Prespecified Primary End Point Research Articles

Efficacy and safety of mosunetuzumab monotherapy for Japanese patients with relapsed/refractory follicular lymphoma: FLMOON-1.

In a global phase I/II study (GO29781; NCT02500407), single-agent mosunetuzumab had a manageable safety profile and induced durable complete responses in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma, including in patients with R/R follicular lymphoma (FL). In this analysis, the efficacy and safety of mosunetuzumab monotherapy were evaluated in an expansion cohort, FLMOON-1, in Japanese patients with R/R FL who had received ≥ 2 prior lines of therapy in a phase I study (JO40295, jRCT2080223801). Mosunetuzumab was administered intravenously at the recommended phase II dose (with cycle 1 step-up dosing) for eight cycles or up to 17 cycles, or until disease progression or unacceptable toxicity. The pre-specified primary endpoint was Independent Review Facility (IRF)-assessed complete response rate (CRR; as best overall response). Secondary objectives included investigator (INV)-assessed CRR, INV- and IRF-assessed objective response rate (ORR), and safety. At the data cutoff (October 13, 2023), 19 patients (median age 72years) were evaluated. The IRF-assessed CRR and ORR were 68.4% and 78.9%, respectively; the INV-assessed CRR and ORR were 63.2% and 84.2%, respectively. Grade 3-4 adverse events (AEs) were observed in 89.5% of patients, with a low incidence of AEs leading to mosunetuzumab discontinuation (10.5%) and one fatal AE unrelated to mosunetuzumab. Cytokine release syndrome occurred in 47.4% of patients and were mostly Grade 1 in severity. These findings indicate mosunetuzumab has a consistent efficacy and manageable safety profile in Japanese patients with R/R FL compared with previously reported data from the global phase I/II study.

CTIM-24. PHASE II TRIAL OF RHIL-7-HYFC IN PATIENTS WITH HIGH-GRADE GLIOMA DEMONSTRATED ACCEPTABLE SAFETY PROFILE AND REDUCED LYMPHOPENIA

Abstract BACKGROUND Lymphopenia, a common finding in patients with high-grade gliomas (HGGs), is associated with poor outcomes including worse survival, fatigue, and in some cases, increased opportunistic infections. Interleukin-7 (IL-7) is a cytokine crucial for lymphocyte survival and proliferation. We previously demonstrated long-acting IL-7 (rhIL-7-hyFc, efineptakin alfa, NT-I7) increases absolute lymphocyte counts (ALCs) and extends survival in preclinical murine models of HGG. Here, we report results using rhIL-7-hyFc to effectively reduce lymphopenia in patients with HGG. METHODS We performed a phase II randomized, placebo-controlled, double-blind study of rhIL-7-hyFc in patients with newly diagnosed HGGs (82% IDH-wildtype glioblastoma in both groups). Patients received rhIL-7-hyFc (720mcg/kg) or placebo one-week post-radiation and temozolomide, with subsequent doses at weeks 13, 25, and 37. The primary endpoint was ALC four weeks post-initial administration; exploratory endpoints included CD4 count, progression-free survival (PFS), and overall survival (OS). RESULTS We enrolled 22 patients (median age 59.5 years, range 33-74; 40.9% female) with HGG. Both groups exhibited comparable demographics, including MGMT methylation status, and received a median of 2 doses of rhIL-7-hyFc or placebo. At 4 weeks, the pre-specified primary endpoint, ALC significantly increased relative to baseline in the treatment group, compared to placebo (median percent change=148% vs. 16.7%, p=0.007), as did CD4 count (121% vs. 10.5%, p=0.011). There were no treatment-related grade 4/5 adverse events. Exploratory endpoints of PFS and OS will be reported at time of conference. CONCLUSIONS rhIL-7-hyFc is safe and effective in improving ALC and CD4 count in patients with newly diagnosed HGG undergoing temozolomide and concurrent radiation therapy. This study was powered to meet the primary endpoint; larger trials will likely be required to demonstrate clinical efficacy. Nevertheless, these data support the continued exploration of rhIL-7-hyFc as an adjunct to standard therapy to mitigate lymphopenia and potentially extend survival for patients with HGG.

Intestinal subtype as a biomarker of response to neoadjuvant immunochemotherapy in locally advanced gastric adenocarcinoma: insights from a prospective phase II trial.

Neoadjuvant immunochemotherapy (NAIC) markedly induces pathologic regression in locally advanced gastric adenocarcinoma (GAC). However, specific biomarkers are still lacking to effectively identify the beneficiary patients for NAIC. A prospective, single-arm, phase II study was conducted to treat locally advanced GAC with NAIC (NCT05515796). Correlation between clinicopathological characteristics and neoadjuvant efficacy was investigated. Bulk RNA-seq data from 104 samples (from 75 patients in two independent cohorts) and scRNA-seq data from 105 treatment-naïve GACs were comprehensively analyzed to decipher the association of epithelial and microenvironmental characteristics and clinical responses. The pre-specified primary endpoints were achieved: pathological complete regression (pathCR) rate was 30%, major pathological regression (MPR) rate was 43%, while the regimen was well tolerated. Analysis of baseline clinical-pathological parameters revealed the intestinal subtype of Lauren's classification as a key feature stratifying patients with increased sensitivity to NAIC. Mechanistically, an increased pool of DNA damage repair (DDR)-active cancer cells and enrichment of CLEC9A+ dendritic cells (DCs) in the tumor microenvironment were associated with enhanced responsiveness of the intestinal subtype GAC to NAIC. More importantly, an intestinal-subtype specific signature model was constructed by the machine learning algorithm NaiveBayes via integrating the transcriptomic features of both DDR-active cancer cells and CLEC9A+ DCs, which accurately predicted the efficacy of NAIC in multiple independent GAC cohorts. Intestinal subtype is a histological biomarker of enhanced sensitivity of GAC to NAIC. The Intestinal-subtype specific signature model is applicable to guide NAIC for patients with locally advanced GAC.

Tirzepatide Reduces LV Mass and Paracardiac Adipose Tissue in Obesity-Related Heart Failure: SUMMIT CMR Substudy.

Obesity is a known risk factor for heart failure with preserved ejection fraction (HFpEF) and is considered a distinct phenotype with more concentric remodeling. Epicardial adipose tissue (EAT) is also increased in obesity-related HFpEF and is associated with adverse events. The Cardiac Magnetic Resonance (CMR) Substudy of the SUMMIT trial was aimed to examine the effects of tirzepatide on cardiac structure and function with the underlying hypothesis that it would reduce left ventricular (LV) mass and EAT in obesity-related HFpEF. One hundred seventy-five patients with obesity-related HFpEF from the parent study of tirzepatide (2.5mg SQ weekly, increasing to a maximum of 15mg weekly) or matching placebo underwent CMR at baseline, which consisted of multiplanar cine imaging. One hundred six patients completed the CMR and had adequate image quality for analysis of LV and LA structure and function and paracardiac (epicardial plus pericardial) adipose tissue at both baseline and 52 weeks. The prespecified primary endpoint of this substudy was between-group changes in LV mass. LV mass decreased by 11 g (95% C.I. -19 to -4) in the treated group (n = 50) when corrected for placebo (n =56) (p=0.004). Paracardiac adipose tissue decreased in the treated group by 45 ml (95% C.I. -69 to -22) when corrected for placebo (p<0.001). The change in LV mass in the treated group correlated with changes in body weight (p<0.02) and, tended to correlate with changes in waist circumference and blood pressure (p=0.06 for both). The LV mass change also correlated with changes in LV end diastolic volume and LA end diastolic and end systolic volumes (p<0.03 for all). The CMR substudy of the SUMMIT trial demonstrated that tirzepatide therapy in obesity-related HFpEF led to reduced LV mass and paracardiac adipose tissue as compared to placebo and the change in LV mass paralleled weight loss. These physiologic changes may contribute to the reduction in heart failure events seen in the main SUMMIT trial.

Transcatheter versus surgical aortic valve replacement in lower-risk patients: an updated meta-analysis of randomised controlled trials

Abstract Background Long-term clinical outcomes after transcatheter [TAVI] and surgical [SAVR] aortic valve replacement are of utmost importance in lower-risk patients. Event rates are diminished in lower-risk patients, therefore individual trials may be separately underpowered to assess low-frequency outcomes. New randomised data has emerged, including 4, 5 and 10-year follow-up from the Evolut Low Risk, PARTNER-3 and NOTION trials, respectively. Purpose To perform a systematic review and meta-analysis of randomised trials studying long-term outcomes in patients with severe aortic stenosis at low-surgical risk undergoing TAVI versus SAVR. Methods Trials randomising patients at lower surgical risk in trials comparing TAVI with SAVR were systematically identified. The prespecified primary endpoint was all-cause death. Key secondary endpoints included stroke, death or disabling stroke, cardiac death, new permanent pacemaker, aortic valve reintervention, and new-onset atrial fibrillation. Reconstructed individual patient data [IPD] was obtained via digitisation of Kaplan-Meier survival curves. Using these data, Cox proportional hazards regression was performed using frailty models on the primary outcome of all-cause death. To assess total lifetime lost, the restricted mean survival time [RMST] was calculated. Conventional pairwise random effects meta-analyses were also performed. This analysis was prospectively registered [CRD42023484976]. Results 4 eligible trials contributed data from 3557 patients with a weighted mean follow-up duration of approximately 4 years (47.6 months). In the reconstructed IPD pooled analyses, there was no significant difference in the hazard of death [hazard ratio 1.15, 95% CI 0.93 to 1.41, p=0.20] or RMST [Δ-0.8 months, p=0.09] (Figure 1). In pairwise meta-analyses, there was no difference between TAVI and SAVR in all-cause death [relative risk (RR) 0.94, 95% confidence interval (CI) 0.78 to 1.13, p=0.51] (Figure 2). There was also no significant difference for stroke [RR 0.94, 95% CI 0.59 to 1.50, p=0.80], or a composite of death or disabling stroke [RR 0.92, 95% CI 0.70 to 1.22, p=0.57]. There was an increase in new pacemaker implantation with TAVI [RR 2.15, 95% CI 1.50 to 3.07, p&amp;lt;0.001], and a reduction in new AF with TAVI [RR 0.43, 95% CI 0.26 to 0.70, p&amp;lt;0.001]; there was no significant difference in any other endpoint (Figure 2). Conclusions The present analysis demonstrates no difference in major clinical outcomes with TAVI or SAVR in lower-risk patients at 4-years follow-up. These results were consistent when analysed using pooled reconstructed IPD or conventional meta-analyses and there were no differences in RMST. These data are informative for lower-risk patients and clinicians, but longer-term follow-up is required to confirm whether equivalence is maintained.Kaplan-Meier plot comparing TAVI vs SAVRForest plot for key clinical endpoints

Accuracy of coronary computed tomography angiography-derived quantitative flow ratio for onsite assessment of coronary lesions.

Coronary computed tomography angiography (CCTA)-derived Murray law-based quantitative flow ratio (CT-μFR) is a novel non-invasive method for fast computation of fractional flow reserve (FFR) from CCTA images, yet its diagnostic performance remains to be prospectively validated. We aimed to evaluate the diagnostic performance of onsite CT-μFR in patients with coronary artery disease. This prospective, single-centre trial enrolled patients with ≥1 lesion with 30-90% diameter stenosis on CCTA and planned invasive coronary angiography (ICA) within 30 days. CT-μFR, ICA-derived μFR and FFR were evaluated separately in a blinded fashion. The primary endpoint was the diagnostic accuracy of CT-μFR in identifying patients with haemodynamically significant coronary stenosis defined by the invasive standard: FFR ≤0.80, or μFR ≤0.80 when FFR was not available. Between December 2020 and August 2023, 260 patients were consecutively enrolled. Paired comparison between CT-μFR and the invasive standard was obtained in 706 vessels from 260 patients. The patient-level accuracy of CT-μFR was 89.6% (95% confidence interval [CI]: 85.9-93.4%), which was significantly higher than the prespecified target of 72.0% (p<0.001). Sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios for CT-μFR were 93.1%, 86.1%, 87.1%, 92.5%, 6.7, and 0.1, respectively. Out of the 231 vessels investigated by FFR, the accuracy of CT-μFR in vessels without extensive calcification was non-inferior to that of μFR (90.6% vs 88.9%; difference=1.8% [95% CI: -2.8 to 5.5%]; p for non-inferiority<0.001). The study met its prespecified primary endpoint of the diagnostic accuracy of CT-μFR in identifying patients with haemodynamically significant coronary stenosis. CT-μFR was non-inferior to ICA-derived μFR in vessels without extensive calcification. (ClinicalTrials.gov: NCT04665817).

Sex and outcomes after stenting and endarterectomy in asymptomatic severe carotid stenosis patients

ObjectivesTo determine if sex was an effect modifier in a pooled analysis of asymptomatic patients from CREST and ACT I. Materials and MethodsWe analyzed data from 2544 patients aged <80 with ≥70 % asymptomatic carotid stenosis randomized to CAS or CEA (nCREST = 1091; nACT-1 = 1453). The pre-specified primary endpoint in both trials was any stroke, myocardial infarction or death during the peri-procedural period, or ipsilateral stroke within 4 years of randomization. The secondary endpoint was any stroke or death during the peri-procedural period, or ipsilateral stroke within 4 years of randomization. ResultsThere was no significant difference in the frequency of events for men or women between CAS and CEA for the primary or secondary endpoints. When assessing for an interaction of sex and risks between procedures, the treatment-by-sex interaction was not significant for either primary or secondary endpoints in the four-year period or the peri-procedural period. However, women had significantly fewer post-procedural events (ipsilateral stroke) with CAS than CEA (HR = 0.33, 95 % CI: 0.09–1.18) compared to men (HR = 2.09, 95 % CI: 0.78–5.61), p = 0.02 for interaction. ConclusionsIn this large, pooled analysis of asymptomatic patients comparing CAS to CEA, sex did not act as an effect modifier of treatment differences in the four-year primary stroke-MI-or-death endpoint or the secondary stroke-or-death endpoint. However, during the post-procedural period men treated with CAS were at higher risk than their female counterparts.

Potassium Supplementation and Prevention of Atrial Fibrillation After Cardiac Surgery

Supplementing potassium in an effort to maintain high-normal serum concentrations is a widespread strategy used to prevent atrial fibrillation after cardiac surgery (AFACS), but is not evidence-based, carries risks, and is costly. To determine whether a lower serum potassium concentration trigger for supplementation is noninferior to a high-normal trigger. This open-label, noninferiority, randomized clinical trial was conducted at 23 cardiac surgical centers in the United Kingdom and Germany. Between October 20, 2020, and November 16, 2023, patients with no history of atrial dysrhythmias scheduled for isolated coronary artery bypass grafting (CABG) surgery were enrolled. The last study patient was discharged from the hospital on December 11, 2023. Patients were randomly assigned to a strategy of tight or relaxed potassium control (only supplementing if serum potassium concentration fell below 4.5 mEq/L or 3.6 mEq/L, respectively). Patients wore an ambulatory heart rhythm monitor, which was analyzed by a core laboratory masked to treatment assignment. The prespecified primary end point was clinically detected and electrocardiographically confirmed new-onset AFACS in the first 120 hours after CABG surgery or until hospital discharge, whichever occurred first. All primary outcome events were validated by an event validation committee, which was masked to treatment assignment. Noninferiority of relaxed potassium control was defined as a risk difference for new-onset AFACS with associated upper bound of a 1-sided 97.5% CI of less than 10%. Secondary outcomes included other heart rhythm-related events, clinical outcomes, and cost related to the intervention. A total of 1690 patients (mean age, 65 years; 256 [15%] females) were randomized. The primary end point occurred in 26.2% of patients (n = 219) in the tight group and 27.8% of patients (n = 231) in the relaxed group, which is a risk difference of 1.7% (95% CI, -2.6% to 5.9%). There was no difference between the groups in the incidence of at least 1 AFACS episode detected by any means or by ambulatory heart rhythm monitor alone, non-AFACS dysrhythmias, in-patient mortality, or length of stay. Per-patient cost for purchasing and administering potassium was significantly lower in the relaxed group (mean difference, $111.89 [95% CI, $103.60-$120.19]; P <.001). For AFACS prophylaxis, supplementation only when serum potassium concentration fell below 3.6 mEq/L was noninferior to the current widespread practice of supplementing potassium to maintain a serum potassium concentration greater than or equal to 4.5 mEq/L. The lower threshold of supplementation was not associated with any increase in dysrhythmias or adverse clinical outcomes. ClinicalTrials.gov Identifier: NCT04053816.

Toripalimab plus chemotherapy and radiotherapy for treatment-naive advanced esophageal squamous cell carcinoma: a single-arm phase 2 trial

This single-arm phase 2 trial (ChiCTR2100046715) examined previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) who received four cycles of paclitaxel with carboplatin every 3 weeks. Toripalimab was infused intravenously every 3 weeks for 12 months, or until disease progression or intolerable toxicity. Radiotherapy that encompassed the primary lesions and metastases commenced in the third cycle. The median progression-free survival time was 9.8 months (95% confidence interval [CI]: 6.8–not estimable) in the intent-to-treat population, failing to meet the pre-specified primary endpoints. Secondary endpoints included an objective response rate of 45.5%, a disease control rate of 57.6%, and a median duration of response of 11.5 months (interquartile range, 6.4–15.0). The 1-year progression-free survival and overall survival rates were 41.9% (95% CI: 27.7–63.5) and 69.7% (95% CI: 55.7–87.3), respectively. Lymphopenia was the most frequent grade ≥3 adverse event (82%), and an esophageal fistula developed in three patients (9.1%). No treatment-related deaths occurred. In prespecified exploratory biomarker analysis, higher densities of CD8 + T cells, CD11c+ dendritic cells, and CD68+ macrophages correlated with improved tumor response and prognosis. Radiotherapy supplementation to first-line chemo-immunotherapy for treatment-naive advanced ESCC demonstrated some antitumor activity and manageable safety profiles, warranting further randomized controlled trials.

Efficacy and safety of MIL62, a novel glycoengineered type Ⅱ anti-CD20 monoclonal antibody, combined with lenalidomide in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma: a multicentre, single-arm, phase 1b/2 trial

MIL62, a novel glycoengineered type Ⅱ anti-CD20 monoclonal antibody, with a nearly completely afucosylated N-glycans in Fc region, has demonstrated superior activity compared with rituximab and obinutuzumab invitro and invivo, respectively. This multicentre, single-arm, phase 1b/2 trial aimed to explore the efficacy, pharmacokinetics, and safety of MIL62 combined with lenalidomide in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or marginal zone lymphoma (MZL). Eligible patients included those who had histopathologically confirmed CD20 positive FL (grade 1-3a) or MZL and failed to be treated with rituximab. Patients received intravenously infused MIL62 1000mg (cycle 1: day 1, 15; cycles 2-8: day 1, cycles 10 and 12: day 1) combined with oral lenalidomide (once a day, days 2-22, the initial dose was 10mg, and the maximum dose was 20mg) for 12 cycles, 28 days as a cycle. The primary endpoint was objective response rate (ORR) assessed by investigator per Lugano 2014 criteria every 3 cycles. This study was registered in ClinicalTrials.gov (NCT04110301). Between November 22, 2019 and December 22, 2020, 54 patients were enrolled from 11 hospitals in China and received study treatment. Fifty patients were included in the efficacy analysis set, and 43 patients (86%, 95% CI: 73, 94) achieved objective response, meeting the pre-specified primary endpoint. Disease control rate was 96% (48/50, 95% CI: 86, 100), proportion of patients with duration of response (DoR) > 6 months was 77% (33/43). The median follow-up for survival was 12.3 months (IQR 12.0-12.6). The 1-year progression-free survival rate was 72% (95% CI: 57, 83), 9-month DoR rate was 74% (95% CI: 58, 85), and 1-year overall survival rate was 98% (95% CI: 85, 100). Most common TRAEs were neutropenia (93%, 50/54), leukopenia (85% 46/54), thrombocytopenia (61% 33/54), lymphopenia (32% 17/54), and alanine aminotransferase increased (20% 11/54). MIL62 combined with lenalidomide showed promising efficacy in patients with R/R FL and MZL. A multicentre, randomized, open-label, phase Ⅲ trial of MIL62 combined with lenalidomide versus lenalidomide in anti-CD20 monoclonal antibody refractory FL patients is ongoing (NCT04834024). Beijing Mabworks Biotech Co. Ltd, Beijing China and the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).

A randomized, double-blind, placebo-controlled trial to evaluate the effect of nabiximols oromucosal spray on clinical measures of spasticity in patients with multiple sclerosis

BackgroundSpasticity is a common and potentially debilitating symptom of multiple sclerosis (MS) with a highly variable presentation. Understanding, quantifying, and managing MS-associated spasticity (MSS) is a challenge for research and in clinical practice. The tetrahydrocannabinol:cannabidiol oromucosal spray nabiximols has demonstrated beneficial effects in the treatment of MSS in clinical studies as well as real-world observational studies, and is approved for the treatment of MSS in 29 countries globally. Most randomized studies evaluated the efficacy of nabiximols using the change in average daily spasticity scores reported by patients using the spasticity Numeric Rating Scale as a primary endpoint. This study, RELEASE MSS1 (NCT04657666), was conducted using a prespecified primary endpoint of change in spastic muscle tone (Modified Ashworth Scale Lower Limb Muscle Tone-6 [MAS LLMT-6]) to corroborate the efficacy of nabiximols as adjunctive therapy observed with the patient-measured spasticity Numeric Rating Scale primary endpoint in the previous pivotal studies. MethodsThis was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 2-treatment, 2-period, crossover trial. Because of the prevalence and functional impact of lower limb spasticity on the individual patient's overall experience of MS spasticity, the MAS LLMT-6 was derived from the clinician-rated MAS. The MAS LLMT-6 is the average transformed MAS score of 6 muscle groups (knee flexors, knee extensors, and ankle plantar flexors; all assessed bilaterally). Secondary measures included MAS LLMT-4 scores, defined as the average of the 4 individual MAS-transformed scores of knee flexors and knee extensors bilaterally. Patients had a diagnosis of MS and an untransformed MAS score of at least 2 in ≥2 of 6 LLMT-6 muscle groups despite current treatment with ≥1 of the following oral antispasticity agents: baclofen, tizanidine, or dantrolene. Eligible participants were randomly assigned to 1 of 2 treatment sequences. Each treatment sequence consisted of two treatment periods, each consisting of a 14-day dose titration phase followed by a 7-day dose maintenance phase. ResultsOf 68 patients enrolled, 33 were assigned to nabiximols followed by placebo and 35 were assigned to placebo followed by nabiximols. Least squares mean changes in MAS LLMT-6 scores from baseline to day 21 were −0.23 for nabiximols and −0.26 for placebo; the least squares mean treatment difference in MAS LLMT-6 scores for nabiximols versus placebo was 0.04, which was not statistically significant (P = 0.7152). Mean changes in MAS LLMT-4 scores from baseline to day 21 also were not significantly different between the nabiximols and placebo groups. Safety results in this study were consistent with the known safety profile of nabiximols in patients with MSS. ConclusionDespite the established efficacy of nabiximols in MSS observed using patient-reported measures, the primary endpoint was not met in this study. The findings from this study reflect and emphasize some of the challenges in the evaluation and treatment of MS spasticity. Clinical trial registration number (ClinicalTrials.gov): NCT04657666

Data wobbles in hidradenitis suppurativa clinical trials and potential contributing factors: a retrospective review

Background: In some hidradenitis suppurativa (HS) clinical trial study arms, there is an unexpected decline in efficacy between the penultimate visit and the prespecified primary endpoint week, which we have termed a “wobble.” Objective: We aimed to establish how often study arms in HS programs wobble. Methods: In a retrospective review, we identified HS clinical trials listed on ClinicalTrials.gov testing systemic, nonantibiotic medications that utilized Hidradenitis Suppurativa Clinical Response (HiSCR) as an outcome measure. We identified study arms demonstrating greater improvement in a visit prior to the primary endpoint week. Baseline subject characteristics were compared between studies with HiSCR wobble and no HiSCR wobble. Results: A total of 21 studies (randomized control trial [RCT], n = 14; open-label, n = 7) with 35 study drug arms (RCT, n = 27; open-label, n = 8) and 14 placebo arms were identified. HiSCR wobble occurred significantly more often in RCT compared to open-label study drug arms (11/27 [40.7%] vs 0/8 [0%]). In RCT study arms with HiSCR wobble, baseline draining fistula counts were significantly lower (2.3 vs 3.2), and numerically fewer Hurley stage 3 patients (33.2% vs 42.5%), lower weighted total abscess and nodule counts (12.1 vs 12.6), lower weighted dermatology life quality index scores (12.5 vs 14.5), and a higher proportion of female patients (63.9% vs 58.3%) were observed. Limitations: Include low number of HS clinical trials and insufficient data reported in many studies to assess for wobble, degree of wobble, and to compare all baseline characteristics. Conclusion: Nonlinear improvement in study arm response occurs in some HS RCTs. Potential contributing factors include a higher proportion of less severe patients at baseline and more female patients.

A phase II study of nivolumab in patients with recurrent or metastatic carcinosarcomas.

6041 Background: We aimed to determine the activity of anti-PD-1 inhibitor, nivolumab in metastatic and/or recurrent carcinosarcoma. Methods: In this phase 2 trial, eligible patients had histologically confirmed metastatic and/or recurrent carcinosarcoma, measurable disease, 1-3 prior chemotherapy, and adequate renal/hepatic/hematologic function. In this single arm phase 2 trial, treatment consisted of nivolumab 3 mg/kg every 2 weeks. Primary outcome was progression free rate (PFR) at 6 months and secondary outcomes included overall response rate, progression-free survival (PFS), overall survival, and safety. Results: Between July 2020 and Nov 2023, 28 patients enrolled and received trial treatment. As of the time of data cut-off (Feb 1, 2024), 4 remains on treatment. Of the 28 patients evaluable, 4 (14.3%) achieved confirmed partial response, and 9 (32.1%) had stable disease, yielding and disease control rate of 46.4%. The median PFS was 2.6 months. The pre-specified primary endpoint was met with 6-months PFR of 30.8%. The common-treatment related adverse events included urticaria (5 [17.9%]), dyspepsia (4 [14.3%]), elevated aspartate aminotransferase (3 [10.7%]), and anemia (3 [10.7%]). The genomic analysis will be available at the meeting. Conclusions: Nivolumab demonstrated promising efficacy with favourable toxicity profile in metastatic/recurrent carcinosarcoma. Clinical trial information: NCT05224999 .

Biodegradable Polymer Versus Polymer-Free Ultrathin Sirolimus-Eluting Stents: Analysis of the Stent Arm Registry From the HOST-IDEA Randomized Trial.

The efficacy and safety of each third-generation drug-eluting stent with ultrathin struts and advanced polymer technology remain unclear. We investigated the clinical outcomes of percutaneous coronary intervention using the Coroflex ISAR polymer-free sirolimus-eluting stent (SES) or Orsiro biodegradable polymer SES. The HOST-IDEA trial (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Coronary Intervention With Next-Generation Drug-Eluting Stent Platforms and Abbreviated Dual Antiplatelet Therapy), initially designed with a 2×2 factorial approach, sought to randomize patients undergoing percutaneous coronary intervention based on dual antiplatelet therapy duration (3 versus 12 months) and stent type (Coroflex ISAR versus Orsiro). Despite randomizing 2013 patients for dual antiplatelet therapy duration, the stent arm transitioned to a registry format during the trial. Among these, 328 individuals (16.3%) were randomized for Coroflex ISAR or Orsiro SES, while 1685 (83.7%) underwent percutaneous coronary intervention without stent-type randomization. In this study, the Coroflex ISAR (n=559) and Orsiro groups (n=1449) were matched using a propensity score. The prespecified primary end point was target lesion failure, a composite of cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization at 12 months. The baseline patient and procedural characteristics were well balanced between the Coroflex ISAR and Orsiro groups after propensity score matching (n=559, each group). The Coroflex ISAR group was significantly associated with a higher rate of target lesion failure, mainly driven by clinically driven target lesion revascularization, compared with the Orsiro group (3.4% versus 1.1%; hazard ratio, 3.21 [95% CI, 1.28-8.05]; P=0.01). A higher risk of target lesion failure in the Coroflex ISAR group was consistently observed across various subgroups. The rates of any bleeding (hazard ratio, 0.85 [95% CI, 0.51-1.40]; P=0.52) and major bleeding (hazard ratio, 1.58 [95% CI, 0.61-4.08]; P=0.34) were comparable between the 2 groups. In this propensity score-matched analysis of the stent arm registry from the HOST-IDEA trial, the Orsiro SES was associated with significantly better outcomes in terms of 1-year target lesion failure, mainly driven by clinically driven target lesion revascularization, than the Coroflex ISAR SES. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02601157.

Safety, efficacy, and reliability evaluation ofa novel small-diameter defibrillation lead: Global LEADR pivotal trial results

BackgroundImplantable cardioverter-defibrillators last longer, and interest in reliable leads with targeted lead placement is growing. The OmniaSecure defibrillation lead is a novel, small-diameter, catheter-delivered lead designed for targeted placement, based on the established SelectSecure SureScan MRI Model 3830 lumenless pacing lead platform. ObjectiveThis trial assessed safety and efficacy of the OmniaSecure defibrillation lead. MethodsThe worldwide LEADR pivotal clinical trial enrolled patients indicated for de novo implantation of a primary or secondary prevention implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator, all of whom received the study lead. The primary efficacy end point was successful defibrillation at implantation per protocol. The primary safety end point was freedom from study lead–related major complications at 6 months. The primary efficacy and safety objectives were met if the lower bound of the 2-sided 95% credible interval was >88% and >90%, respectively. ResultsIn total, 643 patients successfully received the study lead, and 505 patients have completed 12-month follow-up. The lead was placed in the desired right ventricular location in 99.5% of patients. Defibrillation testing at implantation was completed in 119 patients, with success in 97.5%. The Kaplan-Meier estimated freedom from study lead–related major complications was 97.1% at 6 and 12 months. The trial exceeded the primary efficacy and safety objective thresholds. There were zero study lead fractures and electrical performance was stable throughout the mean follow-up of 12.7 ± 4.8 months (mean ± SD). ConclusionThe OmniaSecure lead exceeded prespecified primary end point performance goals for safety and efficacy, demonstrating high defibrillation success and a low occurrence of lead-related major complications with zero lead fractures.

Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia

A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M1/M4 preferring muscarinic receptor agonist with no direct D2 dopamine receptor blocking activity. KarXT combines xanomeline with the peripheral muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation. In prior trials, xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia. To evaluate the efficacy and safety of xanomeline-trospium vs placebo in adults with schizophrenia. EMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine. Data were analyzed from February to June 2023. Participants were randomized 1:1 to receive xanomeline-trospium chloride (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks. The prespecified primary end point was change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures were change from baseline to week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also evaluated. A total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group). At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , -20.6; placebo, -12.2; least squares mean difference, -8.4; 95% CI, -12.4 to -4.3; P < .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between the xanomeline-trospium (8 participants [6.4%]) and placebo (7 participants [5.5%]) groups. The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]). Measures of extrapyramidal symptoms, weight gain, and somnolence were similar between treatment groups. Xanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the previously reported and consistent results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity. ClinicalTrials.gov Identifier: NCT04738123.

Safety and Efficacy of Vocacapsaicin for Management of Postsurgical Pain: A Randomized Clinical Trial.

Nonopioid management of postsurgical pain remains a major unmet need. Few studies have evaluated transient receptor potential vanilloid subfamily member 1 agonists for analgesia after surgery. This study examines intraoperative vocacapsaicin, a novel prodrug of the transient receptor potential vanilloid subfamily member 1 agonist capsaicin, in a validated model of postsurgical pain. This was a triple-blinded, randomized, placebo-controlled, dose-ranging trial in patients undergoing bunionectomy. Patients were randomized 1:1:1:1 to surgical site administration of 14 ml of placebo or one of three vocacapsaicin concentrations: 0.30, 0.15, or 0.05 mg/ml. The prespecified primary endpoint was the area-under-the-curve of the numerical rating scale pain score at rest through 96 h for the 0.30 mg/ml group. Prespecified ordered, secondary endpoints for the 0.30 mg/ml group included the percentage of patients who did not require opioids from 0 to 96 h, total opioid consumption through 96 h, and the area-under-the-curve of the numerical rating scale pain score for the first week. The 147 patients were randomized. During the first 96 h, vocacapsaicin (0.30 mg/ml) reduced pain at rest by 33% versus placebo (primary endpoint, 95% CI [10%, 52%], effect size [Cohen's d] = 0.61, P = 0.005). Of patients receiving vocacapsaicin (0.30 mg/ml), 26% did not require postoperative opioids for analgesia (P = 0.025) versus 5% of patients receiving placebo. Vocacapsaicin (0.30 mg/ml) reduced opioid consumption over the first 96 h by 50% versus placebo (95% CI [26%, 67%], effect size = 0.76, P = 0.002). Vocacapsaicin (0.30 mg/ml) reduced pain over the first week by 37% versus placebo (95% CI [12%, 57%], effect size = 0.62, P = 0.004). The treatment effect persisted for at least 2 weeks. All study endpoints showed an administered concentration-versus-response relationship. Vocacapsaicin was well tolerated with no differences between groups in any safety parameter. A single, local administration of vocacapsaicin during surgery reduced pain and opioid consumption for at least 96 h after surgery compared to control.

Bispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial

Despite the high therapeutic response achieved with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapy in relapsed and refractory multiple myeloma (R/R MM), primary resistance and relapse exist with single-target immunotherapy. Here, we design bispecific BC19 CAR T cells targeting BCMA/CD19 and evaluate antimyeloma activity in vitro and in vivo. Preclinical results indicate that BC19 CAR specifically recognize target antigens, and BC19 CAR T cells mediate selective killing of BCMA or CD19-positive cancer cells. BC19 CAR T cells also exhibit potent antigen-specific anti-tumor activity in xenograft mouse models. We conduct an open-label, single-arm, phase I/II study of BC19 CAR T cells in 50 patients with R/R MM (ChiCTR2000033567). The primary endpoint was safety. BC19 CAR T cells are well tolerated with grade 3 or higher cytokine release syndrome in 8% of patients and grade 1 neurotoxic events in 4% of patients, which meet the pre-specified primary endpoint. Secondary endpoints include overall response rate (92%), median progression-free survival (19.7 months), median overall survival (19.7 months) and median duration of response (not reached). Our study demonstrates that bispecific BC19 CAR T cells are feasible, safe and effective in treating patients with R/R MM.

Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study

Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints included the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that treatment with immunotherapy containing arms (nivolumab or a combination of nivolumab plus capecitabine) leads to an increase in PIS from baseline to week 6 compared with capecitabine alone, meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) is associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.

Abstract 6389: An exosome-based liquid biopsy powered by machine learning predicts progression-free and overall survival before commencing first-line EGFR inhibitors for metastatic colorectal cancer: The EXONERATE Study

Abstract Introduction: We developed a liquid biopsy assay based on exosomal and cell-free microRNA (exo- and cf-miRNA, respectively) for patients with chemotherapy-naïve, metastatic, unresectable, RAS and BRAF wild-type colorectal cancer (mCRC), to predict progression-free (PFS) and overall survival (OS) before the commencement of first-line treatment with EGFR inhibitors (EXONERATE). Methods: Patients with mCRC were consecutively enrolled in two open-label, nationwide clinical trials and received first-line cetuximab or panitumumab. Cf- and exo-miRNA expression was quantified using RT-qPCR in plasma samples obtained before exposure to EGFR inhibitors. The prespecified primary endpoint was 12-month PFS, hierarchically tested in left-sided mCRC, right-sided mCRC, and the entire cohort. As secondary endpoints, the EXONERATE status was correlated with PFS and OS hazard ratios (HR). Results: After excluding those with RAS/BRAF mutations and unavailable samples, the complete analysis dataset comprised 120 patients (94 with left-sided and 26 with right-sided mCRC; 87 received cetuximab and 33 panitumumab). As expected, right-sided mCRC patients showed inferior PFS and OS outcomes (HR 1.80 [CI95% = 1.13 - 2.80] and 1.80 [CI95% = 1.00 - 3.27], respectively). Genome-wide small RNA sequencing on 20 patient samples identified 12 cf- and 14 exo-miRNA candidates, then narrowed to 8 and 9 based on best performance. We employed machine learning algorithms to develop two liquid biopsy assays, one based on cf- and the other on exo-miRNAs, predicting 12mPFS with AUC values of 0.84 and 0.81, respectively. These were then combined to establish the EXONERATE assay for left-sided mCRC (AUC = 0.89), successfully validated in right-sided mCRC patients (AUC= 0.84). Among left-sided mCRC patients, 35% were EXONERATE-high, exhibiting shorter median PFS (mPFS = 9.5 vs. 18.5 months, p&amp;lt;.001) and a higher mortality rate (HR 0.21 [CI95% = 0.10 - 0.42]). In the right-sided mCRC cohort, the EXONERATE-high panel robustly identified patients with shorter mPFS (8.6 vs. 23.7 months, p=.0042) and predicted 12mPFS with high accuracy (sensitivity 100%, NPV 81%, PPV 100%). Although in univariate analysis both the EXONERATE panel and sidedness showed associations with PFS and OS, in multivariate analysis only the EXONERATE panel could fully account for the differences in PFS and OS (HR 0.22 and HR 0.19, respectively). Hence, we employed the EXONERATE panel agnostically of tumor sidedness and observed that EXONERATE-high patients demonstrated poorer survival outcomes in mPFS (8.9 vs. 19.6 months, HR 0.27 [CI95% = 0.17 - 0.41]) and mOS (22.6 vs. &amp;gt;60 months, HR 0.18 [CI95% = 0.09 - 0.37]). Conclusion: The EXONERATE panel robustly predicted PFS and OS outcomes in both right- and left-sided mCRC patients before receiving either EGFR inhibitor. Citation Format: Xu Caiming, Alessandro Mannucci, Roy Souvick, Esposito Francis, Oliveres Helena, Alonso-Orduña Vicente, Escudero Pilar, Fernández-Martos Carlos, Salud Antonieta, Gallego Javier, Rodriguez Jose Ramon, Martín-Richard Marta M. Marta, Fernández-Plana Julen, Manzano Hermini, Aparicio Jorge, Feliu Jaime, Maurel Joan, Ajay Goel. An exosome-based liquid biopsy powered by machine learning predicts progression-free and overall survival before commencing first-line EGFR inhibitors for metastatic colorectal cancer: The EXONERATE Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6389.