Fatal Adverse Events Research Articles

6937 A Rare Case of Pembrolizumab-induced Multiple Endocrinopathies Presenting with Acute Adrenal Crisis Secondary to Isolated ACTH Deficiency - A Case Report

Abstract Disclosure: R. Abdelmasih: None. W. Pan: None. Introduction: Pembrolizumab is an immune checkpoint inhibitor (ICI) that blocks programmed cell death receptor 1 (PD-1) which took a massive leap in the oncology world. However, we are still understanding more about its immune-related adverse events (irAEs). Here we report a case of adrenal crisis due to pembrolizumab-induced hypophysitis and adrenalitis. Case Description: A 74-year-old male with a history of left renal cell carcinoma post left nephrectomy 5 years ago, complicated with lung metastasis for which Pembrolizumab was started. 5 months after, patient developed hypothyroidism and was started on Levothyroxine. 3 months later, Patient presented with lethargy and hypotension. Physical exam revealed hypotension (MAP of 55), fever, and acute encephalopathy. AM cortisol 4.2 ug/dL, Patient was started on IV pressors and a stress dose of Hydrocortisone. Hemodynamics improved, and Hydrocortisone was tapered down. ACTH stimulation test revealed a subnormal response of cortisol 0.2, 1.7, and 2.7 ug/dL at 0, 30, and 60 minutes respectively in the setting of very low ACTH of < 1.5 pg/ml, other pituitary hormones were checked, revealing normal insulin-like growth factor was 116 ng/mL, LH 15.29 mIU/mL, and FSH 27.45 mIU/mL. TSH was high 15 mIU/mL and free T4 was 1.4 ng/dl, levothyroxine dose was increased, and hydrocortisone was maintained at 10 in am and 5 in pm with excellent response. Discussion:ICIs inhibit the immunological pathways that control T-cell activation, leading to multiple immune-related endocrinopathies. Thyroiditis is the most reported one (30%), though anti-PD1-induced hypophysitis is exceptionally rare (< 1%). To date, the pathophysiology of pembrolizumab-induced central AI is not clearly understood, it’s presumed that it causes lymphocytic hypophysitis often presenting with isolated ACTH deficiency. Also, Pembrolizumab-induced primary adrenal insufficiency has seldom been reported and not yet understood, interestingly, anti-steroidogenic enzyme antibodies were absent in those few most reported cases which suggests a different mechanism compared to traditional primary AI. We suggest that our patient had combined primary and secondary adrenal insufficiency based on ACTH stim test result with very low cortisol responses in the setting of very low ACTH, which we believe is what led to such severe presentation of adrenal crisis. Diagnosis of PD1-induced AI can be challenging due to the overlapping of advanced malignancy and AI presentation. A higher level of suspicion is prompted especially in patients who experienced other endocrine irAEs (as our patient who had PDL-1-induced hypothyroidism). We present this case to shed light on this rare yet potentially fatal endocrine adverse event that can be reversed by prompt diagnosis and timely management due to the increasing use of pembrolizumab. More cases are needed for a better understanding of such a rare adverse event. Presentation: 6/2/2024

Adverse events after colonoscopy in a randomised colorectal cancer screening trial

ObjectiveColonoscopy-related adverse events increase the burden of colorectal cancer (CRC) screening. This cross-sectional study evaluates adverse events during and after colonoscopy in a large, randomised CRC screening trial in Norway...

Regional diversity in drug-induced lung diseases among the USA, European Union, and Japan.

Drug-induced lung disease (DILD) is a considerable and potentially fatal adverse event with poorly understood risk factors. Large-scale, data-driven analyses investigating regional discrepancies in DILD incidence are lacking. The aim of this study was to investigate the potential association among DILD prevalence, regional differences and other factors based on large-scale data base. This retrospective observational study analyzed spontaneous adverse event reports from the FDA Adverse Event Reporting System (FAERS) database between January 2010 and December 2020. Regional disparities in DILD incidence were assessed among reports from the United States of America (USA), the European Union (EU), and Japan (JP). Using multivariate logistic regression accounting for age, sex, and reporting years, we calculated the reporting odds ratios (RORs) with 95% confidence intervals. Subgroup analyses were performed for different types of anticancer agents, including tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), antibody-drug conjugates (ADCs), and cytotoxic agents. Regional differences in RORs were observed for anticancer drugs in reports from JP and the EU compared with those from the USA (JP, ROR 4.432; EU, ROR 1.291) and for non-anticancer drugs (JP, ROR 3.481; EU, ROR 1.086). Significantly higher RORs were observed for all anticancer drug regimens reported in JP than in the USA (TKIs, ROR 3.274; ICIs, ROR 2.170; ADCs, ROR 2.335; cytotoxic agents, ROR 3.989). The EU reports exhibited higher RORs for TKIs and cytotoxic agents than the USA reports, with no significant differences in ICIs or ADCs (TKIs, ROR 1.679; ICIs, ROR 1.041; ADCs, ROR 1.046; cytotoxic agents, ROR 1.418). The prevalence of DILD in JP, the EU, and the USA differed. These findings have important implications in evaluating the safety profiles of drugs and patient safety in drug development and clinical practice. This study is the first to identify regional differences in DILDs using a large global database.

Clinical efficacy and immune response of BCL-2 inhibitors combined with hypomethylating agents in the treatment of acute myeloid leukemia

ObjectiveAcute myeloid leukemia (AML) is a malignant clonal proliferative disease with a high mortality rate. The combination therapy of BCL-2 inhibitor Venetoclax (VEN) and hypomethylating agents (HMAs) has significant anti-leukemia activity.MethodsWe analyzed the efficacy, safety and immune response characteristics of AML patients who were unfit for high-dose chemotherapy and accepted the medication of VEN + HMAs.ResultsAfter VEN + HMAs treatment, 31 newly diagnosed AML patients had the morphologic leukemia-free state rate (MLFS%) of 80.6% (25/31), complete response rate (CR%) of 54.8% (17/31), the minimal residual disease negative rate (MRD-%) of 51.6% (16/31), and the median progression-free survival (PFS) of 14 months. After treatment, the proportion of bone marrow primitive cells, the MRD level, white blood cell (WBC) count, fibrinogen (FIB) level and the proportion of B cells were significantly decreased. The red blood cell (RBC) count, hemoglobin (HGB) level, platelet count (PLT) count, activated partial thromboplastin time (APTT), the proportion of total T cells, CD8 + T cells and the IFN-γ level were significantly increased. After VEN + HMAs treatment, 12 relapsed AML patients had a MLFS% of 50% (6/12), CR% of 33.3% (4/12), MRD-% of 25% (3/12), and a median PFS of 7 months. After treatment, the proportion of bone marrow primitive cells and MRD level were slightly decreased, the proportions of CD8 + T cells and NK cells were significantly increased, the proportion of B cells and IL-10 level were significantly decreased. 12 AML patients who receive microtransplantation (MST) treatment using VEN + HMAs as a pretreatment regimen had a PFS of 20.5 months, which was much greater than VEN + HMAs group alone. Hematological recovery was better in the MST group with significantly increased RBC count, HGB level and PLT count. The most common adverse events were myelosuppression, agranulocytosis, infection and cardiovascular toxicity. No fatal adverse events were reported.ConclusionThe combination of BCL-2 inhibitors and HMAs had good efficacy and safety in AML patients who were unfit for high-dose chemotherapy, which may improve the immune microenvironment and enhance anti-leukemia immune response.

Proton pump inhibitors and cardiovascular adverse events: a meta-analysis of randomized controlled trials.

Some observational studies suggest a cardiovascular risk from proton pump inhibitor (PPI) treatment, but observational data may be subject to bias. We conducted a meta-analysis of randomized controlled trial data on cardiovascular events during PPI treatment. Manufacturers of PPIs provided data from their PPI clinical trial programs. We included randomized trials with at least 100 subjects, treatment duration >30 days, and a non-PPI comparator (active or placebo). We obtained person-time of exposure per trial, to calculate summary incidence rate ratios (primary analysis) and incident rate differences (secondary analysis). Our primary composite outcome was major adverse cardiovascular events-plus (MACE+), which included nonfatal myocardial infarction, nonfatal stroke, fatal cardiovascular adverse events, hospitalization for unstable angina, or coronary revascularization; events were adjudicated blindly. Cardiovascular outcomes were infrequent in randomized trials of PPIs and our primary analysis found no overall association (summary incident rate ratio, MACE+ events, PPI:placebo, 0.72 (95% confidence interval [CI] 0.42-1.26). There was some heterogeneity by indication category, and by the incidence rate difference metric, gastroesophageal reflux disorder (GERD) trials had 1.04 (95% CI 0.58, 1.50) excess MACE+ events per 100 person-years of treatment versus placebo. Comparisons to active controls generally showed positive incidence rate differences with PPI treatment. Overall, we found no association of cardiovascular events with PPI treatment. Cardiovascular events appeared more frequent with PPI treatment in GERD trials, but results from this subgroup should be interpreted with the limitations of the analysis in mind, including sparse outcome counts and lack of individual patient data.

Subjective symptoms are triggers for the detection of immune checkpoint inhibitor-induced interstitial lung disease and associate with disease severity: a single-center retrospective study

BackgroundInterstitial lung disease (ILD) is one of the most common fatal immune-related adverse events (irAEs). ILD development adversely affects the continuation of anticancer drug therapy, including immune checkpoint inhibitor (ICI) therapy and prognosis. There are no established useful clinical indicators for the early detection of ILD. Furthermore, the factors that lead the attending physician to suspect ICI-induced ILD (ICI-ILD) remain unclear. This study aimed to investigate the ICI-ILD detection based on subjective symptoms and their relationship with disease severity in patients receiving anti-PD-1/PD-L1 antibody.MethodsThis was a retrospective observational study. We enrolled the patients who received anti-PD-1/PD-L1 antibody at Kyoto University Hospital between September 2014 and April 2021. Patients who developed ICI-ILD were stratified into two distinct groups based on factors that triggered the suspicion of ILD development. The “Subjective symptoms” group was defined as patients in whom ILD was detected based on subjective symptoms. Conversely, the “Routine examinations” group was defined as patients in whom ILD was suspected based on scheduled routine examinations. The severity of ILD in each group was assessed and its association with changes in the respiratory symptoms was examined.ResultsOf 926 patients who received anti-PD-1/PD-L1 antibody, 51 patients (5.5%) developed ICI-ILD. The incidence of ICI-ILD in patients with lung cancer was significantly higher than that in patients with other cancers (P < 0.001). Among the patients with ICI-ILD, 27 patients (52.9%) were classified into the “Subjective symptoms” group. The “Subjective symptoms” group exhibited a significantly higher proportion of Grade 3–5 ICI-ILD cases than the “Routine examinations” group (76.2% vs. 23.8%, P = 0.010). At the last visit, before the suspected onset of ILD, 21 of the 27 patients (77.8%) had no symptoms or no change in the respiratory symptoms.ConclusionSubjective symptoms triggered the suspicion of Grade 3–5 ICI-ILD. Enhanced monitoring and patient education could be essential for the early detection of ICI-ILD because ILD may develop rapidly. Our findings might help to manage ICI-ILD in clinical practice.

Palliative use of self-expanding metal stents in initially anticancer treatment-intolerant patients with esophageal cancer

BackgroundThe post-insertion clinical course of esophageal self-expandable metal stents (SEMS) in initially frail patients with esophageal carcinoma (EC) with dysphagia remains unclear. This study aimed to assess dysphagia improvement and evaluate prognosis in initially frail patients with advanced EC following SEMS insertion.MethodsWe retrospectively reviewed EC patients with EC who underwent esophageal SEMS insertion at our institution between January 2014 and March 2023. Inclusion criteria comprised Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 3 or ECOG PS 2 for individuals aged ≥ 75 years and recommendation for best supportive care by a multidisciplinary team.ResultsForty-six patients met the inclusion criteria. Among them, 37 patients (80.4%) were ≥ 75 years old, and 21 patients (45.7%) exhibited ECOG PS 3 or 4. Dysphagia score (DS) ≥ 3 was observed in 27 patients (58.7%). All esophageal SEMS insertions were successfully completed. Post-procedure, there were two fatal cases of aspiration pneumonia and one perforation incident. DS improved to ≤ 1 in 25 patients (54.3%), with multivariate analysis indicating DS 3–4 and Glasgow Prognostic Score (GPS) 1–2 as negative predictive factors. The median overall survival was 4.1 months (95% confidence interval 1.8–6.5).ConclusionsEsophageal SEMS insertion effectively alleviated dysphagia in initially frail EC patients, yet prognosis remained poor, with occurrences of some fatal adverse events. Careful selection of candidates for esophageal SEMS insertions is crucial in this demographic, particularly considering the challenges in improving dysphagia for patients with DS 3–4 and GPS 1–2.

The potential role of lung microbiota and lauroylcarnitine in T-cell activation associated with checkpoint inhibitor pneumonitis

Checkpoint inhibitor pneumonitis (CIP) is a potentially fatal adverse event characterized by new pulmonary infiltrates in cancer patients receiving immune checkpoint inhibitor therapy. This study aims to explore the interplay between lung microbiota, dysregulated metabolites, and host immunity in CIP. We recruited thirteen hospitalized CIP patients, eleven idiopathic pulmonary fibrosis (IPF) patients, and ten new-onset non-small cell lung cancer patients. Bronchoalveolar lavage fluid samples were collected for 16S rRNA gene sequencing. The percentages of immune cells were determined using manual counting and flow cytometry. Interactions among microbiota, metabolites, and lymphocytes were analyzed using cultured mouse splenocytes and human T cells. Proteobacteria emerged as the dominant phylum, notably abundant in both the CIP and IPF groups. Vibrio, Halomonas, Mangrovibacter, and Salinivibrio were the predominant microbiota because of their discriminative abundance patterns. Vibrio (r=0.72, P-adj=0.007) and Halomonas (r=0.65, P-adj=0.023) demonstrated strong correlations with lymphocytes. Vibrio metschnikovii and Mangrovibacter plantisponsors were more abundant in the CIP group than in the IPF group. Lauroylcarnitine, a key intermediary metabolite co-occurring with the predominant microbiota, exhibited a potent effect on cytokine secretion by mouse and human T cells, notably enhancing IFN-γ and TNF-α production from CD4 and CD8 cells invitro. Lauroylcarnitine, co-occurring with the predominant lung microbiota in CIP, could activate T cells invitro. These findings suggest potential involvement of lung microbiota and acylcarnitine metabolism dysregulation in the pathogenesis of CIP. This work was supported by Peking University People's Hospital Scientific Research Development Funds (RDJ2022-15) and Provincial Key Clinical Specialty Capacity Building Project 2020 (Department of the Respiratory Medicine).

Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study

Hexanucleotide repeat expansion of C9orf72 is a common genetic cause of amyotrophic lateral sclerosis (ALS). No C9orf72-targeted treatments are available. BIIB078 is an investigational antisense oligonucleotide targeting C9orf72 sense RNA. We aimed to assess the safety, tolerability, and pharmacokinetics of BIIB078 in participants with C9orf72-associated ALS. This phase 1, randomised controlled trial was done at 22 sites in six countries (Canada, Ireland, Netherlands, Switzerland, UK, and USA). Adults with ALS and a pathogenic repeat expansion in C9orf72 were randomly assigned within six cohorts, via Interactive Response Technology in a 3:1 ratio per cohort, to receive BIIB078 (5 mg, 10 mg, 20 mg, 35 mg, 60 mg, or 90 mg in cohorts 1-6, respectively) or placebo, via an intrathecal bolus injection. The treatment period consisted of three loading doses of study treatment, administered approximately once every 2 weeks, followed by monthly maintenance doses during a treatment period of about 3 months for cohorts 1-3 and about 6 months for cohorts 4-6. Patients and investigators were masked to treatment assignment. The primary endpoint was the incidence of adverse events and serious adverse events. This trial was registered with ClinicalTrials.gov (NCT03626012) and is completed. Between Sept 10, 2018, and Nov 17, 2021, 124 patients were screened for inclusion in the study. 18 patients were excluded and 106 participants were enrolled and randomly assigned to receive 5 mg (n=6), 10 mg (n=9), 20 mg (n=9), 35 mg (n=19), 60 mg (n=18), or 90 mg (n=18) of BIIB078, or placebo (n=27). 58 (55%) of 106 patients were female. All patients received at least one dose of study treatment and were included in all analyses. All participants had at least one adverse event; most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. The most common adverse events in BIIB078-treated participants were falls, procedural pain, headache, and post lumbar puncture syndrome. 14 (18%) of 79 patients who received any dose of BIIB078 reported serious adverse events, compared with nine (33%) of 27 patients who received placebo. Five participants who received BIIB078 and three participants who received placebo had fatal adverse events: respiratory failure in a participant who received 10 mg BIIB078, ALS worsening in two participants who received 35 mg BIIB078, traumatic intracerebral haemorrhage in one participant who received 35 mg BIIB078, pulmonary embolism in one participant who received 60 mg BIIB078, and respiratory failure in three participants who received placebo. All deaths were assessed as not related to the study treatment by the reporting investigator. On the basis of these phase 1 study results, including secondary and exploratory findings showing no reduction in neurofilament levels and no benefit on clinical outcomes relative to the placebo cohort, BIIB078 clinical development has been discontinued. However, these results will be informative in furthering our understanding of the complex pathobiology of C9orf72-associated ALS. Biogen.

A tumor-responsive nanostrategy for reducing the risk of immunotherapy-related myocarditis

Immune checkpoint blockade (ICB) therapy using anti-programmed cell death 1 (PD1) and cytotoxic T lymphocyte antigen 4 (CTLA4), either individual or in combination, has emerged as a pioneer in clinical immunotherapy for various human cancers. However, immune-related adverse effects (irAEs) remain the significant hindrances to their clinical development. In particular, immune-related myocarditis has emerged as a fatal adverse event with the highest fatality rate. For this purpose, we report herein the first example of uncoupling efficacy and myocarditis toxicity in checkpoint blockade cancer therapy. This efficient, yet highly safe access to ICB therapy was achieved by a simple nanoplatform that masked anti-PD1/CTLA4 antibodies to albumin via a ROS-cleavable linker. An in-depth investigation of the experimental autoimmune myocarditis (EAM) mouse model revealed the avoiding exacerbation of myocarditis of our nanomedicine. Notably, the on-demand release of antibodies at the tumor sites enables the combined checkpoint antibody activity. The present study uncouples the ICB efficacy and toxicity, and highlights the irresistible charm of TME-responsive nanoantibodies in clinical cancer immunotherapy, offering solutions to challenges in the advancement of TME-responsive drug delivery toward clinical application.

Cardiotoxic profiles of CAR-T therapy and bispecific T-cell engagers in hematological cancers

BackgroundChimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engagers, which redirect T-cells to tumor antigens, have immensely benefitted patients with relapsed/refractory B-cell cancers. How these therapies differ in cardiotoxicity is underexplored. We used the World Health Organization pharmacovigilance database, VigiBase, to compare cardiotoxicity profiles between CD19-targeted CAR-T therapy and blinatumomab (a CD19/CD3-targeted bispecific T-cell engager).MethodsSafety reports in VigiBase were filtered for diffuse large B-cell lymphoma (DLBCL, n = 17,479) and acute lymphocytic leukemia (ALL, n = 28,803) for all adverse reactions. Data were further filtered for patients taking CAR-T therapy or blinatumomab. Reporting odds ratios (ROR) and fatality rates were compared between CAR-T cell products (e.g. tisagenlecleucel and axicabtagene ciloleucel), and between CAR-T therapy and blinatumomab.ResultsTisagenlecleucel is associated with cardiac failure (IC025 = 0.366) with fatality rates of 85.7% and 80.0% in DLBCL and pediatric ALL patients respectively. For DLBCL patients, axicabtagene ciloleucel has greater reporting for hypotension than tisagenlecleucel (ROR: 2.54; 95% CI: 1.28–5.03; p = 0.012), but tisagenlecleucel has higher fatality rates for hypotension than axicabtagene ciloleucel [50.0% (tisagenlecleucel) vs 5.6% (axicabtagene ciloleucel); p < 0.001]. Blinatumomab and tisagenlecleucel have similar fatality rates for hypotension in pediatric ALL patients [34.7% (tisagenlecleucel) vs 20.0% (blinatumomab); p = 0.66].ConclusionsTisagenlecleucel is associated with severe and fatal adverse cardiac events, with higher fatality rates for hypotension compared to axicabtagene ciloleucel in DLBCL patients, but similar hypotension fatality rates compared to blinatumomab in pediatric ALL patients. Effective management necessitates experienced physicians, including cardio-oncologists, skilled in interdisciplinary approaches to manage these toxicities.

Application of immune checkpoint inhibitors and microsatellite instability in gastric cancer

In this editorial we comment on the article by Li published in the recent issue of the World Journal of Gastroenterology . We focus specifically on the application of immune checkpoint inhibitors (ICIs) and microsatellite instability (MSI) in gastric cancer (GC). The four pillars of GC management have long been considered, including surgery, chemotherapy, radiotherapy and targeted therapy. However, immunotherapy has recently emerged as a ”fifth pillar”, and its use is rapidly expanding. There are four principal strategies for tumor immunotherapy: ICIs, tumor vaccines, adoptive immunotherapy and nonspecific immunomodulators. Of them, ICIs are the most advanced and widespread type of cancer immunotherapy for GC. Recent breakthrough results for ICIs have paved the way to a new era of cancer immunotherapy. In particular, inhibition of the PD-1/PD-L1 axis with ICIs, including nivolumab and pembrolizumab, has emerged as a novel treatment strategy for advanced GC. Unfortunately, these therapies are sometimes associated with often subtle, potentially fatal immune-related adverse events (irAEs), including dermatitis, diarrhea, colitis, endocrinopathy, hepatotoxicity, neuropathy and pneumonitis. We must be aware of these irAEs and improve the detection of these processes to prevent inappropriate discharges, emergency department revisits, and downstream complications. Recent studies have revealed that MSI-high or mismatch- repair-deficient tumors, regardless of their primary site, have a promising response to ICIs. So, it is important to detect MSI before applying ICIs for treatment of GC.

Efficacy and safety evaluation of Allisartan Isoproxil in patients with hypertension: a meta-analysis.

This study aimed to evaluate the effectiveness and safety of Allisartan Isoproxil in the management of hypertension. A comprehensive search was conducted across both English and Chinese databases, including the Cochrane Library, Embase, PubMed, Web of Science, Chinese Journal Full Text Database (CNKI), Wanfang Digital Periodical Full Text Database, and VIP Chinese Periodical Database (VIP), up to March 24, 2024. Randomized controlled trials (RCTs) investigating alisartan axetil for hypertension management were selected. Literature quality was assessed, and data were extracted for meta-analysis using Stata 15.1 software. The quality of evidence for outcome indicators was evaluated using the GRADE system level. Six RCTs involving 767 participants were included. Meta-analysis revealed that, compared to placebo, the Allisartan Isoproxil group exhibited a significant reduction in systolic blood pressure (SBP) [WMD = -8.08, 95% CI (-11.81, 4.10), p = 0.000] and brachial-ankle pulse wave velocity (baPWV) [SMD = -0.69, 95% CI (-1.17, 0.20), p = 0.006]. However, the reduction in diastolic blood pressure (DBP) was not statistically significant [WMD = -5.48, 95% CI (-11.07, 0.10), p = 0.054]. Additionally, compared to calcium channel blockers (CCB) and angiotensin II receptor blockers (ARB), Allisartan Isoproxil did not significantly affect SBP [WMD = 0.20, 95% CI (-3.71, 4.10), p = 0.921] or DBP [WMD = 0.16, 95% CI (-2.11, 2.43), p = 0.891]. Allisartan Isoproxil demonstrated superior effects in increasing nitric oxide (NO) levels and decreasing endothelin (ET) levels compared to control groups [WMD = 9.56, 95% CI (6.42, 12.71), p = 0.000], [WMD = -7.42, 95% CI (-11.13, -3.71), p = 0.000], and showed a higher effective control rate of blood pressure [RR = 1.26, 95% CI (1.13, 1.41), p = 0.000]. Subgroup analysis did not reveal significant differences. Regarding safety, there were no statistically significant differences in adverse events between the Allisartan Isoproxil group and the control groups [RR = 0.99, 95% CI (0.74, 1.32), p = 0.928], and no fatal adverse events were reported. Allisartan Isoproxil is effective in reducing SBP and baPWV, increasing NO, decreasing ET, and achieving a higher control rate of blood pressure in patients with essential hypertension. These benefits are achieved with minimal adverse reactions. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023467869, identifier PROSPERO CRD42023467869.

Superior outcomes and high-risk features with carfilzomib, lenalidomide, and dexamethasone combination therapy for patients with relapsed and refractory multiple myeloma: Results of the multicenter KMMWP2201 study.

Carfilzomib, lenalidomide, and dexamethasone (KRd) combination therapy improves the survival of patients with relapsed and/or refractory multiple myeloma (RRMM). Nonetheless, evidence on the use of KRd in Asian populations remains scarce. Accordingly, this study aimed at investigating this regimen's efficacy in a large group of patients. This retrospective study included patients with RRMM who were treated with KRd at 21 centers between February 2018 and October 2020. Overall, 364 patients were included (median age: 63 years). The overall response rate was 90% in responseevaluable patients, including 69% who achieved a very good partial response or deeper responses. With a median follow-up duration of 34.8 months, the median progression-free survival (PFS) was 23.4 months and overall survival (OS) was 59.5 months. Among adverse factors affecting PFS, highrisk cytogenetics, extramedullary disease, and doubling of monoclonal protein within 2 to 3 months prior to start of KRd treatment significantly decreased PFS and overall survival (OS) in multivariate analyses. Patients who underwent post-KRd stem cell transplantation (i.e.delayed transplant) showed prolonged PFS and OS. Grade 3 or higher adverse events (AEs) were observed in 56% of the patients, and non-fatal or fatal AE's that resulted in discontinuation of KRd were reported in 7% and 2% of patients, respectively. Cardiovascular toxicity was comparable to that reported in the ASPIRE study. In summary, KRd was effective in a large real-world cohort of patients with RRMM with long-term follow-up. These findings may further inform treatment choices in the treatment of patients with RRMM.

Safety of Extended Pirtobrutinib Exposure in Relapsed and/or Refractory B-Cell Malignancies.

Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment. Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs). Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy. Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.

Lenvatinib (Lenv) plus tislelizumab (Tis) combined with or without transarterial chemoembolization (TACE) in first-line treatment of unresectable hepatocellular carcinoma (uHCC): A prospective, non-randomized, open-label, phase II cohort study.

e16169 Background: The synergistic potential of programmed death protein-1 inhibitors and tyrosine kinase inhibitors in treating uHCC has been established. TACE, a cornerstone in uHCC therapy, primes the tumor microenvironment for immunotherapy by releasing neoantigens and inducing ischemia. This study explores the efficacy and safety of Lenv plus Tis, combined with or without TACE, in a first-line setting. Methods: This phase II study enrolled patients (pts) with pathologically and/or radiologically diagnosed uHCC eligible for embolization, with at least one measurable lesion, Child-Pugh class A/B, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Pts received Tis (200mg every 3 weeks) and Lenv (oral dose adjusted by weight: 8mg for &lt;60kg and 12mg for ≥60kg) with or without conventional TACE, as determined by the treating physician. The primary endpoint was the objective response rate (ORR), with secondary endpoints including overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). Results: By the data cutoff on January 27, 2024, 37 pts were enrolled: 12 received Lenv+Tis (cohort 1), and 25 received Lenv+Tis+TACE (cohort 2). Median follow-up time was 10.66 months. The ORR was 33.3% in cohort 1 and 68.0% in cohort 2, with DCRs of 100% and 96%, respectively (mRECIST). Median OS was 10.85 months (95% CI, 4.76-16.95) for cohort 1 and 13.61 months (95%CI, NE-NE) for cohort 2. Median PFS was 10.85 months (95% CI, NE-NE) for cohort 1, and 11.86 months (95% CI, 6.49-16.73) for cohort 2. Grade 3-4 treatment-emergent adverse events (teAE) occurred in 50% of cohort 1 and 68% of cohort 2. No fatal adverse event was reported. The most common grade 3-4 teAE (incidence &gt;10%) were anaemia (17%) in cohort 1, and decreased platelet count (16%), hypertension (16%), rash (16%), fatigue (12%), elevated ALT (12%) in cohort 2. Conclusions: Both Lenv+Tis and Lenv+Tis+TACE showed promising efficacy and manageable safety in the first-line treatment of uHCC. More pts were recruiting to further prove these results. Clinical trial information: NCT05842317 . [Table: see text]

Glofitamab monotherapy in patients with heavily pretreated relapsed/refractory (R/R) mantle cell lymphoma (MCL): Updated analysis from a phase I/II study.

7008 Background: Glofitamab, a bispecific antibody with a novel 2:1 (CD20:CD3) format, engages and redirects T cells to eliminate malignant B cells. In a Phase I/II study (NCT03075696), fixed-duration glofitamab monotherapy showed high, durable complete responses (CR) and manageable safety in patients (pts) with heavily pretreated R/R MCL (Phillips et al. ASH 2022). We report updated efficacy and safety data for pts with R/R MCL. Methods: Pts received obinutuzumab pretreatment (Gpt; 1000mg or 2000mg) 7 days before their first glofitamab dose. Glofitamab step-up dosing was given on Cycle (C) 1 Day (D) 8 (2.5mg) and D15 (10mg), and target dose (16mg or 30mg) from C2D1 to C12 as a fixed-duration therapy. Efficacy endpoints were CR, overall response rate (ORR), duration of CR (DOCR), duration of response (DOR) and progression-free survival (PFS). Post-hoc PFS and overall survival (OS) landmark analyses were performed in pts with a CR at end of treatment (EOT). Results: As of Sept 4, 2023, 61 pts were enrolled; 60 received study treatment (1000mg Gpt, n=16; 2000mg Gpt, n=44). Median number of prior lines of therapy was 2 (range: 1–5); 73.3% were refractory to the last line of prior therapy. Median duration of glofitamab therapy was 7.4 months; median number of cycles was 12. Of the 31 pts (51.7%) who received prior Bruton’s tyrosine kinase inhibitor (BTKi) therapy, 29 (93.5%) were BTKi refractory; median number of prior lines of therapy was 3 (range: 1–5); 90.0% were refractory to the last line of prior therapy. At a median PFS follow-up of 17.2 months, ORR and CR rate were 85.0% and 78.3%, respectively. Median DOCR was 15.4 months; the majority of CRs (28/47; 59.6%) were ongoing at data cut-off. Of 19 pts with a CR, 9 had disease progression and 10 died (fatal adverse event [AE], n=8; COVID, n=7; septic shock, n=1). Estimated 12-month DOCR and DOR rates were 71.0% and 66.6%, respectively. Median PFS was 16.8 months. Landmark analyses indicated that most pts with a CR at EOT were alive and progression free 15 months post-EOT (OS rate, 72.7%; PFS rate, 59.2%). Observed efficacy data were consistent across both Gpt cohorts. In post-BTKi pts after a median PFS follow-up of 26.1 months, ORR and CR rate were 74.2% and 71.0%, respectively. Median DOCR was 12.6 months; median PFS was 8.6 months. No new safety signals were observed. Cytokine release syndrome (CRS) remained the most common AE (42/60, 70.0%; Grade 1/2, 58.3%) and was lower in the 2000mg (63.6%) vs the 1000mg (87.5%) Gpt cohort. Glofitamab monotherapy (2000mg Gpt) is currently under investigation in the Phase III GLOBRYTE study (NCT06084936). Conclusions: Fixed-duration glofitamab continues to demonstrate compelling response rates that are maintained beyond EOT, with long-term durability observed in heavily pretreated pts with R/R MCL, including pts with prior BTKi therapy. The safety profile was manageable and CRS mainly low grade. Clinical trial information: NCT03075696 .

Safety, tolerability and efficacy of 212Pb-DOTAMTATE as a targeted alpha therapy for subjects with unresectable or metastatic somatostatin receptor-expressing gastroenteropancreatic neuroendocrine tumors (SSTR+ GEP-NETs): A phase 2 study.

4020 Background: 212Pb-DOTAMTATE is a Targeted Alpha Therapy (TAT) in clinical development for subjects with SSTR+ neuroendocrine tumors. A phase I dose-escalation study has already been completed (Delpassand et al. J Nucl Med 2022). TAT holds the promise to improve outcomes versus Peptide Receptor Radionuclide Therapy (PRRT) with beta-emitters like 177Lu-DOTATATE, currently considered the standard of care for subjects with GEP-NETs. Methods: ALPHAMEDIX 02 is a Phase II, open-label, multicenter study evaluating the safety, tolerability and efficacy of 212Pb-DOTAMTATE in PRRT-naïve (Cohort 1, N = 36) and PRRT-refractory (Cohort 2, Target N = 30) subjects with histologically confirmed unresectable or metastatic GEP-NETs, positive somatostatin analogue imaging and at least 1 site of measurable disease per RECIST 1.1. 212Pb-DOTAMTATE was administered at 67.6 μCi/kg per cycle, with a maximum activity administered per cycle of 5.5 mCi every 8 weeks, for up to 4 cycles. Primary endpoints include overall response rate (ORR) per RECIST1.1, and incidence and severity of adverse events (AEs). Secondary endpoints include progression free survival, overall survival , and health-related quality of life. Initial results of the already completed cohort 1 are presented. Results: In cohort 1, 17 out of 36 subjects with metastatic SSTR+ GEP-NETs achieved a confirmed response (ORR 47.2% (32.0-63.0%)). In the Phase I trial, five out of eight PRRT- naïve subjects with SSTR+ GEP-NETs treated with the same regimen of 212Pb-DOTAMTATE achieved a response (ORR 62.5% (30.6-86.3%)): the combined ORR from both studies is 50% (22 out of 44, 95%-CI:36% - 64%). Median Duration of Response (DOR) has not been reached in both studies. Four out of five subjects (80%) with confirmed response in Phase I had a DOR of ≥ 12 months. In the ongoing Phase II study the response follow-up for 10 subjects with confirmed response is currently shorter than 6 months: so far 7 out of 17 subjects (41%) with confirmed response had a DOR of ≥ 6 months, and one of these subjects had a DOR of ≥ 12 months. Lymphocytopenia is a lead cause of the 59% grade 3 and 4 AEs reported in subjects in cohort 1. Overall, 4 fatal AEs were reported: death / progressive disease (N = 2), carcinoid syndrome (N = 1) and sepsis (N = 1). Conclusions: In PRRT-naïve subjects with SSTR+ unresectable or metastatic GEP-NETs treatment with up to 4 cycles of ²¹²Pb-DOTAMTATE (67.6 μCi/kg/cycle) was well-tolerated, with a safety profile consistent with the underlying disease and expected toxicities of radioligand therapy, similar to 177Lu-DOTATATE. The ORR of 47.2% in cohort 1 (50% in the pooled dataset) appears to be substantially higher than the ORR previously reported for 177Lu-DOTATATE in the pivotal NETTER-1 study (ORR 18% (10–25%)). Clinical trial information: NCT05153772 .

Safety of tabelecleucel with pembrolizumab in recurrent/metastatic Epstein–Barr virus-associated nasopharyngeal carcinoma.

6096 Background: Despite standard treatment with radiation and/or chemotherapy, approximately one in four patients (pts) with nasopharyngeal carcinoma (NPC) will develop recurrent/metastatic (RM) disease that is associated with poor prognosis. Programmed cell death ligand 1 (PD-L1) expression is upregulated in NPC due to Epstein–Barr virus (EBV) activation. Tabelecleucel (tab-cel), an off-the-shelf, allogeneic, EBV-specific T-cell immunotherapy, has shown promising antitumor activity in pts with RM EBV+NPC (Prockop, JCO 2016). The anti-PD-1 antibody pembrolizumab (pembro) is also active in NPC. To characterize the safety profile and preliminary efficacy of tab-cel combined with pembro in RM EBV+NPC, we initiated a phase 1b/2 study (NCT03769467). Here we report safety outcomes in 12 subjects treated in the phase 1b portion of the study. Methods: The multicenter, open-label, single-arm phase 1b portion of the study was designed to evaluate the safety of tab-cel in combination with pembro in pts with incurable RM EBV+NPC previously treated with platinum-containing therapy. Pts were either checkpoint-inhibitor naïve (n=6) or experienced to anti-PD-1/PD-L1 therapy (n=6). Tab-cel was administered intravenously (IV) on days 1, 8, and 15 of a 21-day cycle. Initial tab-cel dose was 2x106 cells/kg. Pembro was administered at 200 mg IV Q3W. Primary endpoints of phase 1b focused on assessing safety. Results: As of the final data cutoff, 12 subjects were treated as part of the phase 1b portion of the study. Subjects were 75% Asian and 50% male, with a median age (min, max) of 51 (20, 72) years and a median time from initial diagnosis to first dose of tab-cel (min, max) of 47.7 (8.0, 221.8) months. All subjects had received prior platinum-based chemotherapy/chemoradiation. No dose-limiting toxicities or fatal treatment-emergent adverse events (TEAEs) were identified. All 12 subjects reported ≥1 TEAE; the most common TEAEs reported by ≥4 subjects were disease progression (8 subjects, 66.7%), myalgia (5 subjects, 41.7%), pyrexia, arthralgia, and hyponatremia (4 subjects, 33.3%, each). No ≥ grade 3 TEAEs were considered related to tab-cel or pembro. No TEAEs considered related to tab-cel or pembro led to study discontinuation. No clinically significant abnormal trends were identified in laboratory parameters or vital signs. Although the phase 1b portion of the study was not designed to assess efficacy, the best response seen was stable disease in 6 of 12 pts (50%). Conclusions: Phase 1b data demonstrated combination therapy of tab-cel and pembro to be well tolerated and identified a recommended phase 2 dose in subjects with platinum-pretreated RM EBV+NPC. The study was discontinued after the phase Ib portion due to an evolving immunotherapy treatment landscape for this disease, which would need to be considered for further clinical development. Clinical trial information: NCT03769467 .

Phase 1 Study of JNJ-81201887 Gene Therapy in Geographic Atrophy Secondary to Age-Related Macular Degeneration

ObjectiveTo evaluate the safety and tolerability of a single intravitreal injection of JNJ-81201887 (JNJ-1887) in patients with geographic atrophy (GA) secondary to advanced dry age-related macular degeneration (AMD). DesignPhase 1, open-label, single-center, first-in-human clinical study. SubjectsAdult patients (aged ≥50 years) with GA secondary to AMD in the study-treated eye (treated eye) with a best corrected visual acuity (BCVA) Snellen equivalent of 20/200 or worse in the treated eye (20/80 or worse after the first 3 patients), a total GA lesion size between 5 and 20 mm2 (2-8 disc area), and BCVA of 20/800 or better in fellow, non-treated eye were included. MethodsPatients (N=17) were sequentially enrolled into low (3.56×1010 viral genome [vg]/eye; n=3), intermediate (1.07×1011 vg/eye; n=3), and high (3.56×1011 vg/eye; n=11) dose cohorts without steroid prophylaxis and assessed for safety and tolerability over 24 months. Main Outcome MeasuresSafety and tolerability outcomes included assessment of ocular and non-ocular treatment-emergent adverse events (AEs) over 24 months. Secondary outcomes included GA lesion size and growth rate. ResultsBaseline patient characteristics were consistent with the disease under study, and all enrolled patients had foveal center–involved GA. JNJ-1887 was well tolerated across all cohorts, with no dose-limiting AEs. There were no serious or systemic AEs related to study intervention. Overall, 5/17 (29%) patients experienced 6 events of mild ocular inflammation related to study treatment; exam findings in all resolved, and AEs resolved in 4 of 5 patients following topical steroids or observation. One unresolved vitritis event, managed with observation, occurred in a patient with an unrelated fatal AE. No endophthalmitis or new-onset choroidal neovascularization was reported. GA lesion growth rate was similar among all cohorts over 24 months. For treated eyes in the high-dose cohort, GA lesion growth rate showed continued decline through 24 months, with a reduction in mean square root lesion growth from 0.211 mm at months 0-6 to 0.056 mm at months 18-24. ConclusionsAll 3 studied doses of JNJ-1887 had a manageable safety profile through 24 months of follow-up. Further investigation of JNJ-1887 for the treatment of GA is warranted.