Bhavanam, Sravani

e13082 Background: Human epidermal growth factor receptor 2 (HER2)–low breast cancer, defined as HER2 immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization–negative, represents a newly targetable subtype comprising nearly half of all breast cancers. Brain metastases are a common and morbid complication of metastatic breast cancer, yet patients with active central nervous system (CNS) disease are frequently excluded from clinical trials. Trastuzumab deruxtecan (T-DXd), an antibody–drug conjugate with a cleavable linker and potent topoisomerase I inhibitor payload, has demonstrated substantial intracranial activity in HER2-positive disease. However, the intracranial efficacy of T-DXd in patients with HER2-low breast cancer remains incompletely characterized. Methods: A systematic literature search was conducted across PubMed/MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and Web of Science from database inception through January 1, 2025. A total of 2,275 records were identified and screened. Eligible studies included randomized controlled trials and prospective or retrospective clinical studies evaluating trastuzumab deruxtecan in patients with HER2-low metastatic breast cancer and measurable brain metastases. Studies were required to report intracranial objective response rate (IC-ORR), defined as complete or partial intracranial response among CNS-evaluable patients, assessed by study-defined criteria (RECIST 1.1 or RANO-BM). Results: Five studies comprising 62 patients with HER2-low metastatic breast cancer and brain metastases were included. Using a random-effects proportional meta-analysis with Freeman–Tukey double arcsine transformation, the pooled intracranial objective response rate (IC-ORR) was 46% (95% CI, 27–65%). Between-study heterogeneity was moderate (I² = 47.7%, p = 0.11), with consistent directionality of intracranial activity observed across included cohorts. Conclusions: Across five studies, T-DXd demonstrated clinically meaningful intracranial activity in HER2-low metastatic breast cancer with brain metastases, yielding a pooled IC-ORR of 46%. This provides one of the first quantitative benchmarks of CNS response in HER2-low disease, where evidence has been limited to small, heterogeneous cohorts. These findings support dedicated prospective trials in HER2-low patients with active CNS disease and standardized intracranial endpoints to refine patient selection and expected benefit. Summary of outcomes. Study Year CNS-Evaluable Patients (N) Intracranial Responders (CR+PR) IC-ORR (%) Zhou et al. 2025 15 7 46.7 (21.0–73.0) Batista et al. 2024 6 3 50.0 (12.0–88.0) Lazaratos et al. 2024 6 4 66.7 (22.0–96.0) Duan et al. 2025 9 6 66.7 (30.0–93.0) Burnside et al. 2024 26 6 23.1 (9.0–44.0) Pooled estimate (random effects) — 62 26 46.0 (27.0–65.0)*

8075 Background: The role of definitive local thoracic therapy in metastatic non–small cell lung cancer (NSCLC) remains controversial. While stereotactic body radiation therapy (SBRT) is increasingly utilized, comparative survival outcomes with surgical resection in real-world populations remain limited. We evaluated survival and pulmonary outcomes associated with surgery versus SBRT in patients with stage IV NSCLC. Methods: We conducted a retrospective cohort study using the TriNetX Research Network including adults (≥18 years) with stage IV NSCLC treated between January 2013 and December 2023 who underwent definitive local thoracic therapy with either surgical resection or SBRT. Patients with small cell lung cancer, prior lung cancer diagnoses, prior thoracic radiation, or incomplete survival data were excluded. Propensity score matching (1:1) was performed to balance demographics, comorbidities, smoking history, and exposure to systemic therapy including chemotherapy and immunotherapy within 6 months of index treatment. Primary outcomes included landmark 1-year all-cause mortality and overall survival. Secondary outcomes included pneumonia and respiratory failure. Kaplan–Meier analysis and Cox proportional hazards regression were performed. Results: After matching, 1,934 patients were included (967 per cohort). At 1 year, surgical resection was associated with significantly lower mortality compared with SBRT (17.5% vs 31.4%; RR 0.56, 95% CI 0.47–0.66; p < 0.001), corresponding to an absolute risk reduction of 13.9% and an estimated number needed to treat of approximately 7. Kaplan–Meier analysis demonstrated superior survival in the surgical cohort (log-rank p < 0.001). Surgical resection remained associated with significantly improved long-term survival, with a 64% lower hazard of death (HR 0.36, 95% CI 0.30–0.44; p < 0.001) and prolonged median survival (3,942 vs 1,182 days). Pulmonary outcomes favored surgery. Pneumonia incidence was significantly lower in the surgical cohort at both 1 year (12.9% vs 29.3%; RR 0.44; p < 0.001) and 3 years (5.9% vs 14.2%; RR 0.42; p < 0.001). Rates of respiratory failure did not differ significantly between treatment groups. Conclusions: In this large real-world propensity-matched study, surgical resection was associated with significantly improved survival compared with SBRT in carefully selected patients with stage IV NSCLC. Surgery was additionally associated with lower long-term pulmonary infectious complications without increased respiratory failure risk. These findings suggest a potential role for aggressive local therapy in selected metastatic patients and support prospective trials to refine patient selection strategies.