Daiichi-Sankyo (Japan)

Abstract Background: The DESTINY-Breast04 (DB-04) trial established trastuzumab deruxtecan (T-DXd) as the standard of care for patients (pts) with the metastatic breast cancer (mBC) newly classified as HER2-low status (HER2 IHC 1+, or 2+/ISH−). However, in the DB-04 trial, the number of pts with hormone receptor-negative (HR−)/HER2-low mBC was limited, and pts with stable brain metastases (BMs) were included, while those with active BMs were excluded. The HALLOW study (UMIN000051259) is a large-scale ongoing prospective observational study conducted in Japan with the aim of providing effectiveness and safety data for T-DXd in these clinically important populations, which were underrepresented in the DB-04 trial. Here, we report the interim analysis results for pts with BMs. Methods: The HALLOW study enrolled, from June 2023, approximately 600 pts diagnosed with HER2-low mBC (HR+/−, with/without BMs, including active BMs) who had previously received chemotherapy and were scheduled to receive T-DXd treatment. This interim analysis included pts diagnosed with BMs (current or past) by local investigators. For the effectiveness analysis, only those with BMs confirmed by Brain-independent central review (ICR) based on brain MRI and/or CT images were included. Active BMs were defined as cases where no local treatment was performed on the brain lesion or where there was regrowth or symptom worsening after local treatment. Effectiveness outcomes included intracranial progression-free survival (IC-PFS) and intracranial objective response rate (IC-ORR) assessed by Brain-ICR according to RECIST version 1.1, while progression-free survival (PFS) and overall survival (OS) were assessed by investigators. For the safety analysis, pts who had received T-DXd at least once were included. Safety outcomes include incidence of treatment-emergent adverse events (TEAEs) graded by CTCAE, including ≥ grade (Gr) 3 TEAEs, ≥ Gr1 interstitial lung disease (ILD), and ≥ Gr1 TEAEs that led to discontinuation of T-DXd treatment. Follow-up plan will continue until July 2026. Results: At the data cutoff date of August 31, 2024, 42 pts had physician-diagnosed BMs, of whom 33 were Brain-ICR confirmed and met the criteria for active BMs. In this set, the median age was 55 (range: 42-79) years; the median prior line of chemotherapy in the metastatic setting was 2 (range: 0-7); HER2 status at each local site was IHC 2+/ISH− in 7 pts (21%) and IHC 1+ in 26 pts (79%); 25 pts (76%) were HR+, 8 pts (24%) were HR−. 5 pts (15%) had Brain-ICR-confirmed leptomeningeal disease. At a median follow-up period of 4.1 months (mo) (range: 1.4-12.6), the median IC-PFS was 8.0 mo (95% confidence interval [CI]: 3.9-not estimated), and the 6-mo IC-PFS rate was 57.6% (95% CI: 30.7-77.4) until the data cutoff date. A total of 22 pts was eligible for proper tumor evaluation during the follow-up period by Brain-ICR. Among the 22 pts who could be properly evaluated, the IC-ORR was 9.1% (complete response n=0, partial response n=2; 95% CI: 1.1-29.2). The median PFS was 6.7 mo (95% CI: 4.0-11.1), with a 6-mo PFS rate of 59.0% (95% CI: 34.9-76.7). The median OS was not reached, and the 6-mo survival rate was 77.1% (95% CI: 51.5-90.3). In the safety analysis set (n=42; median follow-up period: 4.1 mo [range: 0.4-12.6]), ≥ Gr3 TEAEs and ≥ Gr3 TEAEs related to T-DXd treatment occurred in 18 (43%) and 11 (26%) pts, respectively. ≥ Gr1 ILD occurred in 2 pts (5%), 1 (2%) of whom experienced Gr 5 ILD, and ≥ Gr1 TEAEs that led to T-DXd discontinuation occurred in 3 pts (7%), with two of these being ILD and the other seizure. Conclusions: While longer follow-up and additional data are needed to confirm these findings, the current data provide tentative support for the effectiveness and safety of T-DXd in this BMs population including active BMs, which was not included in the DB-04 trial. Citation Format: N. Niikura, T. Yamanaka, Y. Aoyama, A. Kataoka, T. Toyama, S. Sakai, M. Endo, K. Kaneko, H. Iwata, T. Yamashita, J. Tsurutani, R. Horii, Y. Kikawa, Y. Hirakawa, S. Yamazaki, W. Hashimoto, E. Tokuda, S. Saji. Interim analysis results for the effectiveness and safety of trastuzumab deruxtecan in patients with HER2-low breast cancer and brain metastases: The HALLOW study [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 PD13-11.

<h3>Background</h3> Human epidermal growth factor receptor 2 (HER2) is overexpressed in ∼20% of advanced gastroesophageal adenocarcinomas (GEAs). Trastuzumab (T-mab) is the standard first-line treatment for HER2-positive GEA, and trastuzumab deruxtecan (T-DXd) has demonstrated clinical efficacy in later-line settings. However, the potential loss of HER2 expression following T-mab treatment raises concerns about the subsequent effectiveness of T-DXd. The temporal dynamics of HER2 expression across treatment lines are not well understood. <h3>Design</h3> We designed a prospective, single-arm, multicenter study to investigate the association between the efficacy of third-line T-DXd and changes in HER2 status in tumor tissue and blood after first-line T-mab treatment in patients with HER2-positive GEA. The aim is to inform the optimal clinical use of T-DXd. Serial tumor and/or blood re-biopsies will be carried out at each line of treatment following first-line therapy. The study consists of two parts. In part 1, we will evaluate biomarker dynamics—specifically HER2 status and circulating tumor DNA alterations—during second-line therapy. In part 2, we will assess the efficacy and safety of third-line T-DXd in relation to these biomarker changes. Approximately 120 patients will be enrolled in part 1 and 50 in part 2.

We have developed the methylotrophic yeast Ogataea minuta as a useful host for producing heterologous proteins. In this study, a double mutant that lacks the Prb1 protease and alcohol oxidase was generated and applied for heterologous protein production. Upon our optimization of the fermentation conditions, such as feeding of carbon and nitrogen sources and pH control, this mutant showed increased production of human serum albumin, resulting in a yield of approximately 7.5 g/L at 21 days in the production phase. The established optimal fermentation condition with the double mutant was successfully applied to manufacture a candidate biologic protein: lipocalin derivative which is designed to attach to the calcitonin gene-related peptide, on an industrial scale. The candidate biologic protein was successfully manufactured at an industrial scale in a 4500 L bioreactor under well-controlled conditions. This first successful case highlights the potential of our O. minuta-based production system, and this study is helpful for a large-scale cultivation of a methylotrophic yeast for protein production.

Understanding the role of transcript isoforms is essential for elucidating disease mechanisms. TDP-43 regulates RNA splicing, and its dysfunction in neurons is a hallmark of some neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). While an association between TDP-43-dependent cryptic exons and disease pathogenesis has been suggested, an approach to investigate how cryptic exons disrupt transcript isoforms has yet to be established. In this study, we developed IsoRefiner, a novel method for identifying full-length transcript structures using long-read RNA-seq. Leveraging this method, we performed long-read RNA-seq, guided by prior short-read RNA-seq, to comprehensively determine the full-length structures of aberrant transcripts due to TDP-43 dysregulation in human iPSC-derived motor neurons. We identified a novel TDP-43-dependent cryptic exon in the MNAT1 gene, along with its full-length transcript structure. Furthermore, we confirmed the presence of the MNAT1 cryptic exon in patients with ALS and FTD. Our findings deepen understanding of TDP-43 proteinopathy and advance splicing research.