Abstract Background: T-DXd is approved for the treatment of adult pts with HER2+ mBC who have received a prior anti-HER2-based regimen. Recent results from the planned interim analysis of the Phase 3 DESTINY-Breast09 study demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) by blinded independent central review for T-DXd + pertuzumab versus standard of care (taxane + trastuzumab + pertuzumab) in first-line (1L) HER2+ mBC (median 40.7 vs 26.9 months; hazard ratio 0.56 95% CI 0.44, 0.71). The T-DXd monotherapy module remains blinded until final PFS analysis. DESTINY-Breast07 (NCT04538742; initiated prior to DESTINY-Breast09) was a Phase 1b/2 multicenter, open-label, modular study exploring the safety, tolerability, and antitumor activity of T-DXd ± other anticancer agents in HER2+ mBC. Results presented are from the final analysis of the dose-expansion phase assessing T-DXd ± pertuzumab as 1L treatment in HER2+ mBC. Methods: Eligible pts had locally assessed HER2+ (immunohistochemistry IHC 3+ or IHC 2+ / in situ hybridization-positive) mBC. No prior therapy for mBC was allowed and a disease-free interval of ≥12 months from (neo)adjuvant therapy was required. Pts were stratified by hormone receptor status (positive estrogen or progesterone receptor ≥1% vs negative), disease status (recurrent vs de novo), and PD-L1 expression (positive IHC ≥1% vs negative). Pts received T-DXd 5.4 mg/kg intravenously (IV) every 3 weeks (Q3W) as monotherapy or in combination with pertuzumab 420 mg IV Q3W, with an 840-mg loading dose. Primary endpoints were safety and tolerability; secondary endpoints included objective response rate (ORR), duration of response, and PFS, per RECIST 1.1 by investigator, as well as time to progression on subsequent therapy (PFS2) by investigator, and overall survival (OS). Results: At final data cutoff (January 31, 2025), 75 pts in the T-DXd module and 50 pts in the T-DXd + pertuzumab module had received study treatment; demographics and disease characteristics were well balanced. Median follow up was 37.1 months with T-DXd and 38.6 months with T-DXd + pertuzumab. Median total treatment duration was 26.8 months in the T-DXd module, and 27.6 months for T-DXd and 26.0 months for pertuzumab in the T-DXd + pertuzumab module. Confirmed ORR (80% CI) was 78.7% (71.4, 84.7) with T-DXd and 84.0% (75.3, 90.5) with T-DXd + pertuzumab. At 36 months, 65.5% and 69.4% of pts remained in response in the T-DXd and T-DXd + pertuzumab modules, respectively. At study completion, median PFS and median OS were not reached for either module. The 80% CI lower limit for median PFS was 40.2 months for T-DXd + pertuzumab; all other CI limits were not evaluable. PFS rate (80% CI) at 24 months was 71.4% (63.5, 77.8) with T-DXd and 67.8% (58.2, 75.7) with T-DXd + pertuzumab. Grade ≥3 adverse events (AEs) occurred in 57.3% (n=43/75) and 62.0% (n=31/50), and serious AEs in 21.3% (n=16/75) and 28.0% (n=14/50), of pts in the T-DXd and T-DXd + pertuzumab modules, respectively. Adjudicated drug-related interstitial lung disease / pneumonitis events occurred in 11 (14.7%; Grade 1, n=3; Grade 2, n=8) pts who received T-DXd and 7 (14.0%; Grade 2, n=6; Grade 3, n=1) who received T-DXd + pertuzumab. Additional data by subgroup, including biomarker analyses, will be presented. Conclusion: In this Phase 1b/2 DESTINY-Breast07 study, safety profiles for T-DXd and pertuzumab were generally consistent with the known profiles of each agent. Encouraging clinical activity was demonstrated in pts who received either T-DXd monotherapy or T-DXd + pertuzumab as a 1L treatment for HER2+ mBC; results from the T-DXd + pertuzumab module are consistent with the interim findings from the Phase 3 DESTINY-Breast09 study. Citation Format: F. André, E. Hamilton, S. Loi, C. Anders, P. Schmid, E. Artamonova, R. Villanueva-Vázquez, J. Pedrini, D. Doval, S. C. Chen, S. Boston, A. Konpa, M. Markowska, G. Fabbri, K. Jhaveri. Trastuzumab deruxtecan (T-DXd) monotherapy and T-DXd + pertuzumab in patients (pts) with previously untreated HER2+ unresectable/metastatic breast cancer (mBC): final results from DESTINY-Breast07 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 PS5-01-14.
Andre et al. (2026) studied this question.