Citations

4032 Background: RATIONALE-306 (NCT03783442) is the first global study to investigate anti-programmed cell death protein 1 therapy in combination with different chemotherapy (chemo) options in the first-line (1L) treatment of advanced/metastatic esophageal squamous cell carcinoma (ESCC). At interim analysis (IA), tislelizumab (TIS) plus chemo demonstrated a statistically significant, clinically meaningful improvement in overall survival (OS) versus placebo (PBO) plus chemo, with a manageable safety profile. Here, we report updated efficacy and safety data with minimum 3 years’ follow-up after study unblinding at IA. Methods: Adults with unresectable locally advanced recurrent/metastatic ESCC and no prior systemic treatment for advanced disease were enrolled and randomized (1:1; stratified by region, prior definitive therapy, and investigator [INV]-chosen chemo) to receive TIS 200 mg (Arm A) or PBO (Arm B) IV every 3 weeks plus chemo (platinum plus fluoropyrimidine or platinum plus paclitaxel), until disease progression or intolerable toxicity. The primary endpoint was OS in the intent-to-treat population. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR), all per INV, and safety. Results: In total, 649 patients (pts) were randomized (Arm A, n=326; Arm B, n=323). At a minimum study follow-up of 36.0 months, improvements in OS, PFS, and DoR in Arm A versus B (Table) were maintained relative to the IA. The hazard ratio (HR) for OS with TIS plus chemo versus PBO plus chemo was 0.70 (95% confidence interval: 0.59, 0.83). Similar to the IA, incidences of any-grade (96.6% vs 96.3%) or grade ≥3 (67.0% vs 64.5%) treatment-related adverse events (TRAEs) were comparable between Arms A and B, respectively; treatment-emergent adverse events leading to treatment discontinuation were higher in Arm A (32.1%) versus B (22.1%). In Arm A versus B, respectively, serious TRAEs occurred in 29.9% vs 19.6% of pts; TRAEs leading to death occurred in 1.9% and 1.2%. Conclusions: After minimum 3 years’ follow-up, 1L TIS plus chemo continued to demonstrate clinically meaningful improvements in OS and PFS and durable antitumor response benefit versus PBO plus chemo in pts with advanced/metastatic ESCC, with no new safety signals. Clinical trial information: NCT03783442 . [Table: see text]

TPS11588 Background: Imatinib is the worldwide standard for first-line therapy of advanced KIT-mutant GIST. However, secondary resistance mutations in the KIT ATP-binding domain (exons 13, 14), activation loop (exons 17, 18), or both develop and result in loss of imatinib-sensitivity. Bezuclastinib has a highly selective inhibition profile, leading to minimal off-target toxicities and allowing for combination with sunitinib. While no single tyrosine kinase inhibitor (TKI) inhibits all KIT mutations, the combination of bezuclastinib + sunitinib targets commonly occurring primary (exons 9, 11) and secondary (exons 13, 14, 17, and 18) KIT mutations and may provide more durable responses. The early signs of clinical activity, tolerability, and safety observed with the combination thus far in Peak Part 1 (Somaiah et al. [presentation] CTOS 2023. Paper 62) are consistent with the completed Phase 1/2 study (PLX121-01). Methods: Peak (NCT05208047) is a global, randomized, open-label, multi-part Phase 3 study evaluating the efficacy and safety of bezuclastinib + sunitinib versus sunitinib as second-line treatment in adult pts who were intolerant to imatinib or whose tumors had imatinib-resistance. Current Peak study sites are located in North America (3 countries), South America (3 countries), Europe (12 countries), and Asia-Pacific (4 countries). The lead-in portion to test a new formulation of bezuclastinib, (Part 1) completed enrollment in April 2023. Based upon PK and safety, a dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD was determined for Part 2 of the Peak study. Part 2 will enroll ~388 pts to be randomized (1:1) to bezuclastinib 600 mg QD + sunitinib 37.5 mg QD or sunitinib 37.5 mg QD alone. Key inclusion: >1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, Eastern Cooperative Oncology Group Performance Status 0-2, adequate organ function, and prior imatinib therapy (no other prior therapy). Key exclusion: known PDGFR mutations or succinate dehydrogenase deficiency, clinically significant cardiac disease, and use of strong CYP3A4 inhibitors or inducers. The primary endpoint is progression-free survival (PFS) confirmed by blinded independent central review per mRECIST v1.1. Additional efficacy (including overall survival and objective response rate) and safety endpoints will be evaluated and circulating tumor DNA (ctDNA) will be collected and assessed. Clinical trial information: NCT05208047 .

AbstractObjectivesThis needs assessment aimed to improve understanding of flexible endoscopic intubation training and practice in emergency medicine (EM), providing insights to educators and practice leaders seeking to improve education and practices.MethodsWe conducted a multicenter, mixed‐methods needs assessment of emergency physicians (EPs) incorporating focus groups and a survey. Focus groups comprised community EPs, academic EPs, and resident EPs. We analyzed focus group transcripts using grounded theory, qualitatively describing EM endoscopic intubation. The qualitative analysis shaped our survey instrument, which we deployed in cross‐sectional fashion. We report survey data with descriptive statistics.ResultsFocus groups with 13 EPs identified three themes: indications for use of endoscopic intubation, factors impacting a physician's decision to endoscopically intubate, and attaining and maintaining endoscopic intubation competency. Of 257 surveyed EPs (33% response rate), 79% had received endoscopic intubation training during residency, though 82% had performed this procedure 10 or fewer times in their career. Despite 97% acknowledging the necessity of competency, only 23% felt highly confident in their ability to perform endoscopic intubation. Participants (93%) reported scarce opportunities to perform the procedure and identified factors believed to facilitate competency acquisition and maintenance, including opportunities to perform endoscopic intubation in practice (98%), local champions (93%), and performing nasopharyngoscopy (87%).ConclusionsWhile most EPs acknowledged the importance of competency in endoscopic intubation, they reported scarce procedural opportunities and commonly expressed low confidence. Further research is needed on this topic, and we propose avenues to enhance education and practices related to endoscopic intubation. These include development of robust procedural curricula, support of local champions, and incorporating nasopharyngoscopy into EM practice.

BACKGROUND COVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined. METHODS This secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low posttransfusion antibody levels was established by 2 methods: (i) analyzing virus neutralization–equivalent anti–Spike receptor-binding domain immunoglobulin G (anti-S-RBD IgG) responses in donors or (ii) receiver operating characteristic (ROC) curve analysis. RESULTS SARS-CoV-2 anti–S-RBD IgG antibody was volume diluted 21.3-fold into posttransfusion seronegative recipients from matched donor units. Virus-specific antibody delivered was approximately 1.2 mg. The high-antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP-recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma), with antibody cutoffs established by both methods-donor-based virus neutralization cutoffs in posttransfusion recipients (0/85 [0%] versus 15/276 [5.6%]; P = 0.03) or ROC-based cutoff (0/94 [0%] versus 15/267 [5.4%]; P = 0.01). CONCLUSION In unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors’ antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use. TRIAL REGISTRATION ClinicalTrials.gov NCT04373460. FUNDING Department of Defense (W911QY2090012); Defense Health Agency; Bloomberg Philanthropies; the State of Maryland; NIH (3R01AI152078-01S1, U24TR001609-S3, 1K23HL151826NIH); the Mental Wellness Foundation; the Moriah Fund; Octapharma; the Healthnetwork Foundation; the Shear Family Foundation; the NorthShore Research Institute; and the Rice Foundation.

Prescribed opioids are a mainstay pain treatment after traumatic injury, but a subgroup of patients may be at risk for continued opioid use. We evaluated the predictive utility of a traditional screening tool, the Opioid Risk Tool (ORT), and two other measures: average in-hospital milligram morphine equivalents (MME) per day and an assessment of opioid demand in predicting pain outcomes. Assessments of pain-related outcomes (pain intensity, interference, injury-related stress, and need for additional pain treatment) were administered at 2 weeks and 12 months post-discharge in a sample of 34 patients hospitalized for traumatic injury. Bayesian linear models were used to evaluate changes in responses over time as a function of predictors. High-risk ORT, higher MME per day, and greater opioid demand predicted less change in outcomes over time. This report provides first evidence that malleable factors of opioid and opioid demand have utility in predicting pain outcomes following traumatic injury.

PURPOSE Nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. METHODS Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. RESULTS We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). CONCLUSION In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

Abstract Background: Recent studies indicate a correlation between increased stromal composition in tumors and resistance to immune checkpoint inhibitors (ICIs) across various cancer types. Specifically, the extracellular matrix (ECM) within the stromal compartment significantly influence the tumor microenvironment, affecting cancer cell proliferation and immune cell recruitment. However, identifying and quantifying the ECM at the collagen fiber level in whole slide images (WSIs) is challenging due to its inherent heterogeneity and complexity. In this work, we utilized statistical analysis and a deep learning (DL)-based approach to identify and assess collagen in the ECM, examining its characteristics in relation to the ICIs treatment response in gastric cancer. Methods: We analyzed 116 WSIs of hematoxylin and eosin (H&E) stained slides before ICIs treatment from three institutions. Responders were defined as those with a complete response or partial response (N=18); those with stable disease (SD) (N=34) or progressive disease (PD) (N=64) were considered non-responders (N=98). For non-responders, post-treatment H&E slides were available for 21 patients; SD (N=5) and PD (N=16). We applied a DL-based second harmonic generation (SHG) synthesis algorithm to tumor regions identified by a tumor detection model. We then calculated various collagen properties, including volume, fiber orientation and alignment, waviness, straightness, and fiber thickness, based on collagen fiber centerlines extracted from the generated SHG images. An attention-based multiple instance learning (ABMIL) model was trained to automatically predict the treatment response solely based on collagen features. The dataset of 116 pre-treatment slides was divided into training and validation subsets using stratified 3-fold cross-validation. The area under the curve (AUC) was used to assess the performance of the trained models. Results: Collagen fiber features were significantly associated with ICIs response. Notably, ICIs responders have a decrease in collagen waviness and fiber orientation variation (p-value&lt;0.05, by Mann-Whitney U test). Among non-responders, the PD group showed a statistical decrease in waviness after treatment (p-value&lt;0.05, by Mann-Whitney U test). The ABMIL model achieved a mean AUC score of 0.823, with a standard deviation of 0.023. Conclusion: This study provides a comprehensive analysis of collagen in the ECM, and its properties in relation to gastric cancer ICIs response within Tumor Immune Microenvironment. We also developed a model using collagen features and demonstrated high accuracy in predicting treatment response. Citation Format: Minji Kim, Ekaterina Redekop, Yoonho Choi, Sung Hak Lee, Jae-Ho Cheong, Yu Aoki, Kohei Shitara, Tae Hyun Hwang. AI-driven analysis of collagen characteristics in the tumor immune microenvironment predicts immune checkpoint inhibitors treatment responsiveness in gastric cancer [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 4262.

Abstract Traditional cancer research methodologies predominantly focus on 2D tumor modeling, including spatial profiling and AI-driven analysis at the 2D level. To advance beyond these limitations, we implemented Holotomography (HT), a 3D, label-free optical imaging method. This technique, leveraging refractive index contrasts, allows for enhanced visualization of tumor tissues, organoids, and cells in three dimensions. Using serial H&E sections and unstained slides, we created detailed 3D tumor models in gastric cancer, providing insights into tumor, immune, and stromal composition, as well as cell-cell interactions and extracellular matrix characteristics. AI algorithms further enhanced our 3D tumor modeling, offering novel perspectives on the initiation and progression of tumor, immune, and stromal components at the subcellular level. Analyzing gastric tumors treated with immune checkpoint inhibitors before, during, and after treatment revealed dynamic changes in spatial composition over time, offering unique insights into the evolution of the 3D tumor ecosystem. Additionally, by integrating spatial transcriptomic and in situ molecular imaging data, we developed a novel Multimodal 3D Tumor Model. This model not only uncovers subcellular-level molecular characteristics but also elucidates cellular interactions during treatment, suggesting potential biomarkers and therapeutic approaches. Lastly, by constructing 3D cellular interaction networks incorporating true 3D interactions, we provided an in-depth view of cellular communication within the tumor microenvironment. This pioneering approach, representing the first Multimodal 3D Tumor Model at the subcellular level, offers novel insights into gastric cancer's spatial evolution, potentially revolutionizing our understanding and treatment of gastric cancer. Citation Format: Yoon Ho Choi, Minji Kim, Katya Redekop, Inyeop Jang, Jean R. Clemenceau, Isabel Barnfather, Sumanth Reddy Nakkireddy, Changjin Hong, Sunho Park, Ji-Youn Sung, Jeong Hwan Park, Shitara Kohei, Aoki Yu, Sung Hak Lee, Sam Wang, Jaeho Cheong, Tae Hyun Hwang. AI-driven multimodal 3D tumor modeling with spatial molecular insights for predicting ICI response in gastric cancer [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 7400.

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 ( FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202 ) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. METHODS Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. RESULTS Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). CONCLUSION Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

748 Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with 3 or more kinase inhibitors, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. In the second interim analysis of overall survival (OS) from the phase 3 INTRIGUE study, the OS event rate was 41% in the all-patient (AP) intent-to-treat (ITT) population, and OS was similar between treatment arms in both the KIT exon 11 ITT and AP ITT populations. Here, we present the final OS and updated safety from INTRIGUE. Methods: INTRIGUE (NCT03673501) is an open-label, phase 3 study of adults with advanced GIST who had disease progression on or intolerance to imatinib. Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 weeks on/2 weeks off) and was stratified by KIT mutational status and imatinib intolerance. OS was a key secondary endpoint (the primary endpoint of progression-free survival was reported previously); final OS analysis was prespecified to occur with ≥200 and ≥145 events in the AP ITT and KIT exon 11 ITT populations, respectively. Data cutoff was March 15, 2023. Results: Of 453 pts, 444 received treatment; 40 remain on treatment (ripretinib, 28/223 [13%]; sunitinib, 12/221 [5%]). Treatment discontinuation was due to progressive disease (PD) by independent radiologic review (56%), PD by investigator (11%), clinical PD (6%), withdrawal of consent (6%), and adverse events (AEs; 5%). Fewer pts discontinued treatment due to AEs with ripretinib vs sunitinib (3% vs 6%). There were 211 OS events (47%) in the AP ITT population and 151 OS events (46%) in the KIT exon 11 ITT population. OS was similar with ripretinib vs sunitinib in the 2 ITT populations (Table). Fewer pts had grade 3/4 treatment-emergent AEs with ripretinib vs sunitinib (43% vs 67%). Dose interruptions and reductions were lower with ripretinib vs sunitinib. Median treatment duration for ripretinib vs sunitinib was 7.9 vs 6.5 months. Conclusions: In the finalOS analysis from the INTRIGUE study, OS was similar between treatment arms. The safety profile remained consistent and more favorable for ripretinib vs sunitinib in pts with advanced GIST previously treated with imatinib. Clinical trial information: NCT03673501 . [Table: see text]