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Objective: To report a case of fatal super-refractory status epilepticus associated with amyloid-related imaging abnormalities (ARIA)., Methods: We describe the history, neuroimaging, EEG, and brain pathology findings of a 75-year-old patient with mild cognitive impairment due to Alzheimer disease (homozygous ε4 apolipoprotein status) and a remote history of 3 asymptomatic ARIA episodes, who developed super-refractory status epilepticus related to severe ARIA., Results: The patient was participating in an extended open-label trial of aducanumab when she was admitted to hospital for focal seizures and ARIA in 2 noncontiguous regions of the left frontal and occipital lobes. Despite aggressive treatment with high-dose corticosteroids, sedation, and antiseizure medications, she died from refractory focal status epilepticus. In retrospect, routine surveillance brain magnetic resonance imaging performed 11 weeks before hospitalization had signs of ARIA, which had not been identified., Discussion: Clinicians should be aware that anti-amyloid therapies may cause rare serious adverse events. A high degree of vigilance is required in the interpretation of surveillance imaging for ARIA. Longitudinal studies are justified to further characterize the safety profile of anti-amyloid antibody therapies and identify participants at high risk of serious adverse events.

Objective: Several monoclonal antibodies (MoAbs) targeting specific type 2 immune reactions have been developed as innovative therapeutic approaches for chronic inflammatory airway diseases, such as chronic sinusitis with nasal polyps (CRSwNP) and asthma. However, the clinical safety of these MoAbs and how to choose them are not clear. Therefore, we aimed to assess the systemic drug- and dose-based safety of MoAbs in chronic airway inflammation using network meta-analysis (NMA)., Methods: Electronic databases were systematically searched for relevant studies published in English between January 2009 and December 2022. Eligible studies must have clearly reported adverse events (AEs) among the MoAbs' safety data., Results: 1). Regarding serious AEs, mepolizumab was significantly safer than placebo; in terms of permanent treatment discontinuation, reslizumab and dupilumab were significantly safer than benralizumab. 2). Regarding asthma worsening, dupilumab was associated with the best safety profile; was safer than dupilumab/300 mg/q2-4w. 3). In terms of injection-site reactions, dupilumab posed a higher risk than placebo; dupilumab/300 mg/qw posed a higher risk than dupilumab/300 mg/q2w and dupilumab/300 mg/q2-4w; lebrikizumab/250 mg/q4w posed a higher risk than lebrikizumab/37.5 mg/q4w; mepolizumab/100 mg/q4w posed a higher risk than mepolizumab/75 mg/q4w; benralizumab/30 mg/q4-8w posed a higher risk than benralizumab/20 mg/q4-8w. 4) In CRSwNP patients combined with asthma, the risks of experiencing AEs were not increased., Conclusion: Overall, biologics are safe and well tolerated in chronic inflammatory airway disease. This drug- and dose-based NMA provides further evidence on the different safety profiles of different emerging MoAbs. This information may help guide rational drug use and provide clinical recommendations for choosing MoAbs., Trial Registration: SYSTEMATIC REVIEW REGISTRATION (PROSPERO #CRD42023387610)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Eftilagimod alpha (efti), a soluble LAG3 protein, activates antigen-presenting cells (APC) and downstream T cells. TACTI-002 (part C) evaluated whether combining efti with pembrolizumab led to strong antitumor responses in patients with second-line recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) while demonstrating good tolerability., Patients and Methods: In this multinational phase II trial using Simon's two-stage design, patients who were PD-L(1)-naïve with R/M HNSCC who had failed first-line platinum-based therapy, unselected for PD-L1, received intravenous pembrolizumab (200 mg, once every 2 weeks) combined with subcutaneous efti (30 mg once every 2 weeks for 24 weeks and once every 3 weeks thereafter). The primary endpoint was objective response rate per RECIST 1.1 modified for immune-based therapy by investigator assessment. Additional endpoints included duration of response, progression-free survival, overall survival, and tolerability. Pharmacodynamic effects (absolute lymphocyte count) and Th1 cytokine biomarkers (IFNγ/CXCL10)] were evaluated in liquid biopsies., Results: Between March 2019 and January 2021, 39 patients were enrolled; 37 were evaluated for response. All patients received prior chemotherapy, and 40.5% were pretreated with cetuximab; 53.1% of patients had PD-L1 combined positive score <20. With a median follow-up of 38.8 months, the objective response rate was 29.7%, including 13.5% complete responders. The median duration of response was not reached. Rapid and sustained absolute lymphocyte count increase was observed in patients who had an objective response. Th1 biomarkers increased sustainably after first treatment. No unexpected safety signals were observed., Conclusions: Efti plus pembrolizumab was safe and showed encouraging antitumor activity and pharmacodynamic effects in patients with second-line head and neck squamous cell carcinoma (HNSCC), thus supporting further evaluation of this combination in earlier treatment lines., (©2024 American Association for Cancer Research.)

Purpose: Lenvatinib, a potent multikinase inhibitor, improves progression-free survival (PFS) in patients with radioiodine (RAI)-refractory differentiated thyroid cancer; however, most patients experience disease progression, warranting further therapy. We evaluated the efficacy and safety of lenvatinib plus pembrolizumab in these patients., Patients and Methods: We enrolled patients with progressive, RAI-refractory differentiated thyroid cancer who were either naïve to multikinase inhibitors (cohort 1) or who had progressed on lenvatinib (cohort 2). Patients received oral lenvatinib daily (cohort 1, 20 mg; cohort 2, dose at progression) and intravenous pembrolizumab (200 mg) every 21 days., Results: In cohorts 1 and 2, 30 and 27 patients were enrolled, respectively. Adverse events were consistent with those observed in other cancers. In cohort 1, the confirmed overall response rate was 65.5%. There were no complete responses (primary endpoint). The 12- and 18-month PFS were 72.0% and 58.0%, respectively, and the median PFS was 26.8 months. In cohort 2, the confirmed overall response rate was 16% (primary endpoint), and the median PFS was 10.0 months (95% confidence interval, 7.0-17.9 months). Tumor histology, driver mutations, and immune-related biomarkers, including PD-L1 expression, thyroid-specific antibody levels, and CD8+ T-cell tumor infiltrate, did not correlate with response to therapy. Increased baseline peripheral blood monocytes and neutrophil to lymphocyte ratio were associated with a worse PFS in cohort 1., Conclusions: Lenvatinib plus pembrolizumab may enhance the durability of lenvatinib monotherapy in lenvatinib-naïve patients. Furthermore, the addition of pembrolizumab may be a viable salvage therapy for patients who have progressed on lenvatinib., (©2024 American Association for Cancer Research.)

Background: Biologic medications are a common therapy for those with inflammatory bowel disease (IBD). There are limited data on the outcomes of home-based biologic infusions for patients with IBD. The aim of this study was to compare the safety and efficacy of biologic infusions for IBD patients who receive either home- or office-based administration., Methods: Patients receiving infliximab or vedolizumab were analyzed retrospectively over a period of 152 weeks. Survival free of major adverse events including delayed infusion reaction, steroid initiation, drug discontinuation, or IBD-related emergency department visits, admission, and surgery were compared using a Kaplan-Meier curve. Individual adverse events, infusion-.related quality measures, and markers of patient adherence were analyzed., Results: Adverse event-free survival was greater among those receiving home-based infusion (n = 154) compared with office-based infusion (n = 133). The office infusion cohort had higher rates of delayed infusion reactions (4 vs 0), IBD-related surgery (6 vs 0), and drug discontinuation (44 vs 35); this was a sicker cohort of patients compared with those in the home infusion group. Home infusion patients were less likely to receive correct weight-based dosing for infliximab (71.7% vs 89.3%), obtain labs for drug monitoring (53.2% vs 71.4%), and adhere to routine clinic visits (37.9% vs 58.1%)., Conclusions: The home-based infusion of biologics for IBD appears safe with lower rates of major adverse events compared with office-based infusions. However, those receiving home infusion were less likely to receive correct weight-based dosing for infliximab and were poorly adherent to routine follow-up., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: In this single-institution phase II investigator-initiated study, we assessed the ability of MAPK and VEGF pathway blockade to overcome resistance to immunotherapy in microsatellite-stable metastatic colorectal cancer (MSS mCRC)., Patients and Methods: Patients with MSS, BRAF wild-type mCRC who progressed on ≥2 prior lines of therapy received pembrolizumab, binimetinib, and bevacizumab until disease progression or unacceptable toxicity. After a safety run-in, patients were randomized to a 7-day run-in of binimetinib or simultaneous initiation of all study drugs, to explore whether MEK inhibition may increase tumor immunogenicity. The primary endpoint was objective response rate (ORR) in all patients combined (by Response Evaluation Criteria in Solid Tumors v1.1)., Results: Fifty patients received study drug treatment; 54% were male with a median age of 55 years (range, 31-79). The primary endpoint, ORR, was 12.0% [95% confidence interval (CI) 4.5%-24.3%], which was not statistically different than the historical control data of 5% (P = 0.038, exceeding prespecified threshold of 0.025). The disease control rate was 70.0% (95% CI, 55.4%-82.1%), the median progression-free survival 5.9 months (95% CI, 4.2-8.7 months), and the median overall survival 9.3 months (95% CI, 6.7-12.2 months). No difference in efficacy was observed between the randomized cohorts. Grade 3 and 4 adverse events were observed in 56% and 8% of patients, respectively; the most common were rash (12%) and increased aspartate aminotransferase (12%)., Conclusions: Pembrolizumab, binimetinib, and bevacizumab failed to meet its primary endpoint of higher ORR compared with historical control data, demonstrated a high disease control rate, and demonstrated acceptable tolerability in refractory MSS mCRC., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Pembrolizumab plus cisplatin and 5-fluorouracil administered as first-line therapy for advanced esophageal cancer patients has shown a better objective response and survival than conventional chemotherapy with less severe hematological adverse events. The safety and efficacy of this regimen were evaluated in patients with T4b esophageal squamous cell carcinoma (ESCC)., Methods: Eight consecutive patients with T4b ESCC received this regimen according to KEYNOTE-590 as induction, and they were evaluated after 1-3 courses. The programmed death-ligand 1 (PD-L1) combined positive score (CPS) was also evaluated before chemotherapy. Efficacy for the primary lesion was evaluated by our original formula for the tumor reduction rate., Results: The numbers of patients with partial response (PR), stable disease, and progressive disease (PD) were 5, 1, and 2, respectively. The tumor reduction rate ranged from 69 to 87% in PR patients, and all PR patients had relief from T4b. Two patients underwent conversion surgery with R0 resection. PD-L1 CPS was over 90 in 2 PR patients, but under 10 in 2 other PR patients. PD-L1 CPS was under 10 in PD patients. One patient had hyperprogression, resulting in an esophago-pulmonary fistula. Greater than grade 3 adverse events were bleeding gastric ulcer in one patient (12.5%), neutropenia without G-CSF in 3 patients (37.5%), and hypopotassemia in 1 patient (12.5%). No patient had febrile neutropenia., Conclusions: Marked tumor reduction was confirmed in 62.5% of patients with pembrolizumab plus cisplatin and 5-fluorouracil with less adverse events. This regimen could be administered as induction chemotherapy for patients with T4b ESCC., (© 2024. The Author(s).)

Background: Effectiveness and safety of advanced therapies for ulcerative colitis (UC) warrant assessment in the real world., Objective: To perform a systematic review and summarize real-world evidence of advanced therapies approved for moderate-to-severe UC., Methods: A systematic literature review was conducted using real-world studies of biologics or small molecules in UC using Embase, MEDLINE, and MEDLINE-In Process databases. Only products approved in any jurisdiction during the search were included. English-language full-papers (January 2005 to February 2022) and congress abstracts (January 2019 to February 2022) were included. Studies with less than 30 patients or only biologic-naive patients were excluded., Results: A total of 139 studies were included out of 3,930 identified articles (75%, published between 2019 and 2022; 64%, retrospective observational; 53%, from 5 countries [Italy, United States, Spain, United Kingdom, and Belgium]). Most studies were single agent (highest: vedolizumab = 50, tofacitinib = 24, and adalimumab = 18), and rates of clinical remission (CR) and adverse events varied widely. From the published comparative effectiveness studies (16), the rates of CR were numerically higher with vedolizumab vs anti-tumor necrosis factor (TNF)-α agents. Compared with vedolizumab, the effectiveness of tofacitinib was numerically greater in CR (occasionally significant). Rates of steroid-free CR were comparable between ustekinumab and tofacitinib. Infliximab was the most effective anti-TNFα agent, as reported by 2 studies. Remarkably, adverse events were similar across therapies in comparative studies., Conclusions: Vedolizumab and tofacitinib were the most assessed therapies. In comparative studies, remission rates were numerically higher with tofacitinib vs vedolizumab and for vedolizumab vs anti-TNFα. Tofacitinib was comparable with ustekinumab for steroid-free CR. Safety was comparable across therapies. Future studies should explore the literature gaps identified, including limited comparative studies with small sample sizes, variations in study designs and patient characteristics, varied definitions of CR, and limited use of patient-reported outcome measures in real-world settings.

Background/aim: Near-infrared photoimmunotherapy (NIR-PIT) is a recently developed cancer treatment modality that selectively kills cancer cells and may induce a therapeutic host immune response. The aim of this study was to determine the feasibility of combining NIR-PIT with immune checkpoint inhibitor (ICI) therapy for unresectable recurrent head and neck cancer., Patients and Methods: Five patients underwent NIR-PIT at Ryukyu University Hospital between January 2022 and April 2024. These patients had unresectable recurrent head and neck squamous cell carcinoma. Among these five patients, four received a combination NIR-PIT and pembrolizumab administration., Results: A total of seven lesions in the oropharynx and oral cavity were targeted. One patient was treated for three different target lesions. The best observed response (BOR) rate was 100%, with three complete responses and four partial responses. The most common treatment-related adverse event was Grade 1 or 2 local pain lasting one to two days postoperatively, which occurred in all patients. Grade 3 adverse events occurred in three cases (42.9%), including pneumonia, pharynx-cutaneous fistula, and trismus. Three patients received ICI therapy following NIR-PIT, achieving a 60% BOR rate. No immune-related adverse events were noted, and the aforementioned Grade 3 adverse events did not worsen during ICI therapy. At a median follow-up of 376 days (range=157-845 days), four target lesions showed no recurrence, while three had recurred. All five patients were alive, including three with no evidence of disease., Conclusion: The combination of NIR-PIT and ICI therapy for unresectable recurrent head and neck cancer was feasible., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Maintaining liver function throughout the treatment of hepatocellular carcinoma (HCC) is crucial, yet the impact of durvalumab plus tremelimumab (DT) treatment on liver function is not well understood. This multicenter study aimed to examine the changes in liver function during DT treatment., Patients and Methods: This nationwide multicenter study included 80 patients who received DT treatment for unresectable HCC. The primary outcome was changes in albumin-bilirubin (ALBI) scores at baseline, week 8, week 12, and at the time of progressive disease (PD)., Results: The median (interquartile range) ALBI scores at baseline, week 8, week 12, and the time of PD were -2.24 (-2.49 to -1.94), -2.13 (-2.51 to -1.86), -2.23 (-2.51 to - 1.77), and -2.06 (-2.53 to -1.72), respectively. No significant differences were observed at 8 weeks (p=0.06), at 12 weeks (p=0.4), and at PD (p=0.8) compared to baseline. Subgroup analyses were conducted for patients with an ALBI grade of 2 at baseline and for those who received DT treatment as a second-line or later treatment. No deterioration in liver function was observed at any time point in both analyses., Conclusion: DT treatment can maintain liver function throughout the treatment period. Maintaining liver function is crucial in managing HCC, and this is an advantage of using DT treatment as a first-line treatment for unresectable HCC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: In the European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 study, adjuvant pembrolizumab improved recurrence-free survival and distant-metastasis-free survival in patients with resected stage III melanoma. Earlier results showed no effect of pembrolizumab on health-related quality of life (HRQOL). Little is known about HRQOL after completion of treatment with pembrolizumab, an important research area concerning patients who are likely to become long-term survivors. This study reports long-term HRQOL results., Methods: This double-blind, randomised, controlled, phase 3 trial compared adjuvant pembrolizumab with placebo in patients aged 18 years or older with previously untreated stage IIIA, IIIB, or IIIC resected cutaneous melanoma and an Eastern Cooperative Oncology Group performance status score of 1 or 0, recruited from 123 academic centres and community hospitals in 23 countries. Patients were randomly assigned (1:1) with a minimisation technique stratified for stage and geographical region to receive 200 mg of intravenous pembrolizumab or placebo every 3 weeks for up to 18 doses. Investigators, patients, and those collecting or analysing data were masked to group assignment. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, measured with the EORTC Quality of Life Questionnaire-Core 30. All patients with a baseline HRQOL evaluation available who were alive 108 weeks from randomisation were included in this analysis of long-term HRQOL. Long-term HRQOL included assessments measured every 6 months between 108 weeks and 48 months after randomisation. The threshold of clinical relevance for all HRQOL scales used was an average change of 5 points. The trial is ongoing, recruitment is completed, and HRQOL data collection is finalised. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37., Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were randomly assigned to pembrolizumab (n=514) or placebo (n=505). Completion of the HRQOL evaluation at baseline exceeded 90% (481 [94%] patients in the pembrolizumab group and 467 [92%] in the placebo group), and ranged between 60% and 90% for post-baseline timepoints. Among patients with a baseline HRQOL evaluation, 365 (39%) were female and 583 (61%) were male. The mean change from baseline to long-term HRQOL was -0·56 (95% CI -2·33 to 1·22) in the pembrolizumab group and 1·63 (-0·12 to 3·38) in the placebo group. The difference between the two groups was -2·19 (-4·65 to 0·27, p=0·081). Differences for all other scales were smaller than 5 and not statistically significant., Interpretation: Adjuvant pembrolizumab did not have a significant impact on long-term HRQOL compared with placebo in patients with resected stage III melanoma. These findings, together with earlier results on efficacy and HRQOL, support the use of pembrolizumab in this setting., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests EB's spouse and daughter hold shares in Sandoz, Galenica, Alcon, Roche, and Novartis. MK reports study funding paid to the institution by Merck Sharp & Dohme (MSD) since the initial planning of the work, and study funding paid to the institution from Bristol Myers Squibb (BMS), Immunocore, Johnson & Johnson, and Pierre Fabre in the past 36 months. MM reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sun Pharma. GVL reports consulting fees from Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, BMS, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics, IOBiotech, Immunocore, Innovent Biologics USA, MSD, Novartis, PHMR, Pierre Fabre, Regeneron, Scancell, and SkylineDX BV. VA reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, MSD, Novartis; support from BMS for attending meetings or travel; participation on a data safety monitoring board or advisory board for BMS, MSD, Novartis, and Immunocore; CUB reports personal fees from MSD, grants and personal fees from Novartis and BMS, personal fees from Roche, GSK, AstraZeneca, Pfizer, Lilly, GenMAB, Pierre Fabre, and Third Rock ventures, grants from NanoString and 4SC, during the conduct of the study. CUB has patents pending (WO 2021/177822 A1 and WO 2023/022596 A1), and reports stock ownership: co-founder of Immagene BV and Signature Oncology. AH reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, and Novartis; payments for participation on a data safety monitoring board or advisory board with BMS, MSD, and Novartis. SD reports research funding from BMS, MSD, and Pierre Fabre to the institution; payment or honoraria to the institution for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS and MSD; support for attending meetings or travel from BMS and MSD; trim 24 patent pending; participation on a data safety monitoring board or advisory board at BMS and MSD, with payments made to the institution; spouse being a Sanofi employee. AK reports consulting fees for an advisory role at Moderna and speaker honorarium from MSD. MSC reports honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, MSD and Novartis; having served on advisory boards for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck, and Sanofi. AM reports support of scientific and educational conference from Janssen. SS reports grants or contracts from Novartis/Advanced Accelerator Applications (AAA), AstraZeneca, MSD, Genentech, Senhwa, and Pfizer; funding goes to the institution to undertake investigator initiated clinical trial and translational research. SS reports participation on advisory boards for MSD, BMS, AstraZeneca—fees for attending go to research funds at the institution. SS is the chair of DSMB for two Novartis/AAA sponsored phase 3 trials—no fee accepted for chair role. SP reports payment or honoraria to her and her institution for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, and Novartis, and to her partner and her institution from Amgen and Phylogen; payments to her institution for participation on a data safety monitoring board or advisory board with MSD; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid from GEM, EORTC melanoma group, and ASEICA. DS reports research grants to his institution from Amgen, Array/Pfizer, BMS, MSD, Novartis, and Roche; consulting fees paid personally from 4SC, Amgen, Array Biopharma, AstraZeneca, BMS, Daiichi Sankyo, Haystack, Immunocore, InFlarX, Innovent, Labcorp, Merck Serono, MSD, Nektar, Neracare, Novartis OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, and Sun Pharma; personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, Merck Serono, Novartis, Roche, Sanofi, and SunPharma; personal support for attending meetings or travel from BMS, Merck Serono, MSD, Novartis, Sanofi, and Pierre Fabre; personal payments for participation on a data safety monitoring board or advisory board at 4SC, Amgen, Array Biopharma, AstraZeneca, BMS, Daiichi Sankyo, Haystack, Immunocore, InFlarX, Merck Serono, MSD, Nektar, Neracare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, and Sun Pharma; leadership or fiduciary role, paid or unpaid, at Dermatologic Cooperative Oncology Group, German Cancer Society, Hiege Stiftung, Deutsche Hautkrebsstiftung, Nationale Versorgungskonferenz Hautkrebs eV, and European Melanoma Registry; drug supply (nivolumab, ipilimumab) from BMS. RJ reports research funding from Iovance Biotherapeutics; honoraria for advisory role or speaker presentation from Merck, BMS, Medison, Pfizer, and Novartis. PR reports consulting fees paid to himself from MBS, MSD, Novartis, Pierre Fabre, Philogen, and Pfizer; honoraria for lectures, presentations, speakers bureau, manuscript writing, or educational events paid to himself from BMS, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, MSD, and AstraZeneca; speakers bureau Pfizer, Novartis, Pierre Fabre, MSD, and BMS paid to himself; support for attending meetings or travel from Orphan Europe and Pierre Fabre paid to himself; research funding to his institution from Novarits, Pfizer, Roche, and BMS. AJMvdE reports study grants from BMS and Idera; travel expenses from Ipsen; advisory board from BMS, MSD Oncology, Ipsen, Pierre Fabre, and Janssen Cilag BV. CC reports support for attending meetings or travel from Orphan Europe and Pierre Fabre. DG reports stock or stock options from Merck & Co. CK reports stock or stock options from Merck & Co and being an employee of Merck & Co. CR reports consulting fees (payments made to her) from BMS, Roche, Pierre Fabre, Novartis, Sanofi, Pfizer, MSD, Merck, Sunpharma, Ultimovacs, Regeneron, Egle, Philogen, Maat Pharma, and IO Biontech; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events (payments made to her) from Pierre Fabre, Sanofi, BMS, MSD, and Novartis; support for attending meetings or travel from Pierre Fabre; participation on a data safety monitoring board or advisory board (payments made to her) with BMS, Roche, Pierre Fabre, Novartis, Sanofi, Pfizer, MSD, Merck, Sunpharma, Ultimovacs, Regeneron, Egle, Philogen, and Maat Pharma. AMME reports honoraria for scientific advisory board or independent data monitoring committee functions from Agenus, BioInvent, BioNTech, Boehringer Ingelheim, Brenus, CatalYm, Ellipses, EikonTX, Eurobio, Galecto, IO Biotech, IQVIQ, ISA Pharmaceuticals, Merck & Co, MSD, Pfizer, Pierre Fabre, Scorpion TX, Sairopa, Sellas, SkylineDX, TigaTx, and Trained Therapeutics Discovery; honoraria from Acetra, GenOway, GSK, Moderna, and Trained Immunity Tx; equity from IO Biotech, Sairopa, and SkylineDx; being the Editor in Chief of the European Journal of Cancer. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objectives: To evaluate otologic adverse reactions (OARs), including hearing loss (OARs-HL) among patients taking teprotumumab, a new biologic approved for the treatment of active thyroid eye disease, using publicly available pharmacovigilance reporting data., Study Design: Retrospective database review., Methods: The Food and Drug Administration Adverse Events Reporting System (FAERS) was queried for cases involving teprotumumab from 2020Q1 to 2023Q1. Patient demographics and adverse reactions (OAR and OAR-HL) were evaluated. Logistic regression was used to predict OAR and OAR-HL, and disproportionality analysis was performed using OpenVigil., Results: A total of 2,109 teprotumumab-AR cases were reported, of which 296 (14.05%; mean age 55.46 yr) were OARs. Of these, 149 (7.06%) reported OAR-HL and 194 (9.20%) reported other OAR (e.g., tinnitus, ear discomfort, vertigo), with 47 (2.23%) reporting both. Disproportionality analysis showed a reported odds ratio (ROR) for OARs-HL of 44.33 (95% confidence interval [CI], 37.40-52.55; p < 0.001). Age was associated with RORs of 1.02 (95% CI, 1.01-1.04) and 1.04 (95% CI, 1.02-1.07) for developing OARs and specifically OARs-HL, respectively (p < 0.01). Age 50 and 65 years and older were associated with RORs of 2.54 (95% CI, 1.16-6.38) and 3.36 (95% CI, 1.75-6.53), respectively, for OARs-HL (p < 0.05)., Conclusion: This study using FAERS data suggests an increased risk of OARs, specifically hearing loss, associated with teprotumumab. Increasing age was a significant predictor of OARs. Audiometric counseling and evaluation should be considered with teprotumumab therapy in Graves' orbitopathy patients, especially in older patients., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2024, Otology & Neurotology, Inc.)

Competing Interests: I declare no competing interests.

Eculizumab is an orphan drug with indications for extremely rare autoimmune disorders. It is primarily prescribed for use in patients with paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome; but is also highly effective in the treatment of myasthenia gravis, among others. By binding to the C5 protein in the complement system, eculizumab effectively inhibits cellular hemolysis and autoimmune reactions. Despite this effective treatment, some patients reported no improvement in symptoms. Genetic sequencing revealed three distinct C5 mutations in the non-responders and these polymorphisms appeared to be most prevalent among Japanese, Korean and African populations. Here, we present an overview of the current and potential future applications of eculizumab, as well as the disadvantages of eculizumab treatment in patients with C5 polymorphisms., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Randomized clinical trials (RCTs) of PCSK9 monoclonal antibody(mAb) specifically for Chinese patients have been limited. This multi-center RCT is to clarify the efficacy and safety of a novel mAb, Ebronucimab, in Chinese patients. Patients diagnosed with primary hypercholesterolemia, including Heterozygous Familial Hypercholesterolemia, or mixed dyslipidemia, were categorized by ASCVD risk and randomly assigned at a ratio of 2:1:2:1 to receive Ebronucimab 450 mg or matching placebo every 4 weeks (Q4W), or Ebronucimab 150 mg or matching placebo every 2 weeks (Q2W). The primary outcome was the percentage change of LDL-C from baseline to week 12 for all groups. The least squares mean reduction difference (95 %CI) in LDL-C from baseline to week 12 of Ebronucimab 450 mg Q4W and Ebronucimab 150 mg Q2W groups versus the placebo group was -59.13 (-64.103, -54.153) (Adjusted p<0.0001) and -60.43 (-65.450, -55.416) (Adjusted p<0.0001), respectively. Meanwhile, the Ebronucimab group exhibited notably high rates in reaching LDL-C goals of each cardiovascular risk stratification. In addition, Ebronucimab effectively improved other lipid panel. During the double-blind treatment period, relatively frequently reported adverse events (AEs) were injection site reactions (ISR), urinary tract infection, and hyperuricemia (Incidence rate are 6.9 %, 4.8 % and 3.5 %). Among treatment-associated AEs, only injection site reactions (ISR) occurred more in the dose groups. In conclusion, Ebronucimab, with either 450 mg Q4W or 150 mg Q2W doses, demonstrated significant efficacy in lowering serum LDL-C level with a favorable safety and immunogenicity profile among hypercholesterolemic patients., Competing Interests: Declaration of Competing Interest Binge Yu, Guoqin Wang, Fang Xu, Dongmei Lu, Zhimei He, Benchao Chen, Lei Ma, Max Wang, Baiyong Li, and Michelle Xia are employees of Akeso Pharmaceutical (Guangzhou) Co., Ltd. The remaining co-authors have nothing to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Background: At the time of AtTEnd trial design, standard treatment for advanced or recurrent endometrial cancer included carboplatin and paclitaxel chemotherapy. This trial assessed whether combining atezolizumab with chemotherapy might improve outcomes in this population., Methods: AtTEnd was a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done in 89 hospitals in 11 countries across Europe, Australia, New Zealand, and Asia. Enrolled patients were aged 18 years or older, and had advanced or recurrent endometrial carcinoma or carcinosarcoma, an Eastern Cooperative Oncology Group performance status of 0-2, and received no previous systemic chemotherapy for recurrence. Patients were randomly assigned (2:1) using an interactive web response system (block size of six) to either atezolizumab 1200 mg or placebo given intravenously with chemotherapy (carboplatin at area under the curve of 5 or 6 and paclitaxel 175 mg/m 2 intravenously on day 1 every 21 days) for 6-8 cycles, then continued until progression. Stratification factors were country, histological subtype, advanced or recurrent status, and mismatch repair (MMR) status. Participants and treating clinicians were masked to group allocation. The hierarchically tested co-primary endpoints were progression-free survival (in patients with MMR-deficient [dMMR] tumours, and in the overall population) and overall survival (in the overall population). Primary analyses were done in the intention-to-treat population, defined as all randomly assigned patients who gave their full consent to participation in the study and data processing. Safety was assessed in all patients included in the intention-to-treat population who received at least one dose of study treatment. Here, we report the primary progression-free survival and the interim overall survival results. This study is ongoing and is registered with ClinicalTrials.gov, NCT03603184., Findings: Between Oct 3, 2018, and Jan 7, 2022, 551 patients were randomly assigned to atezolizumab (n=362) or placebo (n=189). Two patients in the atezolizumab group were excluded from all analyses due to lack of consent. Median follow-up was 28·3 months (IQR 21·2-37·6). 81 (23%) patients in the atezolizumab group and 44 (23%) patients in the placebo group had dMMR disease by central assessment. In the dMMR population, median progression-free survival was not estimable (95% CI 12·4 months-not estimable [NE]) in the atezolizumab group and 6·9 months (6·3-10·1) in the placebo group (hazard ratio [HR] 0·36, 95% CI 0·23-0·57; p=0·0005). In the overall population, median progression-free survival was 10·1 months (95% CI 9·5-12·3) in the atezolizumab group and 8·9 months (8·1-9·6) in the placebo group (HR 0·74, 95% CI 0·61-0·91; p=0·022). Median overall survival was 38·7 months (95% CI 30·6-NE) in the atezolizumab group and 30·2 months (25·0-37·2) in the placebo group (HR 0·82, 95% CI 0·63-1·07; log-rank p=0·048). The p value for the interim analysis of overall survival did not cross the stopping boundary; therefore, the trial will continue until the required number of events are recorded. The most common grade 3-4 adverse events were neutropenia (97 [27%] of 356 patients in the atezolizumab group vs 51 [28%] of 185 in the placebo group) and anaemia (49 [14%] vs 24 [13%]). Treatment-related serious adverse events occurred in 46 (13%) patients in the atezolizumab group and six (3%) patients in the placebo group. Treatment-related deaths occurred in two patients (pneumonia in one patient in each group)., Interpretation: Atezolizumab plus chemotherapy increased progression-free survival in patients with advanced or recurrent endometrial carcinoma, particularly in those with dMMR carcinomas, suggesting the addition of atezolizumab to standard chemotherapy as first-line treatment in this specific subgroup., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests EB, FG, ER, and SU report grants from Roche to their institution to support the conduct of the study. NC reports personal fees from AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, Mersana, MSD/Merck, Nuvation Bio, OncXerna, Pieris, Pfizer, Roche, and Novocure; and grants or research support from GSK and AstraZeneca. KH reports personal fees from AstraZeneca, Chugai, Eisai, MSD/Merck, Taiho, and Takeda; and grants or research support from MSD/Merck, Chugai, Takeda, AstraZeneca, and Daiichi Sankyo. EH reports personal fees from GSK and Clovis. FM reports personal fees from Roche, Eisai, Novartis, AstraZeneca, Pfizer, Lilly, Daiichi Sankyo, MSD/Merck, GSK, Clovis, Gilead, Myriad Genetics, Seagen, and Stemline Menarini; grants or research support from Roche; and participation on data safety monitoring or advisory boards for Immutep, Amgen, and Palleos Healthcare. CM reports personal fees from Roche, Novartis, MSD/Merck, AstraZeneca, Pfizer, PharmaMar, ImmunoGen, Daiichi Sankyo, Novocure, BioNTtech, Eisai, and GSK. LF-M reports personal fees from AstraZeneca, GSK, MSD/Merck, Eisai, and Pharma&. YCL reports personal fees from AstraZeneca, and grants or research support from BeiGene. EP reports personal fees from GSK and AstraZeneca. BP reports personal fees from AstraZeneca, GSK, MSD/Merck, and Pharma&. CZ reports personal fees from Roche, Eisai, Novartis, AstraZeneca, Pfizer, QuintilesIMS, Clovis, Eli Lilly, Istituto Gentili, Daiichi Sankyo, Seagen, MSD/Merck, GSK, and Gilead; and grants or research support from Roche, Novartis, AstraZeneca, Pfizer, Eisai, Clovis, Gilead, Seagen, Eli Lilly, Daiichi Sankyo, and MSD/Merck. KT reports personal fees from AstraZeneca, Chugai Pharma, Takeda, MSD/Merck, Nippon Kayaku, Eisai, and Sanofi; and grants or research support from Chugai Pharma. AF reports personal fees from GSK, AstraZeneca, and MSD/Merck. MP reports personal fees from AstraZeneca, Eisai, GSK, and MSD/Merck. MPBG reports personal fees from AstraZeneca, GSK, MSD/Merck, PharmaMar, Clovis Oncology, Eisai, Pharma&, and Kyowa Kirin; and a leadership role for Geico. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Stapokibart/CM310, a humanized monoclonal antibody targeting the interleukin-4 receptor α chain, has shown promising treatment benefits in patients with moderate-to-severe atopic dermatitis in previous phase II clinical trials., Objective: We aimed to evaluate the long-term efficacy and safety of stapokibart in adults with moderate-to-severe atopic dermatitis., Methods: Enrolled patients who previously completed parent trials of stapokibart received a subcutaneous stapokibart 600-mg loading dose, then 300 mg every 2 weeks up to 52 weeks. Efficacy outcomes included the proportions of patients with ≥ 50%/75%/90% improvements from baseline of parent trials in the Eczema Area and Severity Index, Investigator's Global Assessment, and weekly average of the daily Peak Pruritus Numerical Rating Scale., Results: In total, 127 patients were enrolled, and 110 (86.6%) completed the study. At week 52, the Eczema Area and Severity Index-50/75/90 response rates were 96.3%, 87.9%, and 71.0%, respectively. An Investigator's Global Assessment 0/1 with a ≥ 2-point reduction was achieved in 39.3% of patients at week 16, increasing to 58.9% at week 52. The proportions of patients with ≥ 3-point and ≥ 4-point reductions in the weekly average of daily Peak Pruritus Numerical Rating Scale scores were 80.2% and 62.2%, respectively, at week 52. Improvement in patients' quality of life was sustained over a 52-week treatment period. Treatment-emergent adverse events occurred in 88.2% of patients, with an exposure-adjusted event rate of 299.2 events/100 patient-years. Coronavirus disease 2019, upper respiratory tract infection, and conjunctivitis were the most common treatment-emergent adverse events., Conclusions: Long-term treatment with stapokibart for 52 weeks showed high efficacy and good safety profiles, supporting its use as a continuous long-term treatment option for atopic dermatitis., Clinical Trial Registration: ClinicalTrials.gov identifier: NCT04893707 (15 May, 2021)., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Ocrelizumab is the only disease-modifying therapy (DMT) approved for the treatment of people with primary progressive multiple sclerosis (pwPPMS)., Objectives: To provide real-world evidence of ocrelizumab effectiveness and safety in pwPPMS in Croatian MS centers., Methods: A retrospective observational multi-center study of pwPPMS who were started on ocrelizumab in 7 MS centers in Croatia., Results: We identified 230 pwPPMS of whom 176 fulfilled the inclusion criteria. The median follow-up of the cohort was 2.73 (0.51-5.77) years. During the follow-up, 50 (28.4%) pwPPMS experienced confirmed disability worsening (CDW) and 19 (10.8%) stopped treatment with ocrelizumab. Baseline EDSS >5 was a statistically significant positive predictor for the development of CDW and/or stop of the treatment due to any cause (OR 2.482, 95% C.I. 1.192-5.166, p = 0.015). However, there was no significant difference in the development of CDW and/or stop of the treatment due to any cause if stratifying the patients based on active PPMS, age at treatment start (≤55 years vs >55 years), disease duration at treatment start (≤10 years vs >10 years), or EDSS at treatment start (≤5.0 vs >5.0). During the follow-up, 26 (14.8%) pwPPMS experienced infusion reactions, 64 (36.4%) had an infection and 4 (2.3%) developed a tumor. The percentage of pwPPMS with low levels of IgG was persistently above 10% and with low levels of IgM was persistently above 20% after cycle 4., Conclusion: Our real-world data support the use of ocrelizumab in a much broader pwPPMS population than in the original randomized controlled trial., Competing Interests: Declaration of competing interest MH, IA, BB, TG, MKS: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Sanofi Genzyme, Merck, Novartis, Pliva/Teva, Roche, Zentiva, Actelion, Alexion Pharmaceuticals, TG Pharmaceuticals. VBK: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Sanofi Genzyme, Merck, Pliva/Teva, Roche. NG: Nothing to disclose. IL: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Novartis, Roche, Merck, Biogen, Sanofi, Pliva. SP: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Novartis, Roche, Merck, Biogen, Zentiva, Pliva. TMZ: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Roche, Biogen, Teva/Pliva, Merck, Sanofi, Novartis. MK: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Novartis, Biogen, Merck, Sanofi. SKP: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Roche, Biogen, Boerhringer, Teva/Pliva, Merck, Novartis. AA: Nothing to disclose. There was no support from any organization for the submitted work; no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening inflammatory skin disease. Interleukin (IL)-36 signalling may play a central role in GPP pathogenesis. Spesolimab is a humanized anti-IL-36 monoclonal antibody inhibiting the IL-36 signalling pathway. Here, we investigated the pharmacokinetics and safety of spesolimab in healthy Chinese subjects., Methods: In this Phase 1, single-dose, parallel-group, open-label study, healthy Chinese subjects aged 18-45 years received a single spesolimab dose by intravenous infusion (IV; 450 mg, 900 mg, or 1200 mg) or subcutaneous (SC) administration (300 mg or 600 mg). Primary endpoints were spesolimab exposure (area under the plasma concentration-time curve and maximum plasma concentration); secondary endpoints were treatment-emergent adverse events (TEAEs) and drug-related adverse events (AEs)., Results: Fifty subjects received IV (n = 30) or SC (n = 20) spesolimab (n = 10 per dose group); 60.0% were male, mean ± standard deviation age was 31.5 ± 6.6 and 31.0 ± 6.5 years in the IV and SC groups, respectively. Spesolimab exposure increased in a dose-proportional manner in both groups. TEAEs were reported in 83.3% and 80.0% of subjects in the IV and SC groups, the most common TEAE was upper respiratory tract infection (20.0% and 25.0%, respectively). One serious AE of hand fracture was reported in the 900 mg IV group that was not considered drug-related. Drug-related AEs were reported in 53.3% and 55.0% of subjects in the IV and SC groups. All laboratory-related AEs were mild and resolved., Conclusion: Spesolimab exposure increased in a dose-proportional manner after a single dose by IV and SC administration. Spesolimab was well tolerated in healthy Chinese subjects., Clinical Trial Registration: Clinicaltrials.gov registration: NCT04390568., (© 2024. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Purpose: Standard-of-care first-line treatment for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is pembrolizumab plus platinum and fluorouracil (FU). However, FU is associated with potential challenges (continuous 4-day infusion, high administration costs, and cardiovascular and gastrointestinal toxicities), creating a clinical need for alternative chemotherapy combinations. We evaluated the efficacy and safety of first-line pembrolizumab plus carboplatin and paclitaxel for R/M HNSCC in the open-label, single-arm, phase IV KEYNOTE-B10 study (ClinicalTrials.gov identifier: NCT04489888)., Methods: Eligible adults had previously untreated, histologically or cytologically confirmed R/M HNSCC regardless of PD-L1 status, measurable disease per RECIST v1.1 by blinded independent central review (BICR), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received pembrolizumab 200 mg intravenously once every 3 weeks for ≤35 cycles and carboplatin AUC 5 mg/mL/min intravenously once every 3 weeks for ≤6 cycles and investigator's choice of paclitaxel 100 mg/m 2 on days 1 and 8 or 175 mg/m 2 on day 1, intravenously once every 3 weeks. The primary end point was objective response rate per RECIST v1.1 by BICR., Results: Between October 27, 2020, and April 29, 2022, 149 patients were screened and 101 received treatment. As of February 20, 2023, the median follow-up was 18.9 months (range, 9.1-27.0). At this final analysis, 49 (49%) of 101 patients had an objective response (95% CI, 38.4 to 58.7), including seven patients (7%) with a confirmed complete response. Of the 101 treated patients, grade 3-5 and serious treatment-related adverse events occurred in 76 (75%) and 27 (27%), respectively. There were no new safety signals., Conclusion: Pembrolizumab plus carboplatin and paclitaxel showed promising antitumor activity and a manageable safety profile in first-line R/M HNSCC, suggesting this combination may be an alternative option for this patient population.

Platinum-based chemotherapy has been the cornerstone of first-line treatment for advanced urothelial carcinoma for decades, based on its proven efficacy and well-characterized safety profile. Although enfortumab vedotin (EV) plus pembrolizumab showed superior efficacy versus platinum-based chemotherapy in the EV-302 phase 3 trial, common and potentially cumulative toxicities associated with EV plus pembrolizumab may make this combination less suitable for some patients, such as those with pre-existing neuropathy, hyperglycemia, or hepatic impairment, or patients likely to have favorable outcomes with platinum-based chemotherapy. The availability of EV plus pembrolizumab in various countries may also be limited by financial considerations. Thus, platinum-based chemotherapy is likely to remain a valuable option for advanced urothelial carcinoma. Eligibility for cisplatin- or carboplatin-based regimens can be determined by assessing renal function, performance status, and specific comorbidities. In cisplatin-eligible and -ineligible patients without disease progression following platinum-based chemotherapy, avelumab first-line maintenance is standard of care based on findings from the JAVELIN Bladder 100 phase 3 trial, which showed that avelumab first-line maintenance plus best supportive care prolonged overall survival and progression-free survival compared with best supportive care alone across clinically relevant subgroups. Adverse events associated with avelumab were generally consistent with those observed with other immune checkpoint inhibitors, and long-term follow-up showed no new safety concerns with prolonged treatment. Efficacy benefits and safety profiles were similar in patients who received avelumab first-line maintenance after cisplatin- or carboplatin-based chemotherapy. The effectiveness and safety of avelumab first-line maintenance have been confirmed in several real-world studies. Overall, these data support the use of avelumab first-line maintenance for all platinum-treated patients without disease progression. In this podcast, we discuss the evolving role of platinum-based chemotherapy in this disease setting in the context of EV-302 trial results and describe practical considerations in patients receiving first-line cisplatin- or carboplatin-based chemotherapy followed by avelumab maintenance therapy., (© 2024. The Author(s).)

Objective: This proof-of-principle pharmacovigilance study used Electronic Health Record (EHR) data to examine the safety of sotrovimab, paxlovid and molnupiravir in prehospital treatment of Covid-19., Method: With NHS England approval, we conducted an observational cohort study using OpenSAFELY-TPP, a secure software-platform which executes analyses across EHRs for 24 million people in England. High-risk individuals with Covid-19 eligible for prehospital treatment were included. Adverse events (AEs) were categorised into events in the drug's Summary of Product Characteristics (SmPC), drug-reactions and immune-mediated. Cox models compared risk across treatments. A pre-pandemic record analysis was performed for comparative purposes., Results: Between 2021-2023, 37,449 patients received sotrovimab, paxlovid or molnupiravir whilst 109,647 patients made up an eligible-but-untreated population. The 28-day rates of AEs were low: SmPC 0.34 per 1000 patient-years (95% CI 0.32-0.36); drug-reactions 0.01 (95% CI 0.01-0.02) and immune-mediated 0.03 (95% CI 0.03-0.04), and similar or lower than the pre-pandemic period. Compared with the eligible but untreated population, sotrovimab and paxlovid associated with a risk of SmPC AE [adjHR 1.36 (95% CI 1.15-1.62) and 1.28 (95% CI 1.05-1.55), respectively], whilst sotrovimab associated with a risk of drug-reactions [adjHR 2.95 (95% CI 1.56-5.55)] and immune-mediated events [adjHR 3.22 (95% CI 1.86-5.57)]., Conclusion: Sotrovimab, paxlovid and molnupiravir demonstrate acceptable safety profiles. Although the risk of AEs was greatest with sotrovimab, event rates were lower than comparative pre-pandemic period., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AG, BMK, BZ, RMS, SB, SN and ZY have no known competing financial interests. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AM is a senior clinical researcher at the University of Oxford in the Bennett Institute, which is funded by contracts and grants obtained from the Bennett Foundation, Wellcome Trust, NIHR Oxford Biomedical Research Centre, NIHR Applied Research Collaboration Oxford and Thames Valley, Mohn-Westlake Foundation, and NHS England. AMe received 3 days of consultancy for https://inductionhealthcare.com/ (last date feb 2022) - paid direct to me. Member of RCGP health informatics group and the NHS Digital GP data Professional Advisory Group that advises on access to GP Data for Pandemic Planning and Research (GDPPR); payment direct to me for the GDPPR role. Last invoiced Dec 2022. BG has received research funding from the Laura and John Arnold Foundation, NIHR, NIHR School of Primary Care Research, NHS England, NIHR Oxford Biomedical Research Centre, the Mohn-Westlake Foundation, NIHR Applied Research Collaboration Oxford and Thames Valley, the Wellcome Trust, the Good Thinking Foundation, Health Data Research UK, the Health Foundation, the World Health Organisation, UKRI MRC, Asthma UK, the British Lung Foundation, and the Longitudinal Health and Wellbeing strand of the National Core Studies programme; he is a Non-Executive Director at NHS Digital; he also receives personal income from speaking and writing for lay audiences on the misuse of science. JBG has received honoraria from Abbvie, Amgen, Celgene, Chugai, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sobi, and UCB, and has research funding from Amgen, Aztra-Zeneca, Gilead, Janssen, Medicago, Novovax and Pfizer. KB has received honoraria from Galapagos, UCB and Viforpharma. MDR has received honoraria from AbbVie, Biogen, Lilly, Galapagos, Menarini, UCB, and Viforpharma., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

To assess the efficacy and safety of burosumab in children and adults with X-linked hypophosphatemia based on real-world evidence. MEDLINE (via PubMed) and Cochrane Library were searched until 18 October 2023 for single-arm (before-after) studies. Registries including Clinicaltrials.gov, EU Clinical Trials, WHO International Clinical Trials Registry Platform, and conference abstracts. The outcomes were a change in serum phosphorus concentrations and change in RSS, a change in serum ALP, bone-specific ALP, a change in the ratio of Tubular maximum reabsorption of Phosphate to Glomerular Filtrate rate, a change in serum 1,25(OH) 2 D and 25(OH) 2 D concentrations, change in height Z-score, McMaster Universities Osteoarthritis Index (WOMAC) and safety outcomes. An inverse variance random-effects meta-analysis was applied for data synthesis. Fifteen studies (289 participants) were included. Burosumab treatment improved serum phosphate concentrations [mean difference 0.88 mg/dl, 95% confidence interval 0.70 to 1.07, I 2  = 92%), Rickets Severity score (mean difference - 1.86, 95% confidence interval - 2.5 to - 1.21, I 2  = 71%), serum alkaline phosphate concentrations (mean difference - 1.86, 95% confidence interval - 2.5 to - 1.21, I 2  = 71%), serum 1,25(OH) 2 D concentrations (mean difference 18.91 pg/ml, 95% confidence interval 6.39 to 31.43, I 2  = 96%) and renal phosphate reabsorption (mean difference 1.22 mg/dl, 95% confidence interval 0.70 to 1.74, I 2 93%). Burosumab treatment improved overall clinical and laboratory findings in patients with X-linked hypophosphatemia., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Atezolizumab, carboplatin, and etoposide (ACE) therapy is a standard of care for extensive-disease small cell lung cancer (SCLC); however, its safety data are scarce, limiting generalization to the Japanese population., Methods: This study aimed to compare the safety of ACE versus carboplatin and etoposide (CE) therapies in Japanese patients using the Diagnosis Procedure Combination (DPC) database by comparing the incidence of adverse events (AEs). Retrospective data on clinical background and AEs were extracted from the DPC database. Incidence rates and restricted mean survival times (RMSTs) up to 6 months were analyzed for 19 clinically important AEs. Covariates were adjusted using the inverse probability weighting method., Results: A total of 330,774 patients were identified using the International Statistical Classification of Diseases and Related Health Problems 10th Revision codes, of whom 277 were included in the ACE cohort and 478 in the CE cohort. Among the 19 AEs, the incidence of skin disorder and thyroid dysfunction was significantly higher in the ACE cohort compared with the CE cohort. The adjusted incidence rate ratios were 2.38 (95% confidence interval [CI] 1.04-5.43) for skin disorder and 6.92 (95% CI 2.00-23.89) for thyroid dysfunction. The adjusted RMST differences were - 8.2 days (95% CI - 16.0 to - 0.4 days) for skin disorder and - 8.8 days (95% CI - 15.7 to - 1.9 days) for thyroid dysfunction., Conclusions: This study provides evidence regarding the safety of ACE combination therapy in Japanese clinical practice using the DPC database, with results comparable to those reported in pivotal clinical trials., Trial Registration: UMIN Clinical Trials Registry ID UMIN000041508., (© 2024. The Author(s).)

Introduction: Mogamulizumab is an anti-C-C chemokine receptor 4 antibody that is increasingly being used to treat T-cell malignancies such as cutaneous T-cell lymphoma, adult T-cell leukemia-lymphoma, and peripheral T-cell lymphoma. Because CCR4 is expressed on both malignant T-cells and regulatory T-cells (Tregs), mogamulizumab can be associated with increased immune-related adverse events (irAEs). While there is abundant literature on mogamulizumab-associated rash (MAR) and graft-versus-host disease (GVHD), other reported irAEs have not been collated into a single review., Areas Covered: This narrative review covers irAEs associated with mogamulizumab in patients with T-cell lymphomas, focusing on events other than MAR and GVHD. We searched PubMed and Google Scholar for case reports, case series, chart reviews, and clinical trials published from inception to March 2024. Identified events include alopecia, vitiligo, arthritis, psoriasis, myocarditis, myositis/polymyositis, hepatitis, and others., Expert Opinion: Mogamulizumab's ability to augment the host immune response through Treg depletion adds to its efficacy but has wide-ranging implications for autoimmunity across multiple organ systems, similar to immune checkpoint inhibitor therapy. Occurrence of irAEs may be associated with improved overall clinical response, although long-term follow-up studies are needed.

Introduction: Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) combination therapy is a standard of care for advanced non-squamous non-small cell lung cancer (NSQ-NSCLC); however, the lack of safety data limits its clinical application in Japan., Methods: This study compared the safety of ABCP with that of bevacizumab, carboplatin, and paclitaxel (BCP) combination for the treatment of advanced NSQ-NSCLC in Japanese patients by evaluating the clinical background and incidence of adverse events (AEs) based on data extracted from the Diagnosis Procedure Combination (DPC) database. Incidence rates and restricted mean survival times (RMSTs) for up to 1 year were analyzed for 19 clinically important AEs. Covariates were adjusted using the inverse probability weighting method., Results: A search conducted using the International Statistical Classification of Diseases and Related Health Problems 10th Revision codes identified 350,987 patients, of whom 202 were included in the ABCP cohort and 232 in the BCP cohort. Among the 19 AEs, the incidence of skin disorder and febrile neutropenia (FN) was significantly higher in the ABCP cohort versus the BCP cohort. The adjusted incidence rate ratios were 2.65 [95% confidence interval (CI) 1.43-4.91] for skin disorder and 1.70 (95% CI 1.01-2.85) for FN. The adjusted RMST differences were - 64.2 days (95% CI - 93.0 to - 35.4 days) and - 46.0 days (95% CI - 73.5 to - 18.5 days) for skin disorder and FN, respectively. These results were comparable to those of other pivotal clinical trials., Conclusions: The findings of this DPC database study highlight the safety of ABCP in Japanese clinical practice, and this methodology may facilitate more efficient research in real-world settings., Trial Registration: UMIN Clinical Trials Registry ID UMIN000041507., (© 2024. The Author(s).)

Background and Aims: Guillain-Barré syndrome (GBS) is an acute, self-limited, immune-mediated peripheral neuropathy. Current treatments for GBS include intravenous immunoglobulin (IVIg) and plasma exchange, which may not sufficiently benefit severely affected patients. This study evaluated the efficacy and safety of eculizumab add-on therapy to IVIg (standard-of-care treatment) in patients with severe GBS., Methods: This phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial (NCT04752566), enrolled Japanese adults (age ≥ 18 years) with severe GBS (Hughes functional grade [FG] score FG3 or FG4/FG5 within 2 weeks of onset of GBS). Participants were randomized 2:1 to receive intravenous infusion of eculizumab or placebo (once weekly for 4 weeks) with IVIg treatment with 20 weeks of follow-up. Primary efficacy endpoint was the time to first reach FG score ≤1 (able to run). Key secondary endpoints were proportion of participants achieving FG ≤1 at weeks 8 and 24 and FG improvement ≥3 at week 24. Pharmacodynamic analysis of serum free C5 concentration over time was performed. Safety was evaluated., Results: The analysis included 57 participants (eculizumab, n = 37; placebo, n = 20). Primary endpoint was not achieved (hazard ratio, 0.9; 95% CI, 0.45-1.97; p = .89). Key secondary endpoints did not reach statistical significance. Serum C5 concentration was reduced by 99.99% at 1 h postdose and sustained to week 5 but returned to baseline at the end of follow-up period. No new safety signals for eculizumab were identified., Interpretation: Although well tolerated, eculizumab treatment did not show significant effects on motor function recovery compared to placebo in patients with GBS., (© 2024 The Author(s). Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Background: Combining PARP inhibitors (PARPis) with immune checkpoint inhibitors may improve clinical outcomes in selected cancers. We evaluated rucaparib and atezolizumab in advanced gynaecological or triple-negative breast cancer (TNBC)., Methods: After identifying the recommended dose, patients with PARPi-naive BRCA-mutated or homologous recombination-deficient/loss-of-heterozygosity-high platinum-sensitive ovarian cancer or TNBC received rucaparib plus atezolizumab. Tumour biopsies were collected pre-treatment, during single-agent rucaparib run-in, and after starting combination therapy., Results: The most common adverse events with rucaparib 600 mg twice daily and atezolizumab 1200 mg on Day 1 every 3 weeks were gastrointestinal effects, fatigue, liver enzyme elevations, and anaemia. Responding patients typically had BRCA-mutated tumours and higher pre-treatment tumour levels of PD-L1 and CD8 + T cells. Markers of DNA damage repair decreased during rucaparib run-in and combination treatment in responders, but typically increased in non-responders. Apoptosis signature expression showed the reverse. CD8 + T-cell activity and STING pathway activation increased during rucaparib run-in, increasing further with atezolizumab., Conclusions: In this small study, rucaparib plus atezolizumab demonstrated acceptable safety and activity in BRCA-mutated tumours. Increasing anti-tumour immunity and inflammation might be a key mechanism of action for clinical benefit from the combination, potentially guiding more targeted development of such regimens., Clinical Trial Registration: ClinicalTrials.gov (NCT03101280)., (© 2024. The Author(s).)

Background: Palmoplantar pustulosis (PPP), a refractory skin disease characterized by repeated eruptions of sterile pustules and vesicles on palms and/or soles, involves interleukin-17 pathway activation. Brodalumab, a fully human anti-interleukin-17 receptor A monoclonal antibody, is being investigated for use in PPP treatment., Objective: The aim was to assess the efficacy and safety of brodalumab in Japanese PPP patients with moderate or severe pustules/vesicles., Methods: A phase 3, randomized, double-blind, placebo-controlled trial was conducted between July 2019 and August 2022, at 41 centers in Japan. Patients aged 18-70 years with a diagnosis of PPP for ≥ 24 weeks, a PPP Area Severity Index (PPPASI) score of ≥ 12, a PPPASI subscore of pustules/vesicles of ≥ 2, and inadequate response to therapy were included. Participants were randomized 1:1 to receive brodalumab 210 mg or placebo, subcutaneously (SC) at baseline, weeks 1 and 2, and every 2 weeks (Q2W) thereafter until week 16. Changes from baseline to week 16 in the PPPASI total score (primary endpoint) and other secondary skin-related endpoints and safety endpoints were assessed., Results: Of the 126 randomized patients, 50 of 63 in the brodalumab group and 62 of 63 in the placebo group completed the 16-week period. Reasons for discontinuation were adverse event (n = 6), withdrawal by patient/parent/guardian (n = 3), progressive disease (n = 3), and lost to follow-up (n = 1) in the brodalumab group and Good Clinical Practice deviation (n = 1) in the placebo group. Change from baseline in the PPPASI total score at week 16 was significantly higher (p = 0.0049) with brodalumab (least-squares mean [95% confidence interval {CI}] 13.73 [10.91-16.56]) versus placebo (8.45 [5.76-11.13]; difference [95% CI] 5.29 [1.64-8.94]). At week 16, brodalumab showed a trend of rapid improvement versus placebo for PPPASI-50/75/90 response (≥ 50%/75%/90% improvement from baseline) and Physician's Global Assessment 0/1 score: 54% versus 24.2%, 36.0% versus 8.1%, 16.0% versus 0.0%, and 32.0% versus 9.7%, respectively. Infection was the dominant treatment-emergent adverse event (TEAE); the commonly reported TEAEs were otitis externa (25.4%/1.6%), folliculitis (15.9%/3.2%), nasopharyngitis (14.3%/4.8%), and eczema (14.3%/12.9%) in the brodalumab/placebo groups, respectively. The severity of most TEAEs reported was Grade 1 or 2 and less frequently Grade ≥ 3., Conclusions: Brodalumab SC 210 mg Q2W demonstrated efficacy in Japanese PPP patients. The most common TEAEs were mild infectious events., Trial Registration: NCT04061252 (Date of Trial Registration: August 19, 2019)., (© 2024. The Author(s).)

The aim of this study was to observe the therapeutic effect of sintilimab combined with a modified docetaxel + cisplatin + fluorouracil (DCF) regimen on advanced gastric cancer and its effect on Th1/Th2 immune balance. Ninety-eight cases of advanced gastric cancer patients who visited our hospital from April 2020 to May 2022 were selected and divided into 48 cases each in the conventional group and the research group by random number table method; the DCF regimen was adopted in the conventional group, and sintilimab combined with modified DCF regimen was adopted in the research group, and the therapeutic effects of the patients in the two groups and the changes of Th1/Th2 immune indexes were compared. CEA, CA199, CA242, CD168 AQ3, and IL-4 in the study group were lower than those in the conventional group at the end of three cycles of treatment, and the difference was statistically significant ( P  < 0.001). The levels of IFN-γ and IL-4 in the study group at the end of three cycles of treatment were higher than those in the conventional group ( P  < 0.001). The incidence of adverse reactions during treatment in the study group was lower than that in the conventional group ( P  < 0.001), and the grading of adverse reactions in the study group was milder than that in the conventional group. Sintilimab combined with a modified DCF regimen in the treatment of advanced gastric cancer not only improves the therapeutic effect but also positively affects the Th1/Th2 immune balance, which provides better immune regulation for patients with advanced gastric cancer., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Pembrolizumab, a monoclonal antibody against PD-1, has shown limited efficacy in patients with microsatellite stable or mismatch repair proficient (MSS/pMMR) metastatic colorectal cancer (CRC). We evaluated vicriviroc (small-molecule C-C motif chemokine ligand 5 antagonist) plus pembrolizumab in patients with advanced or metastatic MSS/pMMR CRC., Patients and Methods: This open-label, phase 2 trial (NCT03631407) enrolled adults with histologically confirmed, locally advanced, unresectable or metastatic CRC that was MSS per local assessment. All patients had received previous treatment with standard therapies. Patients were randomized 1:1 to vicriviroc 150 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks or vicriviroc 250 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles (2 years). Primary endpoints were the objective response rate (ORR) as assessed by the investigator per RECIST v1.1, dose-limiting toxicities (DLTs), adverse events (AEs), and discontinuations due to AEs., Results: Forty patients were enrolled and treated. ORR was 5% (95% CI, 0.1%-24.9%) in both treatment groups. There were no complete responses; 1 patient in each treatment group experienced a partial response. No patient in the vicriviroc 150 mg plus pembrolizumab group experienced a DLT. Two patients in the vicriviroc 250 mg plus pembrolizumab group experienced DLTs (1 grade 4 encephalopathy and 1 grade 4 pneumonitis)., Conclusion: The combination of vicriviroc at doses of 150 or 250 mg plus pembrolizumab 200 mg showed limited antitumor activity in patients with advanced or metastatic MSS/pMMR CRC. Toxicity with the combination was manageable., Competing Interests: Disclosure Xiaofu Zhu: Advisory Board—Pfizer, Novartis, Lilly, AstraZeneca, Genomic Health, Apobiologix, Merck & Co., Inc., Rahway, NJ, USA, Leo Pharma, Amgen, and Taiho Pharma. Educational Support – Taiho Pharma and Novartis. Lucas Wong: Research funding to support study conduct from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Vincent Giranda: Former employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and stockholder in Merck & Co., Inc., Rahway, NJ, USA. Leah Suttner, Fang Liu, and Manash Chatterjee: Employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and stockholders in Merck & Co., Inc., Rahway, NJ, USA. Sunil Sharma: Received fees from Barricade Therapeutics, Celularity Inc., Elevar Therapeutics, Incyte, Stemline Therapeutics, Inc., Rappta Therapeutics, Processa Pharmaceuticals, and Novelty Nobility. All other authors have nothing to disclose., (Copyright © 2024. Published by Elsevier Inc.)

The purpose of this study is to evaluate the efficacy and safety of belimumab combined with the standard regimen in treating children with active lupus nephritis. This single-center, retrospective cohort study used clinical data of children with newly active lupus nephritis hospitalized in the Department of Nephrology between December 2004 and February 2023. Patients were divided into a belimumab or traditional treatment group according to whether or not they received belimumab. Renal remission and recurrence rates and glucocorticoid dose were compared between groups. Forty-seven children (median age 11 years) were enrolled, including 30 and 17 children in the traditional treatment and belimumab groups, respectively. The Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2000) score of children in the belimumab group (23.59 ± 7.78) was higher than that in the traditional treatment group (19.13 ± 6.10) (P = 0.035). The two groups showed no significant difference in the frequency of pyuria, gross hematuria, and the levels of 24-h proteinuria and estimated glomerular filtration rate. The complement C3/C4 in the belimumab group recovered faster than that in the traditional treatment group (P < 0.05). There were no between-group differences in the complete renal remission rate at 6 or 12 months (P = 0.442, P = 0.759). There were no between-group differences in 1-year recurrence rate (P = 0.303). Furthermore, 6 and 12 months after treatment, glucocorticoid doses were lower in the belimumab than the traditional treatment group (17.87 ± 6.96 mg/d vs. 27.33 ± 8.40 mg/d, P = 0.000; 10.00 (5.3) mg/d vs. 13.75 (10.0) mg/d, P = 0.007), respectively., Conclusion: With an equivalent renal remission rate, belimumab combined with the standard traditional regimen might promote the tapering of glucocorticoids, and the incidence of adverse events is low., What Is Known: • Belimumab is documented as an adjunctive treatment with systemic lupus erythematosus (c-SLE) LN with efficacy. • Due to the paucity of studies, its effects and side effects in children with LN remain unclear., What Is New: • This single-center, retrospective cohort study evaluated the efficacy and safety of belimumab combined with the standard regimen in treating children with proliferative LN. • Belimumab combined with the standard traditional treatment might promote the tapering of glucocorticoids, while exhibiting a low occurrence of adverse events., (© 2024. The Author(s).)

Consensus diagnostic and risk stratification of transplantation-associated thrombotic microangiopathy (TA-TMA) was recently achieved from international transplantation groups. Although the proposed diagnostic criteria have been applied to multiple pediatric cohorts, there are scant data applying the novel risk stratification approach in children with TA-TMA. In this retrospective cohort study, all children undergoing an allogeneic HCT or autologous HCT for neuroblastoma were prospectively screened for TA-TMA, diagnosed, and risk-stratified using the Jodele criteria from August 2019 to October 2023. Our institutional practice during the study period was treat all Jodele intermediate-risk (IR) and high-risk (HR) patients with eculizumab. Harmonization risk stratification criteria were applied retrospectively. All survival analyses were calculated from the day of TA-TMA diagnosis. To identify which specific harmonization high-risk features were the most important predictors for nonrelapse mortality (NRM), full and reduced logistical regression models were tested. The lowest Bayes information criterion and optimal Mallows CP statistic were used to identify the best subset. The analysis was performed with SAS 9.4 (SAS Institute, Cary, NC). Fifty-two children were diagnosed with TA-TMA during the study period, at a median of 37.5 days post-HCT (range, 3 to 735 days). Using Jodele risk stratification, 11 (21%) were SR, 21 (40%) were IR, and 20 (39%) were HR. Forty (77%) were treated with eculizumab. There were no statistically significant differences in NRM among Jodele risk groups, although overall survival (OS) differed significantly. Using the harmonized stratification, 49 children (94%) were stratified as HR and 3 as standard risk (SR), there were no statistically significant differences in NRM or OS between groups. Eight children (15.4%) were classified as SR using Jodele risk stratification but restratified as HR using the harmonization criteria. One child (12.5%) died in the setting of severe GVHD, and the remaining 7 were alive at the last follow-up. In a best subset model, lactate dehydrogenase (LDH) level >2 times the upper limit of normal (ULN) (odds ratio [OR], 6.52, 95% confidence interval [CI], .96 to 44.3; P = .05), grade II-IV acute graft-versus-host disease (GVHD) at the time of TA-TMA diagnosis (OR, 15.4; 95% CI, 2.14 to 110.68; P = .01), and organ dysfunction at the time of TA-TMA (OR, 21.5; 95% CI, 2.96 to 156.37; P = .002) were significantly associated with NRM; elevated sC5b-9, urine protein/creatinine ratio, and viral infections were not significantly associated with NRM. Using these best-fit criteria, 14 patients were classified as SR and 38 were classified as HR, NRM was significantly higher, and OS was significantly lower. In this cohort of children with TA-TMA, retrospective application of the harmonization criteria resulted in more patients stratified as HR compared to use of the previously described Jodele criteria. The intention of the harmonization criteria was to identify those at greatest risk of poor outcomes; while all harmonization SR patients survived, this risk stratification was very sensitive. Previous criticisms of harmonization risk stratification include limited access to sC5b-9 testing. These data suggest that organ dysfuncion, acute GVHD, and LDH >2 times ULN are the most important predictors of NRM in this cohort, allowing risk stratification even in the absence of available sC5b-9 testing. Additional studies are needed to validate these findings., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Crovalimab, a novel C5 inhibitor, allows for low-volume, every-4- week, subcutaneous self-administration. COMMODORE 1 (NCT04432584) is a phase 3, global, randomized trial evaluating crovalimab versus eculizumab in C5 inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). Adults with lactate dehydrogenase ≤1.5 × upper limit of normal and receiving approved eculizumab doses for ≥24 weeks were randomized 1:1 to receive crovalimab (weight-based tiered dosing) or continue eculizumab. The original primary study objective was efficacy; however, given the evolving treatment landscape, target recruitment was not met, and all efficacy endpoints became exploratory, with safety as the new primary objective. Exploratory efficacy endpoints included transfusion avoidance, hemolysis control, breakthrough hemolysis, hemoglobin stabilization, FACIT-Fatigue score, and patient preference (crovalimab vs. eculizumab). Eighty-nine patients were randomized (45 to crovalimab; 44 to eculizumab). During the 24-week primary treatment period, adverse events (AEs) occurred in 77% of patients receiving crovalimab and 67% receiving eculizumab. No AEs led to treatment withdrawal or death, and no meningococcal infections occurred. 16% of crovalimab-treated patients had transient immune complex reactions (also known as Type III hypersensitivity events), an expected risk when switching between C5 inhibitors that bind to different C5 epitopes; most were mild/moderate and all resolved without treatment modification. Crovalimab-treated patients had sustained terminal complement activity inhibition, maintained disease control, and 85% preferred crovalimab over eculizumab. Together with phase 3 COMMODORE 2 results in complement inhibitor-naive patients, these data support crovalimab's favorable benefit-risk profile. Crovalimab is a new C5 inhibitor for PNH that is potentially less burdensome than existing therapies for this lifelong disease., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Background: Pembrolizumab is associated with the development of gastritis, but its clinical features have not been characterized. To explore the clinical features of pembrolizumab induced gastritis and provide reference for the prevention and treatment of gastritis., Methods: Case reports and case series related to pembrolizumab induced gastritis were retrospectively analyzed by searching the database from inception to September 30, 2023., Results: Thirty-nine patients with gastritis entered the study with a median age of 63 years (range 34, 81). The median time to gastritis was 11.1 months (range 0.3, 60) and 7 cycles (range 1, 27) after administration. Epigastric pain (24 cases, 61.5%), nausea (17 cases, 43.6%), and vomiting (16 cases, 41.0%) were the most frequently complained symptoms. Esophagogastroduodenoscopy mainly showed erythematous (16 cases, 41.0%), hemorrhage (14 cases, 35.9%) and erosions (11 cases, 28.2%). Gastric mucosal biopsy shows chronic active gastritis with lymphocytic infiltration. These patients' symptoms and gastric mucosa improved or recovered after receiving systemic steroid and proton pump inhibitor therapy regardless of whether pembrolizumab was discontinued. These patients' symptoms and gastric mucosa improved or recovered after treatment with systemic steroids, proton pump inhibitors, and biological agents., Conclusions: Gastritis is an extremely rare adverse effect of pembrolizumab. When patients receiving pembrolizumab complain of abdominal symptoms, endoscopy, tissue biopsy, and immunohistochemical staining should be actively performed for early identification and diagnosis of gastritis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: IMAGE is a retrospective cohort study of patients enrolled in early access programs (EAPs) in France with relapsed/refractory multiple myeloma (RRMM) receiving isatuximab with pomalidomide and dexamethasone (Isa-Pd)., Methods: Patients aged ≥18 years with RRMM who received ≥1 dose of Isa under the EAPs between July 29, 2019 and August 30, 2020 were included. Effectiveness endpoints included progression-free survival (PFS) and response rates. Verbatim terms for adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities and not graded for severity., Results: A total of 294 and 299 patients were included in the effectiveness and safety populations, respectively. IMAGE included patients who received one prior line of treatment (10.2%) and were daratumumab-refractory (19.1%). At median follow-up of 14.2 months, median PFS in the effectiveness population was 12.4 months (95% CI 9.0-15.0). Overall response and very good partial response rates were 46.3% and 27.9%, respectively. Subgroup analyses reflected similar results. In the safety population, 26.4% of patients reported at least one AE; the most common any-grade AE was neutropenia (9.4%)., Conclusion: IMAGE demonstrated Isa-Pd had meaningful effectiveness in median PFS and depth of response and no new safety signals in a real-world context, consistent with clinical trial results., (© 2024 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Objectives: The aim of this noninterventional, retrospective ALFA study was to describe belantamab mafodotin effectiveness and safety in patients with relapsed/refractory multiple myeloma in a real-world setting in France., Methods: Response rate, progression-free survival (PFS), overall survival (OS), and safety were assessed., Results: Among the 184 patients initiating belantamab mafodotin treatment, the overall response rate was 32.7% (≥very good partial response [VGPR] 20.4%, partial response [PR] 12.3%). The median PFS (mPFS) was 2.4 months (95% confidence interval [CI]: 1.9, 3.3), and median OS (mOS) was 8.8 months (95% CI: 6.3, 11.6). According to best response, mPFS was 20.6 months (95% CI: 12.1, not reached [NR]) in patients with ≥VGPR and 7.1 months (95% CI: 4.6, 9.4) in patients with PR; mOS was NR in patients with ≥VGPR and 17.5 months (95% CI: 7.7, NR) in patients with PR. For both OS and PFS, no differences were found in subgroups of interest. The adverse events (AEs) reported in 159 patients (86.4%) were mostly ocular AEs., Conclusions: ALFA, the largest real-world cohort conducted so far, confirms the results of belantamab mafodotin as reported in the DREAMM-2 clinical trial. The clinical benefit is significant as long as the patient is a responder., (© 2024 GSK and The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Objective: To investigate the safety and efficacy of subcutaneous tocilizumab (SC-TCZ) treatment in a long-term extension (LTE) of clinical trials in polyarticular or systemic juvenile idiopathic arthritis (pJIA or sJIA)., Methods: Patients with pJIA or sJIA from two open-label, 52-week phase 1b core trials of SC-TCZ who had adequate response per investigator assessment entered the LTE and continued SC-TCZ treatment according to body weight-based dosing regimens until commercial availability or up to 5 years. Pharmacokinetics, pharmacodynamics, and efficacy were assessed for up to 3 years, and safety for up to 5 years in the LTE., Results: Forty-four patients with pJIA and 38 patients with sJIA entered the LTE. Tocilizumab trough concentrations were maintained within the range expected to provide clinical benefit (mean values: pJIA, ∼10 μg/ml; sJIA, ∼75 μg/ml over 3 years). Pharmacodynamic parameters (interleukin-6, soluble interleukin-6 receptor, erythrocyte sedimentation rate, C-reactive protein) were maintained throughout the LTE at levels achieved in the core trials. Inactive disease per American College of Rheumatology provisional criteria was reported for 90% (17/19) and 53% (8/15) of patients with pJIA and 91% (10/11) and 92% (12/13) of patients with sJIA in the <30 and ≥30 kg body weight groups, respectively. Serious adverse events in the LTE were reported in six patients with pJIA (13.6%; five serious infections) and five patients with sJIA (13.2%; one serious infection)., Conclusion: Patients with pJIA or sJIA experienced long-term disease control with SC-TCZ treatment. Long-term safety was consistent with the known tocilizumab safety profile., Clinical Trial Registration: clinicaltrials.gov, NCT02165345., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Chimeric antigen receptor (CAR) T-cell therapy causes serious side effects including cytokine release syndrome (CRS). CRS-related coagulopathy is associated with hypofibrinogenemia that has up to now been considered the result of disseminated intravascular coagulation (DIC) and liver dysfunction. We investigated the incidence and risk factors for hypofibrinogenemia in 41 consecutive adult patients with hematologic malignancies (median age 69 years, range 38-83 years) receiving CAR T-cell therapy between January 2020 and May 2023 at the University Medical Center Regensburg. CRS occurred in 93% of patients and was accompanied by hypofibrinogenemia already from CRS grade 1. Yet DIC and liver dysfunction mainly occurred in severe CRS (≥ grade 3). After an initial increase during CRS, fibrinogen levels dropped after administration of tocilizumab in a dose-dependent manner (r = -0.44, P=0.004). In contrast, patients who did not receive tocilizumab had increased fibrinogen levels. Logistic regression analysis identified tocilizumab as an independent risk factor for hypofibrinogenemia (odds ratio = 486, P<0.001). We thus hypothesize that fibrinogen synthesis in CRS is up-regulated in an interleukin-6-dependent acute phase reaction compensating for CRS-induced consumption of coagulation factors. Tocilizumab inhibits fibrinogen upregulation resulting in prolonged hypofibrinogenemia. These observations provide novel insights into the pathophysiology of hypofibrinogenemia following CAR T-cell therapy, and emphasize the need for close fibrinogen monitoring after tocilizumab treatment of CRS.

Background: Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. The RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC., Patients and Methods: This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment-naïve advanced TC. They received ramucirumab, carboplatin and paclitaxel for six cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was objective response rate (ORR) according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Centralized radiologic review was carried out., Results: From November 2018 to June 2023, 52 patients were screened and 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. The Eastern Cooperative Oncology Group performance status was 0 in 68.5% and 1 in 31.4% of patients. At the present analysis carried out some months after the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95% confidence interval (CI) 63.1% to 91.6%]. At the centralized radiological review of 33/35 assessable patients, ORR was 57.6% (95% CI 39.2% to 74.5%). After a median follow-up of 31.6 months, median PFS was 18.1 months (95% CI 10.8-52.3 months) and median OS was 43.8 months (95% CI 31.9 months-not reached). Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE ≥ grade 3., Conclusions: In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background The paradoxical occurrence of psoriasis triggered by Interleukin-17 (IL-17) inhibitors is notable due to its prominent symptoms and the therapeutic dilemma it presents for follow-up care. Objective To describe cases in our clinic, perform an in-depth literature review, and suggest the most probable mechanisms of action. Method We conducted a literature review on published cases of IL-17 inhibitor-induced psoriasis. Results We found 22 articles reporting 30 cases of IL-17 inhibitor-induced paradoxical psoriasis, primarily observed in patients with a previous psoriasis history. Almost 60% of cases showed a change in lesion morphology, with the plaque or pustular type being prevalent. About 73.3% of patients had to discontinue the implicated drug, leading to partial or complete symptom resolution. The mechanism behind this response seemed to involve IL-17 inhibitors downregulating Tumour Necrosis Factor alpha (TNF-α), subsequently upregulating plasmacytoid dendritic cells and triggering unopposed IFN-alpha (IFN-α) production. Limitation Data are confined to case reports and case series. Conclusion More assertive measures are recommended for treating paradoxical psoriasis induced by IL-17 inhibitors than those caused by TNF-α inhibitors. Reintroducing an IL-17 inhibitor is not advised, as patients did not show improvement.

Background: Portal hypertension (PHT) often complicates hepatocellular carcinoma (HCC) treatment and prognosis. We aimed to assess PHT's impact on AtezoBev outcomes and identify predictors of acute variceal bleeding (AVB) and clinical ascites occurrence., Methods: A prospective cohort of 200 HCC patients treated with AtezoBev was studied alongside a retrospective cohort of 123 patients treated with Sorafenib. We assessed factors influencing progression-free survival (PFS), overall survival (OS), AVB and clinical ascites development, focusing on PHT parameters, and comparing outcomes within and between the two cohorts (time-dependent Cox model and adjusted survival curves)., Results: Among the AtezoBev cohort, 10% experienced AVB, 24% had high-risk esophageal varices (EV) and 46% vascular invasion. Median PFS and OS in the AtezoBev cohort was 5.13 and 12.2 months. AVB (HR=1.81;[95%CI:1.03-3.17]) and clinical ascites occurrence (HR=2.29;[95%CI:1.52-3.45]) were independently associated with mortality. AVB incidence was 12% at 12 months in AtezoBev patients and EV, history of AVB<6months and vascular invasion were independently associated with AVB. The Sorafenib cohort had shorter median PFS and OS, with similar AVB incidence and only EV were associated with AVB., Conclusions: PHT-related events significantly affect not only liver decompensation but also OS in AtezoBev-treated patients. We suggest a more widespread use of NSBB to prevent liver decompensation, with intensified prophylaxis for high-risk patients., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Bullous pemphigoid (BP), an autoimmune bullous dermatosis, occurs predominantly in older individuals. Nemolizumab, a humanized monoclonal antibody against the interleukin (IL)-31 receptor A, is used to treat severe atopic dermatitis (AD) in Japan. However, it can cause several adverse events, such as exacerbation of AD, erythema, and eosinophilia. Herein, we describe a case of prurigo-type AD developing BP after nemolizumab administration. A 62-year-old man with prurigo-type AD and asthma presented with serious, refractory itching. After nemolizumab injection, his pruritus was relieved for 2 days. However, on day 3, erythema with blisters and erosions suddenly appeared throughout his body. Pathological examination showed typical BP and the patient's serum anti-BP180-NC16a antibody level was 882.5 U/mL. Oral prednisolone (PSL) was initiated and nemolizumab was never used again. Despite high-dose PSL, new blisters continued to develop, with a rapid elevation of anti-BP180-NC16a antibodies to 6930 U/mL. Adding high-dose cyclosporine and intravenous gamma globulin reduced new blister formation after 9 weeks, and PSL and cyclosporine were gradually tapered. Dupilumab, an anti-IL-4 receptor antibody, was initiated after 16 weeks, resulting in continued remission without PSL and cyclosporine. The sudden occurrence of BP in this case suggested that the patient had occult BP before the nemolizumab initiation and that nemolizumab exacerbated BP and made it overt. Blocking the IL-31 pathway may exacerbate inflammation in AD or BP, resulting in the acceleration of blister formation. This may be countered by blocking the IL-4/13 pathway with dupilumab. To our knowledge, this is the first case of nemolizumab-exacerbated BP., (© 2024 Japanese Dermatological Association.)