Publication Practice Guidelines Research Articles

An Overview of the 2022 Update of Good Publication Practice (GPP) Guidelines: A Medical Writer’s Perspective

The Good Publication Practice (GPP) guidelines are a set of principles and recommendations pertaining to peer-reviewed or peer-orientated publications arising from research funded by or conducted in collaboration with industry sponsors, typically pharmaceutical, biotechnology, and medical device companies.
 This year marks the 20-year anniversary of the first GPP guidelines, which were published in 2003.1 These initial GPP guidelines were developed to promote transparency and to establish standards for publication practice used by pharmaceutical companies. Since then, GPP guidelines have undergone several updates to reflect changes within the publication field and to provide additional practical guidance on publication processes and procedures. These updates include GPP22 published in 2009 and GPP33 published in 2013. Good Practice for Conference Abstracts and Presentations (GPCAP)4 was published in 2019 to provide guidance specifically for congress abstract and presentations. The latest update of the GPP guidelines, the GPP 2022 update, was published in August 20225.

Good Publication Practice (GPP) 2022 Update: An Interview with Dikran Toroser

Dikran Toroser was educated in the UK and has a PhD in Biochemistry from Newcastle University in Newcastle upon Tyne. He did his post-doctoral research in the UK at the Cambridge lab on genetics and then moved to the US to work as a biochemist and researcher for the US Department of Agriculture (USDA). He has an extensive background in scientific publications as well as medical writing. He has led scientific publication teams involved with pre-clinical, clinical, and mature product studies and publications. Dikran is one of the founding faculty for the University of California San Diego medical writing certificate and a consulting director for the program. Active in professional organizations such as American Medical Writers Association (AMWA) and International Society for Medical Publication Professionals (ISMPP), Dikran most recently has been involved in compiling guidelines for the publication professionals, including the AMWA-EMWA-ISMPP joint position statement on the role of professional medical writers1 and GPP 2022, the latest 2022 update of Good Publication Practice (GPP) guidelines for company-sponsored biomedical research2.  

Health care resource utilization and costs among individuals with vs without Huntington disease in a US population.

BACKGROUND: Quantifying the extent of health care resource utilization (HCRU) and costs associated with Huntington disease (HD) is vital for providers, decisionmakers, and payers to understand unmet treatment needs and to ensure limited resources can be used to benefit the maximum number of people with HD. OBJECTIVE: To quantify HCRU and costs for people with HD, overall and by disease stage, and compare these with non-HD controls. METHODS: This was a retrospective cohort study using administrative claims data from the IBM MarketScan Commercial, Multi-State Medicaid, and Medicare Supplemental Databases from January 1, 2009, to December 31, 2018. People with an HD claim between January 1, 2010, and December 31, 2017, were selected for this analysis and matched with non-HD controls for comparison. The HD cohort and the non-HD controls were exact matched on their follow-up duration and propensity score matched 1:4 to create the final analytical cohort. Index date was the first HD diagnosis for the HD cohort (proxy index date assigned to controls), and all individuals were required to have continuous enrollment for 12 or more months pre-index (baseline) and 3 or more months post-index. Proportions of all-cause HCRU (ie, outpatient visits, inpatient visits, emergency department visits, pharmacy fills, radiology visits, and physical/occupational therapy visits) in the 6-months post-index and HCRU counts and costs per patient per month (PPPM) over the entire follow-up were calculated for each cohort. RESULTS: A total of 2,473 individuals with HD and 9,522 matched non-HD controls were identified. HCRU in 6 months post-index was significantly greater in people with HD compared with non-HD controls for all health care service categories; P < 0.0001. The mean number of HCRU PPPM for all measured healthcare services was significantly higher in people with HD compared with non-HD controls (P < 0.001). Mean total costs (2018 USD PPPM) for the HD cohort ($2,260 [SD = $4,682]) were twice the total costs in the non-HD cohort ($1,056 [SD = $3,078]) (P < 0.0001) and were highest across all disease stages. CONCLUSIONS: This study provides current comprehensive HCRU and cost estimates in individuals with HD relative to those without the disease, thus demonstrating the high economic burden imposed by HD. DISCLOSURES: Dr Ta: Employment with Genentech (at time of study) and stock options with Roche; Dr To: Employment and stock options/dividends with Genentech; Dr Patel: Employment and stock options with Roche/Genentech; Dr Fuller: Employment with CHDI Management/CHDI Foundation; Mr Surinach: Employment with Genesis Research (which receives consulting fees from Genentech/Roche); Dr Abbass: Employment and stock options with Genentech; Dr Exuzides: Employment and stock options with Roche/Genentech; and Ms Luo: Employment with CHDI Management/CHDI Foundation. This study was funded by Genentech Inc. The authors thank Greg Rowe of Chrysalis Medical Communications for providing medical writing support, which was funded by F. Hoffmann-La Roche Ltd, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).

Patient perspectives on diagnosis and management of hidradenitis suppurativa: A web-based survey

To the Editor: Hidradenitis suppurativa (HS) is a chronic, recurrent inflammatory disease characterized by inflammatory nodules, abscesses, sinus tracts, and scarring.1Alikhan A. Sayed C. Alavi A. et al.North American clinical management guidelines for hidradenitis suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations: part I: diagnosis, evaluation, and the use of complementary and procedural management.J Am Acad Dermatol. 2019; 81: 76-90Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar,2Ingram J.R. The epidemiology of hidradenitis suppurativa.Br J Dermatol. 2020; 183: 990-998Crossref PubMed Scopus (40) Google Scholar HS is associated with high physical and psychological burden and reduced quality of life.3Kimball A.B. Crowley J.J. Papp K. et al.Baseline patient-reported outcomes from UNITE: an observational, international, multicentre registry to evaluate hidradenitis suppurativa in clinical practice.J Eur Acad Dermatol Venereol. 2020; 34: 1302-1308Crossref PubMed Scopus (11) Google Scholar,4Mac Mahon J. Kirthi S. Byrne N. et al.An update on health-related quality of life and patient-reported outcomes in hidradenitis suppurativa.Patient Relat Outcome Meas. 2020; 11: 21-26Crossref PubMed Google Scholar HS diagnostic delays and management challenges are widely acknowledged; however, limited data are available on patient perspectives through HS diagnosis and treatment.5Saunte D.M. Boer J. Stratigos A. et al.Diagnostic delay in hidradenitis suppurativa is a global problem.Br J Dermatol. 2015; 173: 1546-1549Crossref PubMed Scopus (196) Google Scholar This survey study describes patient experiences from symptom onset to treatment initiation and disease management. This prospective web-based survey study was conducted between December 15, 2020, and January 31, 2021. Of 50 patients with HS invited to complete the 46-question survey, 47 completed it for a response rate of 94%; all provided written informed consent prior to participating. Ethics review and data privacy approvals were obtained through a centralized institutional review board. Patients were questioned on demographics, disease characteristics, journey to care, and disease management. Descriptive analyses were conducted by Guidehouse using SAS statistical software or Microsoft Excel. Patient demographics and clinical characteristics were comparable to those previously described for HS populations in the United States. One-third of patients (31.9%) sought medical help only when symptoms became unbearable (Supplementary Table, available via Mendeley at https://data.mendeley.com/datasets/ydk2byc832/1). Most patients (70.2%) self-treated with nonprescription therapies before seeking medical help (Table I). One-third of patients were referred to a dermatologist; of these, 60% reported that their referral process was “very/somewhat difficult.” Patients experienced substantial diagnostic delays, and 40.4% of patients waited >1 year from diagnosis to the first prescribed treatment. HS symptoms had a major impact on patients’ daily activities, and 57.4% reported feeling embarrassed, anxious/nervous, or down/depressed about their disease.Table IPatient-reported experiences from symptom onset through HS diagnosis and managementCharacteristic (N = 47)∗N = 47 unless otherwise specified.Patients with HS, n (%)Tried nonprescription therapies before seeking medical help†Nonprescription therapies most frequently mentioned by patients included pain killers (eg, acetaminophen, ibuprofen), epsom salt, black salve, and antibacterial washes and ointments.33 (70.2)Referral to dermatologist15 (31.9)Patient experience with the referral process, n = 15‡Only includes patients who had been referred to a dermatologist. No patients reported that the referral process was “very easy.” “Very difficult”7 (46.7) “Somewhat difficult”2 (13.3) “Neutral”5 (33.3) “Somewhat easy”1 (6.7)Time from symptom onset to diagnosis <1 y5 (10.6) 1-5 y13 (27.7) 5-10 y9 (19.1) >10 y20 (42.6)Time from diagnosis to the first prescribed treatment Before diagnosis§Received pharmacological treatment before diagnosis.1 (2.1) Immediately15 (31.9) <1 mo7 (14.9) <1 y5 (10.6) 1-5 y10 (21.3) 5-10 y4 (8.5) >10 y5 (10.6)Time from the first treatment to biologic initiation, n = 22 1-6 mo6 (27.3) 7-11 mo2 (9.1) 1-2 y5 (22.7) >2 y9 (40.9)Patient-reported biggest disadvantages of biologic treatment, n = 22‖Patients could select more than 1 response; other included “quarterly blood work and increased chance of TB/infections” and “adalimumab no longer worked, taken more than once.” Satisfaction with disease control10 (45.5) Side effects9 (40.9) Expensive cost7 (31.8) Forget to take treatment3 (13.6) Does not work as fast as desired3 (13.6) Other2 (9.1) Does not like needles/injections1 (4.5) Too much time needed to take it/travel to treatment center1 (4.5)Patient concerns that their current treatment will stop working “Very worried”17 (36.2) “Somewhat worried”8 (17.0) “Little worried”11 (23.4) “Not worried”11 (23.4)“Extreme/very much” feelings reported by patients about HS “Embarrassed”27 (57.4) “Nervous/anxious”27 (57.4) “Down/depressed”25 (53.2)HS, Hidradenitis suppurativa.∗ N = 47 unless otherwise specified.† Nonprescription therapies most frequently mentioned by patients included pain killers (eg, acetaminophen, ibuprofen), epsom salt, black salve, and antibacterial washes and ointments.‡ Only includes patients who had been referred to a dermatologist. No patients reported that the referral process was “very easy.”§ Received pharmacological treatment before diagnosis.‖ Patients could select more than 1 response; other included “quarterly blood work and increased chance of TB/infections” and “adalimumab no longer worked, taken more than once.” Open table in a new tab HS, Hidradenitis suppurativa. Patients reported mixed feelings upon receiving their diagnosis, with 51% feeling relieved to have a diagnosis for their symptoms and 28% feeling discouraged about the chronic/progressive nature of HS (Fig 1). Only 36% of patients reported that their disease was well managed by their current physician. The majority (74%) reported they were never prompted to talk about HS with a mental health professional, and 40% were never counseled on lifestyle modifications (Supplementary Fig 1, available via Mendeley at https://data.mendeley.com/datasets/ydk2byc832/1). Of the 22 patients (46.8%) who were prescribed biologics, 66% reported biologics as the most helpful treatment class (Supplementary Fig 2, available via Mendeley at https://data.mendeley.com/datasets/ydk2byc832/1). Over one-half of patients (53.2%) expressed that they were very/somewhat worried that their current HS treatment would stop working (Table I). Furthermore, the top patient-reported disadvantages of biologics included dissatisfaction with disease control (45.5%), side effects (40.9%), and expensive cost (31.8%) (Table I). These findings are limited in their generalizability due to the modest sample size, the uncontrolled setting, and the localized geography. Patient perspectives substantiated major diagnosis and treatment delays, mixed emotions upon receiving the diagnosis of HS, and perceived poor disease management. Strategies to help improve HS diagnosis and delivery of care may include public awareness campaigns, transparent and compassionate patient–physician interactions about HS, increased education about treatment options, and development of novel accessible and affordable therapeutics with durable efficacy. Multidisciplinary care and increased patient and provider awareness are needed to address gaps in delivering comprehensive and timely HS care with improved patient satisfaction. J.L. Hsiao is on the board of directors for the Hidradenitis Suppurativa Foundation (HSF) and has served as an advisor for Boehringer Ingelheim, Novartis, and UCB and as a speaker and advisor for AbbVie. V.Y. Shi is on the board of directors for the HSF; serves as an advisor for the National Eczema Association; is a stock shareholder of Learn Health; and has served as an advisory board member, investigator, speaker, and/or received research funding from Sanofi Genzyme, Regeneron, AbbVie, Eli Lilly, Novartis, SUN Pharma, LEO Pharma, Pfizer, Incyte, Boehringer Ingelheim, Aristea Therapeutics, Menlo Therapeutics, Dermira, Burt’s Bees, Galderma, Kiniksa, UCB, Target-PharmaSolutions, Altus Lab/cQuell, MYOR, Polyfins Techology, GpSkin, and Skin Actives Scientific. E. Muscianisi and J. Darcy are employees of Novartis Pharmaceuticals Corporation. E. Nguyen is an employee of Novartis Gene Therapies. J.S. Kirby is on the board of directors for the HSF and has served as an advisory board member, investigator, speaker, and/or consultant for AbbVie, ChemoCentryx, CSL Behring, DermTech, InflaRx, Incyte, Novartis, Janssen, Pfizer, and UCB. Medical writing support was provided by Charli Dominguez, PhD, CMPP, of Health Interactions, Inc, Chicago, IL, and was funded by Novartis Pharmaceuticals Corporation. This manuscript was developed in accordance with Good Publication Practice (GPP3) guidelines. The authors had full control of the content and made the final decision on all aspects of this publication.

Annals for Educators - September 2022

Web ExclusivesSeptember 2022Annals for Educators - September 2022FREEChristine Laine, MD, MPHChristine Laine, MD, MPHSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/AWED202209200 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Clinical Practice PointsRisk for Myocardial Infarction, Stroke, and Pulmonary Embolism Following COVID-19 Vaccines in Adults Younger Than 75 Years in FranceSevere cardiovascular events (myocardial infarction, pulmonary embolism, and stroke) have been reported after COVID-19 vaccination. This registry-based analysis assessed short-term risk for severe cardiovascular events after COVID-19 vaccination in France's 46.5 million adults younger than 75 years.Use this article to:Discuss the adverse effects associated with the different COVID-19 vaccines.Review indications and timing for the bivalent COVID-19 vaccines that became available in September 2022.Preventing Obesity in Midlife Women: A Systematic Review for the Women's Preventive Services InitiativePreventing Obesity in Midlife Women: A Recommendation From the Women's Preventive Services InitiativeWomen in midlife are particularly at risk for weight gain. This systematic review summarizes the evidence for the effectiveness of behavioral interventions to prevent weight gain and obesity among women in midlife. The guideline synopsis discusses the recommendations of the Women's Preventive Services Initiative on prevention of obesity among women in midlife.Use these articles to:View the video summary of the systematic review as a group. Discuss the strengths and weaknesses of the evidence included in the systematic review.Invite a nutritionist to join your session to review dietary strategies to maintain normal weight.Role-play counseling a hypothetical woman with normal weight about strategies to prevent weight gain.Clinical Practice Guidelines From the Association for the Advancement of Blood and Biotherapies (AABB): COVID-19 Convalescent PlasmaThe Fast and the Furious: Chasing a Clinical Niche for COVID-19 Convalescent PlasmaThe Association for the Advancement of Blood and Biotherapies developed clinical practice guidelines for appropriate use of COVID-19 convalescent plasma (CCP). The first article describes the evidence and rationale for recommendations on inpatient and outpatient treatment and prophylaxis. The accompanying editorial discusses the recommendations and the lessons the experience with CCP provides for use of passive immunotherapy for future emerging infectious diseases.Use this article and the editorial to:Discuss the clinical scenarios in which use of CCP should and should not be considered.Review the procedures at your institution for prescribing CCP.Invite an infectious disease specialist to join your session and discuss other clinical situations in which convalescent plasma may be beneficial.Research and Reporting MethodsGood Publication Practice (GPP) Guidelines for Company-Sponsored Biomedical Research: 2022 UpdateThe Good Publication Practice (GPP) guidelines provide recommendations for individuals and organizations that contribute to the publication of results of research supported by pharmaceutical, medical device, diagnostics, and biotechnology companies. This update reflects changes in the medical publications environment and aims to improve reporting of research initiated by commercial organizations.Use this article to:List the features of trustworthy industry-funded research.List the features that identify industry-funded research that may not be trustworthy.Find several clinical trials supported by the pharmaceutical industry, and evaluate whether they meet the criteria for trustworthiness identified in this article.Humanism and ProfessionalismUnintended Consequences of SCOTUS Abortion Decision for Patients With Rheumatic DiseasesUrgent Call to Action: Engaging Hospitalists in Family PlanningI Remember MarjorieThe first article discusses the Supreme Court's ruling in Dobbs v. Jackson and the concerns it raises for patients with rheumatic disease and their clinicians, including access to medically indicated abortion, access to necessary medications that are teratogenic, and laws that interfere with patient–clinician discussions about reproductive issues. The second article argues that hospitalists should be addressing contraceptive needs among inpatients despite possible challenges. In the third article, the author recalls a patient who died of complications from an unsafe abortion.Use these articles to:Review the implications of the Dobbs v. Jackson ruling on access to pregnancy termination in the state where your institution is.Invite an OB-GYN to your session to review the different types of contraception to help prepare your learners to provide contraception counseling to their patients.Role-play counseling a patient who just learned that she is pregnant about her desire to continue the pregnancy.Deep Venous ThrombosisVenous thromboembolism (VTE) is the third most common cardiovascular disorder, affecting up to 5% of the population. It commonly manifests as lower-extremity deep venous thrombosis (DVT) or pulmonary embolism. Half of these events are associated with a transient risk factor and may be preventable with prophylaxis. Direct oral anticoagulants are effective, are safe, and carry a lower risk for bleeding than vitamin K antagonists. Many patients with VTE will have a chronic disease requiring long-term anticoagulation. Postthrombotic syndrome affects 25% to 40% of patients with DVT and significantly impacts function and quality of life.Use this article to:Discuss the criteria for the diagnosis of VTE.Review the indications for VTE prophylaxis.Review the recommendations for anticoagulation in patients with provoked and unprovoked VTE.Discuss the criteria for hospitalization of a patient with VTE.Test your learners' knowledge by having them complete the quiz that accompanies the article and then reviewing the correct answers.Do you like reading Annals for Educators? Receive it direct to your inbox. Sign up for the Annals for Educators alert today. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: From the Editors of Annals of Internal Medicine and Education Guest Editor, Gretchen Diemer, MD, FACP, Associate Dean of Graduate Medical Education and Affiliations, Thomas Jefferson University. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics September 2022Volume 175, Issue 9Page: ED9 ePublished: 20 September 2022 Issue Published: September 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...

1779TiP Phase II clinical study evaluating the efficacy and safety of disitamab vedotin in patients (pts) with HER2-expressing urothelial carcinoma (RC48G001)

More than 212,000 deaths annually are related to bladder cancer worldwide (Sung 2021), with 5-year survival rates of <5% in metastatic urothelial carcinoma (UC) (Witjes 2021). Nearly half of all pts cannot tolerate standard cisplatin-based first line (1L) chemotherapy and opportunity still exists to improve outcomes in both 1L and later lines of therapy. Human epidermal growth factor receptor 2 (HER2) is overexpressed in multiple malignant tumors and overexpression of HER2 may be associated with poor outcomes in UC (Zhao 2015). No HER2-directed therapies are currently approved for locally advanced unresectable or metastatic UC (LA/mUC). Disitamab vedotin (DV; RC48-ADC) is an investigational antibody–drug conjugate (ADC) comprised of a HER2-directed monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable linker. DV elicits antitumor activity through MMAE-directed cytotoxicity and bystander effect (Li 2020). DV is conditionally approved in LA/mUC and gastric cancer in China and was granted Breakthrough Therapy designation by the FDA for second-line treatment of HER2-expressing LA/mUC after platinum-containing chemotherapy. RC48G001 (NCT04879329) is a phase 2, multicohort, open-label, multicenter trial to evaluate DV in pts with HER2-expressing LA/mUC. Pts are enrolled in 2 cohorts defined by HER2 expression (by immunohistochemistry [IHC]) and gene amplification (by in situ hybridization [ISH]) by central laboratory: Cohort A (IHC 3+, or 2+ and ISH+) and Cohort B (IHC 2+ and ISH-, or IHC 1+). Eligible pts must have measurable disease per RECIST v1.1, ECOG Performance Status of 0 or 1, and must have received 1 or 2 lines of prior systemic therapy, including 1 line of platinum-containing chemotherapy. The primary endpoint is confirmed objective response rate (ORR) assessed by blinded independent central review. Secondary endpoints include ORR assessed by investigator, duration of response, progression-free survival, disease control rate, overall survival, safety, and pharmacokinetic parameters. Enrollment for cohorts A and B is ongoing in North America and EU, and planned in LATAM, APAC, and Israel. NCT04879329. Under guidance of the authors, assistance in medical writing was provided by Hanna Thomsen, PhD, of Seagen Inc. and was funded by Seagen Inc. in accordance with Good Publication Practice (GPP3) guidelines. Seagen Inc.

Good Publication Practice (GPP) Guidelines for Company-Sponsored Biomedical Research: 2022 Update.

These updated Good Publication Practice (GPP) guidelines include recommendations for publishing company-sponsored biomedical research. The GPP guidelines apply to peer-reviewed or peer-oriented biomedical publications, such as manuscripts, meeting presentations, posters, and abstracts, as well as enhanced content, such as plain-language summaries. The current GPP guidelines incorporate guidance on ethics and transparency as well as the planning, development, review, and approval of biomedical publications and policies and procedures that describe these practices. Supplemental materials lay out processes for steering committees, publication plans, publication working groups, determining authorship, and documentation. Information about new topics, such as alliances and working with patients, has been included where appropriate within these supplemental materials. Incorporating the principles and best practices presented in these GPP guidelines will result in increased transparency and a firm ethical footing. This guidance is also intended to enable the compliant incorporation of new and emerging publication tools for the ethical publication of company-sponsored research.

P-156 MOUNTAINEER-02: Phase 2/3 study of tucatinib, trastuzumab, ramucirumab, and paclitaxel in previously treated HER2+ gastric or gastroesophageal junction adenocarcinoma: Trial in progress

Tucatinib (TUC), a highly selective HER2-directed tyrosine kinase inhibitor (TKI) approved in multiple regions for HER2+ metastatic breast cancer, is being developed as a novel therapy for patients with GI tumors including gastric or gastroesophageal junction adenocarcinoma (GEC). While trastuzumab (Tras) with chemotherapy is standard in the first-line setting for metastatic HER2+ GEC, no anti-HER2 therapy has demonstrated an OS benefit over chemotherapy as second-line therapy, possibly due to loss of HER2 expression following Tras-based therapy. In GEC xenograft models, dual targeting of HER2 with TUC and Tras showed superior activity to either agent alone. (Kulukian 2020) Interim results from the MOUNTAINEER study have shown promising activity for TUC and Tras for HER2+ mCRC.(Strickler 2019) The MOUNTAINEER-02 study (NCT04499924) is evaluating the efficacy and safety of TUC with Tras, ramucirumab (Ram), and paclitaxel (Pac) in patients with HER2+ GEC in the second-line setting. MOUNTAINEER-02 is a phase 2/3 study evaluating TUC + Tras with Ram and Pac. Eligible patients have locally-advanced unresectable or metastatic HER2+ GEC and have received a HER2-directed antibody and 1 prior line of therapy for advanced disease. Patients are ≥18 years of age; have an ECOG ≤1; and have had no prior exposure to Ram, an anti-HER2 or anti-EGFR TKI, HER2-directed antibody-drug conjugates, or taxanes ≤12 months before enrollment. Patients receive TUC 300 mg or placebo PO BID and Tras or placebo (IV on Days 1 and 15 of each 28-day cycle) in combination with Pac (IV on Days 1, 8, and 15) and Ram (IV on Days 1 and 15). The study includes an initial Pac-dose optimization stage because of the potential impact of TUC on Pac metabolism. The open-label phase 2 part determines the recommended dose of Pac (60 or 80 mg/m2) combined with TUC, Tras, and Ram in 6–18 patients and evaluates safety and activity of the regimen in Cohorts 2A and 2B (30 patients each). The randomized, double-blind, phase 3 part compares the efficacy and safety of TUC and Tras (Arm 3A, ∼235 patients) vs placebo (Arm 3B, ∼235 patients), both in combination with Ram and Pac, and evaluates activity of TUC with Ram and Pac (Arm 3C, ∼30 patients). The coprimary phase 3 endpoints are OS and PFS per investigator, and secondary endpoints include DOR, confirmed ORR, and DCR. Secondary objectives include patient-reported outcomes. HER2 status is determined by blood-based NGS assay or IHC/ISH assay of a tumor tissue sample (IHC3+ or IHC2+/ISH+) at screening. In Cohort 2A and phase 3, patients must be HER2+ by blood-based NGS. In Cohort 2B, patients must be HER2+ by biopsy but HER2 negative by blood-based NGS after progression in first-line or subsequent therapy. Disease assessments per RECIST v1.1 occur q6 weeks for 36 weeks, then q9 weeks. The pharmacokinetics of TUC, Pac, and their metabolites are evaluated in a subset of patients, including a cohort with gastrectomies. Enrollment in phase 2 is ongoing. NCT04499924. The authors thank Joseph Giaconia of MMS Holdings, Michigan, USA for providing medical writing support/editorial support, which was funded by Seagen Inc., Bothell, WA, USA in accordance with Good Publication Practice (GPP3) guidelines. Seagen Inc.

A case of normal C1 esterase inhibitor hereditary angioedema successfully treated with berotralstat

Hereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable, recurrent, localized episodes of swelling that often affect the extremities, face, abdomen, and larynx.1Busse PJ Christiansen SC Riedl MA Banerji A Bernstein JA Castaldo AJ et al.US HAEA medical advisory board 2020 guidelines for the management of hereditary angioedema.J Allergy Clin Immunol Pract. 2021; 9 (e3): 132-150Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar,2Caballero T. Treatment of hereditary angioedema.J Investig Allergol Clin Immunol. 2021; 31: 1-16Crossref PubMed Scopus (12) Google Scholar HAE is most typically caused by mutations in the C1-esterase inhibitor (C1-INH) gene (serpin family G member 1; SERPING1) that result in deficient (type 1) or dysfunctional (type 2) C1-INH protein.3Longhurst HJ Bork K. Hereditary angioedema: an update on causes, manifestations and treatment.Br J Hosp Med. 2019; 80: 391-398Crossref PubMed Scopus (41) Google Scholar These mutations lead to dysregulation of the kallikrein-bradykinin cascade and increases in bradykinin production and vascular permeability, which are thought to be the main causes of HAE attacks.4Banday AZ Kaur A Jindal AK Rawat A Singh S. An update on the genetics and pathogenesis of hereditary angioedema.Genes Dis. 2019; 7: 75-83Crossref PubMed Scopus (32) Google Scholar Type 1 and type 2 HAE, which are collectively known as HAE-C1-INH, are associated with lower-than-normal plasma levels of both complement component 4 (C4) and C1-INH functionality in laboratory tests and represent 95% of HAE cases.3Longhurst HJ Bork K. Hereditary angioedema: an update on causes, manifestations and treatment.Br J Hosp Med. 2019; 80: 391-398Crossref PubMed Scopus (41) Google Scholar,4Banday AZ Kaur A Jindal AK Rawat A Singh S. An update on the genetics and pathogenesis of hereditary angioedema.Genes Dis. 2019; 7: 75-83Crossref PubMed Scopus (32) Google Scholar However, some patients present with a form of HAE that is typically associated with normal plasma C1-INH levels and functionality (HAE-nl-C1-INH), normal plasma C4 complement levels, and attacks that are predominately facial in nature.3Longhurst HJ Bork K. Hereditary angioedema: an update on causes, manifestations and treatment.Br J Hosp Med. 2019; 80: 391-398Crossref PubMed Scopus (41) Google Scholar Diagnosis of HAE-nl-C1-INH represents a considerable challenge and is reliant on genetic testing.3Longhurst HJ Bork K. Hereditary angioedema: an update on causes, manifestations and treatment.Br J Hosp Med. 2019; 80: 391-398Crossref PubMed Scopus (41) Google Scholar,5Henao MP Kraschnewski JL Kelbel T Craig TJ. Diagnosis and screening of patients with hereditary angioedema in primary care.Ther Clin Risk Manag. 2016; 12: 701-711Crossref PubMed Scopus (42) Google Scholar Current evidence suggests that, similar with HAE-C1-INH, HAE-nl-C1-INH is mediated by increased bradykinin production.3Longhurst HJ Bork K. Hereditary angioedema: an update on causes, manifestations and treatment.Br J Hosp Med. 2019; 80: 391-398Crossref PubMed Scopus (41) Google Scholar,6Bork K. Diagnosis and treatment of hereditary angioedema with normal C1 inhibitor.Allergy Asthma Clin Immunol. 2010; 6: 15Crossref PubMed Google Scholar Consistent with this, mutations in genes involved in bradykinin formation, such as factor XII, plasminogen, angiopoietin-1, kininogen-1, and myoferlin genes, have been identified in patients with HAE-nl-C1-INH.7Bork K Machnig T Wulff K Witzke G Prusty S Hardt J. Clinical features of genetically characterized types of hereditary angioedema with normal C1 inhibitor: a systematic review of qualitative evidence.Orphanet J Rare Dis. 2020; 15: 289Crossref PubMed Scopus (39) Google Scholar However, the genetic basis of HAE-nl-C1-INH is still unknown in many cases,7Bork K Machnig T Wulff K Witzke G Prusty S Hardt J. Clinical features of genetically characterized types of hereditary angioedema with normal C1 inhibitor: a systematic review of qualitative evidence.Orphanet J Rare Dis. 2020; 15: 289Crossref PubMed Scopus (39) Google Scholar which, in combination with the lack of an available confirmatory biomarker or diagnostic test,1Busse PJ Christiansen SC Riedl MA Banerji A Bernstein JA Castaldo AJ et al.US HAEA medical advisory board 2020 guidelines for the management of hereditary angioedema.J Allergy Clin Immunol Pract. 2021; 9 (e3): 132-150Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar can make it difficult for patients to access insurance coverage for their treatment. Therefore, physicians of patients with suspected HAE-nl-C1-INH may choose to initiate a trial course of an HAE-specific therapy to observe a treatment response,8Riedl MA Banerji A Gower R. Current medical management of hereditary angioedema: follow-up survey of US physicians.Ann Allergy Asthma Immunol. 2021; 126: 264-272Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar which can provide a rationale for insurance coverage of long-term treatment costs. Here, we report a case of HAE-nl-C1-INH occurring in the context of a family history of HAE-C1-INH (type 1) disease, which was difficult to treat because of the patient's needle phobia, but ultimately responded well to oral berotralstat therapy. The patient was a 60-year-old woman who reported several previous episodes of swelling that came on over the course of a day and were atypically limited mostly to her hands, feet, breasts, or abdomen. The patient reported that these painful swelling episodes occurred at a frequency of 2 to 3 times a month and typically lasted 2 to 4 days, during which she struggled to go about her usual daily activities. Before undergoing a total hysterectomy in her 40s, the patient had also experienced severe abdominal pain and swelling during her menstrual cycle, occasionally including genital involvement. The patient's mother, sister, cousin, and daughter experienced similar symptoms, and her daughter had received a diagnosis of laboratory-supported HAE-C1-INH (type 1). Therefore, the patient's family history and presenting symptoms led to a suspicion of undiagnosed HAE. During laboratory assessments for HAE in August 2020, the patient had normal serum levels of C1-INH antigen (21 mg/dL), C1-INH functionality that was 90% of normal, and normal serum levels of C4 complement (30 mg/dL). These values remained at normal levels when measured during 2 swelling attacks and the patient also had normal tryptase levels during attacks. These clinical findings indicated that the patient likely had HAE-nl-C1-INH despite having a family history of HAE-C1-INH (type 1). Analysis of the patient's SERPING1 gene using the GeneDx HAE-C1-INH (type 1 and type 2) panel (GeneDx, Gaithersburg, Maryland) did not identify any reportable variants, consistent with HAE-nl-C1-INH. The patient declined additional genetic testing because of cost. A review of the patient's medical history indicated that previous use of antihistamines (cetirizine and diphenhydramine), hydroxychloroquine for rheumatoid arthritis, and steroids for asthma did not noticeably affect her swelling attacks. However, the patient reported (and documented with photographs) that the use of recombinant C1-INH replacement therapy (conestat alfa) had resolved swelling attacks within an hour of administration on 2 separate occasions before our involvement. Her positive response to recombinant C1-INH replacement therapy was supportive of an HAE diagnosis and consistent with the successful treatment of HAE-nl-C1-INH attacks with C1-INH concentrate and icatibant reported in the literature.7Bork K Machnig T Wulff K Witzke G Prusty S Hardt J. Clinical features of genetically characterized types of hereditary angioedema with normal C1 inhibitor: a systematic review of qualitative evidence.Orphanet J Rare Dis. 2020; 15: 289Crossref PubMed Scopus (39) Google Scholar At the time of the patient's presentation, typically prescribed HAE-specific prophylactics included intravenous and subcutaneous treatments.2Caballero T. Treatment of hereditary angioedema.J Investig Allergol Clin Immunol. 2021; 31: 1-16Crossref PubMed Scopus (12) Google Scholar Therefore, we initially prescribed the patient lanadelumab prophylaxis (300 mg) every 2 weeks and icatibant (30 mg) on demand. However, because of severe needle phobia, the patient declined treatment with lanadelumab or icatibant. Therefore, documentation of treatment response to standard HAE therapeutics could not initially be obtained for this patient, causing considerable challenges in acquiring long-term insurance coverage for treatment. From the fall of 2020 through February 2021, the patient continued to have 2 to 3 swelling attacks per month. During this time, we were able to offer the patient oral treatment with berotralstat, a plasma kallikrein inhibitor that was approved as a once-daily prophylactic therapy to prevent HAE attacks in patients 12 years and older by the Food and Drug Administration in December 2020.9US Food and Drug Administration. ORLADEYO (berotralstat) capsules, for oral use. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214094s000lbl.pdf. Accessed September 14, 2021.Google Scholar During the first 2 to 3 weeks of berotralstat therapy, the patient reported experiencing mild to moderate upset stomach and diarrhea, which were self-resolving and managed by taking the medication with food. Follow-up of the patient after 6 months of berotralstat treatment indicated that her HAE was well-controlled with no breakthrough swelling attacks since starting berotralstat. The patient also reported a noticeable improvement in her anxiety levels because berotralstat prophylaxis reassured her that she would be much less likely to need injectable medication for on-demand or abortive HAE therapy. On the basis of our findings, berotralstat may benefit other patients with HAE-nl-C1-INH and needle phobia. Medical writing support was provided by Jennifer Shepherd, PhD, Porterhouse Medical Group and funded by BioCryst Pharmaceuticals, Inc, Durham, North Carolina, United States, in accordance with good publication practice guidelines.

AMWA, EMWA, and ISMPP Promote Ethical, Professional Medical Writing in JAMA Oncology Letter to the Editor

In March 2021, Del Paggio et al. published an article in JAMA Oncology that included disparaging comments about medical writers. American Medical Writers Association (AMWA) leaders, in partnership with representatives from the European Medical Writers Association (EMWA) and the International Society for Medical Publication Professionals (ISMPP), immediately and swiftly drafted and submitted a letter of response to this article, which was published on August 26, 2021, along with 2 other letters and the authors‘ response to all 3 letters. Del Paggio et al.’s article reported on multiple aspects of randomized clinical trials in oncology, including the use of professional medical writers. Specifically, the authors stated, “There is reason to be concerned that medical writers may unduly influence the interpretation of trials, … as it is unlikely that medical writers have a neutral effect on the clinical trial reporting.” Although we all share an understanding of the value of medical writers, it is imperative that we respond publicly to these attacks to safeguard the reputation of our profession. As highlighted in our letter, the use of our profession’s expertise improves accuracy, timeliness, and adherence to ethical conduct. Evidence from independent research on the benefits of working with medical writers was included in the response. The commitment of medical writers to adhere to Good Publication Practice (GPP3) guidelines and to ethical principles in scientific publishing as well as to the professional codes of conduct of their professional organizations was also identified as a significant benefit of working with professional medical writers. 

Effectiveness of Sodium Zirconium Cyclosilicate in Hemodialysis Patients With Severe Hyperkalemia

Severe hyperkalemia is often defined as predialysis serum potassium (sK+) concentration ≥6.0 mmol/l and is associated with a greater risk of hospitalization, major adverse cardiovascular events, and all-cause mortality versus referent predialysis sK+ concentrations.1Einhorn L.M. Zhan M. Hsu V.D. et al.The frequency of hyperkalemia and its significance in chronic kidney disease.Arch Intern Med. 2009; 169: 1156-1162https://doi.org/10.1001/archinternmed.2009.132Crossref PubMed Scopus (397) Google Scholar,2Karaboyas A. Zee J. Brunelli S.M. et al.Dialysate potassium, serum potassium, mortality, and arrhythmia events in hemodialysis: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS).Am J Kidney Dis. 2017; 69: 266-277https://doi.org/10.1053/j.ajkd.2016.09.015Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar Several approaches are available for managing potassium homeostasis in hemodialysis patients.3Pun P.H. Middleton J.P. Dialysate potassium, dialysate magnesium, and hemodialysis risk.J Am Soc Nephrol. 2017; 28: 3441-3451https://doi.org/10.1681/ASN.2017060640Crossref PubMed Scopus (32) Google Scholar A challenge in selecting an appropriate dialysate potassium concentration is balancing removal of potassium to avoid hyperkalemia while minimizing the risk of adverse events associated with lowering potassium too rapidly. The use of nondialytic measures, such as potassium binders during the interdialytic period, to improve potassium homeostasis decreases the need to expose patients to a dialysate with low potassium concentrations.3Pun P.H. Middleton J.P. Dialysate potassium, dialysate magnesium, and hemodialysis risk.J Am Soc Nephrol. 2017; 28: 3441-3451https://doi.org/10.1681/ASN.2017060640Crossref PubMed Scopus (32) Google Scholar Sodium zirconium cyclosilicate (SZC) is a novel, highly selective potassium binder that preferentially captures potassium in the gastrointestinal lumen, increasing potassium fecal excretion and thereby reducing sK+ concentration.4Stavros F. Yang A. Leon A. Nuttall M. Rasmussen H.S. Characterization of structure and function of ZS-9, a K+ selective ion trap.PLoS One. 2014; 9e114686https://doi.org/10.1371/journal.pone.0114686Crossref PubMed Scopus (97) Google Scholar,5Kosiborod M. Rasmussen H.S. Lavin P. et al.Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial.JAMA. 2014; 312: 2223-2233Crossref PubMed Scopus (228) Google Scholar The phase IIIb DIALIZE study (NCT03303521) revealed that SZC is an effective and well-tolerated treatment for hyperkalemia in patients with end-stage kidney disease undergoing maintenance hemodialysis.6Fishbane S. Ford M. Fukagawa M. et al.A phase 3b, randomized, double-blind, placebo-controlled study of sodium zirconium cyclosilicate for reducing the incidence of predialysis hyperkalemia.J Am Soc Nephrol. 2019; 30: 1723-1733https://doi.org/10.1681/ASN.2019050450Crossref PubMed Scopus (52) Google Scholar Here, we report the results of a post hoc analysis of DIALIZE that assessed the efficacy of SZC versus placebo in patients with severe hyperkalemia (predialysis sK+ concentration ≥6.0 mmol/l) at baseline. In DIALIZE, at baseline (visit 1, day −7), 88 patients (SZC n = 46, placebo n = 42) had predialysis sK+ concentration ≥6.0 mmol/l and 106 patients (SZC n = 49, placebo n = 57) had predialysis sK+ concentration <6.0 mmol/l (Supplementary Results and Supplementary Table S1). Treatment responders were defined as patients who, during the 4-week evaluation period, maintained target predialysis sK+ concentration for ≥3 of 4 hemodialysis treatments after the long interdialytic interval (LIDI) and did not require rescue therapy to lower sK+ concentration. Among patients with baseline severe hyperkalemia, the proportions of treatment responders were significantly greater with SZC versus placebo using target predialysis sK+ ranges of 4.0 to 5.0 mmol/l (34.8% vs. 0%, respectively; Figure 1a) and an extended range of 4.0 to 5.5 mmol/l (67.4% vs. 19.0%, respectively; Figure 1b) (both P < 0.0001 for SZC vs. placebo). For patients receiving SZC, there was no statistical difference between baseline predialysis sK+ ≥6.0 mmol/l versus <6.0 mmol/l subgroups in responder rates using a target predialysis sK+ range of 4.0 to 5.0 mmol/l (34.8% vs. 46.9%, respectively; P = 0.2974) and an extended range of 4.0 to 5.5 mmol/l (67.4% vs. 71.4%, respectively; P = 0.8239). In the baseline severe hyperkalemia subgroup, the proportions of patients achieving target predialysis sK+ ranges at ≥1, ≥2, ≥3, and 4 LIDI visits in the 4-week evaluation period were greater with SZC versus placebo at both target predialysis sK+ ranges (Figure 2a and b ). In the baseline severe hyperkalemia subgroup, 17.4% and 47.8% of patients receiving SZC achieved target predialysis sK+ ranges of 4.0 to 5.0 mmol/l and 4.0 to 5.5 mmol/l at all 4 LIDI visits, respectively, versus 0% and 2.4% of patients receiving placebo, respectively (Figure 2a and b). Logistic regression analysis indicated that differences in the proportions of patients achieving target predialysis sK+ ranges at ≥1, ≥2, ≥3, and 4 LIDI visits were significant for SZC versus placebo, based on 95% CIs not crossing 0% (Figure 2a and b).Figure 2Proportions of patients with target predialysis sK+ range of (a) 4.0 to 5.0 mmol/l and (b) 4.0 to 5.5 mmol/l at ≥1, ≥2, ≥3, and 4 LIDI visits and corresponding mean sK+ concentrations, by baseline predialysis sK+ subgroup. Visit 1 (day −7) predialysis sK+ measurement was used as baseline. Only sK+ data from LIDI visits during the evaluation period (days 36, 43, 50, and 57) were used. Patients who received rescue therapy were included. Percentages were calculated for each treatment arm using the number of patients in each predialysis sK+ subgroup at baseline as the denominator; no imputation of missing data was conducted. sK+ concentrations are overall mean (SD) for patients with target predialysis sK+ range at ≥1, ≥2, ≥3, or 4 LIDI visits. LIDI, long interdialytic interval; sK+, serum potassium; SZC, sodium zirconium cyclosilicate.View Large Image Figure ViewerDownload Hi-res image Download (PPT) With both SZC and placebo, mean predialysis sK+ concentrations over the LIDI visits in the 4-week evaluation period were numerically greater for patients with baseline predialysis sK+ ≥6.0 mmol/l than those with <6.0 mmol/l. Mean predialysis sK+ concentrations were consistently and significantly lower with SZC versus placebo in both baseline predialysis sK+ subgroups (P < 0.0001 for SZC versus placebo at each LIDI visit) (Supplementary Figure S1). The frequency of predialysis hypokalemia (sK+ <3.5 mmol/l) was low overall (Supplementary Table S3). The proportions of patients with hypokalemia were numerically higher with SZC in the baseline predialysis sK+ <6.0 mmol/l subgroup than ≥6.0 mmol/l subgroup (Supplementary Table S3). To the best of our knowledge, this is the first assessment of the efficacy of a potassium binder in maintenance hemodialysis patients with severe hyperkalemia (predialysis sK+ concentration ≥6.0 mmol/l) based on data from a randomized controlled trial. Among the patients with severe hyperkalemia, the rates of treatment response were significantly greater with SZC versus placebo, regardless of target predialysis sK+ range used (i.e., 4.0–5.0 mmol/l or 4.0–5.5 mmol/l). Among the patients receiving placebo with severe hyperkalemia, mean predialysis sK+ concentrations over 4 weeks remained at approximately 6.0 mmol/l, indicating without additional strategies these patients continued to be at risk of persistent severe hyperkalemia and associated adverse events.1Einhorn L.M. Zhan M. Hsu V.D. et al.The frequency of hyperkalemia and its significance in chronic kidney disease.Arch Intern Med. 2009; 169: 1156-1162https://doi.org/10.1001/archinternmed.2009.132Crossref PubMed Scopus (397) Google Scholar,2Karaboyas A. Zee J. Brunelli S.M. et al.Dialysate potassium, serum potassium, mortality, and arrhythmia events in hemodialysis: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS).Am J Kidney Dis. 2017; 69: 266-277https://doi.org/10.1053/j.ajkd.2016.09.015Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar Among SZC-treated patients, the extended predialysis sK+ range of 4.0 to 5.5 mmol/l reduced the impact of severe hyperkalemia on the efficacy outcomes evaluated. Findings from the treatment responder analysis indicate that some SZC-treated patients had reductions from baseline in predialysis sK+ concentration but were not deemed as responders using the target predialysis sK+ range of 4.0 to 5.0 mmol/l because their sK+ concentration was between 5.0 mmol/l and 5.5 mmol/l. Nevertheless, the extended predialysis sK+ range of 4.0 to 5.5 mmol/l reflects one deemed to be acceptable in clinical practice, while avoiding concentrations >5.5 mmol/l associated with increased hospitalization and mortality.2Karaboyas A. Zee J. Brunelli S.M. et al.Dialysate potassium, serum potassium, mortality, and arrhythmia events in hemodialysis: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS).Am J Kidney Dis. 2017; 69: 266-277https://doi.org/10.1053/j.ajkd.2016.09.015Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar These findings suggest that, among hemodialysis patients with severe hyperkalemia, SZC lowers and maintains predialysis sK+ concentrations to a clinically acceptable range in most patients over 4 weeks. The frequency of predialysis hypokalemia events was low overall and generally comparable for SZC and placebo. The events of postdialysis hypokalemia were numerically greater with SZC versus placebo, and among the baseline predialysis sK+ <6.0 mmol/l versus ≥6.0 mmol/l subgroups, consistent with the potassium-lowering effects of SZC in addition to hemodialysis and the smaller reduction in sK+ required to meet the hypokalemia threshold, respectively. A challenging aspect of hyperkalemia management is the lack of a standardized definition for the grading of severity.7Alfonzo A. Harrison A. Baines R. Chu A. Mann S. MacRury M. Clinical practice guidelines: treatment of acute hyperkalaemia in adults. The Renal Association.https://ukkidney.org/sites/renal.org/files/RENAL%20ASSOCIATION%20HYPERKALAEMIA%20GUIDELINE%202020.pdfGoogle Scholar,8Clase C.M. Carrero J.J. Ellison D.H. et al.Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference.Kidney Int. 2020; 97: 42-61https://doi.org/10.1016/j.kint.2019.09.018Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar Collectively, there is consensus to immediately assess and treat patients with severe hyperkalemia.7Alfonzo A. Harrison A. Baines R. Chu A. Mann S. MacRury M. Clinical practice guidelines: treatment of acute hyperkalaemia in adults. The Renal Association.https://ukkidney.org/sites/renal.org/files/RENAL%20ASSOCIATION%20HYPERKALAEMIA%20GUIDELINE%202020.pdfGoogle Scholar,8Clase C.M. Carrero J.J. Ellison D.H. et al.Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference.Kidney Int. 2020; 97: 42-61https://doi.org/10.1016/j.kint.2019.09.018Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar The recent Renal Association Clinical Practice Guidelines on Hemodialysis recommend maintaining a predialysis sK+ concentration range of 4.0 to 6.0 mmol/l,9Ashby D. Borman N. Burton J. et al.Renal Association clinical practice guideline on haemodialysis.BMC Nephrol. 2019; 20: 379https://doi.org/10.1186/s12882-019-1527-3Crossref PubMed Scopus (46) Google Scholar as a sK+ concentration ≥6.0 mmol/l is associated with a greater risk of hospitalization and all-cause mortality.1Einhorn L.M. Zhan M. Hsu V.D. et al.The frequency of hyperkalemia and its significance in chronic kidney disease.Arch Intern Med. 2009; 169: 1156-1162https://doi.org/10.1001/archinternmed.2009.132Crossref PubMed Scopus (397) Google Scholar Nevertheless, the increased rates of hospitalization and mortality associated with predialysis sK+ concentration >5.5 mmol/l2Karaboyas A. Zee J. Brunelli S.M. et al.Dialysate potassium, serum potassium, mortality, and arrhythmia events in hemodialysis: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS).Am J Kidney Dis. 2017; 69: 266-277https://doi.org/10.1053/j.ajkd.2016.09.015Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar challenge the use of a target of 6.0 mmol/l. In our analysis, nearly two-thirds of hemodialysis patients with severe hyperkalemia receiving SZC achieved a target predialysis sK+ concentration range of 4.0 to 5.5 mmol/l for ≥3 of 4 hemodialysis treatments after the LIDI and will be expected to be at lower risk of adverse events associated with higher predialysis sK+ concentrations. These analyses have limitations. The analyses are post hoc and were not prespecified; therefore, the results are exploratory. Patient numbers within each predialysis sK+ subgroup were small and not powered to investigate treatment associations, which limits the interpretation of our findings. Finally, we did not evaluate the impact of severe hyperkalemia on safety outcomes, such as cardiovascular events. Regarding this point, the DIALIZE-Outcomes study (EudraCT 2020-005561-14) will evaluate the effect of SZC on arrhythmia-related cardiovascular outcomes among chronic hemodialysis patients with recurrent hyperkalemia (predialysis sK+ concentration ≥5.5 mmol/l). In conclusion, these post hoc findings suggest that SZC could be an effective addition to maintenance hemodialysis in reducing predialysis sK+ concentration in patients with end-stage kidney disease and severe hyperkalemia who are at high risk of adverse events. The extended target predialysis sK+ range of 4.0 to 5.5 mmol/l seemed to negate the impact of severe hyperkalemia. Evidence of the effectiveness of SZC in this subgroup of DIALIZE has clinical relevance and potential applicability beyond the tight confines of a clinical trial setting. MF reports receiving travel support from Amgen and AstraZeneca and serving as an advisory board member for AstraZeneca. SF reports receiving research support and consulting fees from AstraZeneca. BS reports receiving research grants, lecture fees, and/or consulting fees from AstraZeneca, Akebia, Reata Pharmaceuticals, and Fresenius Medical Care. AR reports receiving research or travel support from and/or is a speaker, consultant, or advisory board member for AstraZeneca, Vifor Pharma, Fresenius Medical Care, Sanofi, Kadmon, AMAG, Otsuka, Genzyme, GlaxoSmithKline, Omeros, Janssen, Reata Pharmaceuticals, Ironwood, and Amgen. NG reports being an employee of AstraZeneca. KM reports being an academic grant holder and an advisory board member for AstraZeneca. The primary DIALIZE study and this post hoc analysis were supported by AstraZeneca . The authors thank the patients, their families, and all investigators involved in the DIALIZE study, the dialysis services and research staff in each participating center, and the following members of the data monitoring committee: David Charytan, MD, Charles Herzog, MD, and David Wheeler, MD. Medical writing support was provided by Shaun W. Foley, BSc (Hons) CMPP, and editorial support was provided by Sinead Stewart, both of Core, London, UK, supported by AstraZeneca according to Good Publication Practice guidelines (https://www.acpjournals.org/doi/10.7326/M15-0288). The sponsor was involved in the study design; collection, analysis, and interpretation of data; and data checking of information provided in the manuscript. Ultimate responsibility for opinions, conclusions, and data interpretation lies with the authors. Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data-sharing policy described at https://astrazenecagroup-dt.pharmacm.com/DT/Home. All authors contributed to the data interpretation, critically reviewed the manuscript, approved the final version, and accept accountability for the overall work. Download .pdf (.33 MB) Help with pdf files Supplementary File (PDF) Supplementary Methods. Supplementary Results. Supplementary References. Table S1. Baseline patient characteristics by baseline predialysis sK+ subgroup (<6.0 mmol/l and ≥6.0 mmol/l). Table S2. Doses of SZC and placebo at the end of the dose titration period, by baseline predialysis sK+ subgroup (<6.0 mmol/l and ≥6.0 mmol/l). Table S3. Events of pre- and post-dialysis hypokalemia (sK+ <3.5 mmol/l), by baseline predialysis sK+ subgroup (<6.0 mmol/l and ≥6.0 mmol/l). Figure S1. Mean predialysis sK+ concentrations at LIDI visits during the 4-week evaluation period by treatment arm and baseline predialysis sK+ subgroup (≥6.0 mmol/l and <6.0 mmol/l). STROBE Statement (PDF)

Economic impact of abrocitinib monotherapy and combination therapy in patients with moderate-to-severe atopic dermatitis: Results from JADE MONO-2 and JADE COMPARE

To the Editor: Atopic dermatitis (AD) places a substantial financial burden on patients and society.1Drucker A.M. Wang A.R. Li W.Q. Sevetson E. Block J.K. Qureshi A.A. The burden of atopic dermatitis: summary of a report for the National Eczema Association.J Invest Dermatol. 2017; 137: 26-30Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar Abrocitinib, a once-daily oral selective Janus kinase 1 inhibitor in development for moderate-to-severe AD, was effective and well tolerated in patients with moderate-to-severe AD as monotherapy (JADE MONO-2 [NCT03575871])2Silverberg J.I. Simpson E.L. Thyssen J.P. et al.Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: a randomized clinical trial.JAMA Dermatol. 2020; 156: 863-873Crossref PubMed Scopus (84) Google Scholar or in combination with topical therapy (JADE COMPARE [NCT037204700]).3Thaci T, Bieber T, Simpson EL, et al. A phase 3 study to investigate the efficacy and safety of abrocitinib and dupilumab in comparison with placebo in adults with moderate-to-severe atopic dermatitis. Paper presented at: 29th EADV Congress (Virtual); October 28-November 1, 2020. Poster P0207.Google Scholar However, the economic impact of abrocitinib in terms of direct health care costs and indirect costs remains unknown. This preliminary post hoc economic analysis examined short-term direct and indirect cost reductions, from health care payer and societal perspectives, respectively, associated with abrocitinib (200 mg and 100 mg) treatment versus dupilumab or placebo in patients with moderate-to-severe AD. Outcomes included the number of physician visits in the past 3 months from JADE COMPARE and the overall work impairment (ie, absenteeism and presenteeism measured using the Work Productivity and Activity Impairment Questionnaire: Atopic Dermatitis, Version 2.0) from JADE MONO-2. Physician cost savings (annualized, mean per patient) were based on the reduction in physician visit frequency from baseline to week 16 multiplied by the physician visit unit cost ($265 [2016]).4Machlin S.R. Mitchell E.M. Statistical brief #517: expenses for office-based physician visits by specialty and insurance type, 2016. Agency for Healthcare Research and Quality, 2018https://meps.ahrq.gov/data_files/publications/st517/stat517.shtmlDate accessed: February 8, 2021Google Scholar Indirect cost savings were estimated based on the reduction in the overall work impairment1Drucker A.M. Wang A.R. Li W.Q. Sevetson E. Block J.K. Qureshi A.A. The burden of atopic dermatitis: summary of a report for the National Eczema Association.J Invest Dermatol. 2017; 137: 26-30Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar from baseline to week 12 and multiplied by the annual median wage in the United States ($49,348 [the first quarter of 2020]).5US Bureau of Labor Statistics Usual weekly earnings of wage and salary workers. First quarter 2020. US Department of Labor, 2020https://www.bls.gov/news.release/pdf/wkyeng.pdfDate accessed: February 8, 2021Google Scholar The demographic and baseline characteristics were similar among the patients in JADE COMPARE (n = 837)3Thaci T, Bieber T, Simpson EL, et al. A phase 3 study to investigate the efficacy and safety of abrocitinib and dupilumab in comparison with placebo in adults with moderate-to-severe atopic dermatitis. Paper presented at: 29th EADV Congress (Virtual); October 28-November 1, 2020. Poster P0207.Google Scholar and JADE MONO-2 (n = 391).2Silverberg J.I. Simpson E.L. Thyssen J.P. et al.Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: a randomized clinical trial.JAMA Dermatol. 2020; 156: 863-873Crossref PubMed Scopus (84) Google Scholar Of the included patients, 720 in JADE COMPARE (abrocitinib 200 mg, n = 196; abrocitinib 100 mg, n = 204; dupilumab injection 300 mg, n = 211; and placebo, n = 109) had physician visit data, and 347 patients in JADE MONO-2 (abrocitinib 200 mg, n = 138; abrocitinib 100 mg, n = 139; and placebo, n = 70) completed the Work Productivity and Activity Impairment-AD questionnaires. The patients treated with abrocitinib (200 mg and 100 mg), dupilumab, or placebo in JADE COMPARE reported similar decreases in the mean number of physician visits from the baseline (mean [SD], 2.8 [3.4], 3.0 [5.0], 2.8 [3.1], and 3.0 [3.4], respectively) to week 16 (mean [SD], 0.9 [2.3], 1.0 [2.3], 1.3 [2.8], and 1.6 [2.6], respectively; Table I). The patients treated with abrocitinib (200 mg or 100 mg) in JADE MONO-2 reported a greater reduction in overall work impairment at week 12 versus placebo (least squares mean change from baseline [95% CI], −22.9 [−28.2, −17.6] or −18.7 [−23.4, −14.0] versus −5.0 [−12.8, 2.8], respectively; Fig 1). The estimated annualized indirect/direct (total) cost reductions from baseline in patients who received abrocitinib 200 mg or abrocitinib 100 mg versus placebo were $11,301/$1636 ($12,937) and $9228/$1723 ($10,951), respectively.Table IPhysician visits in JADE COMPARE at week 16Study periodAbrocitinib200 mg QD n = 226Abrocitinib100 mg QD n = 238Dupilumab300 mg Q2W n = 242Placebo n = 131Baseline n224237236129 Mean (SD)2.8 (3.4)3.0 (5.0)2.8 (3.1)3.0 (3.4)Week 16 n196204211109 Mean (SD)0.9 (2.3)1.0 (2.3)1.3 (2.8)1.6 (2.6)Allowed medicated topical therapies included low- or medium-potency topical corticosteroids, topical calcineurin inhibitors, and topical phosphodiesterase-4 inhibitors.QD, Once daily; Q2W, every 2 weeks; SD, standard deviation. Open table in a new tab Allowed medicated topical therapies included low- or medium-potency topical corticosteroids, topical calcineurin inhibitors, and topical phosphodiesterase-4 inhibitors. QD, Once daily; Q2W, every 2 weeks; SD, standard deviation. This preliminary economic analysis suggests that, although all patients in JADE COMPARE reported a similar decrease in physician visits, abrocitinib (200 mg and 100 mg) was associated with greater improvements in overall work impairment and associated costs versus placebo, as demonstrated in JADE MONO-2. The limitations of this economic analysis include not accounting for other health care costs and the extrapolation from short-term periods to annual costs, particularly since treatment nonresponders would likely be switched to another therapy in a real-world setting (thus, potentially improving their outcomes over the course of a full year). Future claims analyses can address these limitations; however, these findings represent a preliminary assessment of whether abrocitinib might provide a meaningful improvement in economic outcomes. Dr Gooderham has received grants, personal fees, honoraria, and/or nonfinancial support from Pfizer Inc , AbbVie , Amgen , Akros Pharma , Arcutis , Bristol Myers Squibb , Boehringer Ingelheim , Celgene , Dermira , Dermavant , Eli Lilly , Galderma , Janssen , Kyowa Kirin , LEO Pharma , MedImmune , Merck , Novartis , Roche , Sanofi Genzyme , Regeneron , Sun Pharma , UCB , and Bausch Health ( Valeant ). Dr Chu is an investigator for Pfizer Inc, AbbVie, Dermira, Eli Lilly, Novartis, Oneness Biotech, Regeneron, Roche, and Sanofi; a consultant for Pfizer Inc, AbbVie, Eli Lilly, Novartis, Roche, and Sanofi; a speaker for Pfizer Inc, AbbVie, Eli Lilly, Mylan, Novartis, Roche, and Sanofi; and is on advisory boards for Pfizer Inc, Mylan, Roche, and Sanofi. Drs Rojo, Valdez, Biswas, Cameron, Feeney, Encinas, Peeples-Lamirande, Cappelleri, and DiBonaventura and Ms Myers are employees and stockholders of Pfizer Inc. Editorial/medical writing support under the guidance of the authors was provided by Susanna Bae, PharmD (ApotheCom, San Francisco, CA), and Gauri Saal, MA Economics (ApotheCom, London, United Kingdom). It was funded by Pfizer Inc, New York, NY, in accordance with the Good Publication Practice (GPP3) guidelines (Ann Intern Med. 2015;163:461-464).

FRI0271 IMPACT OF HLA-B27 STATUS ON CLINICAL OUTCOMES AMONG PATIENTS WITH ANKYLOSING SPONDYLITIS TREATED WITH SECUKINUMAB

Background:Ankylosing spondylitis (AS) is strongly associated with the genetic marker HLA-B27. Approximately 80%-90% of white patients with AS express HLA-B27 compared with &lt; 8% of the general population. In patients with AS, negative HLA-B27 status is a predictor of worse response to TNFis.1The impact of HLA-B27 status on clinical efficacy of secukinumab, a fully human monoclonal antibody that selectively inhibits IL-17A, has not been studied.Objectives:To analyze the impact of HLA-B27 status on clinical outcomes at Week 16 in patients with AS treated with secukinumab vs placebo.Methods:Patients with AS were pooled from the MEASURE 1-4 studies (NCT01358175,NCT01649375,NCT02008916, andNCT02159053) and stratified by HLA-B27 status. All trials included patients who received secukinumab 150 mg every 4 weeks with or without an initial loading dose (10 mg/kg IV at Weeks 0, 2, 4 or 150 mg SC at Weeks 0, 1, 2, and 3) or placebo control. MEASURE 3 included patients receiving secukinumab 300 mg every 4 weeks following the initial IV loading dose. Efficacy at Week 16 was determined by the proportion of patients achieving ASAS20/40, ASAS5/6, ASAS partial remission, BASDAI50, ASDAS-CRP &lt; 2.1, ASDAS-CRP &lt; 1.3, and improvement in Patient Global Assessment (VAS) and total spinal/back pain (VAS) scores. In MEASURE 1, 2, and 4, quality of life (QOL) was assessed at Week 16 by the SF-36 PCS, SF-36 MCS, and ASQOL. ASAS, BASDAI, and ASDAS-CRP responses were analyzed by nonresponder imputation, and all other outcomes by mixed models for repeated measures. For hypothesis generation, outcomes at Week 16 with secukinumab vs placebo within HLA-B27 strata were compared by logistic regression analysis without adjustment for multiple comparisons.Results:Baseline characteristics were balanced across treatment groups, although more HLA-B27+ patients than HLA-B27− patients were male (71%-73% vs 43%-50%). HLA-B27+ patients receiving any dose of secukinumab were significantly more likely to achieve ASAS, BASDAI50, and ASDAS-CRP responses vs those receiving placebo (P&lt; .05; Figure 1). HLA-B27− patients receiving secukinumab 300 mg were significantly more likely to achieve ASAS40, ASAS partial remission (Figure 1A), and BASDAI50 (Figure 1B) responses than those receiving placebo (P&lt; .05). Patients receiving any dose of secukinumab were more likely to achieve ASAS5/6 and ASDAS-CRP &lt; 2.1 than those receiving placebo, regardless of HLA-B27 status (P&lt; .05; Figure 1B). All secukinumab-treated patients experienced significant improvement in Patient Global Assessment at Week 16 vs placebo, regardless of HLA-B27 status, while only HLA-B27+ patients experienced significant reduction in total spinal/back pain vs placebo (P&lt; .05; Figure 2A). Numerical improvements in QOL were observed in all patients receiving secukinumab 150 mg vs placebo; these reached significance for HLA-B27+ patients (Figure 2B).Conclusion:Secukinumab is effective in patients with AS regardless of HLA-B27 status; HLA-B27+ patients may derive increased therapeutic benefit compared with HLA-B27− patients.Reference:[1]Alazmi M, et al.Arthritis Care Res (Hoboken). 2018;70:1393-9.Acknowledgments:This study was funded by Novartis Pharmaceuticals Corporation. The authors thank Rich Karpowicz, PhD, of Health Interactions, Inc, for providing medical writing support/editorial support, which was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).Disclosure of Interests:Atul Deodhar Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau, Denis Poddubnyy Grant/research support from: AbbVie, MSD, Novartis, and Pfizer, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB, Renato Calheiros Shareholder of: Novartis, Employee of: Novartis, Xiangyi Meng Shareholder of: Novartis, Employee of: Novartis, Vibeke Strand Consultant of: AbbVie, Amgen, Biogen, Celltrion, Consortium of Rheumatology Researchers of North America, Crescendo Bioscience, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Hospira, Janssen, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, UCB, Marina Magrey Grant/research support from: AbbVie, Amgen, and UCB, Consultant of: Eli Lilly and Novartis

THU0162 LIKELIHOOD OF CLINICAL WORSENING AMONG RHEUMATOID ARTHRITIS PATIENTS WHO ACHIEVED A PARTIAL RESPONSE TO ADALIMUMAB AND WERE SUBSEQUENTLY SWITCHED TO SARILUMAB

Background: Rheumatoid arthritis (RA) patients who achieve a response to therapy but fail to reach low disease activity (LDA) or remission (partial responders) may decline treatment changes for fear of clinical worsening and losing their achieved response. Little is known about the likelihood of worsening after switching therapy in partial responders, and this limits patients’ ability to make informed treatment decisions. Objectives: This post hoc analysis of the open-label extension (OLE) of MONARCH (NCT02332590) assesses the effects of switching from adalimumab to sarilumab in patients with RA who achieved a partial response to adalimumab but not remission or LDA. Methods: MONARCH was a 24-week, head-to-head monotherapy trial comparing sarilumab with adalimumab. At study end, patients randomized to adalimumab were switched to sarilumab 200 mg q2w for the OLE. Partial responders to adalimumab were defined as patients who had improved more than the minimal clinically important difference (MCID) in the Clinical Disease Activity Index (CDAI) during MONARCH, but who continued to have moderate to high disease activity (CDAI >10) at OLE baseline (BL). MCID was defined as a CDAI decrease ≥12 from a BL CDAI >22 or ≥6 from a BL CDAI >10 to ≤22. Response following treatment switch was assessed by change in CDAI and other outcomes from OLE BL to OLE Week 24. The effect of switching was analyzed descriptively and categorized: worsening = CDAI increase ≥6; improvement = CDAI decrease ≥6; stable = CDAI absolute change Results: Of 369 patients enrolled in MONARCH, 320 (87%) entered the OLE; 155 were switched from adalimumab to sarilumab, and of these, 91 were partial responders, who had a mean (SE) CDAI at OLE BL of 19.56 (0.86). Mean (SE) improvement in CDAI from OLE BL to OLE Week 24 in these patients was 7.37 (1.10). At OLE Week 24, only 6% of adalimumab partial responders had worsened after switching to sarilumab, while 57% had improved; the remaining 37% maintained stable disease activity. Analyses of other efficacy measures—patient and physician global assessments, disease activity score 28-joint erythrocyte sedimentation rate, and swollen and tender joint counts—demonstrated similar results: improvement was seen in 27–78% and worsening in 2–17%. No new safety signals emerged during the OLE. The adverse event profile among patients switching from adalimumab to sarilumab was consistent with the established safety profile of sarilumab. Conclusion: Among adalimumab CDAI partial responders who switched to sarilumab, there was a low likelihood of clinical worsening, while more than half of such patients achieved clinically meaningful improvement. Similar results were observed for other efficacy measures. This small risk of worsening coupled with the substantial likelihood of improvement after switch may help alleviate patients’ concerns around loss of response and help inform shared decision-making. Acknowledgments: Study funding and medical writing support (Gregory Bezkorovainy, Adelphi Communications, New York) were provided by Sanofi Genzyme (Cambridge, USA) and Regeneron Pharmaceuticals, Inc. (Tarrytown, USA) in accordance with Good Publication Practice (GPP3) guidelines. Amy Praestgaard (Sanofi Genzyme employee) contributed to the statistical analysis for this abstract. Disclosure of Interests: Jeffrey Curtis Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB, Daniel Aletaha Grant/research support from: AbbVie, Novartis, Roche, Consultant of: AbbVie, Amgen, Celgene, Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi Genzyme, Speakers bureau: AbbVie, Celgene, Lilly, Merck, Novartis, Pfizer, Sanofi Genzyme, UCB, Gerd Rudiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Kerri Ford Shareholder of: Sanofi Genzyme, Employee of: Sanofi Genzyme, Hubert van Hoogstraten Shareholder of: Sanofi, Employee of: Sanofi, Henry Leher Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Karthinathan Thangavelu Shareholder of: Sanofi Genzyme, Employee of: EMD Serono, Sanofi Genzyme, Vivian Bykerk: None declared

LBA2 First-line durvalumab plus platinum-etoposide in extensive-stage (ES)-SCLC: Safety, pharmacokinetics (PK) and immunogenicity in CASPIAN

Abstract Background CASPIAN is a phase 3, open-label study of 1L platinum-etoposide (EP) ± durvalumab (D) ± tremelimumab (T) for pts with ES-SCLC. D+EP significantly improved OS vs EP alone (HR 0.73 [95% CI 0.59–0.91]; p = 0.0047) at a planned interim analysis. Rates of all-cause AEs and AEs leading to discontinuation were similar between arms. Immune-mediated AEs (imAEs) were higher with D+EP vs EP, while numerically fewer pts in the D+EP arm had serious AEs (SAEs; 30.9 vs 36.1%). Here we present further safety, PK and immunogenicity results. Methods Treatment-naive pts with ES-SCLC were randomised 1:1:1 to D 1500 mg + EP q3w, D 1500 mg + T 75 mg + EP q3w, or EP q3w. Investigator’s choice of carboplatin or cisplatin was allowed. In the IO arms, pts received 4 cycles of EP, followed by D 1500 mg q4w until progression; up to 6 cycles of EP and optional PCI were permitted in the control arm. Safety, PK and immunogenicity were secondary endpoints. Results 265 pts received D+EP and 266 received EP. Serum concentrations were within the expected range for D and were similar across both arms for EP. Of 201 anti-drug antibody (ADA)-evaluable pts in the D+EP arm, 11 (5.5%) were +ve for ADA to D at baseline only; no pts were +ve for treatment-emergent ADA or neutralising antibodies. The most common AEs, grade 3/4 AEs and SAEs in both arms were haematological toxicities. These were well managed using standard therapies per local practice; colony stimulating factor use was 50.4% in the D+EP arm and 56.9% in the EP arm, and 12.7% and 20.8% received blood transfusions. When events that coincided with cycles 5 and 6 of EP in the control arm were removed, the overall SAE rate was similar between arms (30.9% for D+EP vs 30.1% for EP). Most imAEs were low grade, endocrine-related and managed with corticosteroid or endocrine therapy; median time to onset was generally >60 days (table). Table . LBA2 D+EP (n = 265) EP (n = 266) imAE (group term) * Any grade, n (%) Grade ≥3, n (%) Median time to onset, † days (range) Any grade, n (%) Grade ≥3, n (%) Median time to onset, † days (range) Any imAE 52 (20) 13 (5) – 7 (3) 2 (1) – Hypothyroid 24 (9) 0 141 (42–283) 2 (1) 0 63 (62–64) Hyperthyroid 14 (5) 0 85.5 (22–372) 0 0 – Pneumonitis 7 (3) 2 (1) 191 (80–365) 2 (1) 2 (1) 177 (141–213) Hepatic 7 (3) 6 (2) 93 (31–256) 0 0 – Dermatitis/rash 4 (2) 0 33.5 (16–91) 2 (1) 0 31 (27–35) Diarrhoea/colitis 4 (2) 1 (0.4) 28 (9–114) 1 (0.4) 0 64 (64–64) Thyroiditis 4 (2) 0 144 (43–260) 0 0 – Type 1 diabetes 4 (2) 4 (2) 104 (38–316) 0 0 – * imAEs with incidence ≥2% in either arm are shown. † Time from first dose to onset of any grade imAEs. Conclusion In CASPIAN, the incidence of ADA to D was low and the safety profile of D+EP was consistent with previous reports of both D and EP. Clinical trial identification NCT03043872 (release date: February 6, 2017). Editorial acknowledgement Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Craig Turner, MSc, of Cirrus Communications (Macclesfield, UK), an Ashfield company, and was funded by AstraZeneca. Legal entity responsible for the study AstraZeneca PLC. Funding AstraZeneca. Disclosure M. Ozguroglu: Advisory / Consultancy, Advisory board participation: Janssen / Sanofi / Astellas; Honoraria (self): Novartis / Roche / Janssen / Sanofi / Astellas; Travel / Accommodation / Expenses: Bristol-Myers Squibb / Janssen. J.W. Goldman: Advisory / Consultancy: AstraZeneca / Genentech / Lilly; Research grant / Funding (self): AstraZeneca/MedImmune / Eli Lilly / Genentech / Bristol-Myers Squibb / Array BioPharma / Celgene / AbbVie; Speaker Bureau / Expert testimony: Merck. N. Reinmuth: Travel / Accommodation / Expenses, Personal fees and non-financial support: AstraZeneca / Boehringer-Ingelheim / Hoffmann La-Roche / Bristol-Myers Squibb / Pfizer; Non-remunerated activity/ies, Non-financial support: Abbvie; Travel / Accommodation / Expenses, Personal fees: MSD Sharp & Dohme / Takeda. Y. Chen: Research grant / Funding (self): AstraZeneca / ISPEN / Roche / Bristol-Myers Squibb; Travel / Accommodation / Expenses, Personal fees: AstraZeneca / Genentech / Bristol-Myers Squibb / Merck / Novartis / Takeda / Eli Lilly / Guardant Health / Pfizer / Array Biopharma. K. Hotta: Research grant / Funding (self), Grants and personal fees: AstraZeneca / Lilly / Bristol-Myers Squibb; Travel / Accommodation / Expenses, Personal fees: MSD / Ono / Nipponkayaku / Taiho / Boehringer-Ingelheim / Chugai. F. Verderame: Research grant / Funding (self): AstraZeneca. M. Thomas: Full / Part-time employment: AstraZeneca. Y. Zheng: Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options: AstraZeneca. A. Lloyd: Full / Part-time employment: AstraZeneca. H. Jiang: Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options: AstraZeneca. L. Paz-Ares: Leadership role, Myself: Genomica; Leadership role, Immediate family member: European Medicines Agency; Honoraria (self), Myself: Roche/Genentech, Lilly, Pfizer, Boehringer-Ingelheim, Bristol-Myers Squibb, MSD, AstraZeneca, Merck Serono, PharmaMar, Novartis, Celgene, Sysmex, Amgen, Incyte; Travel / Accommodation / Expenses, Myself: Roche, AstraZeneca, AstraZeneca Spain, Merck, MSD, Bristol-Myers Squibb, Lilly, Pfizer; Spouse / Financial dependant, Other relationship [immediate family member]: Novartis, Ipsen, Pfizer, Servier, Sanofi, Roche, Amgen, Merck. All other authors have declared no conflicts of interest.

474O - Efficacy and safety of first-line durvalumab (D) ± tremelimumab (T) vs chemotherapy (CT) in Asian patients with metastatic NSCLC: Results from MYSTIC

BackgroundIn MYSTIC, an open-label, phase 3 trial of first-line D (anti-PD-L1) ± T (anti-CTLA-4) vs CT, while not statistically significant, a clinically meaningful improvement in overall survival (OS) was seen with D vs CT in patients with tumour cell PD-L1 expression ≥25% (TC ≥ 25% [primary analysis population]; D vs CT, HR 0.76 [97.54% CI 0.56–1.02]; D+T vs CT, HR 0.85 [98.77% CI 0.61–1.17]). Here we report results in a subpopulation of Asian patients. MethodsImmunotherapy/CT-naïve patients with metastatic NSCLC were randomized (1:1:1) to D (20 mg/kg q4w); D (20 mg/kg q4w) + T (1 mg/kg q4w ≤4 doses); or CT. In this analysis in a subpopulation of Asian patients, efficacy outcomes were evaluated in patients with PD-L1 TC ≥25%; safety was evaluated in all treated patients (regardless of PD-L1 expression). ResultsOf the 488 patients in the primary analysis population (PD-L1 TC ≥25%), 156 (32%) were Asian (D, 59; D+T, 50; CT, 47). Baseline characteristics in the Asian population were balanced between treatment arms. OS was improved in Asian patients (PD-L1 TC ≥25%) with D vs CT (HR 0.69 [95% CI 0.43–1.09]) and D+T vs CT (HR 0.64 [95% CI 0.40-1.03]); more patients receiving D or D+T remained in response at 6 months vs CT (Table). Grade ≥3 treatment-related adverse events (TRAEs) and any grade TRAEs leading to discontinuation occurred in 19.7% and 9.0% (D); 23.9% and 14.5% (D+T); 23.4% and 7.2% (CT) patients in the Asian subpopulation, respectively.Table474OTableDurvalumabDurvalumab + tremelimumabChemotherapyOverall (n = 163)Asian (n = 59)Overall (n = 163)Asian (n = 50)Overall (n = 162)Asian (n = 47)Median OS, mo16.3 (12.2–20.8)18.8 (9.2–28.4)11.9 (9.0–17.7)17.7 (11.6–27.3)12.9 (10.5–15.0)10.6 (7.0–14.6)24-mo OS rate, %38.343.835.442.022.722.3OS HR vs CT (95% CI)0.76 (0.56–1.02)*0.69 (0.43–1.09)0.85 (0.61–1.17)†0.64 (0.40–1.03)––ORR, n (%)58 (35.6)19 (32.2)56 (34.4)18 (36)61 (37.7)17 (36.2)Patients remaining in response (%) at6 mo66.968.467.652.732.434.312 mo61.362.254.926.318.0NROverall and Asian populations include patients with PD-L1 TC ≥25%;.*97.54% CI; †98.77% CI; ORR occurred on June 1, 2017; DoR, duration of response; NR, not reached; ORR, objective response rate; OS, overall survival. ConclusionsDurvalumab resulted in a favourable HR for OS compared to CT in patients with PD-L1 TC≥25% in the Asian subpopulation, which was consistent with the primary analysis population. OS HR for D+T vs CT appeared to be more favourable in the Asian subpopulation compared to the primary analysis population, although results should be interpreted with caution due to small sample sizes. The safety profile of D±T in the subpopulation of Asian patients was manageable and consistent with the primary analysis population. Clinical trial identificationNCT02453282. Editorial acknowledgementMedical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Beena John, PhD of Cirrus Communications (Macclesfield, UK), an Ashfield company, and was funded by AstraZeneca. Legal entity responsible for the studyAstraZeneca. FundingAstraZeneca. DisclosureB.C. Cho: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): MOGAM Institute; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy, Research grant / Funding (institution): Ono; Advisory / Consultancy, Research grant / Funding (institution): Yuhan; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Champions Oncology; Research grant / Funding (institution): Dong-A ST; Research grant / Funding (institution): Dizal Pharma; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Takeda; Shareholder / Stockholder / Stock options: TheraCanVac Inc. K.H. Lee: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: BMS. S. Lucien Geater: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Samsung. T.V. Ngoc: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Novartis. S. Clarke: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. S. Kuyama: Speaker Bureau / Expert testimony, Lecture fees: AstraZeneca; Speaker Bureau / Expert testimony, Lecture fees: Pfizer; Speaker Bureau / Expert testimony, Lecture fees: Eli Lilly; Speaker Bureau / Expert testimony, Lecture fees: Boehringer Ingelheim; Speaker Bureau / Expert testimony, Lecture fees: MSD; Speaker Bureau / Expert testimony, Lecture fees: Taiho; Speaker Bureau / Expert testimony, Lecture fees: Chughai. K. Nakagawa: Honoraria (institution), Research grant / Funding (institution): MSD / Takeda / SymBio Pharmaceuticals / Daiichi Sankyo; Honoraria (self), Research grant / Funding (institution): Eli Lilly Japan; Honoraria (self), Research grant / Funding (institution): BMS; Honoraria (self), Research grant / Funding (institution): Taiho /Ono / Chughai; Honoraria (self), Research grant / Funding (institution): AstraZeneca / Astellas Pharma / Novartis / Nippon Boehringer Ingelheim / Pfizer Japan; Research grant / Funding (institution): Merck Serono / ICON Japan /PAREXEL / IQVIA Services Japan / A2 Healthcare / AbbVie; Research grant / Funding (institution): EP-CRSU / Linical / Otsuka Pharmaceuticals / EPS International / Quintiles / CMIC Shift Zero / Eisai / Kissei Pharmaceutical ; Research grant / Funding (institution): Kyowa Hakko Kirin / EPS Corporation / Bayer Yakuhin / inVentiv Health Japan / Gritstone Oncology / GSK / Yakult Honsha / Covance ; Honoraria (self): Kyorin Pharmaceutical / CareNet / Nichi-Iko Pharmaceutical / Hisamitsu Pharmaceutical / Yodosha / Clinical Trial / Reno Medical / Nanzando / Medical Review; Honoraria (self): Medicus Shuppan / Ayumi Pharmaceutical / Thermo Fisher Scientific / Yomiuri Telecasting Corporation / Nikkei Business Publications. F. Liu: Full / Part-time employment, Full-time employee: AstraZeneca. D. Clemett: Full / Part-time employment, Full-time employee: AstraZeneca. U. Scheuring: Full / Part-time employment, Full-time employee: AstraZeneca. S. Peters: Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca / Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer / Seattle Genetics and Takeda; Honoraria (self), Advisory / Consultancy: Biocartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Clovis; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo / Regeneron / Sanofi; Honoraria (self), Advisory / Consultancy: Debiopharm; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): F Hoffmann-La Roche; Honoraria (self), Advisory / Consultancy: Foundation Medicine; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Illumina; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Honoraria (self), Advisory / Consultancy: Merrimack; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Pharma Mar. N. Rizvi: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Lilly; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Regeneron; Advisory / Consultancy: Janssen; Leadership role, Shareholder / Stockholder / Stock options: ARMO BioSciences; Shareholder / Stockholder / Stock options: Gritstone Oncology. All other authors have declared no conflicts of interest.

322P - Three-year overall survival update from the PACIFIC trial

BackgroundIn the phase 3 PACIFIC study of patients with unresectable, Stage III NSCLC without progression after chemoradiotherapy (CRT), durvalumab demonstrated significant improvements versus placebo in the primary endpoints of progression-free survival (HR, 0.52; 95% CI, 0.42–0.65; P < 0.0001) and overall survival (OS; HR, 0.68; 95% CI, 0.53–0.87; P = 0.00251). Safety was similar and durvalumab had no detrimental effect on patient-reported outcomes. Here, we report 3-year OS rates for all patients randomized in the PACIFIC study. MethodsPatients with WHO PS 0/1 (any tumor PD-L1 status) who received ≥2 cycles of platinum-based CRT were randomized (2:1), 1–42 days following CRT, to receive durvalumab 10 mg/kg intravenously every 2 weeks or placebo, up to 12 months, and stratified by age, sex, and smoking history. OS was analyzed using a stratified log-rank test in the ITT population. Medians and OS rates at 12, 24 and 36 months were estimated by Kaplan-Meier method. ResultsIn total, 713 patients were randomized of whom 709 received treatment (durvalumab, n = 473; placebo, n = 236). The last patient had completed the protocol-defined 12 months of study treatment in May 2017. As of January 31, 2019 (data cutoff), 48.2% of patients had died (44.1% and 56.5% in the durvalumab and placebo groups, respectively). The median duration of follow-up was 33.3 months (range, 0.2–51.3). Updated OS remained consistent with that previously reported (stratified HR 0.69, 95% CI, 0.55–0.86), with the median not reached (NR; 95% CI, 38.4 months–NR) with durvalumab versus 29.1 months (95% CI, 22.1–35.1) with placebo. The 12-, 24- and 36-month OS rates with durvalumab and placebo were 83.1% versus 74.6%, 66.3% versus 55.3%, and 57.0% versus 43.5%, respectively. After discontinuation, 43.3% and 57.8% in the durvalumab and placebo groups, respectively, received subsequent anticancer therapy (9.7% and 26.6% subsequently received immunotherapy). OS subgroup results will be presented. ConclusionsUpdated OS data from PACIFIC, including 3-year survival rates, underscore the long-term clinical benefit with durvalumab following CRT and further establish the PACIFIC regimen as the standard of care in this population. Clinical trial identificationNCT02125461. Editorial acknowledgementMedical writing support during the preparation of this abstract, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Hashem Dbouk, of Cirrus Communications (Macclesfield, UK), an Ashfield company, and was funded by AstraZeneca. Legal entity responsible for the studyAstraZeneca. FundingAstraZeneca. DisclosureY-L. Wu: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self): Sanofi; Advisory / Consultancy: Merck; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim. J.E. Gray: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genentech; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Triptych Health Partners; Research grant / Funding (institution): Array; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Epic Sciences; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Trovagene; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Blueprint; Research grant / Funding (institution): Novartis. A. Villegas: Honoraria (self): AstraZeneca; Honoraria (self): Seattle Genetics. D.B. Daniel: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): E R Squibb & Sons; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Roche; Research grant / Funding (institution): E1 Therapeutics. D. Vicente: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Roche. S. Murakami: Research grant / Funding (institution): Takeda; Honoraria (self): AstraZeneca; Honoraria (self): Chugai; Honoraria (self): Ono; Honoraria (self): Merck Sharp and Dohme. R. Hui: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb. T. Kurata: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Ono; Honoraria (self), Research grant / Funding (institution): Bristol Myers Squibb; Honoraria (self), Research grant / Funding (institution): Chugai; Honoraria (self): Lilly; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): MSD. A. Chiappori: Speaker Bureau / Expert testimony: Genentech; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Speaker Bureau / Expert testimony: Boehringer Ingelheim; Speaker Bureau / Expert testimony: Celgene; Research grant / Funding (institution): Bristol Myers Squibb. B.C. Cho: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): MOGAM Institute; Research grant / Funding (institution): Dong-A ST; Research grant / Funding (institution): Champions Oncology; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Yuhan; Advisory / Consultancy, Research grant / Funding (institution): Ono; Research grant / Funding (institution): Dizal Pharma; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Takeda; Shareholder / Stockholder / Stock options: TheraCanVac Inc. D. Planchard: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: BMS; Advisory / Consultancy: Celgene; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: prIME Oncology; Advisory / Consultancy: PeerCME. L. Paz-Ares: Leadership role: Genomica; Honoraria (self), Travel / Accommodation / Expenses, Spouse / Financial dependant: Roche; Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: MSD; Honoraria (self), Travel / Accommodation / Expenses: BMS; Honoraria (self), Travel / Accommodation / Expenses: Lilly; Honoraria (self), Travel / Accommodation / Expenses, Spouse / Financial dependant: Pfizer; Honoraria (self): Merck Serono; Honoraria (self): Pharma Mar; Honoraria (self), Spouse / Financial dependant: Novartis; Honoraria (self): Celgene; Honoraria (self): Sysmex; Honoraria (self), Spouse / Financial dependant: Amgen; Honoraria (self): Incyte; Spouse / Financial dependant: Ipsen; Spouse / Financial dependant, Leadership Role: European Medicines Agency; Spouse / Financial dependant: SERVIER; Spouse / Financial dependant: Sanofi; Spouse / Financial dependant: Merck. C. Faivre-Finn: Advisory / Consultancy, Speaker Bureau / Expert testimony, To institution: AstraZeneca. J.F. Vansteenkiste: Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Eli-Lilly; Honoraria (self): Apotex; Honoraria (self): Roche. M. Taboada: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. P.A. Dennis: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. M. Özgüroğlu: Advisory / Consultancy: Janssen. S.J. Antonia: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy: Memgen; Advisory / Consultancy, Travel / Accommodation / Expenses: FLX Bio; Honoraria (self), Shareholder / Stockholder / Stock options: CBMG. All other authors have declared no conflicts of interest.

201P - Efficacy and safety of darolutamide in non-metastatic castration-resistant prostate cancer (nmCRPC) in the ARAMIS trial

BackgroundAsymptomatic nmCRPC patients (pts) would benefit from treatments (Tx) that delay disease progression and maintain quality of life (QoL), with minimal Tx-related adverse events (AEs). In ARAMIS, darolutamide (DARO) prolonged metastasis-free survival vs placebo (PBO) (40 vs 18 months; HR 0.41; 95% CI 0.34–0.50; P < 0.001); impact on prostate-specific antigen (PSA), disease progression, safety, and QoL in ARAMIS is reported here. MethodsPts were randomized to DARO 600 mg twice daily (n = 955) or PBO (n = 554), while androgen deprivation therapy continued in both arms. Secondary/exploratory endpoints included safety, time to cytotoxic chemotherapy, time to antineoplastic therapy, time to PSA progression, and QoL. ResultsDARO substantially delayed times to PSA progression (33 vs 7 months; HR 0.13; 95% CI 0.11–0.16; P < 0.001), cytotoxic chemotherapy (not reached [NR] vs 38 months; HR 0.43; 95% CI 0.31–0.60; P < 0.001), and antineoplastic therapy (NR vs NR; HR 0.33; 95% CI 0.23–0.47; P < 0.001) vs PBO. The distribution of sites of distant metastases was similar between groups: 60/130 (46%) and 62/158 (39%) had bone-only metastases, 41/130 (32%) and 63/158 (40%) had lymph node-only metastases, while 17/130 (13%) and 22/158 (14%) had both lymph node and bone metastases, in the DARO and PBO groups, respectively. Distant metastases at other sites were also similar, occurring in 12/130 (9%) and 11/158 (7%) of pts in the DARO and PBO groups, respectively. Incidences of Tx-emergent AEs with ≥5% frequency or of grade 3–5 were comparable between DARO and PBO; none except fatigue occurred in > 10% of pts. Discontinuation rates due to AEs were 8.9% with DARO and 8.7% with PBO. AEs noted with other androgen receptor inhibitors (including fracture, falls, seizures, hypertension and cognitive disorder) showed minimal or no difference in incidence between groups. DARO maintained QoL, and delayed the onset of pain and disease-related urinary symptoms compared with PBO. ConclusionsDARO delays disease progression and subsequent Tx for metastatic castration-resistant prostate cancer vs PBO, maintaining QoL without increasing incidence of key AEs. Clinical trial identificationNCT02200614. Editorial acknowledgementMedical writing support for the development of this abstract was provided by Lucy Smithers, PhD, and editorial support, including formatting, proofreading, and submission was provided by Beth King, both of Scion Medica, London, supported by Bayer according to Good Publication Practice guidelines. Legal entity responsible for the studyOrion Corporation, Orion Pharma and Bayer AG. FundingOrion Corporation and Bayer AG. DisclosureJ.S-T. Pang: Non-remunerated activity/ies, Writing support: Bayer. N. Shore: Advisory / Consultancy, Research grant / Funding (self): Ferring; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Research grant / Funding (self): Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Dendreon; Advisory / Consultancy, Research grant / Funding (self): Tolmar; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (self): Myovant Sciences; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy, Research grant / Funding (self): BMS; Advisory / Consultancy, Research grant / Funding (self): Nymox. M.R. Smith: Honoraria (self): Amgen; Honoraria (self): Astellas; Honoraria (self): Bayer; Honoraria (self): Clovis; Honoraria (self): Gilead; Honoraria (self): Janssen; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Pfizer. T.L. Tammela: Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy: Janssen; Advisory / Consultancy, Research grant / Funding (self): Lidds AB; Advisory / Consultancy, Research grant / Funding (self): Astellas. E. Vjaters: Research grant / Funding (self): Ipsen; Research grant / Funding (self): Bayer; Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Orion. M. Jievaltas: Honoraria (self): Bayer; Honoraria (self): Ipsen; Honoraria (self): Janssen. M. Luz: Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Advisory / Consultancy, Research grant / Funding (self): Janssen; Research grant / Funding (self): AstraZeneca; Travel / Accommodation / Expenses: Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bayer; Research grant / Funding (self): Ferring; Speaker Bureau / Expert testimony: Sanofi. B. Alekseev: Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: Bayer; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: Astellas; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: BMS; Honoraria (self), Non-remunerated activity/ies: Ferring; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: Janssen; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: MSD; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: Pfizer; Research grant / Funding (self), Non-remunerated activity/ies: Sanofi. I. Kuss: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bayer. M-A. Le Berre: Full / Part-time employment: Bayer Healthcare. A. Snapir: Full / Part-time employment: Orion Pharma. T. Sarapohja: Full / Part-time employment: Orion Corporation. K. Fizazi: Honoraria (self), Advisory / Consultancy: Astellas Pharma; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self): Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Sanofi; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Curevac; Advisory / Consultancy: ESSA; Advisory / Consultancy: Orion Pharma; Advisory / Consultancy: Roche/Genentech. All other authors have declared no conflicts of interest.

131P - Cabozantinib in Asian patients with hepatocellular carcinoma and other solid tumours: Population pharmacokinetics analysis

BackgroundCabozantinib, an inhibitor of MET, AXL and VEGF receptors, was recently approved for the treatment of patients with advanced hepatocellular carcinoma (HCC) who had previously received sorafenib, based on findings of the CELESTIAL trial. We previously reported cabozantinib pharmacokinetics (PK) data based on 9 cabozantinib studies (N = 1534), Here, we report updated cabozantinib PK data in Asian and non-Asian ethnicities including patients with HCC. MethodsWe used data from ten cabozantinib studies that included healthy volunteers (HV) and patients with various cancer types (HCC, renal cell carcinoma, castration-resistant prostate cancer, medullary thyroid cancer [MTC], and glioblastoma multiforme). Studies pertinent to HCC were the CELESTIAL trial (NCT01908426) and the HCC cohort of a phase 2 trial (NCT00940225). The impact on PK parameters of selected covariates (age, weight, sex, race, cancer type, formulation, and liver dysfunction according to the National Cancer Institute Organ Dysfunction Working Group [NCI-ODWG]) was evaluated. Steady-state PK parameters were predicted for Asian and non-Asian patients. ResultsData from 2023 individuals were included (cancer patients, n = 1883; HV, n = 140), of whom 211 were of Asian ethnicity and 1812 of non-Asian ethnicity. MTC cancer type had the largest effect on cabozantinib PK parameters, with a 90% increase in apparent clearance (CL/F) relative to HV. Other cancer types, including HCC, and liver dysfunction per NCI-ODWG did not impact cabozantinib PK. However, because CELESTIAL excluded patients with Child-Pugh scores of B or C, results on patients with more compromised liver function are limited. A 24% decrease in CL/F was observed in females; Asian ethnicity, age, and weight had no clinically significant impact on cabozantinib clearance. ConclusionsMinimal cabozantinib PK and predicted exposure differences were observed across various cancer types except for MTC. The PK of cabozantinib was similar in individuals of Asian and non-Asian ethnicity. These findings are consistent with the major metabolic pathway of cabozantinib via cytochrome P450 3A4 which is not prone to genetic polymorphism. Editorial acknowledgementThe authors thank Isabelle Kaufmann, PhD of Oxford PharmaGenesis, Oxford, UK for providing medical writing support, which was sponsored by Ipsen, Abingdon, UK in accordance with Good Publication Practice guidelines. Legal entity responsible for the studyIpsen. FundingIpsen. DisclosureC-H. Hsu: Research grant/Funding (self): Ipsen; Honoraria (self): Ipsen. L. Nguyen: Full / Part-time employment: Exelixis. A-L. Cheng: Honoraria (self): Bayer; Honoraria (self): Eisai; Honoraria (self): Merck Sharp Dohme; Honoraria (self): Merck Serono; Honoraria (self): Novartis; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Roche/Genentech; Honoraria (self): IQVIA. Advisory/Consultancy: Bayer Schering Pharma; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Eisai; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Novartis; Advisory/Consultancy: Ono Pharmaceutical; Advisory/Consultancy: Exelixis; Advisory/Consultancy: Nucleix Ltd.; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: IQVIA. Speaker Bureau/Expert testimony: Bayer Yakuhin, Ltd.; Speaker Bureau/Expert testimony: Novartis; Speaker Bureau/Expert testimony: Eisai; Speaker Bureau/Expert testimony: Ono Pharmaceutical; Speaker Bureau/Expert testimony: Amgen Taiwan. Travel/Accommodation/Expenses: Bayer Yakuhin, Ltd.; Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Eisai; Travel/Accommodation/Expenses: Ono Pharmaceutical; Travel/Accommodation/Expenses: Roche/Genentech; Travel/Accommodation/Expenses: IQVIA. T.X.Q. Nguyen: Full / Part-time employment: Ipsen. K. Brendel: Full / Part-time employment: Ipsen. V. Aslanis: Full / Part-time employment: Ipsen. F. Benzaghou: Full / Part-time employment: Ipsen.

1148P - ACCURACY a phase (P) II trial of AL101, a pan-Notch inhibitor, in recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) patients (pts) with Notch activating mutations (Notch act mut): Preliminary safety and efficacy data

BackgroundNotch signaling plays a key role in tumorigenesis. AL101 is a γ-secretase inhibitor that potently inhibits signaling through Notch receptors 1-4. AL101 has robust antitumor activity in ACC patient-derived xenograft models with Notchact mut (AACR ‘19, Abstr 4885). In P1 testing, AL101 was well tolerated, with manageable AEs and a recommended P2 dose of 4mg IV QW (ASCO ‘18, Abstr 2515). One of the 4 responders in P1 had ACC with Notchact mut. ACC is a rare chemotherapy-refractory cancer of the secretory glands. Notchact mut are found in ∼20% of ACC pts, characterized by a particularly aggressive disease and poor prognosis. There is no proven active treatment for R/M ACC. MethodsACCURACY (NCT03691207) is an open-label, single-arm, multicenter study of AL101 (4mg IV QW) in R/M ACC pts (bone-exclusive disease allowed) with known Notch1-4act mut (ASCO ‘19, Abstr TPS6098). Pts with disease progression ≤6 months of enrollment or newly diagnosed metastatic disease are allowed. Primary endpoint: ORR by RECIST v1.1 (or modified MD Anderson bone criteria), by independent review committee (IRC). Secondary endpoints: ORR by investigator review (IR), duration of response by IRC and IR, PFS by IRC, OS, and safety. Per Simon optimal design, 12 pts are enrolled in stage 1; if≥2 pts respond, 24 additional pts are enrolled in stage 2. If≥6 pts of 36 respond, the trial is deemed positive. This design yields 5% type I error rate and 80% power, if ORR is 25%. ResultsIn stage 1, 12 pts are being treated (median of 1.5 cycles, as of May ‘19). Most pts are males, with ECOG PS of 0, and with Notch mutations in the PEST domain (Table).Table: 1148PDisposition and Baseline characteristics of patients treated with the investigational new drug AL101Table: 1148PScreened/Enrolled (signed consent), n18Screen failures, n6Treated, n12Median number of cycles, n1.5Gender, nMale Female8 4Median age, years56.5Race, nWhite Black Asian Other Not Reported N/A6 1 0 1 2 2ECOG performance status, n0 1 N/A6 4 2Disease status, nWith nodal or visceral metastases With bone-exclusive metastases10 2Type of mutations, nIn the NRR region In the PEST domain In the NRR and PEST regions3 6 3N/A=not available ConclusionsIn the stage 1 of the ACCURACY trial, 12 pts with Notch1-4act mut are being treated with the pan-Notch inhibitor AL101. The trial will advance to stage 2 if≥2 pts respond. Efficacy/safety data on these first 12 pts will be presented at the meeting. Accrual to stage 2 is ongoing. Clinical trial identificationNCT03691207. Editorial acknowledgementFrancesca Balordi, PhD, of The Lockwood Group (Stamford, CT, USA), in accordance with Good Publication Practice (GPP3) guidelines, funded by Ayala Pharmaceuticals, Inc. Legal entity responsible for the studyAyala Pharmaceuticals, Inc. FundingAyala Pharmaceuticals, Inc. DisclosureR. Ferrarotto: Honoraria (self), Advisory / Consultancy: Ayala Pharmaceuticals; Honoraria (self): Regeneron. A. Ho: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Ayala Pharmaceuticals; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Genentech/Roche; Research grant / Funding (self): Celldex Therapeutics; Research grant / Funding (self): Bayer; Research grant / Funding (self): Eli Lilly and Company; Research grant / Funding (self): Astellas Pharma; Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): Allos Therapeutics; Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy: Sanofi Genzyme; Honoraria (self), Advisory / Consultancy: Sun Pharma; Honoraria (self), Advisory / Consultancy: Regeneron; Honoraria (self), Advisory / Consultancy: TRM Oncology; Research grant / Funding (self), Travel / Accommodation / Expenses: Kura Oncology; Travel / Accommodation / Expenses: Ignyta. L.J. Wirth: Honoraria (self), Advisory / Consultancy: Ayala Pharmaceuticals; Honoraria (self), Advisory / Consultancy: Eisai. C. Rodriguez: Honoraria (self), Advisory / Consultancy: Cue Biopharma; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck. E. Dekel: Shareholder / Stockholder / Stock options, Full / Part-time employment: Ayala Pharmaceuticals. R.M. Walker: Shareholder / Stockholder / Stock options, Full / Part-time employment: Ayala Pharmaceuticals. C. Nadri-Shay: Shareholder / Stockholder / Stock options, Full / Part-time employment: Ayala Pharmaceuticals. A. Vergara-Silva: Shareholder / Stockholder / Stock options, Full / Part-time employment: Ayala Pharmaceuticals. All other authors have declared no conflicts of interest.