Population pharmacokinetic modeling of vedolizumab for graft-versus-host disease prophylaxis in adults with allogeneic hematopoietic stem cell transplant.

We aimed to characterize the population pharmacokinetics (PK) of vedolizumab for acute graft-versus-host disease prophylaxis in adults undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and assess potential clinically relevant covariates. Dosing, patient characteristics, and PK from a phase 1b, open-label, dose-finding study of vedolizumab 75 mg initial dose escalated to 300 mg and a phase 3 study of vedolizumab 300 mg in patients receiving allo-HSCT were analyzed using a two-compartment population PK model with linear elimination. Covariates included age, race, weight, sex, albumin, lymphocyte count, GvHD type, and concomitant medications. Weight, albumin, and lymphocyte count were time-varying covariates. Model selection was driven by goodness-of-fit criteria, precision of parameter estimates, and visual predictive checks. In 193 patients undergoing allo-HSCT, vedolizumab PK were well described by a two-compartment, linear PK model. Using reference covariate values, final parameter estimates (95% confidence intervals [CI]) were: clearance, 0.148 (0.136, 0.162) L/day; central volume of distribution, 3.12 (3.03, 3.21) L; intercompartmental clearance, 0.500 (0.408, 0.612) L/day; and peripheral volume of distribution, 3.95 (3.52, 4.44) L. Weight and albumin were the most important predictors of vedolizumab PK, with clearance decreasing by ≈20% for low body weight/high albumin and increasing by ≈30% for high body weight/low albumin. There was an inverse relationship between vedolizumab clearance and age, but no detectable effect for lymphocyte count or GvHD type. Post hoc analyses did not detect any relationship between vedolizumab PK and concomitant medications. In summary, the covariates studied did not have a clinically meaningful effect on the PK of vedolizumab.

The sharp edge of immunosuppressive treatments: infections.

Background and aim: Different side effects, including infections, are encountered in patients receiving anticytokines used for the treatment of severe coronavirus disease 2019 (COVID-19). The aim of this study was to evaluate the infections and the effects of these infections that develop in this patient group. Materials and Methods: This study included 208 patients who were followed-up with the diagnosis of severe COVID-19 in two different hospitals. Patient data were obtained retrospectively from the hospital information system. Results: Of the 208 patients included, 54 were in the anakinra group, and 154 were in the tocilizumab group. Of these patients, 73 (35.1%) developed infection, 160 (76.9%) were admitted to the intensive care unit (ICU), and the 30-day mortality rate was 46.6%. The ICU admission, 30-day mortality, and infection rates were higher in the anakinra group, but it was not statistically significant (p = 0.137, p = 0.127, and p = 0.132, respectively), while pneumonia and bloodstream infection (BSI) rates were higher (p = 0.043 and p = 0.010 respectively). The 30-day mortality rate was significantly higher in patients who developed infection, especially in the tocilizumab group (p < 0.001 and p = 0.001). The independent risk factors affecting the development of infection were evaluated via regression analysis, in which it was found that age, sex, and the type of immunosuppressive treatment had no significant effect, while ICU admission increased the risk of infection by 32.8 times (95% CI: 4.4-245.8) and each day of hospitalization slightly increased the risk of infection by 1.06 times (95% CI: 1.03-1.09). Conclusion: Infection rates were higher in the anakinra group, especially the pneumonia and BSI rates were higher than in the tocilizumab group. The 30-day mortality rates were higher in patients who had an infection, especially in the tocilizumab group. This is one of the rare studies that evaluated infections developing in patients treated with anakinra and tocilizumab together.

Improvement of Fibrous Dysplasia After Burosumab Therapy in a Pediatric Patient with McCune-Albright Syndrome: A Case Report.

CASE: Burosumab is a novel drug developed to treat hereditary fibroblast growth factor 23 (FGF23)-related disorders. We report the case of an 11-year-old girl with McCune-Albright syndrome (MAS) who sustained hypophosphatemia due to excess FGF23 and multiple bone lesions of fibrous dysplasia (FD). Burosumab therapy markedly improved not only the biochemical parameters but also the radiographic appearance of the FD lesions and clinical symptoms. CONCLUSION: This is the first report to demonstrate that burosumab is effective in improving FD lesions in a patient with MAS.

Evaluation of adverse clinical outcomes in patients with inflammatory bowel disease receiving different sequences of first- and second-line biologic treatments: findings from ROTARY.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at risk of developing dysplasia and, subsequently, colorectal cancer (CRC) owing to chronic inflammation. Patients may also experience other severe disease complications, such as hospitalization and surgery. Several biologics are available for the treatment of patients with IBD and some patients require multiple lines of treatment owing to loss of response or tolerability to their prescribed biologic. Previous studies suggest that the choice of initial biologic treatment may impact the outcomes of later treatment lines. In this study, we assessed adverse clinical outcomes in patients with Crohn's disease (CD) or ulcerative colitis (UC) who received different biologic treatment sequences. METHODS: ROTARY part B was a retrospective cohort study using the Optum® Clinical Database that evaluated the incidences of IBD-related hospitalization, IBD-related surgery, dysplasia, CRC, and infections in patients with CD or UC who received two biologics successively. First-line biologics included adalimumab, infliximab, ustekinumab (CD only), and vedolizumab; second-line biologics included infliximab and adalimumab. RESULTS: In patients with CD, the treatment sequence of ustekinumab to infliximab was associated with the highest overall incidences of hospitalization (51.9%), surgery (40.7%), CRC (3.7%), and infection (37.0%). Vedolizumab followed by an anti-tumor necrosis factor alpha (anti-TNFα) treatment was associated with a significantly lower risk of experiencing an adverse medical event (hospitalization, surgery, or infection) than two successive anti-TNFα treatments (odds ratio, 1.526; 95% confidence interval, 1.004-2.320; P < 0.05). In patients with UC, the treatment sequence of vedolizumab to adalimumab resulted in the lowest overall incidence of adverse outcomes (20.3%, 6.3%, 0.0%, 6.3%, and 4.7% for hospitalization, surgery, CRC, dysplasia, and infection, respectively). CONCLUSIONS: We describe differences in adverse clinical outcomes associated with sequencing of biologics in patients with CD or UC and demonstrate favorable results in patients who received vedolizumab as a first-line biologic. These results provide potential guidance to clinicians choosing sequences of biologic treatments in patients with IBD.

A phase II clinical trial of toripalimab in advanced solid tumors with polymerase epsilon/polymerase delta (POLE/POLD1) mutation.

Patients carrying mutations in polymerase epsilon/polymerase delta have shown positive responses to immune checkpoint inhibitors. Yet, prospective trials exploring the efficacy in those with polymerase epsilon/polymerase delta mutations are still lacking. A phase II clinical trial was initiated to evaluate the efficacy of toripalimab, a humanized IgG4K monoclonal antibody to human PD-1, in patients with advanced solid tumors with unselected polymerase epsilon/polymerase delta mutations but without microsatellite instability-high. A total of 15 patients were enrolled, 14 of whom were assessed for treatment efficacy. There was a 21.4% overall response rate, with a disease control rate of 57.1%. The median overall survival and median progression-free survival were 17.9 (95% CI 13.5-not reach) months and 2.5 (95% CI 1.4-not reach) months, respectively. For patients with exonuclease domain mutations, the objective response rate was 66.7% (2/3), with a disease control rate of 66.7% (2/3). For those with non-exonuclease domain mutations, the rates were 9.1% (1/11) and 54.5% (6/11), respectively. Notably, patients with PBRM1 gene mutations exhibited a high response rate to toripalimab at 75.0% (3/4). This study showed that neither the exonuclease domain mutations nor non-exonuclease domain mutations could fully predict the efficacy of immunotherapy, urging the need for more investigations to clarify potential immune sensitization differences within polymerase epsilon/polymerase delta mutation variants.

Comparative early effectiveness across 14 PsA drugs and 5 classes of PsA treatment: 3-month results from the PRO-SPIRIT study.

BACKGROUND: The psoriatic arthritis (PsA) Observational Study of Persistence of Treatment (PRO-SPIRIT) assesses effectiveness and persistence of real-world PsA treatments. Ixekizumab (IXE) is an interleukin (IL)-17A inhibitor (i) (IL-17Ai), approved for the treatment of adult PsA. METHODS: The aim of this predefined interim analysis was to report baseline characteristics along with early (3-month) descriptive and comparative real-world effectiveness in patients with PsA prescribed with advanced treatment including IL-17Ai; IXE or secukinumab (SEC), IL-12/23i, IL-23i, tumour necrosis factor (TNFi) or Janus kinase (JAKi). RESULTS: 1192 patients across 6 countries were analysed. At baseline, patients receiving IXE had longer disease duration and higher previous biological/targeted-synthetic disease-modifying antirheumatic drugs experience than patients starting TNFi and SEC 150, and less concomitant conventional-synthetic DMARD use than TNFi and JAKi. Comparative analyses at 3 months showed that: (a) versus TNFi, IXE exhibited similar improvement in clinical Disease Activity in PsA (cDAPSA) but significantly greater improvement in body surface area affected by psoriasis (BSA) and global assessments (physician GA, patient GA (PatGA)); (b) versus IL-12/23i and IL-23i (pooled), IXE showed significantly greater improvement in cDAPSA and PatGA; (c) IXE was as fast as JAKi in improving joint disease activity. Ad hoc analysis indicated that more patients with active psoriasis (BSA ≥3%) achieved minimal disease activity with IXE than JAKi or IL-12/23i. The responses to SEC varied by dosage. CONCLUSIONS: This study confirms the rapid 3-month effectiveness of IXE on joint disease activity-as fast as TNFi and JAKi (cDAPSA), and exceeding IL-12/23i and IL-23i-along with clear benefits to skin.

Pharmacokinetics and pharmacodynamics of the factor XIa-inhibiting antibody osocimab in healthy male East Asian volunteers: Results from two phase 1 studies.

The pharmacokinetics, pharmacodynamics, immunogenicity, and safety of osocimab single doses in healthy Chinese and Japanese volunteers over 149 days were evaluated. Two phase 1 single-blinded, placebo-controlled studies with 27 Japanese and 50 Chinese participants were conducted. Osocimab was investigated with IV doses of 0.3, 1.25, and 2.5 mg/kg (Chinese study) and 0.3, 1.25, and 5.0 mg/kg (Japanese study), as well as SC doses of 3.0 and 6.0 mg/kg (Chinese study) and 6.0 mg/kg (Japanese study). The maximum plasma concentration was reached 1-3 h and 4-6 days after IV and SC administration, respectively. Osocimab exhibited a deviation from dose-proportional pharmacokinetics for AUC but not Cmax; higher doses had higher apparent clearance and disproportionately lower total exposure. A slightly lower exposure was observed in Japanese compared with Chinese volunteers after IV administration; conversely, relatively higher exposure in Japanese volunteers with SC dosing was identified. Osocimab was associated with a dose-dependent increase in activated partial thromboplastin time (aPTT). Maximal aPTT prolongations were observed 1-4 h and 2-6 days after IV and SC administration, respectively. Anti-drug antibodies of low titer were detected in 1/9 (11.1%) Japanese volunteers administered placebo and 26/40 (65.0%) Chinese volunteers administered osocimab. Adverse events were reported in 8/18 (44.4%) Japanese and 28/40 (70.0%) Chinese volunteers who received osocimab, as well as in 1/9 (11.1%) Japanese and 6/10 (60.0%) Chinese volunteers who received placebo. In conclusion, data did not suggest a clear dose-proportionality for osocimab within the investigated dose range. The effect of osocimab on aPTT was expected per its mechanism of action. Osocimab was generally well tolerated.

Bimekizumab provided rapid improvements in patient-reported symptoms and health-related quality of life in patients with active psoriatic arthritis: pooled 16-week results from two phase 3 studies.

OBJECTIVES: To assess impact of bimekizumab treatment on patient-reported outcomes and health-related quality of life (HRQoL) in patients with active psoriatic arthritis (PsA), using 16-week data from two phase 3 studies. METHODS: BE OPTIMAL (NCT03895203; biologic disease-modifying antirheumatic drug (bDMARD)-naïve) and BE COMPLETE (NCT03896581; tumour necrosis factor inhibitor inadequate response/intolerance (TNFi-IR)) are phase 3 studies of subcutaneous bimekizumab 160 mg Q4W; both were double-blind and placebo-controlled to 16 weeks. Patients were randomised 3:2:1 to bimekizumab, placebo or reference (subcutaneous adalimumab 40 mg Q2W) in BE OPTIMAL; 2:1 to bimekizumab or placebo in BE COMPLETE. Patient-reported outcomes for pain, fatigue, physical function and HRQoL are reported to week 16 using pooled and individual study data for bimekizumab and placebo patients. RESULTS: 1073/1112 (96.5%) patients completed week 16 (bimekizumab:| 677/698 [97.0%]; placebo: 396/414 [95.7%]). Bimekizumab-treated patients achieved rapid improvements vs placebo in pain, fatigue, physical function and HRQoL by week 4, after a single dose. Improvements continued to week 16 for all patient-reported outcomes, including Pain Visual Analogue Scale (VAS; mean (95% CI) change from baseline: bimekizumab: -|25.2 [-27.2, -23.1]; placebo:| -|5.7 [-8.2, -3.3]) and FACIT-Fatigue (bimekizumab: 4.5 [3.9, 5.1]; placebo: 1.1 [0.3, 2.0]); both nominal p<0.001. Greater proportions of bimekizumab-treated patients achieved minimal clinically important differences for patient-reported symptoms vs placebo, including FACIT-Fatigue (bimekizumab: 53.1%; placebo: 36.3%) and HAQ-DI (bimekizumab:| 53.0%; placebo: 28.7%); both nominal p<0.001. CONCLUSION: Bimekizumab treatment demonstrated rapid and greater improvements in patient-reported pain, fatigue, physical function and HRQoL to week 16 vs placebo in bDMARD-naïve and TNFi-IR patients. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT03895203; NCT03896581.

Case series on monoclonal antibodies targeting calcitonin gene-related peptide in migraine patients during pregnancy: Enhancing safety data.

BACKGROUND: Monoclonal antibodies targeting calcitonin gene-related peptide (CGRP-mAbs) are approved for adult migraine prevention but pose safety concerns in pregnancy. We assess the safety of CGRP-mAbs in the periconceptional period through a case series and literature review. METHODS: Six migraine-diagnosed women received CGRP-mAbs; treatment ceased upon pregnancy. We collected data and conducted safety assessments. To provide a comprehensive context, we performed a literature review. RESULTS: The series includes three erenumab, two fremanezumab and one galcanezumab case. A fremanezumab recipient experienced miscarriage; severe perinatal asphyxia linked to dystocia occurred with erenumab (140 mg). Database reviews revealed 63 spontaneous abortions, eight premature births, and seven birth defects among 286 World Health Organization and 65 European Medicines Agency cases. These rates align with untreated population rates. CONCLUSIONS: CGRP-mAbs use in the periconceptional period does not lead to clinically significant increase in pregnancy-related pathology or adverse effects on newborns within our case series and the literature reviewed.

Cost-effectiveness of first-line enfortumab vedotin in addition to pembrolizumab for metastatic urothelial carcinoma in the United States.

Background and objective: The EV-302 trial found that the combination of enfortumab vedotin (EV) with pembrolizumab significantly improved survival for patients with metastatic urothelial carcinoma (mUC). However, given the high cost of the drugs, there is a need to assess its value by considering both efficacy and cost. This study assessed the cost-effectiveness of EV plus pembrolizumab as a first-line treatment for patients with mUC from the perspective of U.S. payers. Methods: A Markov model was developed to compare the lifetime costs and effectiveness of EV in combination with pembrolizumab with chemotherapy in the treatment of mUC patients from U.S. payer perspective. Life-years (LYs), quality-adjusted LYs (QALYs), and lifetime costs were estimated. One-way, two-way and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. Additionally, subgroup analyses were performed. Results: Compared to chemotherapy, the combination of EV and pembrolizumab provided an additional 2.10 LYs and 1.72 QALYs, at an incremental cost of $962,240.8 per patient. The incremental cost-effectiveness ratio (ICER) is $558,973 per QALY. Subgroup analysis indicated that patients ineligible for cisplatin treatment had a lower ICER compared to those who were eligible for cisplatin. Conclusions: From the perspective of US payers, at a willingness-to-pay threshold of $150,000 per QALY, the combination of EV and pembrolizumab is estimated to not be cost-effective compared to traditional chemotherapy in the first-line treatment of mUC patients.

Sintilimab plus GemOx is an effective salvage therapy in patients with refractory/relapsing nodal peripheral T cell lymphomas.

PURPOSE: The retrospective study was to explore the effectiveness and safety of GemOx (gemcitabine, oxaliplatin) plus sintilimab (belongs to the class of drugs known as immune checkpoint inhibitors, particularly targeting the PD-1 receptor) in relapse or refractory nodal PTCLs. METHODS: Patients with nodal PTCL who initiated salvage therapy with sintilimab and GemOx between January 2020 to September 2021 were identified from the database of the hematology department of the Second Affiliated Hospital of Zhejiang University School of Medicine. All patients received 2-4 cycles (3 weeks/cycle) of treatment of sintilimab (200 mg, I.V, D1) in combination with GemOx. Treatment response was assessed every six weeks during the salvage treatment phase. Eligible patients received maintenance therapy according to the investigator's decision. Follow-ups were routinely conducted every three months. RESULTS: 31 patients with r/r nodal PTCLs were enrolled, including 23 PTCL-NOS, 4 AITL, and 4 ALCL. 21 (67.7%) patients received at least two lines of therapy. 71.0% (95% CI, 53.4%-83.9%) of patients documented objective response of 2-4 cycles of sintilimab plus GemOx therapy, including 9 complete response and 13 partial response. 21 (67.7%) patients received consolidation therapy, including 5 autologous stem-cell transplantation and 12 histone deacetylase inhibitors. After a median 25.6 months follow-up, the median PFS was 22.0 (95% CI,11.8-24.7) months, and the median OS was 26.2 (95% CI, 24.4 -NA) months. 29 (93.5%) patients experienced at least one adverse event, and 26 (83.9% patients only had mild (grade 1-2) AEs.Univariable Cox regression showed the progression risk of AITL is 22.7 (3.9- 131.0, p < 0.01) times of PTCL-NOS, while the HR of ALCL was 1.14 (0.33-3.96,p = 0.833). CONCLUSION: Sintilimab plus GemOx showed encouraging activity and manageable toxicity for patients with r/r PTCL.

Efficacy of chemotherapy for patients with gastric cancer with early recurrence during or after adjuvant chemotherapy with S-1 alone: a multicenter retrospective study.

This study aimed to survey the efficacy of chemotherapy regimens in the real world setting and explore the most promising regimen for patients experiencing early recurrence for gastric cancer. We retrospectively reviewed the clinical course of 207 patients with gastric cancer, who developed early recurrence during or within 6 months after completing S-1 adjuvant therapy at 19 Japanese institutions between 2012 and 2016. The treatment regimens after recurrence were fluoropyrimidines plus platinum-based regimens (FP) in 91 (44%) patients, paclitaxel-based regimens (PTX) in 102 (49%), and irinotecan-based regimens (IRI) in 14 (7%). The overall response and disease control rates were 28.7% and 54.1%. Median progression-free survival (PFS) and overall survival (OS) were 5.1 and 12.9 months, respectively. In the FP, PTX, and IRI regimens, the median PFS and OS were 5.9, 4.1, 4.1 months and 12.8, 12.9, and 11.8 months, respectively. The combination of PTX and ramucirumab showed survival comparable to capecitabine plus platinum. Multivariate analyses for OS showed that recurrence during adjuvant chemotherapy and undifferentiated histological type were independent poor prognostic factors. Although the prognosis of patients with early recurrence even with adjuvant S-1 was poor, PTX plus ramucirumab therapy could be a potential treatment option.

Progressive multifocal leukoencephalopathy in systemic lupus erythematosus treated with pembrolizumab.

This case report discusses a patient with systemic lupus erythematosus (SLE) treated with low-dose azathioprine who developed progressive multifocal leukoencephalopathy (PML). PML is a rare, severe, demyelinating disease linked to John Cunningham polyomavirus (JCV) reactivation.Treated with pembrolizumab, an immune checkpoint inhibitor, the patient initially improved. However, after the fourth dose, her condition rapidly worsened resulting in treatment discontinuation and death. Similar cases highlight the complex interplay of factors in PML development in SLE patients, including immunosuppression and genetic factors. The use of pembrolizumab in PML and SLE necessitates careful consideration of potential complications.

Single-cell RNA sequencing analysis of peripheral blood mononuclear cells in PD-1-induced renal toxicity in patients with lung cancer.

BACKGROUND: Although the patient survival rate for many malignancies has been improved with immune checkpoint inhibitors (ICIs), some patients experience various immune-related adverse events (irAEs). IrAEs impact several organ systems, including the kidney. With anti-programmed cell death protein 1 (PD-1) therapy (pembrolizumab), kidney-related adverse events occur relatively rarely compared with other irAEs. However, the occurrence of AKI usually leads to anti-PD-1 therapy interruption or discontinuation. Therefore, there is an urgent need to clarify the mechanisms of renal irAEs (R-irAEs) to facilitate early management. This study aimed to analyse the characteristics of peripheral blood mononuclear cells (PBMCs) in R-irAEs. METHODS: PBMCs were collected from three patients who developed R-irAEs after anti-PD-1 therapy and three patients who did not. The PBMCs were subjected to scRNA-seq to identify cell clusters and differentially expressed genes (DEGs). Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analyses were performed to investigate the most active biological processes in immune cells. RESULTS: Fifteen cell clusters were identified across the two groups. FOS, RPS26, and JUN were the top three upregulated genes in CD4+ T cells. The DEGs in CD4+ T cells were enriched in Th17 differentiation, Th1 and Th2 cell differentiation, NF-kappa B, Nod-like receptor, TNF, IL-17, apoptosis, and NK cell-mediated cytotoxicity signaling pathways. RPS26, TRBV25-1, and JUN were the top three upregulated genes in CD8+ T cells. The DEGs in CD8+ T cells were enriched in Th17 cell differentiation, antigen processing and presentation, natural killer cell-mediated cytotoxicity, the intestinal immune network for IgA production, the T-cell receptor signalling pathway, Th1 and Th2 cell differentiation, the phagosome, and cell adhesion molecules. CONCLUSIONS: In conclusion, R-irAEs are associated with immune cell dysfunction. DEGs and their enriched pathways identified in CD4+ T cells and CD8+ T cells play important roles in the development of renal irAEs related to anti-PD-1 therapy. These findings offer fresh perspectives on the pathogenesis of renal damage caused by anti-PD-1 therapy.

Transarterial chemoembolization combined with sintilimab and lenvatinib for the treatment of unresectable hepatocellular carcinoma: a retrospective study.

BACKGROUND: The treatment of unresectable hepatocellular carcinoma (uHCC) challenging due to unfulfilled clinical requirements. OBJECTIVE: To evaluate the safety and efficacy of combining transarterial chemoembolization (TACE) with sintilimab and lenvatinib in the treatment of uHCC. METHODS: We retrospectively analyzed the data of patients with uHCC who were treated with a combination of TACE, sintilimab, and lenvatinib between May 2019 and December 2021 at the Chinese PLA General Hospital. Systemic treatment was started 1 week after TACE was performed. Sintilimab was administered intravenously at a dosage of 200 mg every three weeks, and lenvatinib was given orally at dosages of 8 mg or 12 mg daily, contingent upon the weight of the patients. The primary endpoint was the objective response rate (ORR) as per the mRECIST. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and treatment-related adverse events (tr-AEs). RESULTS: A total of 32 patients were enrolled in the study. Among them, 9 patients were classified as Barcelona Clinic Liver Cancer-B (BCLC-B), 23 patients were classified as BCLC-C, 14 patients diagnosed with portal vein tumors, and 12 patients were diagnosed with extra hepatic metastases. The ORR and DCR were 75% and 90.6% respectively, with 4 patients exhibiting (12.5%) complete response, 20 patients exhibiting (62.5%) partial response, 5 patients exhibiting (15.6%) stable disease, and 3 patients exhibiting (9.4%) progressive disease. With a median follow-up time of 19.6 months, the median PFS was 9.9 months, and the median OS was 33.3 months. A total of 31 patients experienced different degrees of tr-AEs, of which 2 were grade 3 tr-AEs. CONCLUSION: The combination therapy of TACE, sintilimab, and lenvatinib demonstrates satisfactory efficacy in the treatment of uHCC with manageable tr-AEs.

Dangers of Herpesvirus Infection in SLE Patients Under Anifrolumab Treatment: Case Reports and Clinical Implications.

BACKGROUND Anifrolumab, a monoclonal antibody targeting the type 1 interferon (IFN-I) signaling pathway, holds promise as a therapeutic intervention for systemic lupus erythematosus (SLE). However, its use is associated with an increased risk of infections, particularly viral infections like herpes zoster (HZ). Results from the clinical trials on anifrolumab show yearly rates of upper respiratory tract infections of 34% and HZ of 6.1%. An increased frequency of other specific viral infections, including herpes simplex virus (HSV), was not reported. CASE REPORT Here, we present 2 cases of patients with SLE treated with anifrolumab, both experiencing severe adverse reactions in the form of disseminated herpesvirus infections, specifically disseminated HSV-2 and varicella zoster virus (VZV, HZ encephalitis). To the best of our knowledge, no previous reports of severe disseminated HSV-2 or HZ have been published in anifrolumab-treated patients. The patient in case 1 experienced a primary HSV-2 infection following anifrolumab treatment, potentially explaining the severity of the infection. The patient in case 2 had a history of previous HZ skin infections, which may have increased her risk of disseminated infection. Both patients recovered from the infections with minor sequelae, but they still require prophylactic antiviral treatment. These cases highlight the critical role of IFN-I immunity in protecting against herpesvirus infections. CONCLUSIONS Thorough risk assessment before anifrolumab initiation, considering the patient's viral infection history, vaccination status, and potential exposure risks, is essential. Administration of recombinant zoster vaccine before anifrolumab therapy may benefit susceptible individuals.

Budget impact of dostarlimab plus carboplatin-paclitaxel for primary advanced or recurrent endometrial cancer from a third-party US payer perspective.

AIM: Dostarlimab plus carboplatin-paclitaxel (CP) significantly increased progression-free survival in patients with primary advanced or recurrent endometrial cancer (pA/rEC) vs CP alone in the RUBY trial (NCT03981796). This analysis estimated the per-member-per-month (PMPM) costs of introducing dostarlimab + CP as a treatment alternative from a third-party US payer perspective. MATERIALS AND METHODS: A budget impact model was developed to estimate the costs of introducing dostarlimab + CP into commercial and Medicare health plans over a 3-year time horizon (2023-2025). Costs were sourced from relevant literature and US-specific databases and were calculated using epidemiology data, clinical inputs, treatment costs, and market share estimates. Clinical inputs were sourced from primary clinical trials for each respective treatment (i.e. dostarlimab + CP, CP, pembrolizumab, pembrolizumab plus lenvatinib, bevacizumab + CP, and pembrolizumab + CP). Current and future market shares assumed dostarlimab + CP reduced the market share of CP only. Analyses were performed in mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations using a US 2023 cost year. RESULTS: For a commercial plan, the model estimated (dMMR/MSI-H and overall populations) that 7 and 26 patients would be treated with dostarlimab + CP, respectively; average annual budget impacts per patient treated were $118,257 and $116,094; average budget impacts per patient treated per month (PPPM) were $9,855 and $9,675; average budget impacts PMPM were $0.02 and $0.06. For a Medicare plan, the model estimated that 28 and 93 patients, respectively, would be treated with dostarlimab + CP. Average annual budget impacts per patient treated and PPPM were the same as those for the commercial plan in both populations; average budget impacts PMPM were $0.07 and $0.22, respectively. CONCLUSIONS: Introducing dostarlimab + CP as a first-line treatment for patients with pA/rEC results in minimal budget impact PMPM from a US third-party payer's perspective. Together with the efficacy and safety results from RUBY, these results support the use of dostarlimab + CP as a treatment option.

Dostarlimab with carboplatin­paclitaxel is a recently approved treatment for newly diagnosed advanced or recurrent endometrial cancer. This analysis was done to estimate the added costs that US commercial and Medicare health plans would have over 3 years if this treatment was covered. This analysis found that the budget increase for covering dostarlimab with carboplatin­paclitaxel was small ($0.02­$0.06 per commercial plan member per month; $0.07­$0.22 per Medicare plan member per month).