text]
  • Cyramza® (Ramucirumab)
    Cyramza® (ramucirumab) (Intravenous) -E- Document Number: MODA-0405 Last Review Date: 07/01/2021 Date of Origin: 09/03/2019 Dates Reviewed: 09/2019, 10/2019, 01/2020, 04/2020, 07/2020, 10/2020, 01/2021, 04/2021, 07/2021 I. Length of Authorization Coverage will be provided for 6 months and may be renewed. II. Dosing Limits A. Quantity Limit (max daily dose) [NDC Unit]: • Cyramza 100 mg/10 mL: 4 vials per 14 days • Cyramza 500 mg/50 mL: 2 vials per 14 days B. Max Units (per dose and over time) [HCPCS Unit]: Gastric, Gastroesophageal, HCC, and Colorectal Cancer: • 180 billable units every 14 days NSCLC: • 240 billable units every 14 days III. Initial Approval Criteria 1 Coverage is provided in the following conditions: • Patient is at least 18 years of age; AND Universal Criteria 1 • Patient does not have uncontrolled severe hypertension; AND • Patient must not have had a surgical procedure within the preceding 28 days or have a surgical wound that has not fully healed; AND Gastric, Esophageal, and Gastro-esophageal Junction Adenocarcinoma † Ф 1-3,5-7,14,17,2e,5e • Used as subsequent therapy after fluoropyrimidine- or platinum-containing chemotherapy; AND • Used as a single agent OR in combination with paclitaxel; AND o Used for one of the following: Moda Health Plan, Inc. Medical Necessity Criteria Page 1/27 Proprietary & Confidential © 2021 Magellan Health, Inc. – Patient has unresectable locally advanced, recurrent, or metastatic disease; OR – Used as palliative therapy for locoregional disease in patients who are not surgical candidates
    [Show full text]
  • Coverage of Monoclonal Antibody Products to Treat COVID-19
    Coverage of Monoclonal Antibody Products to Treat COVID-19 Monoclonal antibody products to treat Coronavirus disease 2019 (COVID-19) help the body fight the virus or slow the virus’s growth. Medicare beneficiaries have coverage without beneficiary cost sharing for these products when used as authorized or approved by the Food and Drug Administration (FDA). Disclaimer: The contents of this document do not have the force and effect of law and are not meant to bind the public Medicare in any way, unless specifically incorporated into a contract. This document is intended only to provide clarity to the public regarding existing requirements under the law. This communication was printed, published, or produced and disseminated at U.S. taxpayer expense. Site of Care1 Payable by Expected Patient Expected Payment to Providers: Medicare Cost-Sharing Key Facts • Medicare payment for monoclonal antibody products to treat COVID-19 is similar across Inpatient No patient sites of care, with some small differences. Hospital cost-sharing • Medicare pays for the administration of monoclonal antibody products to treat COVID-19. For example, beginning on May 6, 2021, Medicare will pay approximately Outpatient $450 in most settings, or approximately $750 No patient in the beneficiary’s home or residence, for Hospital or cost-sharing the administration of certain monoclonal “Hospital 4 2 antibody products to treat COVID-19. For without Walls ” monoclonal antibody products to treat COVID-19 that are administered before May 6, 2021, the Medicare payment rate in all No patient settings is approximately $310. Outpatient cost-sharing3 Physician Office/ • CMS will exercise enforcement discretion to Infusion Center allow Medicare-enrolled immunizers working within their scope of practice and subject to applicable state law to bill directly and receive direct reimbursement from the Medicare program for administering Nursing Home monoclonal antibody treatments to No patient (See third bullet in Medicare Part A Skilled Nursing Facility Key Facts on CMS cost-sharing residents.
    [Show full text]