A DESTINY-Breast09 analysis of treatment duration and clinical outcomes by best response to trastuzumab deruxtecan (T-DXd) + pertuzumab (P).

1021 Background: In DESTINY-Breast09 (NCT04784715), first-line (1L) T-DXd + P demonstrated durable responses, a near doubling of complete response (CR) rates, and significantly improved progression-free survival (PFS) vs taxane + trastuzumab + pertuzumab for patients (pts) with HER2+ advanced/metastatic breast cancer (a/mBC). Pts had a median treatment duration of 21.7 months (mo) with T-DXd + P. Safety was consistent with the known profiles of each treatment. These results led to US approval in Dec 2025. Here, we report an exploratory analysis of efficacy and safety outcomes by pts’ best confirmed response to T-DXd + P. Methods: Pts had no prior systemic therapy for a/mBC (1 line of endocrine therapy was allowed). Endpoints included PFS and duration of response (DOR), both by blinded independent central review per RECIST 1.1, and safety. Best response subgroups included CR, partial response (PR), and stable disease / progressive disease (SD/PD). Results: Of 377 evaluable pts assigned to T-DXd + P, 58 (15.4%) had a CR, 268 (71.1%) had a PR, and 51 (13.5%) had SD/PD at interim data cutoff (Feb 26, 2025). Median time to PR was 1.5 mo (95% CI 1.4, 1.5), and median time to CR was 8.4 mo (95% CI 5.6, 11.1). Additionally, median time to achieve maximum tumor reduction (nadir) in the overall population (n=383) was ~11 mo (~16 cycles). Pts with a CR or PR had favorable PFS (see Table) and a longer median treatment duration (CR, 28.0 mo [range 4.8–44.5]; PR, 22.2 mo [range 2.8–42.7]) vs those with SD/PD (4.4 mo [range 0.3–37.2]). Exposure-adjusted incidence rates (EAIRs) of drug-related Grade ≥3 adverse events (AEs) were 0.30, 0.30, and 0.57 per pt-year, respectively. EAIRs of any AEs leading to discontinuation were 0.14, 0.11, and 0.16 per pt-year. Rates of adjudicated drug-related interstitial lung disease (ILD)/pneumonitis by CR, PR, or SD/PD were similar: 12.1% (n=7, all Grade 1/2), 11.9% (n=32, all Grade 1/2), and 12.2% (n=6, two Grade 5), respectively. Pts with a CR had a longer median time to first onset of ILD/pneumonitis (484 days [d] [range 84–967]) than those with a PR (227 d [17–1028]) or SD/PD (99 d [37–211]). Conclusions: In this exploratory analysis of DESTINY-Breast09, achieving a durable CR or PR was associated with favorable PFS outcomes and prolonged treatment duration. Complete response or maximum tumor reduction (nadir) was achieved with sustained T-DXd + P treatment. Safety findings were consistent with previously reported profiles of T-DXd and P. Clinical trial information: NCT04784715 . CR(n=58) PR(n=268) SD/PD(n=51) Median DOR, mo (95% CI)* NC 39.2 (34.8, NC) – Median PFS, mo (95% CI)* NC 40.7 (36.0, NC) 13.0 (4.0, 25.7) 6-mo PFS rate, % (95% CI) 100 (100, 100) 97.7 (95.0, 99.0) 57.2 (41.2, 70.4) 12-mo PFS rate, % (95% CI) 94.8 (84.8, 98.3) 89.8 (85.4, 92.9) 51.9 (35.9, 65.7) 24-mo PFS rate, % (95% CI) 85.1 (72.2, 92.3) 72.9 (66.6, 78.2) 35.5 (21.1, 50.2) *Calculated by Kaplan-Meier technique. NC, not calculable.