Biomedical subjects

Yasushi Goto

Publications and source records attributed to Yasushi Goto.

4 recordsLinked to original sources

PubMed2026

Clinical outcomes and genomic features of uncommon EGFR exon 19 deletion subtypes in osimertinib-treated non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) exon 19 deletion subtypes may be associated with differential survival outcomes following EGFR-tyrosine kinase inhibitor treatment. However, evidence remains scarce, particularly regarding osimertinib, and the underlying biological mechanisms are poorly understood. We aimed to compare survival outcomes among EGFR exon 19 deletion subtypes in patients with non-small cell lung cancer (NSCLC) treated with osimertinib. METHODS: In this multicenter retrospective study, patients with NSCLC were stratified according to exon 19 deletion subtypes. Whole-exome sequencing data from the American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange registry and Memorial Sloan Kettering Clinicogenomic Harmonized Oncologic Real-World Dataset were analyzed to investigate co-occurring genomic alterations. RESULTS: Overall, 111 patients with advanced EGFR exon 19 deletion-positive NSCLC were analyzed and 86.5% received osimertinib as first-line therapy. Patients with non-E746_A750del (n = 25) had shorter progression-free survival (PFS) than those with E746_A750del (n = 86) (median: 14.3 vs. 20.6 months; p < 0.05). Among non-E746_A750del subtypes, L747_A750delinsP (n = 4) had a particularly poor prognosis, with significantly worse survival than those with E746_A750del (median PFS: 3.5 vs. 20.6 months; p < 0.001, and median overall survival: 11.8 vs. 48.5 months; p < 0.001). In public database analyses, non-E746_A750del had a higher rate of RBM10 co-mutations, whereas L747_A750delinsP was characterized by frequent CDKN2A/B homozygous deletions and MYC amplifications. CONCLUSIONS: Non-E746_A750del was associated with poorer outcomes, with L747_A750delinsP potentially being a high-risk subtype. Differences in co-occurring genomic alterations may contribute to the prognostic heterogeneity among exon 19 deletion subtypes.

Humans↗

PubMed2025

Trastuzumab Deruxtecan for ERBB2-Mutant Metastatic Non-Small Cell Lung Cancer With or Without Brain Metastases: A Secondary Analysis of Randomized Clinical Trials.

IMPORTANCE: Brain metastases reduce overall survival rates of patients with non-small cell lung cancer (NSCLC); patients with epidermal growth factor receptor 2 (ERBB2 [formerly HER2])-mutant NSCLC are more likely to have baseline brain metastases. Trastuzumab deruxtecan (T-DXd) is an approved ERBB2-directed treatment for previously treated unresectable or metastatic ERBB2-mutant NSCLC. OBJECTIVE: To assess the clinical effectiveness and safety of T-DXd 5.4 mg/kg and 6.4 mg/kg doses in patients with previously treated ERBB2-mutant metastatic NSCLC with or without untreated or previously treated stable brain metastases. DESIGN, SETTING, AND PARTICIPANTS: This post hoc secondary analysis pooled patients from the DESTINY-Lung01 (data cutoff date: December 3, 2021) and DESTINY-Lung02 (data cutoff date: December 23, 2022) clinical trials by T-DXd dose (5.4 mg/kg and 6.4 mg/kg). DESTINY-Lung01 was a multicenter, open-label, 2-cohort, nonrandomized phase 2 study, while DESTINY-Lung02 was a dose-blinded, multicenter, 2-cohort, randomized phase 2 study. Participants had a previously treated ERBB2-mutant metastatic NSCLC with or without untreated or previously treated stable brain metastases at baseline. All statistical analyses were performed from April 2023 to October 2024. INTERVENTION: Patients received a T-DXd dose of either 5.4 mg/kg or 6.4 mg/kg intravenously every 3 weeks. MAIN OUTCOME AND MEASURE: Systemic and intracranial effectiveness by blinded independent central review using RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1, sites of progression, and safety. RESULTS: This analysis included 102 patients in the T-DXd 5.4-mg/kg dose group (65 females [64%]; median [range] age, 57.5 [37.0-83.0] years and 59.5 [30.0-79.0] years in patients with and without brain metastases, respectively) and 141 patients in the T-DXd 6.4-mg/kg dose group (94 females [67%]; median [range] age, 62.5 [29.0-88.0] years and 59.0 [27.0-83.0] years in patients with and without brain metastases, respectively). In each group, 31% (32 of 102) and 38% (54 of 141) of patients, respectively, had baseline brain metastases and 53% (17 of 32) and 44% (24 of 54), respectively, received prior brain metastasis treatment. In patients with and without brain metastases, systemic confirmed objective response rates (ORRs) were 47% (15 of 32; 95% CI, 29%-65%) and 50% (35 of 70; 95% CI, 38%-62%), respectively, with the T-DXd 5.4-mg/kg dose, and 50% (27 of 54; 95% CI, 36%-64%) and 59% (51 of 87; 95% CI, 48%-69%) with the T-DXd 6.4-mg/kg dose. Median progression-free survival was 7.1 (95% CI, 5.5-9.7) months in the T-DXd 5.4-mg/kg dose group and 7.1 (95% CI, 4.5-9.6) months in the T-DXd 6.4-mg/kg dose group of patients with baseline brain metastases. Among patients with measurable baseline brain metastases, intracranial confirmed ORRs were 50% (7 of 14; 95% CI, 23%-77%) with the T-DXd 5.4-mg/kg dose and 30% (9 of 30; 95% CI, 15%-49%) with the T-DXd 6.4-mg/kg dose. At both doses, the safety profile of T-DXd was generally manageable, regardless of baseline brain metastases, favoring the T-DXd 5.4 mg/kg dose. CONCLUSIONS AND RELEVANCE: In this secondary analysis, T-DXd at the approved dose of 5.4 mg/kg showed antitumor activity in patients with previously treated ERBB2-mutant metastatic NSCLC with or without brain metastases. This finding supports T-DXd 5.4 mg/kg use in this population.

Adult↗

PubMed2025

Implications of EGFR expression on EGFR signaling dependency and adaptive immunity against EGFR-mutated lung adenocarcinoma.

BACKGROUND: In EGFR-mutated lung adenocarcinoma (EGFRm LUAD), EGFR mutations do not necessarily result in increased EGFR expression (EGFR-exp), which differs among patients. However, the factors influencing EGFR-exp and the impact of EGFR-exp on tumor characteristics in patients with EGFRm LUAD remain unclear. PATIENTS AND METHODS: Whole-exome and RNA sequencing were performed for patients with early- and advanced-stage EGFRm LUAD. The patients were classified into low or high EGFR-exp groups based on the median transcripts per million. We retrospectively examined the association between EGFR-exp, genomic characteristics, downstream EGFR signaling activity, tumor microenvironment (TME) status, and clinical outcomes. RESULTS: This study included 450 and 45 patients in the early- and advanced-stage cohorts, respectively. In both cohorts, the EGFR-exp low group exhibited a lower incidence of TP53 co-mutations and EGFR amplification and a higher incidence of EGFR subclonal mutations than the EGFR-exp high group. Furthermore, downstream EGFR signaling pathways, such as the MAPK signaling, were less activated in the EGFR-exp low group. However, this group showed significantly enriched adaptive immune response pathways (Q < 0.0001) and an immune-inflamed TME. Additionally, a low EGFR-exp was a significantly favorable factor for postoperative relapse (odds ratio [OR], 0.6; P = 0.04). However, in the advanced-stage cohort, a low EGFR-exp was a significant risk factor for non-responders to osimertinib (OR, 17.5; P = 0.03). CONCLUSIONS: In EGFRm LUAD, significant associations were observed between EGFR-exp levels and both EGFR signaling pathways and adaptive immune status, which in turn influence clinical outcomes. This large-scale multi-omics analysis highlights the heterogeneity among patients with EGFRm LUAD and emphasizes the need to assess EGFR-exp levels alongside mutation status for optimal treatment strategies in EGFRm LUAD.

Humans↗

PubMed2025

Evolving treatments and prognosis in Stage IV non-small cell lung cancer: 20 years of progress of novel therapies.

BACKGROUND: Advancements in pharmacotherapy, including molecular targeted therapies and immune checkpoint inhibitors, have revolutionized the treatment for Stage IV non-small cell lung cancer (NSCLC) over the past two decades. However, differences in drug approval timelines across countries raise important questions about their impact on survival rates. This study investigates trends in overall survival (OS), patient characteristics, and the association between OS improvements and the introduction of new drugs. PATIENTS AND METHODS: This retrospective review included patients with Stage IV NSCLC treated at the National Cancer Center Hospital in Japan from 2001 to 2021. Using data from the Department of Thoracic Oncology registries, 2,555 patients were identified and categorized into four time periods: 2001-2005 (Group A), 2006-2010 (Group B), 2011-2015 (Group C), and 2016-2021 (Group D). RESULTS: While baseline characteristics remained relatively consistent, Group D had an increased proportion of elderly patients (≥ 75 years) and those with brain metastases. Additionally, the gender ratio became more balanced over time. Notably, Group D patients with EGFR mutations or ALK fusion positivity and older age demonstrated significantly longer OS. Analysis revealed steady and substantial improvements in OS across time periods (median OS: Group A, 10.68 months; Group B, 14.12 months; Group C, 16.49 months; and Group D, 25.46 months, respectively). CONCLUSIONS: This study demonstrates marked improvements in survival for patients with Stage IV NSCLC, particularly in the last six years, despite the increase in brain metastases and elderly patients. This finding suggests the crucial role of novel therapies in enhancing survival outcomes.

Humans↗