Citations

2526 Background: Tumor necrosis factor receptor-2 (TNFR2) is expressed on effector CD8+, CD4+, and regulatory T (Treg) cells, natural killer (NK) cells, and myeloid cells. Activation of TNFR2 is anticipated to yield effective anti-tumor immunity by stimulating T-cell and NK-cell activation and proliferation in the tumor microenvironment. HFB200301 is a first-in-class anti-TNFR2 agonistic monoclonal antibody that triggers both innate and adaptive immune stimulation by binding to a specific epitope on TNFR2. We report initial results of an ongoing Phase I dose escalation, multicenter study (NCT05238883) of HFB200301 in monotherapy and in combination with tislelizumab (TIS) in patients (pts) with advanced refractory solid tumors. Methods: A Phase I trial designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and initial efficacy of HFB200301 in monotherapy and in combination with TIS. Eligible pts, ≥18 years with an ECOG PS 0-1 and advanced solid tumors, will be enrolled in dose escalation at 5 different dose cohorts in monotherapy (Q4W), 3 different dose cohorts in combination with TIS (Q4W), or in dose expansion following determination of safety. Radiographic response is assessed every 8 weeks. Results: A total of 39 pts have been enrolled, 27 pts in monotherapy and 12 pts in combination. All pts received prior systemic therapy (median 2, range 1-4); 23 pts (59%) had prior checkpoint inhibitor treatment. No dose limiting toxicities were observed in either the monotherapy or combination arms. Treatment-related adverse events (TRAEs) occurred in 44% of monotherapy and in 50% of combination pts, with pruritis (11%), tremor (7%), fatigue (7%), asthenia (7%) and nausea (7%) being the most common TRAEs. No ≥ Grade 3 TRAEs were reported, and there were no drug discontinuations due to TRAEs. Preliminary HFB200301 PK analysis demonstrated non-linear clearance of HFB200301, with dose-proportional maximum concentration [Cmax], achieving sufficient exposures for peripheral target engagement in all tested doses. Emerging PD data demonstrates evidence of immune activation and expansion of CD8+ T cells, but not Tregs, in the tumor microenvironment and peripheral blood. Single cell RNAseq analysis of peripheral blood mononuclear cells demonstrated PD modulation in TNFR2 positive immune cell types post-HFB200301 treatment. Early response evaluation reveals ongoing durable clinical responses (> 6 months) in a PD-L1+ pleural mesothelioma pt and an EBV+ gastric cancer pt from combination cohorts. Conclusions: HFB200301 demonstrates a favorable safety profile, dose-dependent PK, with PD and preliminary clinical activity in monotherapy and in combination with TIS in pts with heavily pre-treated refractory solid tumors. Clinical trial information: NCT05238883 .

2531 Background: The immune co-stimulatory receptor OX40 is expressed on CD4+ T cells, including regulatory T cells (Tregs). First generation OX40 agonists faced limitations from interference with endogenous OX40-OX40L binding, leading to decreased surface OX40 levels on T cells. Distinguished by its unique epitope on OX40, the novel next generation IgG1 monoclonal antibody (mAb) HFB301001 facilitates agonistic activity without impeding endogenous OX40 ligand binding. This allows for effective co-stimulation of T cells without diminishing OX40 levels. Additionally, HFB301001 exhibited superior in vivoanti-tumor activity and ability to enhance effector CD8+ T cell function compared to a benchmark first generation OX40 agonist in preclinical studies. Here, we report initial data of an ongoing dose-escalation study (NCT05229601) of HFB301001 in patients (pts) with advanced solid tumors. Methods: A Phase I trial designed to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of HFB301001. Eligible pts ≥18 years old (ECOG PS 0-1) with advanced solid tumors are enrolled in 4 different dose cohorts in monotherapy (Q4W) dose escalation. Solid tumor types were selected using Drug Intelligent Science (DIS®), employing integrative bulk and single cell RNAseq (scRNAseq) analyses to confirm and prioritize prospective targets in specific immune cell types. Sequential analysis of peripheral blood and tumor tissue biomarkers is performed. Radiographic response is assessed every 8 weeks. Results: As of January 06, 2024, 26 pts were enrolled, all having received prior systemic therapy (median 2, range 1-4); 81% received prior checkpoint inhibitor treatment. The majority of pts (77%) were male, median age was 62.5 years (range 41-78). Treatment-related adverse events (TRAEs) occurred in 34.6% of pts, none ≥ grade 3. Common TRAEs included rash (19%), pruritis (12%) and arthralgia (8%). No dose-limiting toxicities were observed. Preliminary results demonstrate dose-proportional increases in maximum concentration, typical mAb volume of distribution, and nonlinear clearance. On treatment biopsies revealed expansion of both natural killer and cytotoxic CD8+ T cells, with no notable expansion of Tregs. Analysis of peripheral blood by scRNAseq and immunophenotyping revealed expansion of cytotoxic CD8+T cells relative to CD4+ T cells post treatment. Preliminary efficacy analysis indicates a disease-control rate (DCR) of > 60% with greatest effect seen in hepato-cellular and renal cell carcinoma. Median time on treatment was 1.9 months (range 0.9-17 months). Conclusions: HFB301001 demonstrates a favorable safety profile, dose-dependent PK and PD immunomodulation, and DCR in heavily pretreated solid tumors. HFB301001 warrants further evaluation and expansion in specific tumor types is planned. Clinical trial information: NCT05229601 .

Abstract Background Delirium is a common complication of older people in hospitals, rehabilitation and long-term facilities. Objective To assess the worldwide use of validated delirium assessment tools and the presence of delirium management protocols. Design Secondary analysis of a worldwide one-day point prevalence study on World Delirium Awareness Day, 15 March 2023. Setting Cross-sectional online survey including hospitals, rehabilitation and long-term facilities. Methods Participating clinicians reported data on delirium, the presence of protocols, delirium assessments, delirium-awareness interventions, non-pharmacological and pharmacological interventions, and ward/unit-specific barriers. Results Data from 44 countries, 1664 wards/units and 36 048 patients were analysed. Validated delirium assessments were used in 66.7% (n = 1110) of wards/units, 18.6% (n = 310) used personal judgement or no assessment, and 10% (n = 166) used other assessment methods. A delirium management protocol was reported in 66.8% (n = 1094) of wards/units. The presence of protocols for delirium management varied across continents, ranging from 21.6% (on 21/97 wards/units) in Africa to 90.4% (235/260) in Australia, similar to the use of validated delirium assessments with 29.6% (29/98) in Africa to 93.5% (116/124) in North America. Wards/units with a delirium management protocol [n = 1094/1664, 66.8%] were more likely to use a validated delirium test than those without a protocol [odds ratio 6.97 (95% confidence interval 5.289–9.185)]. The presence of a delirium protocol increased the chances for valid delirium assessment and, likely, evidence-based interventions. Conclusion Wards/units that reported the presence of delirium management protocols had a higher probability of using validated delirium assessments tools to assess for delirium.

PURPOSE Telisotuzumab vedotin (Teliso-V) is a c-Met–directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536 ) aimed to identify the optimal c-Met protein–overexpressing non–small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor ( EGFR )-wildtype NSCLC. METHODS Eligible patients had locally advanced/metastatic c-Met protein–overexpressing NSCLC and ≤2 previous lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous EGFR -wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%–<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review. RESULTS In total, 172 patients with nonsquamous EGFR -wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 AE was peripheral sensory neuropathy (7%). CONCLUSION Teliso-V was associated with durable responses in c-Met protein–overexpressing nonsquamous EGFR -wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

3509 Background: HER2 overexpression/amplification (HER2+) occurs in ~3%-5% of pts with metastatic colorectal cancer (mCRC) and up to ~10% of pts with RAS/BRAF wild-type (WT) mCRC. The primary results of the MOUNTAINEER study (NCT03043313) demonstrated that the combination of tucatinib (TUC), a highly selective HER2-directed TKI, and trastuzumab (Tras) was well tolerated with clinically meaningful activity in pts with chemo-refractory HER2+ mCRC. Confirmed ORR was 38.1%, median DOR was 12.4 months, and median OS was 24.1 months. Here, we present results from the final analysis of MOUNTAINEER. Methods: MOUNTAINEER is a multi-center, open-label, randomized, phase 2 trial. Eligible pts had HER2+ and RAS WT mCRC with progression on or intolerance to last systemic therapy. Previous HER2-directed therapies were not permitted. The trial consisted of Cohort A, comprising pts treated with TUC (300 mg PO BID) + Tras (8 mg/kg IV then 6 mg/kg IV Q3W), as well as pts randomized 4:3 to receive TUC+Tras (Cohort B) or TUC monotherapy (Cohort C). Pts randomized to Cohort C were allowed to crossover and receive TUC+Tras on radiographic progression or if they did not achieve a complete or partial response by Week 12. Study endpoints evaluated at final analysis include DOR per BICR, PFS per BICR, OS, and safety. Results: The median duration of follow-up was 32.4 months (IQR, 25.1-46.7), with an additional 16.1 months of follow-up since the primary analysis (data cutoff, 02-Nov-2023). A total of 116 pts received at least 1 dose of study treatment (Cohorts A+B, N = 86; Cohort C, N = 30). In Cohorts A+B, median DOR per BICR was 15.2 months (95% CI, 8.9-20.5), median PFS per BICR was 8.1 months (95% CI, 4.2-10.2), and median OS was 23.9 months (95% CI, 18.7-28.3). In Cohort C post-crossover (N = 28), median DOR was not reached (95% CI, 2.8 months-NE). Median OS in Cohort C was 21.1 months (95% CI, 17.0-NE). The most common TEAEs in Cohorts A+B were diarrhea (66.3%), fatigue (44.2%), and nausea (34.9%). The majority of TEAEs were low grade, and rates were stable with longer follow-up. The most common grade ≥3 TEAE was hypertension (7.0%). TEAEs leading to TUC discontinuation in Cohorts A+B occurred in 5.8% of pts, which was unchanged from the primary analysis. In Cohort C, the most common TEAEs post-crossover were diarrhea (39.3%), back pain (21.4%), and pyrexia (21.4%); the most common grade ≥3 TEAE was AST increase (10.7%). No deaths resulted from TEAEs in any cohort and no new safety signals were identified. Conclusions: TUC+Tras continued to be well tolerated with sustained efficacy in pts with chemo-refractory RAS WT HER2+ mCRC, demonstrating clinically meaningful activity of the combination on longer follow-up. TUC+Tras is an important chemotherapy-free treatment option in HER2+ mCRC. TUC+Tras is being further evaluated in the first-line setting in combination with chemotherapy in the ongoing phase 3 MOUNTAINEER-03 trial (NCT05253651) for pts with HER2+ mCRC. Clinical trial information: NCT03043313 .

Background: Infective endocarditis (IE) management is challenging, usually requiring multidisciplinary collaboration from cardiologists, infectious disease specialists, interventional cardiologists, and cardiovascular surgeons, as more than half of the cases will require surgical procedures. Therefore, it is essential for all healthcare providers involved in managing IE to understand the disease’s characteristics, potential complications, and treatment options. While systemic embolization is one of the most frequent complications of IE, the coronary localization of emboli causing acute myocardial infarction (AMI) is less common, with an incidence ranging from 1% to 10% of cases, but it has a much higher rate of morbidity and mortality. There are no guidelines for this type of AMI management in IE. Methods: This narrative review summarizes the current knowledge regarding septic coronary embolization in patients with IE. Additionally, this paper highlights the diagnosis and management challenges in such cases, particularly due to the lack of protocols or consensus in the field. Results: Data extracted from case reports indicate that septic coronary embolization often occurs within the first two weeks of the disease. The aortic valve is most commonly involved with vegetation, and the occluded vessel is frequently the left anterior descending artery. Broad-spectrum antibiotic therapy followed by targeted antibiotic therapy for infection control is essential, and surgical treatment offers promising results through surgical embolectomy, concomitant with valve replacement or aspiration thrombectomy, with or without subsequent stent insertion. Thrombolytics are to be avoided due to the increased risk of bleeding. Conclusions: All these aspects should constitute future lines of research, allowing the integration of all current knowledge from multidisciplinary team studies on larger patient cohorts and, subsequently, creating a consensus for assessing the risk and guiding the management of this potentially fatal complication.

AbstractObjectivesWe aimed to develop consensus on comorbidities (frequency, severity, and prognosis) and overall outcomes in epilepsy, development, and cognition for the five phenotypes of SCN8A‐related disorders.MethodsA core panel consisting of 13 clinicians, 1 researcher, and 6 caregivers was formed and split into three workgroups. One group focused on comorbidities and prognosis. All groups performed a literature review and developed questions for use in a modified‐Delphi process. Twenty‐eight clinicians, one researcher, and 13 caregivers from 16 countries participated in three rounds of the modified‐Delphi process. Consensus was defined as follows: strong consensus ≥80% fully agree; moderate consensus ≥80% fully or partially agree, <10% disagree; and modest consensus 67%–79% fully or partially agree, <10% disagree.ResultsConsensus was reached on the presence of 14 comorbidities in patients with Severe Developmental and Epileptic Encephalopathy (Severe DEE) spanning non‐seizure neurological disorders and other organ systems; impacts were mostly severe and unlikely to improve or resolve. Across Mild/Moderate Developmental and Epileptic Encephalopathy (Mild/Moderate DEE), Neurodevelopmental Delay with Generalized Epilepsy (NDDwGE), and NDD without Epilepsy (NDDwoE) phenotypes, cognitive and sleep‐related comorbidities as well as fine and gross motor delays may be present but are less severe and more likely to improve compared to Severe DEE. There was no consensus on comorbidities in the SeL(F)IE phenotype but strong conesensus that seizures would largely resolve. Seizure freedom is rare in patients with Severe DEE but may occur in some with Mild/Moderate DEE and NDDwGE.SignificanceSignificant comorbidities are present in most phenotypes of SCN8A‐related disorders but are most severe and pervasive in the Severe DEE phenotype. We hope that this work will improve recognition, early intervention, and long‐term management for patients with these comorbidities and provide the basis for future evidence‐based studies on optimal treatments of SCN8A‐related disorders. Identifying the prognosis of patients with SCN8A‐related disorders will also improve care and quality‐of‐life for patients and their caregivers.

AbstractObjectiveWe aimed to develop consensus for diagnosis/management of SCN8A‐related disorders. Utilizing a modified Delphi process, a global cohort of experienced clinicians and caregivers provided input on diagnosis, phenotypes, treatment, and management of SCN8A‐related disorders.MethodsA Core Panel (13 clinicians, one researcher, six caregivers), divided into three subgroups (diagnosis/phenotypes, treatment, comorbidities/prognosis), performed a literature review and developed questions for the modified Delphi process. Twenty‐eight expert clinicians, one researcher, and 13 caregivers from 16 countries participated in the subsequent three survey rounds. We defined consensus as follows: strong consensus, ≥80% fully agree; moderate consensus, ≥80% fully/partially agree, <10% disagree; and modest consensus, 67%–79% fully/partially agree, <10% disagree.ResultsEarly diagnosis is important for long‐term clinical outcomes in SCN8A‐related disorders. There are five phenotypes: three with early seizure onset (severe developmental and epileptic encephalopathy [DEE], mild/moderate DEE, self‐limited (familial) infantile epilepsy [SeL(F)IE]) and two with later/no seizure onset (neurodevelopmental delay with generalized epilepsy [NDDwGE], NDD without epilepsy [NDDwoE]). Caregivers represented six patients with severe DEE, five mild/moderate DEE, one NDDwGE, and one NDDwoE. Phenotypes vary by age at seizures/developmental delay onset, seizure type, electroencephalographic/magnetic resonance imaging findings, and first‐line treatment. Gain of function (GOF) versus loss of function (LOF) is valuable for informing treatment. Sodium channel blockers are optimal first‐line treatment for GOF, severe DEE, mild/moderate DEE, and SeL(F)IE; levetiracetam is relatively contraindicated in GOF patients. First‐line treatment for NDDwGE is valproate, ethosuximide, or lamotrigine; sodium channel blockers are relatively contraindicated in LOF patients.SignificanceThis is the first‐ever global consensus for the diagnosis and treatment of SCN8A‐related disorders. This consensus will reduce knowledge gaps in disease recognition and inform preferred treatment across this heterogeneous disorder. Consensus of this type allows more clinicians to provide evidence‐based care and empowers SCN8A families to advocate for their children.

Abstract Background and Aims Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) has a poor renal prognosis and a high rate of recurrence after kidney transplantation, up to 90%, typically within the first-year post-transplant. Nearly 50% of patients lose their renal allograft within 3 years of recurrence. It has been suggested that pretreatment therapy (with B cell depleting or plasma-cell directed therapy) can help prevent recurrence or modulate the course of disease post-transplant. The aim of our study is to evaluate the effect of pretreatment therapy given within 6 months prior to kidney transplant on outcomes including PGNMID recurrence and all cause graft loss. Method Between 1996 and 2022, a total of 28 patients with biopsy-proven PGNMID as the cause of end stage kidney disease received a total of 31 kidney transplants. All patients had at least one year of follow-up data, for all but one patient this included surveillance kidney transplant biopsies completed at our center. Recurrence was defined histologically by immunofluorescence finding of monoclonal immunoglobulin deposits, independent of other histological or clinical parameters. The incidence of recurrence and all cause graft loss were analyzed by Kaplan-Meier plots. Results Median age of patients at transplant was 57 years, 87% were white, 65% were male, 74% received living donor transplant, 59% received thymoglobulin induction, 81% received maintenance with tacrolimus, mycophenolate, and prednisone. Median follow up time was 80 months. A total of 9 patients received pretreatment within 6 months of transplant, 8 received Rituximab and one received Daratumumab. The pretreatment group was generally younger at transplant (53 years vs 57 years) and had a shorter median follow up time (65 months vs 96.5 months), but neither were statistically significant. Overall recurrence rate was 78% for pretreatment and 91% for control, though difference in time to recurrence was not statistically significant (Fig. 1). The difference in all cause graft loss between groups was not statistically significant, however, none in the pretreatment group had graft loss by 60 months (Fig. 2). One patient who received daratumumab had no recurrence by 1 year post-transplant. Conclusion In kidney transplant recipients with PGNMID, pretreatment (primarily with rituximab) may be modulating the post-transplant course of disease. Further studies are needed to determine the extent of this effect and if plasma-cell directed vs B-cell directed therapy may be superior.