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Importance The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. Objective To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. Design, Setting, and Participants Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. Interventions For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. Main Outcomes and Measures The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. Results Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P < .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups. Conclusion and Relevance Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up. Trial Registration ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135

601 Background: EOP is an I-SPY2 neoadjuvant sub-study designed to test the tolerability and impact of novel endocrine-based strategies in stage 2/3 BC pts predicted to have lower benefit from chemotherapy. Amcenestrant (A) is an oral selective estrogen receptor degrader (SERD) with activity in hormone receptor positive (HR+) HER2- metastatic BC. Methods: EOP eligibility included pts screened for the main I-SPY2 trial with HR+ HER2-, MammaPrint (MP) low risk Stage 2/3 BC. Pts with MP High risk tumor signatures were eligible if clinically node-negative (cN-). Pts were stratified by SET index and menopausal status. Pts were randomized to 3 arms: A 200 mg qd (A), A + abemaciclib 150 mg bid (AA), A + letrozole 2.5 mg qd (AL). Premenopausal pts received concurrent ovarian function suppression. Treatment was for 6 mos followed by surgery. Baseline (BL) and 3-wk biopsies were performed. Breast MRIs were conducted at BL (T0), 3 wks (T1), 12 wks (T2), 6 mos (T3). The primary endpoint was feasibility, defined as >75% of pts completing >75% study therapy. Results: Between May 2021 and Aug 2022, 74 pts were randomized: 31 A, 21 AA, 22 AL. Median age 50 years, 54% premenopausal, 38% clinically node-positive (cN+). 41% pts had ductal, 38% lobular, 11% mixed ductal/lobular histology. Mean BL tumor Ki67 (central testing) was 16.9%, 88% MP low, 76% SET index Hi. Pt and tumor characteristics were balanced across the 3 arms. Treatment in all 3 arms was feasible with 95% of pts completing >75% study therapy. Most common AEs include grade 1-2 hot flashes (69%) and fatigue (66%). Grade 3 AEs include neutropenia (2 pts) and diarrhea (1 pt) in AA. Table summarizes key response endpoints, which were similar between pre- and postmenopausal pts. Of 28 cN+ pts, 2 (7%) were pathologically node-negative (pN-). Mean MRI Functional Tumor Volume (cc) change between T0->T1, T1->T2, T2->T3, T0->T3 was -6.06 (-34.2%), -3.55 (-29.2%), -0.829 (-20.1%), -11.3 (-68.4%), respectively, similar across arms (p=0.396).ctDNA was detected in 10/59 (17%) pts at T0. ctDNA became undetectable in 6 pts, decreased in 4 pts, and went from ctDNA undetectable at baseline to detectable at T3 in 2 pts. Conclusions: Six months of neoadjuvant endocrine therapy (NET) with the oral SERD amcenestrant is feasible, well-tolerated, and demonstrates anti-proliferative and anti-tumor activity in pre- and postmenopausal pts. NET provides a rich platform for biomarker discovery and investigating response to endocrine therapy. Clinical trial information: NCT01042379 . [Table: see text]

e19049 Background: Acala and zanu are 2nd generation Bruton tyrosine kinase inhibitors (BTKis) that have demonstrated improved safety profiles vs 1st generation BTKi ibrutinib in clinical trials. While head-to-head comparison of zanu vs acala is lacking, a recent meta-analysis of clinical trials provided a comprehensive, indirect comparison of the AE profiles in B-cell malignancies (Hwang, Hemasphere. 2023;7(S3):1134). This study aims to evaluate costs and impacts on quality of life (QoL) for zanu vs acala using their AE profiles. Methods: A health economic model was developed to determine cost and QoL associated with AE management for zanu and acala. The incidence rates ( IRs) of all grade and grade ≥3 AEs of interest (n=21, including bleeding events, hypertension, atrial fibrillation, cytopenias, infections, headache, arthralgia, diarrhea) were taken from the meta-analysis. Additional model inputs, such as disutility, average duration of AE, and unit cost of each AE were sourced from published literature and publicly available cost databases in consultation with clinical experts. The model was developed from the US perspective, considering Medicare costs, inflated to 2023 USD. Model outcomes were AE management cost (= IR * unit cost) and quality-adjusted life years (QALYs) lost due to AE (= IR * Disutility * Duration/365.25). Results: In the base-case scenario (considering all AEs), treating a hypothetical cohort of 1000 patients (pts) with zanu instead of acala yielded cost savings of $124K and 3.7 QALY gains (i.e., 3.7 years extra in full health). Subgroup analysis for severe (grade ≥3) and non-severe AEs (grade 1-2) demonstrated similar trends. A sensitivity analysis limited to AEs significantly different between zanu and acala (n=13) yielded consistent results. Additionally, a probabilistic sensitivity analysis, conducted with 1000 iterations to account for uncertainty in model parameters, confirmed robustness of the model, indicating stable conclusions across a wide range of parameter uncertainties. Conclusions: This analysis suggested that zanu is cost-saving and associated with added health benefits compared to acala in terms of AE management in pts with B-cell malignancies. Should these results derived from meta-analysis of clinical trial data be applicable to real-world pt populations across different indications, the potential cost savings could be considerable. These results could be further improved if the differences in efficacy of zanu vs acala are also incorporated. [Table: see text]

Repair and regeneration of a diseased lung using stem cells or bioengineered tissues is an exciting therapeutic approach for a variety of lung diseases and critical illnesses. Over the past decade, increasing evidence from preclinical models suggests that mesenchymal stromal cells, which are not normally resident in the lung, can be used to modulate immune responses after injury, but there have been challenges in translating these promising findings to the clinic. In parallel, there has been a surge in bioengineering studies investigating the use of artificial and acellular lung matrices as scaffolds for three-dimensional lung or airway regeneration, with some recent attempts of transplantation in large animal models. The combination of these studies with those involving stem cells, induced pluripotent stem cell derivatives, and/or cell therapies is a promising and rapidly developing research area. These studies have been further paralleled by significant increases in our understanding of the molecular and cellular events by which endogenous lung stem and/or progenitor cells arise during lung development and participate in normal and pathological remodeling after lung injury. For the 2023 Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases Conference, scientific symposia were chosen to reflect the most cutting-edge advances in these fields. Sessions focused on the integration of “omics” technologies with function, the influence of immune cells on regeneration, and the role of the extracellular matrix in regeneration. The necessity for basic science studies to enhance fundamental understanding of lung regeneration and to design innovative translational studies was reinforced throughout the conference.

Abstract Background: Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer (TNBC). This trial evaluated the efficacy of pembrolizumab in combination with binimetinib, a MEK inhibitor. Methods: Patients with unresectable locally advanced or metastatic TNBC with ≤ 3 prior lines of therapy were enrolled. Treatment includes a 2-week run-in with binimetinib followed by pembrolizumab. There were 2 dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL -1. A standard 3+3 design was used in Phase I, and Simon’s two-stage Optimal design was used in Phase II. PD-L1 22C3 was performed in archival samples with CPS ≥ 10 considered as positive (PD-L1+). Tumor-infiltrating lymphocytes (TILs) were quantified into 0, 1, 2, and 3+. Circulating tumor cells (CTC) and circulating cancer-associated macrophage-like cells (CAML) were isolated using CellSieve microfilters and immunofluorescently labeled with PD-L1 and p-ERK. Wilcoxon rank sum test, Chi-square test, Cox regression model, and Spearman correlation were used for analysis. Results: 22 patients were enrolled with a median age of 58 years old. Dose-limiting toxicity (DLT) was observed in 2 out of 4 patients in DL 0, with grade 3 ALT abnormality, flank pain, and nausea. In the next 6 patients in DL -1, there was 1 DLT with grade 3 AST/ALT abnormality. There were 17 patients treated with DL -1 and were evaluable for response. The objective response rate (ORR) was 29.41% (95% CI: 10.31-55.9) with 1 complete response (CR) and 4 partial responses (PR). The clinical benefit rate (CBR ≥ 24 weeks) was 35.29% (95% CI: 14.21-61.67). ORR in patients without liver metastases was 55.56% (95% CI: 21.20 - 86.30) and CBR was 66.67% (95% CI: 29.93-92.51). No response was observed in all 5 patients with liver metastases. There were 40.9% of patients with PD-L1 CPS ≥ 10. ORR in patients with PD-L1+ was 80%. However, 11.1% of patients with PD-L1 negative tumors also had an objective response and 44.4% of patients had clinical benefit ≥ 24 weeks. PD-L1 expression in archival tissue was associated with ORR (p 0.032) but not CBR (p 0.198), progression-free survival (PFS, p 0.373), and overall survival (p 0.348). TILs in archival tissue were also not associated with CBR (p 0.155) and PFS (p 0.157). One patient with TILs 0 had a stable disease ≥ 24 weeks and 2 patients TILs 1+ also had an objective response. We further evaluated blood-based biomarkers with CTC and CAML. Baseline PD-L1 in CAML (p 0.04) and decline in CAML size (p 0.02) after 1 cycle was significantly associated with CBR. However, baseline CTC count, CAML count (p 0.64), CAML size (p 0.46), p-ERK in CAML (p 0.23), and changes in CTC count, CAML count (p 0.83), p-ERK (p 0.07), and PD-L1 (p 0.08) in CAML were not significantly associated with responses. Using Cox regression analysis, a reduction in CAML count (p 0.02), CAML size (p 0.01), and PD-L1 in CAML (p 0.03) were associated with significant improvement in overall survival but not the reduction in p-ERK (p 0.6). However, PD-L1 expression in CAML is not associated with PD-L1 expression in archival tissue (Spearman correlation 0.13). Conclusions: Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Consistent with the preclinical data that MEKi can restore T cell function, promising activity was observed even in patients with low TILs and PD-L1 negative, particularly in patients without liver metastases. PD-L1 expression in peripheral blood CAML rather than archival tumor tissue may serve as a better biomarker to predict the clinical benefit of this combination. Early reductions in CAML count and size, were also significantly associated with responses. Future larger clinical trials are warranted to further evaluate the efficacy of this chemotherapy-free combination. Citation Format: Saranya Chumsri, Joseph Larson, Daniel Adams, Kathleen Tenner, Cha-Mei Tang, Morgan Weidner, Amanda Arnold, Dana Haley, Pooja Advani, Kostandinos Sideras, Alvaro Moreno-Aspitia, Edith Perez, Keith Knutson. Phase I/II study of pembrolizumab in combination with oral binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-14.

Introduction: Carcinoid heart disease (CHD) is a rare sequelae of hormonally active neuroendocrine tumors that often requires cardiac surgical intervention. Little is reported on cardiac implantable electronic device (CIED) implantation in the CHD patient population. Hypothesis: We sought to establish the safety and efficacy of CIED implantation in patients with CHD. Methods: We retrospectively reviewed patients with a diagnosis of CHD who underwent CIED implantation at our institution (Mayo Clinic) and evaluated indications for implant, perioperative complications, and mortality. Results: A total of 27 patients with a cumulative follow up of 75 patient-years were identified during the study period. The most common indication for device implant was high grade atrioventricular block (n=18, 66.7%). 14 (51.8%) had baseline conduction disease and 26 (96.2%) underwent cardiac surgery prior to CIED implant. The majority of devices implanted were dual chamber permanent pacemakers (PPM) (n=17, 63.0%), while other devices included single chamber PPM, epicardial PPM, chronic resynchronization devices, and intracardiac defibrillators. Peri-operative complication occurred in 6 patients (22.2%), with 2 patients requiring ICU level care. No patient suffered carcinoid crisis during implantation and there was no peri-implant mortality. Long term, 3 patients required device extraction: 1 for infection, 1 for lead related pain, and 1 for generator migration. The median time to death from implant was 2.5 years, with one-year mortality at 15%. Conclusions: In this unique cohort of patients with CHD, CIED can be performed safely. CIED most often occurred in the post cardiac surgical period and carcinoid crisis was uncommon.

Introduction: Surgically implanted epicardial left ventricular (eLV) lead has been used as an alternative approach when implantation of transvenous LV (tLV) lead in patients requiring cardiac resynchronization therapy (CRT) has failed. Recent literatures noted similarities in clinical response between tLV and eLV-CRT patients. However, comparison between CRT patients with ischemic (ICM) and dilated cardiomyopathy (DCM) is currently lacking in eLV-CRT patients. Hypothesis: We hypothesize that DCM patients respond better to eLV-CRT than ICM patients. Methods: Of 1038 patients who underwent tLV-CRT implantation at UCSD and Mayo Clinics between 2002 and 2013, 44 (Age 63±15, 28M) had failed tLV lead placement and received eLV-CRT. Electronic Medical Records of these patients were reviewed. NYHA class and echocardiograph were assessed before and after successful CRT implantation. Results: Following eLV-CRT implantation, improvements were noted in LVEF (26% vs. 31%, p < 0.01), NYHA class (2.9 vs. 2.3, p < 0.01) and LVESD (57mm vs. 52mm, p = 0.03) in the study cohort. In patients with DCM (n=19), the NYHA class (3.0 vs. 2.3, p = 0.01), LVEF (24% vs. 30%, p = 0.02) and LVESD (57mm vs. 52mm, p = 0.04) had significantly improved following CRT implantation compared to baseline (figures). No statistically significant changes in NYHA class, LVEF and LVESD were observed in patients with ICM (all p > 0.05). Conclusion: In this two-center study, eLV-CRT patients with DCM benefited significantly after CRT, as compared to ICM patients. Although larger scaled studies are needed, eLV-CRT may be considered a viable alternative to tLV-CRT, especially in patients with DCM.