Citations

381 Background: In RATIONALE-306 (NCT03783442), patients (pts) with LA unresectable or metastatic ESCC who received TIS (intravenously, 200 mg, every 3 weeks) + CT (platinum + fluoropyrimidine or paclitaxel) had longer median overall survival (OS) than pts who received PBO + CT at the interim analysis; improvement was maintained after a ≥3-year follow-up. Post hoc analyses in the PD-L1 TAP ≥1% subgroup showed clinically meaningful improvement with TIS + CT. These data supported the US FDA approval for unresectable or metastatic ESCC. Here we report the subgroup analysis of pts who had LA ESCC with PD-L1 TAP score ≥1%. Methods: Pts who had LA unresectable ESCC with PD-L1 TAP score ≥1% were included in this post hoc analysis. Efficacy outcomes (OS, progression-free survival [PFS], objective response rate [ORR], duration of response [DoR]) and safety were analyzed. Results: At data cutoff (Feb 28, 2022), of 649 pts randomized, 63 had LA ESCC with PD-L1 TAP score ≥1% (TIS + CT n=31; PBO + CT n=32; median age 67.0 years; 85.7% male). At median follow-up (TIS + CT 24.4 months; PBO + CT 24.5 months), efficacy with TIS + CT was improved vs PBO + CT (Table) and was consistent with the intent-to-treat (ITT) population. Efficacy was maintained after a ≥3-year follow-up (data cutoff: Nov 24, 2023; Table). Conclusions: In this post-hoc analysis, the median OS for pts receiving TIS + CT exceeded two years. The regimen was well tolerated. While the findings require validation in future clinical trials, first-line TIS + CT is an encouraging option for pts who have LA unresectable ESCC with PD-L1 TAP score ≥1%. Clinical trial information: NCT03783442 . Interim Analysis 3-Year Follow-up TIS + CT (n=31) PBO + CT (n=32) TIS + CT (n=32) e PBO + CT (n=31) f Median OS, mo(95% CI) 25.6 (15.3, NE) 11.5(9.0, 21.8) 25.6 (15.3, NE) 12.3(9.0, 21.8) HR (95% CI) a 0.36 (0.17, 0.77) – 0.50 (0.26, 0.95) – Median PFS, a mo(95% CI) 13.2(6.8, NE) 6.7(4.2, 9.7) 13.2(6.8, 27.7) 6.7(4.2, 9.7) HR (95% CI) a 0.46 (0.22, 0.96) – 0.47 (0.23, 0.96) – ORR, b,c n (%) 18 (58.1) 10 (31.3) 19 (59.4) 10 (32.3) Median DoR, b,d mo(95% CI) Not reached (8.4, NE) 5.7 (1.5, 9.6) 22.1 (6.1, NE) 5.7 (1.5, 9.6) a Stratified. b Investigator assessed. c Unconfirmed. d Based on unconfirmed ORR. e One patient’s disease status at baseline was changed to LA after interim analysis. f One patient’s disease status at baseline was changed to metastatic after interim analysis. NE, not estimable.

378 Background: RATIONALE-305 (NCT03777657) enrolled the highest number of pts with PM among similar trials and stratified pts with advanced GC/GEJC by presence of PM. We used statistical modeling to evaluate the impact of varying PM levels on outcomes with TIS+CT. Methods: We randomized adults with GC/GEJC (1:1) to TIS or placebo (PBO) + CT. Primary endpoints: OS in intent-to-treat (ITT) population and pts with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥5%. We weighted pts using the method of moments to match a hypothetical population to ITT, with the same distribution of sex, primary tumor location, PD-L1 (TAP score <5% vs ≥5%), number of metastatic sites (0-2 vs 3+), and liver metastasis. PM representation was set from 20% to 45%. Weighted OS, PFS, and objective response rate (ORR) were estimated. Results: Of 997 pts enrolled, 434 (43.5%) had PM. Among pts with PD-L1 TAP scores ≥5% (54.8%), 39.7% had PM, and among pts with scores ≥1% (88.9%), 43.6% had PM (data cutoff Feb 28, 2024). Fewer pts with (+) PM had PD-L1 high tumors (TAP score ≥5%: 50.0%) and more had primary stomach tumors (86.6%) compared to those without (-) PM (58.4% and 75.5%). TIS+CT improved OS, PFS, and ORR in ITT and in pts +/- PM vs PBO+CT (Table). Across 20%–45% PM, TIS+CT showed consistent benefit, with stable HRs for OS and PFS (20% and 45% shown). TIS+CT showed survival benefits in pts with PM and PD-L1 TAP score ≥5% (OS: HR=0.71; PFS: HR=0.65) and ≥1% (OS: HR=0.79; PFS: HR=0.79) vs PBO+CT. ORR was higher with TIS+CT vs PBO+CT in pts + PM and PD-L1 TAP scores ≥5% (47.3% vs 30.8%) and ≥1% (44.2% vs 33.2%). Conclusions: Our analysis showed that lowering PM representation marginally improved OS and ORR, underscoring the poor prognosis of peritoneal disease. In RATIONALE-305, TIS+CT provides clinically meaningful response and survival benefits irrespective of PM, with higher responses in PD-L1+ GC/GEJC. Clinical trial information: NCT03777657 . Arm(95% CI) ITT + PM - PM 20%+ PM 45%+ PM OS, months TIS+CT 15.0 (13.6, 16.5) 12.3 (10.6, 14.3) 17.3 (15.0, 20.3) 15.4 (13.9, 18.0) 15.0 (13.5, 16.5) PBO+CT 12.9 (12.1, 14.1) 11.8 (10.5, 13.0) 14.0 (12.6, 16.0) 13.1 (12.3, 14.5) 12.8 (12.1, 14.1) HR 0.79 (0.69, 0.91) 0.78 (0.64, 0.96) 0.79 (0.65, 0.95) 0.81 (0.69, 0.95) 0.79 (0.69, 0.90) PFS, months TIS+CT 6.9 (5.7, 7.2) 5.8 (5.6, 7.3) 7.0 (5.7, 8.4) 6.9 (5.7, 7.3) 6.9 (5.7, 7.2) PBO+CT 6.2 (5.6, 6.9) 5.7 (5.3, 6.9) 6.9 (5.7, 7.1) 6.5 (5.6, 7.0) 6.2 (5.6, 6.9) HR 0.79 (0.68, 0.91) 0.80 (0.64, 0.98) 0.77 (0.64, 0.94) 0.79 (0.67, 0.94) 0.79 (0.69, 0.91) ORR, % TIS+CT 47.3 (42.9, 51.8) 43.6 (37.0, 50.5) 50.2 (44.2, 56.2) 48.0(42.9, 53.1) 47.3 (42.8, 51.8) PBO+CT 40.5 (36.2, 45.0) 32.2 (26.0, 39.0) 46.8 (40.9, 52.8) 43.1(38.1, 48.3) 40.3(36.0, 44.8) ORR difference, % 6.8 (0.6, 12.9) 11.4 (2.3, 20.3) 3.4 (-4.9, 11.6) 4.9 (-2.2, 11.9) 6.9 (0.8, 13.0)

Abstract Background Stigma associated with tuberculosis (TB) and TB diagnosis is a major social factor in delay of diagnosis and non-adherence to TB treatment among Asian American and Pacific Islander (AAPI) populations. Main sources of stigma include misconceptions regarding TB transmission and lack of knowledge about symptoms or treatment.Figure 1.Respondent demographicsBreakdown of respondent demographics by age, gender, and AAPI subgroup.Figure 2.Demographic breakdown of TB awarenessTB awareness by AAPI subgroup, age, and gender. Methods A cross-sectional survey of 666 AAPI individuals analyzed TB symptom recognition, transmission misconceptions, and awareness in two AAPI community centers. Data were segmented by AAPI subgroup, metropolitan area (Seattle/Tacoma vs. Las Vegas), age, and gender.Figure 3.TB transmission beliefs.Figure 4.TB treatment, curability, and latent TB infection awareness. Results Overall, 76.6% of respondents reported TB awareness, varying by AAPI subgroup. Awareness was highest among Korean (95%) and Filipino (91%) participants, and lowest among Vietnamese (52%) and Cambodian (50%) respondents. Regionally, TB awareness was similar between Tacoma (76%) and Las Vegas (79%). Age and gender significantly impacted awareness. Respondents under 18 had the lowest TB awareness (59%), while those aged 18-34 had the highest (84%). Females reported higher TB awareness (79%) and symptom recognition (61%) than males (74% and 46%, respectively). Symptom knowledge varied. 55% were aware of TB symptoms, but only 16% were able to recognize five common TB symptoms. Misconceptions about transmission also persisted broadly. Out of the 71% of respondents who were aware that TB is transmissible, many incorrectly believed TB spread via shaking hands (35%), sharing food/drinks (50%), or touching items in public areas (37%). The 45-64 and 65+ age groups were most prone to misconceptions about transmission. While 72% of respondents were aware that TB could be treated, only 57% knew TB could be cured. 30% of respondents were aware of latent TB infection. Conclusion Significant disparities in TB awareness exist in AAPI communities. Females demonstrated greater TB awareness perhaps due to cultural differences (“caretaker role”), while TB transmission misconceptions were prevalent among older individuals. Limited knowledge on LTBI and TB treatment represent significant barriers to effective TB control. Tailored educational efforts will be required to improve TB awareness and reduce misconceptions within AAPI communities. Disclosures All Authors: No reported disclosures

Abstract Background Most existing biomarkers for Alzheimer's disease (AD) inform on core AD pathologies in the central nervous system, namely amyloid, tau and neurodegeneration (ATN). However, molecular disease mechanisms underlying AD are complex and heterogeneous, highlighting the need for cost‐effective blood‐based biomarkers that reflect brain molecular changes in AD beyond ATN. Method Using peripheral blood transcriptome data from the Mayo Clinic Study of Aging(MCSA) and the Alzheimer's Disease Neuroimaging Initiative, we identified genes associated with AD or mild cognitive impairment (MCI) diagnosis, cognitive, and harmonized neuroimaging measures in two cohorts, followed by meta‐analysis. We identified consensus gene co‐expression modules in MCSA and ADNI using WGCNA and assessed the association between module eigengenes and aforementioned measures. Using seven bulk brain RNAseq cohorts, we confirmed the preservation of coexpression modules across blood and brain. Enrichment analyses of Gene Ontology (GO) terms and cell‐types were performed using significant and/or hub genes. The MCSA transcriptome was further deconvoluted to obtain cell‐type proportions and cell‐type specific expression. Result Blood transcriptome modules M5 and M8 are upregulated in AD/MCI and associate with worse cognition, whereas M1, M10, M13, M16, and M21 are downregulated in AD/MCI and associate with better cognition. M17 associates with more microhemorrhages. Cell‐type enrichment analysis revealed that M5 is enriched in basophils, monocytes, and neutrophils; M8 in monocytes and neutrophils; M13 in natural kills cells; M17 in megakaryocytes; M21 in B cells. GO analysis shows broad consistency with the cell‐type enrichment analysis. M1, 5, and 8 are preserved in the brain network modules. From these modules, we prioritized transcripts significantly associated with at least one AD‐related phenotype in both blood and brain. Cell‐type deconvolution analysis shows that prioritized transcripts in M1 associate with better cognition and higher metabolic activity in B cells. Conclusion We identified blood transcripts and modules associated with AD/MCI, cognition, or neuroimaging, with three preserved in brain networks. These three modules represent centrally linked peripheral molecular signatures that can reveal perturbed brain pathways and cell level transcriptional changes in AD/MCI. We aim to further investigate the prioritized transcripts in additional datasets to establish them as potential novel biomarkers and therapeutic targets.

Abstract Background Most existing biomarkers for Alzheimer’s disease (AD) inform on core AD pathologies in the central nervous system, namely amyloid, tau and neurodegeneration (ATN). However, molecular disease mechanisms underlying AD are complex and heterogeneous, highlighting the need for cost‐effective blood‐based biomarkers that reflect brain molecular changes in AD beyond ATN. Method Using peripheral blood transcriptome data from the Mayo Clinic Study of Aging(MCSA) and the Alzheimer's Disease Neuroimaging Initiative, we identified genes associated with AD or mild cognitive impairment (MCI) diagnosis, cognitive, and harmonized neuroimaging measures in two cohorts, followed by meta‐analysis. We identified consensus gene co‐expression modules in MCSA and ADNI using WGCNA and assessed the association between module eigengenes and aforementioned measures. Using seven bulk brain RNAseq cohorts, we confirmed the preservation of coexpression modules across blood and brain. Enrichment analyses of Gene Ontology (GO) terms and cell‐types were performed using significant and/or hub genes. The MCSA transcriptome was further deconvoluted to obtain cell‐type proportions and cell‐type specific expression. Result Blood transcriptome modules M5 and M8 are upregulated in AD/MCI and associate with worse cognition, whereas M1, M10, M13, M16, and M21 are downregulated in AD/MCI and associate with better cognition. M17 associates with more microhemorrhages. Cell‐type enrichment analysis revealed that M5 is enriched in basophils, monocytes, and neutrophils; M8 in monocytes and neutrophils; M13 in natural kills cells; M17 in megakaryocytes; M21 in B cells. GO analysis shows broad consistency with the cell‐type enrichment analysis. M1, 5, and 8 are preserved in the brain network modules. From these modules, we prioritized transcripts significantly associated with at least one AD‐related phenotype in both blood and brain. Cell‐type deconvolution analysis shows that prioritized transcripts in M1 associate with better cognition and higher metabolic activity in B cells. Conclusion We identified blood transcripts and modules associated with AD/MCI, cognition, or neuroimaging, with three preserved in brain networks. These three modules represent centrally linked peripheral molecular signatures that can reveal perturbed brain pathways and cell level transcriptional changes in AD/MCI. We aim to further investigate the prioritized transcripts in additional datasets to establish them as potential novel biomarkers and therapeutic targets.

ABSTRACT Introduction Although covalent Bruton's tyrosine kinase inhibitors (cBTKis) have transformed treatment of chronic lymphocytic leukemia and small lymphocytic leukemia (CLL/SLL), cBTKi‐related cardiotoxicity is a known side effect. This real‐world study evaluated incident cardiovascular adverse events (CVAE), healthcare resource utilization (HCRU), and costs among patients with CLL/SLL receiving cBTKis. Methods Adult patients with CLL/SLL who initiated ibrutinib or acalabrutinib treatment (index date) between 2020 and 2023 were identified using US claims data and followed up to 36 months post‐index. Incident CVAEs (not present pre‐index) were assessed during cBTKi treatment and patients were stratified by CVAE status. HCRU and costs were evaluated per 1000 patient‐months (PPPM). Results Overall, 2069 patients were identified (mean age of 73.7 ± 9.1 years, 40.4% female) with a mean treatment‐specific observation period of 11.4 ± 9.5 months. At least one incident CVAE was observed in 442 (21.4%) patients. The incidence rate was 21.6 PPPM for hypertension, 8.9 PPPM for atrial fibrillation, 8.6 PPPM for ventricular arrhythmias, and 8.3 PPPM for atrial flutter. Patients with incident CVAEs had significantly more total medical service days PPPM (4334 vs. 3138, p < 0.001), primarily driven by increased inpatient (690 vs. 230), outpatient (2798 vs. 2425), other visit (662 vs. 375), and ER days (184 vs. 109) than those without CVAEs. Total healthcare costs (PPPM) were substantially higher for patients with incident CVAEs ($20,250,560 vs. $17,413,460, p < 0.001) mainly due to higher inpatient ($3,417,948 vs. $915,839, p < 0.001), outpatient ($2,415,060 vs. $1,769,628, p < 0.01), and ER costs ($186,820 vs. $87,585, p < 0.001). Conclusions The observed class‐effect of high CVAEs with cBTKis underscores the unmet need for safer, more selective agents for CLL/SLL treatment. The HCRU and economic burden remain high for CLL/SLL, especially among patients experiencing CVAEs during cBTKi treatment. These findings emphasize the importance of optimizing clinical management to reduce CVAE risk and downstream impacts on HCRU and costs.

This economic evaluation estimates the implementation costs and cost per additional patient receiving the vaccine associated with each of the intervention strategies for increasing rates of human papillomavirus (HPV) vaccination in primary care practices.

Abstract Introduction Hodgkin's lymphoma is known to have favorable survival outcomes; however, limited data exist regarding survival disparities between rural and urban populations. In this study, we aimed to investigate the differences in survival outcomes between the two populations. Methods Data for patients diagnosed with Hodgkin lymphoma (HL) between 2000 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Rurality was identified using the Rural-Urban Continuum Codes (RUCC). Patients aged ≥ 20 years with HL as the only primary malignancy were included. Individuals with unknown race or those diagnosed at autopsy were excluded. The Ann Arbor Staging system was utilized for HL staging at diagnosis. HL-specific survival was defined as the time from diagnosis to death attributable to HL and was censored at the time of death from other causes or at last follow-up. Meanwhile, overall survival (OS) was defined as the time from diagnosis to death from any cause and was censored if the patient was still alive. A Cox proportional hazards model was performed to analyze the predictors for 10-year overall and HL-specific mortality. All statistical analyses were conducted using RStudio (version 2024.12.0). Results Between 2000 and 2015, a total of 22,505 patients diagnosed with Hodgkin lymphoma (HL) were included in the analysis. Among them, 13,657 (61%) were aged between 20 and 44 years. Overall, 10,137 patients (47%) were female, 14,885 (66%) were White, 2,672 (12%) were Black, and 3,724 (17%) were Hispanic. The majority of patients resided in urban counties, while only 2,266 (10.1%) lived in rural areas. Among rural patients, 845 (37%) were diagnosed with stage II disease, followed by 475 (21%) with stage III at the time of diagnosis. Notably, both the 10-year overall survival (69.5%) and Hodgkin lymphoma–specific survival (79.7%) were significantly lower among rural patients compared with urban patients (75.3% and 83.5%, respectively; p &lt; 0.001). In the multivariable model for 10-year HL-specific survival, older age (&gt; 65 years) was associated with the highest risk of mortality (HR 10.32; 95% CI 9.42–11.32). Although survival improved over the study period, male patients remained at increased risk of mortality (HR 1.26; 95% CI 1.18–1.35). Urban residence, diagnosis in more recent years, early stage, female sex, White race, and married status were independently associated with improved overall survival (p &lt; 0.01). Conclusion In this population-based study, both the 10-year overall and HL-specific survival were consistently lower among rural vs. urban patients. Male sex, older age, and unmarried status were particularly associated with worse survival outcomes. Further research is warranted to identify possible strategies for improving healthcare access and reducing survival disparities among rural patients.