Daiichi Sankyo (United States)

As Doenças Crônicas Não Transmissíveis (DCNT) representam um dos maiores desafios de saúde pública no mundo, sendo o Diabetes Mellitus (DM) uma das mais prevalentes. Entre as complicações agudas dessa condição, destaca-se a Cetoacidose Diabética (CAD), caracterizada por hiperglicemia, acidose metabólica e cetonemia, configurando-se como emergência médica de elevada morbimortalidade. O presente trabalho consiste em uma revisão bibliográfica narrativa, cujo objetivo foi apresentar as principais abordagens diagnósticas e terapêuticas da CAD em unidades de emergência, analisando protocolos nacionais e internacionais e destacando as práticas mais eficazes na redução de complicações e mortalidade. Para isso, foram consultadas as bases de dados SciELO, PubMed e LILACS, além de documentos oficiais da Sociedade Brasileira de Diabetes (SBD) e da American Diabetes Association (ADA). Os resultados demonstram que o manejo da CAD deve basear-se em três pilares: reposição hídrica vigorosa, correção de distúrbios eletrolíticos e insulinoterapia intravenosa contínua, sempre associado ao monitoramento rigoroso e à identificação precoce dos fatores desencadeantes. Além disso, foi possível observar que apesar da existência de protocolos padronizados, sua aplicação na prática clínica apresenta variações, especialmente em instituições com limitações estruturais. Portanto, conclui-se que a adesão às diretrizes clínicas, a capacitação das equipes multiprofissionais e a educação em saúde dos pacientes são fundamentais para otimizar os desfechos clínicos e reduzir a carga global da CAD nas emergências hospitalares.

Abstract Background: Human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) accounts for 15% to 20% of approximately 300,000 new BC cases diagnosed annually in the US. The treatment landscape for HER2+ metastatic BC (mBC) has evolved significantly, and trastuzumab deruxtecan (T-DXd [a HER2 antibody-drug conjugate]) is now the preferred standard of care in the second-line (2L) setting. Optimal post-T-DXd treatment pathways are unclear due to the lack of data for regimens in the 3L or 4L setting for patients with HER2+ mBC. This study aimed to better characterize real-world (rw) treatment patterns and clinical outcomes in patients with HER2+ mBC who were previously treated with T-DXd in the rw practice setting. Methods: This was a noninterventional, retrospective, observational cohort study of patients diagnosed with HER2+ mBC who initiated a subsequent treatment after receiving T-DXd in the metastatic setting, using the US-based Flatiron Health Enhanced Datamart. The study observation period was from January 1, 2011, to March 31, 2024. Patients with HER2+ mBC treated with ≥1 T-DXd-containing line of therapy (LOT) and a subsequent LOT, with an index date ≥90 days prior to the end of the observation period, were included. Index date was defined as the start of the LOT that followed the first T-DXd-containing LOT. Patient demographics, clinical characteristics, and treatment utilization were assessed descriptively. The primary (rw progression-free survival [rwPFS]) and secondary (rw overall survival [rwOS], rw time to discontinuation or death [rwTTD/D], and rw time to next treatment or death (rwTTNT/D)] endpoints were assessed using Kaplan-Meier methods. Results: The study included 228 patients (mean age, 60.3 years; 99.6% were female and 66.7% were White). Most patients initiated their index treatment in the 4L setting (median of 3 LOTs prior to index date; line of index treatment: 2L [4.4%], 3L [22.4%], 4L [31.1%], 5L [22.8%], 6L [11.0%], 7L+ [8.3%]). 64.5% of patients had ≥3 metastatic sites at the index date; 31.6% had CNS metastases. With a median follow-up of 10.4 months (range, 0.5-42.4 months), the median rwPFS was 4.3 months (95% CI, 3.5-5.0 months) and the median rwOS was 15.7 months (95% CI, 12.1-20.0 months). The median rwTTD/D and rwTTNT/D were 6.2 and 6.9 months, respectively. The most common regimens received as the index LOT were trastuzumab + tucatinib + chemotherapy (TTC; 34.2%), other anti-HER2 (18.9%), trastuzumab + chemotherapy (12.7%), other (12.7%), margetuximab + chemotherapy (8.8%), trastuzumab emtansine (T-DM1; 6.6%), and anti-HER2 TKI + chemotherapy (6.1%). Treatment sequencing varied by index line number. T-DM1-based regimens were more common when the index LOT was 3L (15.7%) vs 4L (5.6%) or 5L (3.8%), and 21% to 22% of patients with index 3L or 4L treatment received other anti-HER2 therapies immediately post T-DXd vs 13.5% with index 5L treatment. Conclusions: Treatment sequencing data suggest that TTC and other anti-HER2 therapies are being used in the post-T-DXd rw setting, though potential differences by line exist. This study demonstrates an ongoing and substantial unmet need for more effective treatments among patients with HER2+ mBC previously treated with T-DXd, as shown by the short rwPFS/OS and short times on subsequent treatments following T-DXd. Citation Format: S. M. Tolaney, S. Valliant, S. Hunter, O. Tymejczyk, A. Yu, J. Earla, E. Pang. Real-world treatment patterns and outcomes in patients with HER2+ metastatic breast cancer after treatment with trastuzumab deruxtecan (T-DXd) in the US [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-05-20.

Abstract Background: Trastuzumab deruxtecan (T-DXd) was initially (12/2019) approved by the FDA for treatment of patients (pts) with HER2+ unresectable or metastatic breast cancer (mBC) with two or more prior anti-HER2 regimens. T-DXd was later (5/2022) approved for use by pts with one prior anti-HER2 regimen. This study examined clinical outcomes in pts with HER2+ mBC treated with T-DXd 2L and 3L+ settings. Methods: This retrospective cohort study used deeply-curated electronic medical record data from practices affiliated with ONCare Alliance. Adult pts with mBC diagnosis, confirmed HER2+ status, who received T-DXd in the 2L or later setting 1/2020 to 8/2024 were included. Pt characteristics, treatment utilization and medical events of interests were assessed descriptively by 2L and 3L+ cohorts. Clinical outcomes (duration of therapy [DoT], real-world time to treatment failure [rwTTF], overall survival [OS] and real-world progression-free survival [rwPFS]) were assessed by 2L and 3L+ cohorts using Kaplan-Meier methods. Clinical outcomes of 1L and 2L rwTTF were examined in an exploratory subgroup of pts with 1L taxane+trastuzumab+pertuzumab based regimen (THP) followed by 2L T-DXd vs. 2L trastuzumab emtansine (T-DM1). Results: A total of 300 pts (70 2L and 230 3L+ pts [61.3% in 3L/4L]) treated with T-DXd were included (overall mean age = 59.3 yrs; 82.3% White). At mBC diagnosis, a greater proportion of pts in the 2L T-DXd cohort vs. 3L+ cohort had distant bone / visceral metastasis (45.7% vs. 38.3%) and visceral only metastasis (47.1% vs. 42.2%), where a significantly lower proportion had bone only metastasis (7.1% vs. 19.6%; p = 0.0493). Fewer 2L pts had brain metastasis at initiation of T-DXd (14.3% vs. 37.0% in 3L+, p = 0.0031), but a higher rate of baseline comorbidities was seen in 2L pts (50.0% vs. 30.4%, p = 0.0027). Prior to the initiation of 2L T-DXd, 64.3% (n=45) pts received a trastuzumab+pertuzumab based regimen and 22.8% (n=16) received T-DM1 in 1L; prior to 3L+ T-DXd use, 38.7% (n=89) received T-DM1 in 2L. Within a median follow-up of 17.0 months (mo), pts receiving T-DXd in 2L had longer median DoT than 3L+ pts (20.5 mo vs. 12.5 mo, p = 0.0390), longer rwPFS (15.3 mo in 2L vs. 12.4 mo in 3L+, p = 0.0179), longer OS (median NR in 2L vs. 29.0 mo in 3L+, p = 0.0050), and numerically longer rwTTF (13.6 mo in 2L vs. 10.4 mo in 3L+, p = 0.0565). Of pts with a response assessment (66 2L, 205 3L+ pts), an overall objective response was observed in 80.3% 2L vs. 71.7% 3L+ pts (p = 0.1672). The overall rates of any grade medical event of interest were consistent across 2L and 3L+ cohorts (fatigue [72.9% vs. 73.0%], nausea/vomiting [78.6% vs. 72.2%], diarrhea [55.7% vs. 43.9%], and interstitial lung disease (ILD)/pneumonitis [8.6% vs. 10.4%], except respiratory infection, which was higher in 2L T-DXd [38.6% vs. 18.7%, p = 0.0006]). Of the pts who had discontinued T-DXd at any point (45 2L and 180 3L+), the most common reason for discontinuation was disease progression (51.1% vs. 55.0%), followed by toxicity other than nausea/vomiting/ILD (17.8% vs. 11.7%), pt choice (8.9% vs. 6.1%) and toxicity related to ILD (6.7% vs. 6.7%). Among exploratory subgroups, median rwTTF was 1L THP 11.6 mo à 2L T-DXd 14.2 mo (n=38) vs. 1L THP 11.6 mo à 2L T-DM1 8.4 mo (n=60) (2L p = 0.0367). Conclusion: The study findings affirm the real-world clinical effectiveness and safety of T-DXd in pts with HER2+ mBC as observed in the DESTINY clinical trials. Despite higher disease and comorbidity burden in this small sample of pts with 2L T-DXd use, longer delays in time to progression and discontinuation were observed compared to later line use of T-DXd; and longer rwTTF compared to 2L T-DM1 use, reinforcing the importance of utilizing T-DXd as early as possible in the treatment pathway to improve long-term pt outcomes. Citation Format: S. Mehta, H. Neuhalfen, A. Peevyhouse, D. Adhikari, C. Williams, M. Garretson, S. Blau, M. Walker, D. Peevyhouse. Real-world Clinical Outcomes in Patients with HER2+ Metastatic Breast Cancer Treated with Trastuzumab Deruxtecan After One or More Prior Lines of Therapy: Data from U.S Community Oncology Practices [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-05-27.

Abstract Background Endocrine therapy (ET) in combination with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is a preferred first-line (1L) treatment for patients (pts) with HR+/HER2− mBC. However, ET resistance frequently emerges after 1L treatment, with many pts receiving subsequent chemotherapy or other targeted regimens. This study aimed to assess treatment patterns and clinical outcomes in pts with HR+/HER2− mBC that progressed on 1L ET + CDK4/6i in real-world (rw) practice settings. Methods This was a noninterventional, retrospective, observational cohort study using the US-based Flatiron Health Enhanced Datamart. Adult pts with HR+/HER2− mBC (with no other actionable genomic alterations [ESR1, PIK3CA, AKT1, PTEN, or gBRCA]) that progressed on 1L ET + CDK4/6i were included if they initiated a second-line (2L) therapy between Jan 2017 and Sep 2024 with ≥90 d of potential follow-up. Pt demographics, clinical characteristics, and treatment utilization were assessed descriptively. Treatment data were recorded as documented by physicians and may reflect off-label use. The primary (rw progression-free survival [rwPFS]) and secondary (rw overall survival [rwOS], rw time to discontinuation or death [rwTTD/D], and rw time to next treatment or death [rwTTNT/D]) endpoints were assessed using Kaplan-Meier methods. Analyses were performed in all pts, by 2L regimen, and by time to progression on 1L treatment. Results 1415 pts with HR+/HER2− mBC were included (median age, 65 y; 66.2% were White). Of these, 57.3% (n=811) had disease progression on ET + CDK4/6i within 12 mo of 1L initiation (early progression; 33.3% in ≤6 mo); 25.5% had disease progression in 12 to 24 mo and 17.2% within >24 mo. In the 2L, 63.6% of pts received an ET-based regimen, 27.1% received chemotherapy (CT; monotherapy, 23.8%; multiagent, 3.3%), and 9.3% received other regimens (including AKTi, PARPi, and the ADC sacituzumab govitecan or trastuzumab deruxtecan). Pts with early vs later times to disease progression on 1L ET + CDK4/6i used 2L CT more frequently (40.6% [≤6 mo] vs 14.0% [>24 mo]); the opposite was true for 2L ET (52.2% [≤6 mo] vs 75.3% [>24 mo]). With a median follow-up of 14.6 mo, the 2L median rwPFS ranged from 4 to 8 mo and median rwOS ranged from 14 to 32 mo; the shortest estimates were among pts on 2L CT and with early disease progression on 1L ET + CDK4/6i (Table). Conclusions In this study of pts with HR+/HER2− mBC that progressed on 1L ET + CDK4/6i, over half had 1L disease progression within 12 mo and about one-third received CT in a subsequent line. The median rwPFS on 2L treatments was shorter among those who were using CT in 2L or had early progression (<12 months) on 1L ET + CDK4/6i, highlighting the emergence of ET resistance and a need for more effective therapeutic alternatives to improve pt outcomes. Citation Format: V. Kaklamani, S. Valliant, S. Hunter, O. Tymejczyk, A. Yu, P. Earla, S. Mehta, E. Pang. Treatment patterns and clinical outcomes following progression on first-line ET + CDK4/6i among patients with HR+/HER2− metastatic breast cancer (mBC) in the US [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-02-20.

Accurate human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) scoring is crucial to identify patients for HER2-directed therapy; however, validated HER2 scoring guidelines are lacking for non-breast/gastric solid tumors. We investigated concordance in IHC scores from independent pathologists using three different scoring algorithms in non-gastric/breast solid tumors. Whole-slide scans of HER2-stained tumor samples from DESTINY-PanTumor02 (NCT04482309) and a commercial pan-tumor sample set were scored by three independent, board-certified pathologists using American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) scoring algorithms for gastric (reference) and breast cancers, and a clinical trial-based algorithm for endometrial cancers (evaluated for endometrial tumors only). The pathologists evaluated 488 samples from multiple solid tumor types. Mean positive percentage agreement (PPA; across pathologists) between the breast and gastric algorithms was higher for samples scored as IHC 3 + or IHC 0 compared with IHC 2 + or IHC 1 + . Inter-pathologist PPA for each algorithm was greatest in samples scored as IHC 3 + and IHC 0. The majority of inter-pathologist pairwise comparisons had Cohen's κ coefficient values > 0.4 when using the gastric or breast algorithm to determine IHC scores, indicating at least moderate agreement between pathologists; Cohen's κ coefficient values were generally lower (range 0.17-0.43) for the endometrial algorithm. ASCO/CAP scoring algorithms for gastric and breast cancer were comparable for identifying HER2 IHC 3 + tumors; lower concordance was observed for IHC 2 + /1 + tumors. These findings highlight a real-world issue of inter-pathologist variability and emphasize a need for greater awareness of best scoring practices.

Multiplex immunofluorescence and immunohistochemistry (mIF/IHC) are increasingly employed antibody-based technologies that use tissue sparingly and facilitate the detection of co-localized or neighboring biomarkers. Specifically, these platforms enable spatial analyses of the tumor microenvironment as well as extended applications, for example, describing normal tissue anatomy, autoimmunity, infectious diseases, etc. mIF/IHC has greatly enhanced biomarker discovery efforts, and a growing number of studies suggest superiority to traditional IHC. Standardization of staining approaches, reporting of image analysis strategies and resultant data is critical for facilitating cross-study comparisons, validation, deployment, and generalization of findings. To address this challenge, The Society for Immunotherapy of Cancer (SITC) previously published two articles providing best practice guidelines for mIF/IHC staining, image analysis, and data sharing. Here, SITC convened stakeholders to develop the third article in the series, a consensus checklist for scientific reporting of mIF/IHC data to support and complement the best practice guidelines. The checklist includes critical components of mIF/IHC applications to be defined within publications such as detailed descriptions of analytical validation; image acquisition, selection, and registration methods; and cell clustering and spatial analysis strategies, amongst others. Such information will help with data reproducibility and comparison across studies towards future drug and assay development.