Bayer (Canada)

Introduction: The Phase III OCEANIC-STROKE trial (NCT05686070) investigates whether the activated Factor XI inhibitor asundexian combined with antiplatelet therapy (APT) reduces the risk of recurrent IS in patients with non-cardioembolic IS (NCIS) or high-risk TIA compared with APT alone. The objective of the present investigation was to describe the characteristics and outcomes of patients compatible with the OCEANIC-STROKE trial population among patients hospitalized for a first-ever NCIS or TIA in real-world settings in Japan. Methods: ASTRIS Japan was a retrospective cohort study using a Japanese nationwide hospital database (RWD Co.). Adults with a first hospitalization for NCIS or TIA between Jan 1, 2015 and Oct 29, 2022 were identified. Among them, a subset of patients compatible with the OCEANIC-STROKE trial population was selected by applying the emulated eligibility criteria of the OCEANIC-STROKE trial. Clinical events were assessed after discharge of the index NCIS or TIA hospitalization. Events that occurred during the hospitalization for index stroke were not considered. Results: In total, 18,719 patients with NCIS or TIA were identified. Of these, 5778 patients were identified for the OCEANIC-STROKE-compatible cohort (Fig 1). The median (Q1, Q3) length of follow-up was 715 (170.8, 1355.3) days. Table 1 shows the baseline characteristics of the OCEANIC-STROKE-compatible cohort. Mean±SD age was 73.1±11.9 years and 37.7% were female. Most (70.4%) patients initiated APT within 2 days of hospital admission. Single APT was used in 4830 (83.6%) patients and dual APT was used in 1991 (34.5%) patients, and were not mutually exclusive. Rates (per 1000 patient-years [95% CI]) of IS, hemorrhagic stroke, and major bleeding were 106.1 (100.0–112.1), 8.9 (7.3–10.5), and 47.2 (43.4–51.0), respectively. Compared with the overall NCIS or TIA cohort, a numerically higher rate of IS and a numerically lower rate of major bleeding were observed in the OCEANIC-STROKE-compatible cohort up to 5 years (Fig 2). Baseline characteristics of the overall NCIS or TIA and the OCEANIC-STROKE-compatible cohorts will be compared with those of patients in the OCEANIC-STROKE trial. Conclusions: In real-world settings, patients compatible with the enrolled OCEANIC-STROKE trial population had a high risk of IS recurrence following hospital discharge in Japan. Further improvements in secondary stroke prevention strategies are merited.

Abstract Background/Introduction Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive myocardial disease that leads to repeated cardiovascular hospitalisations and death within 3 to 10 years if left untreated. A progressive rise in NT-proBNP (>30% and >300 pg/mL) can be a prognostic marker of disease progression and is associated with an increased risk of mortality in people with ATTR-CM. In addition, the 6-minute walk distance (6MWD) test is a tool for evaluating functional capacity and is associated with prognosis in patients with ATTR-CM. Although targeted therapies have shown clinical efficacy, thresholds for clinically meaningful improvements from baseline in ATTR-CM remain unclear. Acoramidis, an oral transthyretin (TTR) stabiliser that achieves near-complete (≥90%) TTR stabilisation, is approved in the US and Europe for the treatment of ATTR-CM. In the phase 3 randomised controlled study ATTRibute-CM, acoramidis demonstrated significant efficacy on the primary endpoint of all-cause mortality, cardiovascular-related hospitalization, change from baseline (CFB) in NT-proBNP, and CFB in 6MWD (p<0.0001). Purpose We assessed the capacity for acoramidis to achieve clinically meaningful improvements from baseline through 30 months in NT-proBNP and 6MWD in participants with ATTR-CM from the phase 3 ATTRibute-CM study. Methods Randomised participants in the ATTRibute-CM study received acoramidis or placebo (2:1) for 30 months. Clinically meaningful improvements from baseline for NT-proBNP were adopted as the inverse of those used to denote progression (reduction of >30% with a minimum decrease of >300 pg/mL) and defined improvement in 6MWD as an increase of >30 m. The proportion of participants who met clinically meaningful improvement in NT-proBNP and/or 6MWD were evaluated at month 30. Participants with missing assessments at month 30 were categorised as worsened. Univariate logistic regression with treatment group as an independent variable was performed to compute the odds ratio (OR) for response. Results A total of 611 participants were analysed in the modified intention-to-treat population (acoramidis: 409; placebo: 202). Participant baseline characteristics were comparable between groups. A total of 106 (25.9%) participants in the acoramidis group showed improvement in at least one parameter compared with 19 (9.4%) in the placebo group (Table 1; OR 3.4, 95% CI 2.0–5.7, p<0.0001). Among those meeting both improvement criteria, 12 (2.9%) were in the acoramidis group compared with two (1.0%) in the placebo group (Table 2; OR 3.0, 95% CI 0.7–13.6, p<0.1502). Conclusion(s) Acoramidis treatment resulted in clinically meaningful improvements from baseline in NT-proBNP and/or 6MWD across 30 months in >25% of patients with ATTR-CM, a finding inconsistent with the natural history of this progressive disease. Further studies are needed to understand patient characteristics and factors that influence these improvements on acoramidis.

399 Background: Androgen receptor inhibitors (ARIs) are recommended for nmCRPC. Darolutamide (DARO) is a structurally distinct & highly potent ARI approved for nmCRPC based on ARAMIS (phase 3). There are no prospective comparative clinical trial data for DARO vs enzalutamide (ENZA) & apalutamide (APA). DEAR (NCT05362149) compared real-world (RW) utilization, tolerability & outcomes of ARIs in 870 patients (pts) with nmCRPC. DEAR-EXT (NCT06013475) expands on DEAR with 1 y more of pt inclusion & follow-up. Methods: DEAR-EXT is a retrospective chart review cohort study of pts in the PPS network of US urology practices who started initial ARI for nmCRPC from 8/2019 to 3/2023. Key outcomes include time to initial ARI discontinuation, reason for discontinuation, time to metastatic CRPC (mCRPC) progression, prostate-specific antigen (PSA) response, overall survival (OS), metastasis-free survival (MFS) & treatment-emergent adverse events (TEAEs). ARI utilization & tolerability were compared using descriptive frequency statistics; time-to-event outcomes were compared using unadjusted Kaplan–Meier estimates & Cox proportional hazards models adjusted for baseline characteristics. Results: Of all 1375 pts meeting eligibility criteria, 565 (41%) received DARO, 609 (44%) ENZA & 201 (15%) APA. During the study, the number of pts with nmCRPC initiating ARI treatment decreased annually but the proportion starting DARO increased vs ENZA & APA. Baseline characteristics were generally similar across treatment groups; median follow-up was similar for DARO (26.2 mo), ENZA (26.2 mo) & APA (25.5 mo). Median time to discontinuation was not reached (NR; 95% CI 35.5–NR) for DARO, 27.6 mo (23.9–35.6) for ENZA & 26.8 mo (22.6–42.8) for APA. Adjusted HRs showed significant discontinuation risk reductions for DARO vs ENZA (27%) & vs APA (31%) (Table). The most frequent reasons for discontinuation were TEAEs (DARO 10%, ENZA 15%, APA 15%) & disease progression/death (15%, 19%, 18%, respectively). Adjusted HRs for mCRPC progression showed significant risk reductions for DARO vs ENZA (37%) & vs APA (28%) (Table). Times to discontinuation & mCRPC progression were similar for ENZA & APA. PSA response, OS & MFS rates were numerically higher for DARO vs ENZA & APA. TEAEs occurred in 25% of pts on DARO, 28% on ENZA & 30% on APA. Conclusions: These data reinforce DARO as an effective, well-tolerated treatment for nmCRPC that demonstrates potentially greater clinical benefits vs ENZA & APA in RW practice. Clinical trial information: NCT06013475 . HRs from adjusted Cox regression models. HR 95% CI P-value Time to initial ARI discontinuation DARO vs ENZA 0.73 0.61–0.88 0.001 DARO vs APA 0.69 0.54–0.89 0.003 ENZA vs APA 0.95 0.75–1.19 0.639 Time to mCRPC progression* DARO vs ENZA 0.63 0.50–0.80 <0.001 DARO vs APA 0.72 0.53–0.98 0.038 ENZA vs APA 1.14 0.85–1.52 0.373 *Not adjusted for multiple testing comparisons.

Objectives: Professionals and practitioners in food science & technology navigate a minefield of challenges stemming from the convergence of scientific inquiry and research, and mass and social media. Escalating skepticism and erosion of trust in science is exacerbated by poorly conducted science, plagiarism, inadequate peer review, predatory publishing, misrepresentation of science in the media, and public perceptions of science that are shaped by politicization and mis- and disinformation. Methods: Key search terms (science, food science & technology, nutrition) were crosslinked with search terms that describe challenges undermining trust in science (media, mis/disinformation, skepticism, hype, generative AI, credibility, politicization, etc.). Over 200 articles covering social media impacts on scientific credibility, the evolution of science & peer review, the rapidly changing rules governing scientific output in academia and industry and codes of ethics meant to govern how professionals work, particularly in the context of food science, food technology, and nutritional science. Results: Contradictory 'facts' presented in mass and social media generate distrust in scientific discoveries. Leveraging the comprehensive literature review, a strategic framework was defined that 1) identifies and manages factors that challenge integrity and credibility of food research, and 2) prescribes strategies that allow professionals to mitigate and manage challenges in this complex space in order to provide credible research results in food & nutritional science and food technologies. Evidence supports a compelling need for strict adherence to common codes of ethics when conducting, reporting and communicating research results in academia and public forums. Conclusions: Tools and a framework for professionals identifies the intersection of factors that contribute to erosion of trust and highlights challenges as they relate to perceived loss of integrity or credibility in food science and technology. Funding Sources: N/A.

3105 Background: NTRK gene fusions are oncogenic drivers identified in <1% of solid tumors. Larotrectinib (laro) is a highly selective TRK inhibitor (i) that was approved in patients (pts) with TRK fusion cancers based on data from single-arm trials. Here we report results from VICTORIA (NCT05192642), a protocol-driven, exact-matching study comparing the outcomes of pts with TRK fusion cancer treated with laro in clinical trials (NCT02122913, NCT02576431, NCT02637687) to pts treated with non-TRKi therapies in the real-world (RW) setting. Methods: Adult (≥18 years old) pts with non-small cell lung cancer, colorectal cancer, soft-tissue sarcoma, thyroid cancer, or salivary gland carcinoma were included. Deduplicated data from RW pts were from US and ex-US databases: American Association for Cancer Research GENIE, Cardinal, Flatiron, and ORIEN, as well as a global chart review. Pts in the laro cohort were exactly matched to RW pts based on tumor type and line of therapy to define index line and date for RW pts. A propensity score (weighting) model was used to balance key pt characteristics between cohorts. Pts were followed from index date to last activity, end of study period, or death, whichever occurred first. RW pts were censored at the start of any TRKi therapy or investigational agent, or censored at their last known alive date. Overall survival (OS) was the primary outcome. Results: In total,164 pts with TRK fusion cancer were matched (82 in each cohort). Balance in the baseline covariates was achieved after weighting. Matched RW pts received standard index treatments for their disease, which comprised chemotherapy (49%), non-TRKi small molecule targeted therapy (27%), chemotherapy + non-TRKi non-small-molecule targeted therapy (11%), or immune checkpoint inhibitor therapy (10%). Laro-treated pts had longer OS compared to RW pts (median not reached [NR] vs 37.2 months; hazard ratio [HR]: 0.44 [95% confidence interval {CI}: 0.23-0.83]) after weighting. In the weighted analysis, laro-treated pts had longer time to next therapy (TTNT; median NR vs 10.6 months; HR: 0.22 [95% CI: 0.13-0.38]), duration of therapy (DoT; median 30.8 vs 3.4 months; HR: 0.23 [95% CI: 0.15-0.33]), and progression-free survival (PFS; median 36.8 vs 5.2 months; HR: 0.29 [95% CI: 0.18-0.46] compared to RW pts. Conclusions: In adult pts with TRK fusion cancer, treatment with laro was associated with longer OS and all measured time-to-event endpoints (TTNT, DoT, and PFS), compared to exactly matched pts treated with standard non-TRKi therapies in the RW. These results furnish additional evidence illustrating the benefit of laro treatment in pts with TRK fusion cancer and support the data generated in the single-arm registrational trials. Clinical trial information: NCT05192642 .

Over the past decade, the treatment of metastatic castration-sensitive prostate cancer (mCSPC) has changed significantly. Current guidelines suggest the use of androgen deprivation therapy (ADT) plus an additional systemic therapy, regardless of disease burden and risk, based on phase 1 evidence showing improved overall survival. We sought to describe treatment patterns of patients with mCSPC in the province of Alberta. This was a retrospective, population-based, cohort study of male patients aged ≥18 with mCSPC at the time of diagnosis and who initiated ADT between 1 January 2016 and 31 December 2020. Data were obtained from the Alberta Cancer Registry. Patients were assigned to an ADT-alone cohort or a treatment intensification cohort (cohorts 2-5). The primary objectives of this study were to describe baseline characteristics and the treatment of mCSPC patients who initiated ADT with or without treatment intensification. Overall survival between cohorts was a secondary objective. Descriptive statistics were used to describe differences in baseline characteristics of each cohort. Overall survival was calculated using the Kaplan-Meier method. All statistical tests were two-sided and are used to call out likely cohort differences descriptively. Between 1 January 2016 and 31 December 2020, we identified a total of 960 patients with mCSPC (median age 74 years, IQR 66-82). Most patients received ADT alone (67%), followed by ADT plus abiraterone (18%), ADT plus docetaxel (12%), and ADT plus enzalutamide or apalutamide (3%). Over the study period, we observed an increase in the utilization of treatment intensification over time, in particular, the increased use of androgen-receptor-axis-targeted (ARAT) therapies. Patients who received ADT alone were older, were more likely to have more than one comorbid condition, had fewer sites of metastatic disease, and were less likely to be on opioid medications. In this study, we show that patients who received ADT alone as treatment for mCSPC are older, have more comorbidities, and have less extensive disease. While there has been a decline over time in the number of patients treated with ADT alone, over 50% of all patients with mCSPC continue to receive ADT alone. Further work is needed to understand barriers to treatment intensification and for knowledge translation initiatives to improve the treatment of patients with mCSPC.

6091 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in a variety of tumor types, including TC. Laro is a first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in pts with TRK fusion cancer based on a rapid, robust, and durable objective response rate (ORR) in both adult and pediatric pts with various cancers. Here, we report data on the subset of pts with TRK fusion TC treated with larotrectinib with long-term follow-up. Methods: Pts with TRK fusion TC enrolled in three laro clinical trials (NCT02576431, NCT02122913, NCT02637687) were included. Laro was administered at 100 mg twice daily to most pts; two pediatric pts received 100 mg/m2. Responses were assessed per independent review committee (IRC) using RECIST v1.1. Data cut-off: July 20, 2022. Results: As of data cut-off, 30 pts were eligible for efficacy assessment by IRC. The median age was 61.5 years (range 6–80) and the median time since initial cancer diagnosis was 5.0 years (range 0–46). The gene fusions involved NTRK1 (n =14; 47%) or NTRK3 (n =16; 53%). Fifteen pts (50%) received no prior systemic therapies, and six (20%) received ≥2; 23 (77%) received prior radioiodine. ORR was 63% (95% confidence interval [CI] 44–80): three (10%) complete response, 16 (53%) partial response (PR), five (17%) stable disease, four (13%) progressive disease, and two (7%) not evaluable. For pts classified as differentiated TC (DTC; n = 23), the ORR was 78% (95% CI 56–93). For pts classified as anaplastic TC (ATC; n = 7), the ORR was 14% (95% CI 0–58). All four pts with CNS metastases at baseline had a PR. Median time to response was 1.9 months, and median duration of response (DoR) was 43.3 months (95% CI 21.6–not estimable [NE]) at a median follow-up of 32.3 months. Median progression-free survival was 35.5 months (95% CI 23.4–NE) at a median follow-up of 34.0 months. Median overall survival (OS) was not reached (NR; 95% CI 48.7–NE) at a median follow-up of 46.4 months; the 48-month OS rate was 71% (95% CI 54–88). Median OS was NR (95% CI 48.7–NE) in DTC and 8.8 months (95% CI 2.6–NE) in ATC. At data cut-off, five pts who had disease progression continued treatment for ≥4 weeks due to continued clinical benefit. Treatment-related adverse events (TRAEs) were predominantly Grade 1–2. Grade ≥3 TRAEs were reported in two (7%) pts (anemia and decreased lymphocyte count). There were no treatment discontinuations due to TRAEs. Conclusions: Laro continues to demonstrate a rapid and durable response, extended survival, and a favorable safety profile in pts with TRK fusion DTC. Limited single-agent activity was observed in ATC. These results support the wider adoption of next generation sequencing panels, which include NTRK gene fusions, in pts with advanced TC prior to the initiation of any systemic therapy. Clinical trial information: NCT02576431 , NCT02122913 , NCT02637687 .

There has been much interest in the evaluation of heterogeneous treatment effects (HTE) and multiple statistical methods have emerged under the heading of personalized/precision medicine combining ideas from hypothesis testing, causal inference, and machine learning over the past 10-15 years. We discuss new ideas and approaches for evaluating HTE in randomized clinical trials and observational studies using the features introduced earlier by Lipkovich, Dmitrienko, and D'Agostino that distinguish principled methods from simplistic approaches to data-driven subgroup identification and estimating individual treatment effects and use a case study to illustrate these approaches. We identified and provided a high-level overview of several classes of modern statistical approaches for personalized/precision medicine, elucidated the underlying principles and challenges, and compared findings for a case study across different methods. Different approaches to evaluating HTEs may produce (and actually produced) highly disparate results when applied to a specific data set. Evaluating HTE with machine learning methods presents special challenges since most of machine learning algorithms are optimized for prediction rather than for estimating causal effects. An additional challenge is in that the output of machine learning methods is typically a "black box" that needs to be transformed into interpretable personalized solutions in order to gain acceptance and usability.