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Context: Patients with chronic fatigue syndrome (CFS) are more likely than healthy persons to develop neurally mediated hypotension (NMH) in response to prolonged orthostatic stress.Objective: To examine the efficacy of fludrocortisone acetate as monotherapy for adults with both CFS and NMH.Design: Randomized, double-blind, placebo-controlled trial conducted between March 1996 and February 1999.Setting: Two tertiary referral centers in the United States.Patients: One hundred individuals aged 18 to 50 years who satisfied Centers for Disease Control and Prevention criteria for CFS and had NMH provoked during a 2-stage tilt-table test. Eighty-three subjects had adequate outcome data to assess efficacy.Intervention: Subjects were randomly assigned to receive fludrocortisone acetate, titrated to 0.1 mg/d (n = 50) or matching placebo (n = 50) for 9 weeks, followed by 2 weeks of observation after discontinuation of therapy.Main Outcome Measure: Proportion of subjects in each group with at least a 15-point improvement on a 100-point global wellness scale.Results: Baseline demographic and illness characteristics between the groups were similar; CFS had been present for at least 3 years in 71%. Using an intention-to-treat analysis, 7 subjects (14%) treated with fludrocortisone experienced at least a 15-point improvement in their wellness scores compared with 5 (10%) among placebo recipients (P =.76). No differences were observed in several other symptom scores or in the proportion with normal follow-up tilt test results at the end of the treatment period.Conclusions: In our study of adults with CFS, fludrocortisone as monotherapy for NMH was no more efficacious than placebo for amelioration of symptoms. Failure to identify symptomatic improvement with fludrocortisone does not disprove the hypothesis that NMH could be contributing to some of the symptoms of CFS. Further studies are needed to determine whether other medications or combination therapy are more effective in treating orthostatic intolerance in patients with CFS. [ABSTRACT FROM AUTHOR]

Purpose: Score reproducibility is an important measurement property of fit-for-purpose patient-reported outcome (PRO) measures. It is commonly assessed via test-retest reliability, and best evaluated with a stable participant sample, which can be challenging to identify in diseases with highly variable symptoms. To provide empirical evidence comparing the retrospective (patient global impression of change [PGIC]) and current state (patient global impression of severity [PGIS]) approaches to identifying a stable subgroup for test-retest analyses, 3 PRO Consortium working groups collected data using both items as anchor measures., Methods: The PGIS was completed on Day 1 and Day 8 + 3 for the depression and non-small cell lung cancer (NSCLC) studies, and daily for the asthma study and compared between Day 3 and 10. The PGIC was completed on the final day in each study. Scores were compared using an intraclass correlation coefficient (ICC) for participants who reported "no change" between timepoints for each anchor., Results: ICCs using the PGIS "no change" group were higher for depression (0.84 vs. 0.74), nighttime asthma (0.95 vs. 0.53) and daytime asthma (0.86 vs. 0.68) compared to the PGIC "no change" group. ICCs were similar for NSCLC (PGIS: 0.87; PGIC: 0.85)., Conclusion: When considering anchor measures to identify a stable subgroup for test-retest reliability analyses, current state anchors perform better than retrospective anchors. Researchers should carefully consider the type of anchor selected, the time period covered, and should ensure anchor content is consistent with the target measure concept, as well as inclusion of both current and retrospective anchor measures., (© 2022. The Author(s).)

BACKGROUND: Among patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC), incidence of brain metastases (BMs) is relatively high and increasing. Despite the high unmet need for patients with HER2+ MBC and BMs, real-world data on treatment patterns and outcomes for these patients are limited. OBJECTIVE: To compare treatment patterns and overall survival (OS) among patients with HER2+ MBC with and without BMs in the United States. METHODS: This was a real-world retrospective cohort study in which adults diagnosed with HER2+ MBC between January 1, 2016, and May 31, 2019, were identified in the Flatiron Health electronic health records database. The cohort was stratified by presence of BMs at MBC diagnosis (baseline) and before the initiation of each line of therapy (LOT). Key outcomes were OS and systemic therapy/regimen used within each LOT. An adjusted Cox proportional hazards model was used to evaluate the impact of BMs on OS. RESULTS: Of 1,755 included patients, 173 (9.9%) had BMs at baseline. Trastuzumab+ pertuzumab-based regimens were the most common first- (n = 689, 44.3%) and second-line (n = 316, 35.3%) treatments for all patients. Among patients with BMs, trastuzumab emtansine was the most common third-line regimen (n = 18, 23.4%). Lapatinib-based regimens were used more frequently among patients with BMs but were used by less than 20% of patients with BMs within any LOT. Median OS was 22.3 and 37.3 months for patients with and without BMs at baseline, respectively. Patients with BMs had a higher risk of death compared with patients without BMs (HR, 3.2; 95% CI = 2.6-3.8). CONCLUSIONS: BMs are associated with an increased risk of mortality among patients with HER2+ MBC. Further studies are needed to evaluate the extent to which novel systemic therapies for HER2+ MBC address the unmet need among patients with BMs. DISCLOSURES: This study was funded by Seagen Inc. Andres Forero-Torres is an employee of and owns stock in Seagen Inc. Kendra DeBusk is an employee of Seagen Inc. and owns stock in Seagen Inc. and Roche. Andy Surinach and Yutong Liu are employees of Genesis Research, which received funding from Seagen Inc. in connection with this study. At the time of this study, Chimeka Ike was an employee of Seagen Inc. and owns stock in Seagen Inc. At the time of this study, Nicolas Lindegger was an employee of Seagen Inc., Seagen International GmbH, and owns stock in Seagen Inc. and Roche. At the time of this study, Naomi Schwartz was a paid consultant to Seagen Inc.; she currently is an employee of and owns stock in Seagen Inc.

Aim: To describe real-world treatment patterns/outcomes among patients with HER2+ metastatic breast cancer (MBC). Materials & methods: Real-world treatments and overall survival (OS) were evaluated among adult women diagnosed with HER2+ MBC, with and without brain metastases (BMs), between 1 June 2012 and  31 May 2018 using electronic medical records from the Definitive Oncology Dataset. Results: Among 372 patients, 69% initiated first-line trastuzumab plus pertuzumab-based therapy; many therapy combinations were utilized in the second- to fourth-line. During follow-up (median 24.8 months), 18% of patients died (22% with and 16% without BMs). Mean OS was shortest among patients with BMs at MBC diagnosis in the third- and fourth-line. Conclusion: OS was poor, and no clear standard of care was observed among patients with HER2+ MBC progressing on trastuzumab-based therapies.

Aim: A systematic literature review and network meta-analysis of randomized controlled trials in patients receiving therapy for HER2+ unresectable/metastatic breast cancer after ≥1 HER2-directed therapy was conducted to compare progression-free survival (PFS) and overall survival (OS). Methods: Hazard ratios (HRs) and relative differences from fractional polynomials (FPs) for PFS and OS were assessed by Bayesian network meta-analyses. Results: For PFS, surface under the cumulative rankogram (SUCRA) ranked tucatinib plus trastuzumab with capecitabine as highest in both HR and FP analyses, followed by T-DM1 monotherapy and neratinib plus capecitabine. For OS, SUCRA ranked tucatinib plus trastuzumab with capecitabine as highest in both HR and FP analyses, followed by pertuzumab plus trastuzumab with capecitabine and T-DM1 monotherapy, with similar scores. Conclusion: Tucatinib plus trastuzumab with capecitabine, and T-DM1 monotherapy, consistently showed improved PFS and OS versus lapatinib/trastuzumab plus capecitabine and non-targeted treatments.

Aim: Compare healthcare resource utilization and costs among patients with HER2+ metastatic breast cancer (MBC) with and without central nervous system (CNS) metastases. Methods: Retrospective matched cohort study using IQVIA's PharMetrics ® Plus claims database. Results: Patients with CNS metastases (n = 753) experienced more outpatient, emergency room and inpatient visits versus controls (n = 753; all p < 0.05). In the post-index year, median total all-cause healthcare costs were significantly higher among patients with CNS metastases versus controls ($112,402 vs $50,835; p < 0.0001); outpatient costs primarily drove the cost differential. Conclusion: More effective therapies are needed that improve clinical outcomes and reduce economic burden associated with CNS metastases in patients with HER2+ MBC.

Aims: In HER2CLIMB, tucatinib significantly improved progression-free and overall survival in patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer. We evaluated the impact of tucatinib on health-related quality of life (HR-QoL) in HER2CLIMB., Methods: Patients were randomised 2:1 to tucatinib or placebo combined with trastuzumab and capecitabine. Starting with protocol version 7, the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire and EQ visual analogue scale (VAS) were administered at day 1 of cycle 1, every two cycles during cycles 3-9, every three cycles during cycle 12 and thereafter and at each patient's 30-day follow-up visit., Results: Among 364 patients eligible for HR-QoL assessment, 331 (91%) completed ≥1 assessment. EQ-VAS scores were similar for both arms at baseline and maintained throughout treatment. EQ-5D-5L scores were similar between the treatment arms, stable throughout therapy and worsened after discontinuing treatment. Risk of meaningful deterioration (≥7 points) on EQ-VAS was reduced 19% in the tucatinib vs. placebo arm (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.55, 1.18); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.8 months (4.3, -) in the placebo arm. Among patients with brain metastases (n = 164), risk of meaningful deterioration on EQ-VAS was reduced 49% in the tucatinib arm (HR: 0.51; 95% CI: 0.28, 0.93); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.5 months (4.2, -) in the placebo arm., Conclusions: HR-QoL was preserved for patients with HER2+ metastatic breast cancer who were treated with tucatinib added to trastuzumab and capecitabine and maintained longer with tucatinib therapy than without it among those with brain metastases., Clinical Trial Registration: NCT02614794., Competing Interests: Conflict of interest statement V.M. reports consultancy for Amgen, AstraZeneca, ClinSol, Daiichi Sankyo, Eisai, Genomic Health, Hexal, Lilly, MSD Oncology, Novartis, Pierre Fabre, Roche, Seagen, Tesaro and Teva and research funding/grants from Novartis, Roche/Genentech and Seagen. A.W. reports corporate board membership for Andrew Wardley Limited, Manchester Cancer Academy and Outreach Research & Innovation Group Limited; consultancy for Accord Research, AstraZeneca, Athenex, Coleman Expert Network, Coleman Research, Daiichi Sankyo, Gerson Lehrman Group, Guidepoint Global, Lilly, MSD Oncology, NAPP Pharmaceuticals, Novartis, Pfizer and Roche; employment at the Christie NHS Foundation Trust and AstraZeneca (as of 11th January 2021); patents and royalties for Outreach Research & Innovation Group; speaker's bureau participation for AstraZeneca, Eisai, Lilly, Novartis, Pfizer and Roche; travel expenses from Daiichi Sankyo, MSD and Roche and other nonfinancial relationships with the Strategy Director for the Association of Cancer Physicians, Committee Member UK Breast Cancer Group, Committee Member NHS England and Chemo Clinical Reference Group, ESMO Breast Cancer Faculty and NCRI Breast Research Group Chair. E.P. reports consultancy for Mylan, Novartis, Pfizer and R-Pharm; research funding/grants from AbbVie, Cascadian, Corcept Therapeutics, Genentech, Hoosier Cancer Research Network, Merck, Novartis and Seagen and travel expenses from Amgen, Genentech, Merck, Novartis and Tesaro. E.H. reports consultancy for AstraZeneca, Black Diamond Therapeutics, Boehringer Ingelheim, Daiichi Sankyo, Genentech/Roche, Lilly, Mersana, Novartis, Pfizer, Puma Biotechnology and Silverback Therapeutics; research funding/grants from AbbVie, AceraPharma, Aravive, ArQule, Arvinas, AstraZeneca, BerGenBio, Black Diamond Therapeutics, Boehringer, Clovis Oncology, Compugen, Curis, CytomX Therapeutics, Daiichi Sankyo, Deciphera, eFFECTOR, Eisai, EMD Serono, Fochon Pharmaceuticals, Fosun Orinove, Fujifilm, G1 Therapeutics, Pfizer, Puma Biotechnology, Radius Health, Regeneron, Rgenix, Seagen, Sermonix Pharmaceuticals, Silverback Therapeutics, Stemcentrx, Sutro Biopharma, Syndax, Syros Pharmaceuticals, Taiho Pharmaceutical, Takeda, TapImmune, Tesaro, Torque, Unum Therapeutics, Verastem, Zenith Epigenetics, Zymeworks, Genentech/Roche, H3 Biomedicine, Harpoon, Hutchison MediPharma, Immunogenics, InventisBio, Karyopharm Therapeutics, Leap Therapeutics, Lilly, Lycera, MacroGenics, MedImmune, Medivation, Mersana, Merus, Millennium, Molecular Templates, Novartis, NuCana and OncoMed and travel expenses from Amgen, AstraZeneca, Bayer, BMS, Clovis, Eisai, EMD Serono, Foundation Medicine, Genentech/Roche, Genentech, Genzyme, Guardant Health, Helsinn Therapeutics, Heron, Lilly, Medivation, Merck, Novartis, Pfizer, Roche, Sysmex and Tesaro. A.Z. reports consultancy for Norvatis and Pfizer and travel expenses from Immunomedics. E.J. reports consultancy for Lilly, Novartis, Pfizer and Roche. F.B. reports consultancy and honoraria from Lilly, Novartis, Lilly and Roche and travel expenses from Novartis. E.H.B. reports travel expenses from Pierre Fabre, Pfizer and Roche. A.B. reports corporate board membership for NanoTx Therapeutics; consultancy for AlaMab Therapeutics, NanoTx Therapeutics, Plus Therapeutics and Vascular Biogenics; equity ownership in NanoTx and Plus Therapeutics; honoraria from Vascular Biogenics; patents and royalties related to intellectual property interest in NanoTx Therapeutics; research funding/grants from Boston Biomedical, Immunomedics, Medicenna, Mirna Therapeutics, Threshold Pharmaceuticals, Upsher-Smith and Vascular Biogenics and travel expenses from Vascular Biogenics. L.C. reports speaker's bureau participation for Astellas, Ipsen and Janssen and other fees for Astellas, Bristol Myers Squibb, Ipsen, Novartis and Pfizer. C.F. reports honoraria from Pfizer, Bayer, Novartis, AstraZeneca, Merck, Astellas Pharma and Roche Canada; a consulting or advisory role for Genomic Health, Merck, AstraZeneca, Bayer and Odonate Therapeutics; speaker's bureau for Merck; research funding/grants to self from Bayer; research funding/grant to the institution from Astellas Pharma, AstraZeneca, Lilly, Merck, Novartis, Roche/Genentech, Sanofi, Pfizer, Janssen Oncology, Zymeworks, Seagen, Immunomedics, Bicycle Therapeutics and Sermonix Pharmaceuticals and travel expenses from Novartis and Roche. M.M.-M. reports advisory board membership for Pierre Fabre; grants for conference attendance from Roche, Pfizer and Lilly and expert testimony for Novartis, Roche and Eisai. H.T.A. reports advisory board membership for Bayer, BeiGene, Bicycle, BioNTech, iOnctura, Roche and Servier and employment at HCA Healthcare UK and Sarah Cannon. N.I. reports consultancy for Janssen, Merck, Novartis and Pfizer. S.A. reports speaker's bureau participation for Novartis, Pfizer, Puma, Daiichi/AstraZeneca, Merck and Seagen. M.C. reports consultancy for Sanofi and travel expenses from Novartis, Bristol Myers Squibb and Ipsen. T.P. reports research funding/grants from Merck, Pfizer and Seagen. E.S.-R. reports consultancy for Lilly and Mylan, research funding/grants from Susan G. Komen Victory Foundation and speaker's bureau participation for Mylan. D.C. reports consultancy for Daiichi Sankyo, GlaxoSmithKline, Novartis, Roche and Synthon; employment at Edinburgh Cancer Research Centre, Edinburgh, United Kingdom and research funding/grants from Daiichi Sankyo, GlaxoSmithKline, Novartis, Roche and Seagen (all funding is to his institution). G.C. reports consultancy from Bristol Myers Squibb, Lilly, Novartis, Pfizer, Roche, Seagen and Daiichi Sankyo; employment at the University of Milano, Istituto Europeo di Oncologia, IRCCS, Milano, Italy and speaker's bureau participation for Lilly, Pfizer, Roche, Seagen and Daiichi Sankyo. K.G. reports consultancy for AstraZeneca, Bristol Myers Squibb, Genentech, Genomic Health, Janssen, Lilly, Merck, Mylan, NanoString, Novartis, Pfizer and Roche and research funding/grants from AstraZeneca, Bristol Myers Squibb, Pfizer and Roche. M.S. reports employment at Seagen Inc. and equity ownership in Seagen Inc. and Moderna Pharma. K.D. reports employment at Seagen Inc. and equity ownership in Seagen Inc. and Roche. J.R. and W.F. report employment at Seagen Inc. and equity ownership in Seagen Inc. M.B., S.C., M.C., E.C., L.F. and O.H. have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In a phase II North American study (NP28761; NCT01871805), the anaplastic lymphoma kinase (ALK) inhibitor alectinib demonstrated both systemic and central nervous system (CNS) efficacy with good tolerability in patients with ALK -positive non-small cell lung cancer. We describe patient-reported outcomes (PROs) from the NP28761 study., Patients and Methods: PROs and health-related quality of life (HRQoL) benefits were assessed using two self-administered questionnaires (the European Organisation for Research and Treatment of Cancer 30-Item Quality of Life Questionnaire-Core (EORTC QLQ-C30), and the 13-item EORTC QLQ-lung cancer-specific module) at enrolment and every 6 weeks until week 66, disease progression or death., Results: Clinically meaningful mean improvements (≥10 point change from baseline) were observed in 10 domains, including global health status (GHS), role and social functioning, fatigue, pain, dyspnoea, and appetite loss. A clinically meaningful improvement was observed in GHS from the first assessment (6 weeks) until week 60. Alectinib demonstrated a rapid effect, with a median time to symptom improvement, using the composite endpoint of cough, dyspnoea and pain in the chest, of 1.4 months (6.1 weeks) (95% CI 1.4 to 1.6) and a median time to symptom deterioration of 5.1 months (22.1 weeks) (95% CI 2.8 to 6.8). Patients with CNS metastases at baseline experienced comparable HRQoL over the duration of the study as patients without CNS metastases. Exploratory analysis showed that the occurrence of an objective response may be associated with a better HRQoL., Conclusions: Patients treated with alectinib in this phase II study achieved clinically meaningful improvements in HRQoL and symptoms and had delayed time to symptom deterioration., Competing Interests: Competing interests: S-HIO has acted in a consulting or advisory role to ARIAD, AstraZeneca, Boehringer Ingelheim, Novartis and Roche, and participated in the speaker bureaus for AstraZeneca, Boehringer Ingelheim and Roche/Genentech. MAS has provided corporate-sponsored research support for Genentech and participated in the speaker bureaus for Genentech. SG has participated in the advisory boards for Genentech/Roche, ARIAD, Novartis and Pfizer. LG received consultancy fees from Genentech/Roche, Pfizer, Merck, AbbVie and AstraZeneca, and personal fees from Merck and BMS IION Foundation. HW has participated in the advisory boards for ARIAD, Genentech/Roche and Takeda, and received honoraria for non-branded presentations for ARIAD and Genentech/Roche. AAC has participated in the advisory boards for Novartis, Takeda, BMS and Lilly, provided corporate-sponsored research for Novartis and BMS, and has relationships with Genentech, Merck, Takeda, Boehringer Ingelheim, Pfizer, Celgene and Novartis. VC has participated in the advisory boards for Pfizer Canada. GJR has acted in a consulting role to Novartis, and provided corporate-sponsored research support to Chugai, Roche, Pfizer, Novartis and Millennium. VS, WB, EW, KD and AZ are employees of F Hoffmann-La Roche and hold shares in the company. ATS has participated in the advisory boards for Pfizer, Novartis, Roche/Genentech, ARIAD, Blueprint Medicines, Loxo and EMD Serono, and received honoraria for non-branded presentations for Pfizer, Novartis, Genentech/Roche, Ignyta, Taiho and Foundation Medicine.

Background: Interleukin (IL)-13 plays a key role in type 2 inflammation and is an emerging pathogenic mediator in atopic dermatitis (AD)., Objective: We investigated the efficacy and safety of lebrikizumab, an IL-13 monoclonal antibody, as an add-on to topical corticosteroid (TCS) treatment., Methods: A randomized, placebo-controlled, double-blind, phase 2 study. Adults with moderate-to-severe AD were required to use TCS twice daily and then randomized (1:1:1:1) to lebrikizumab 125 mg single dose, lebrikizumab 250 mg single dose, lebrikizumab 125 mg every 4 weeks for 12 weeks, or placebo every 4 weeks for 12 weeks, after a 2-week TCS run-in. The primary endpoint was percentage of patients achieving Eczema Area and Severity Index (EASI)-50 at week 12., Results: In total, 209 patients received the study drug. At week 12, significantly more patients achieved EASI-50 with lebrikizumab 125 mg every 4 weeks (82.4%; P = .026) than placebo every 4 weeks (62.3%); patients receiving a single dose of lebrikizumab showed no statistically significant improvements in EASI-50 compared with placebo. Adverse events were similar between groups (66.7% all lebrikizumab vs 66.0% placebo) and mostly mild or moderate., Limitations: Protocol-mandated twice daily TCS treatment limits our understanding of the efficacy of lebrikizumab as a monotherapy. The short study duration did not enable long-term efficacy or safety evaluations., Conclusion: When combined with TCS, lebrikizumab 125 mg taken every 4 weeks led to a significant improvement and was well tolerated in patients with moderate-to-severe AD., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)