ADAPT-T-DXd: Multi-institutional real-world study of dose-adapted trastuzumab deruxtecan in HER2-positive and HER2-low metastatic breast cancer.

1106 Background: Trastuzumab deruxtecan (T-DXd) has demonstrated substantial efficacy in HER2-positive and HER2-low metastatic breast cancer (MBC) at a standard dose of 5.4 mg/kg in the DESTINY trials. But high treatment cost remains a major barrier to access in low/middle-income countries. We evaluated the clinical activity and safety of dose-adapted T-DXd in a multi-institutional real-world Indian cohort, where dose modification was primarily driven by financial constraints. Methods: This retrospective analysis included 63 patients with HER2+ or HER2-low MBC treated with dose-adapted T-DXd across multiple Indian centers. Dose-adapted T-DXd refers to the administration of T-DXd at doses lower than the standard 5.4 mg/kg dose in DESTINY trials. Dose selection was based on affordability. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints were progression-free survival (PFS), duration of response (DoR), and safety. An evaluable cohort (n = 53) was defined as patients receiving ≥2 cycles of therapy. DoR measured from treatment initiation to radiologic progression or last drug exposure. Results: The median age was 57 years; 42.9% had hormone receptor–positive disease. HER2 subtypes included HER2 3+ (63.5%), HER2 2+/ISH+ (11.1%), and HER2-low (22.2%). Patients had received a median of three prior lines of therapy. The median administered dose of trastuzumab deruxtecan was 3.7 mg/kg, corresponding to 68% of the standard dose. At a median follow-up of 8.3 months, the objective response rate (ORR) was 58.7% (95% CI, 46–71%) in the full cohort and 66.0% (95% CI, 53–79%) in the evaluable cohort. The highest ORR was observed in HER2 3+ disease (76.5%). Median progression-free survival was 5.3 months (95% CI, 4.2–6.4) in the full cohort and 7.1 months (95% CI, 5.8–8.4) in the evaluable cohort. Median duration of response was 8.3 months, with 40–45% of responses ongoing at data cutoff. Grade ≥3 neutropenia occurred in 9.0% of patients, and interstitial lung disease occurred in 7.0%; no grade 5 pulmonary events were observed. Dose reductions due to toxicity were uncommon. Conclusions: Dose-adapted trastuzumab deruxtecan demonstrated clinically meaningful activity with a manageable safety profile in patients with HER2-positive and HER2-low metastatic breast cancer in a real-world setting. The shorter median PFS likely reflects reduced dose intensity, limited follow-up and real-world heterogeneity, rather than loss of intrinsic drug activity. These findings support further prospective evaluation of dose-adapted strategies to improve treatment accessibility in resource-limited settings.