Trastuzumab deruxtecan (T-DXd) + durvalumab (D) in patients (pts) with previously untreated HER2+ unresectable/metastatic breast cancer (mBC): Final analysis from DESTINY-Breast07.

1012 Background: T-DXd is approved for adult pts with HER2+ mBC who received a prior anti-HER2–based regimen, or as 1L therapy when given in combination with pertuzumab (P). DESTINY-Breast07 (NCT04538742) is a Phase 1b/2, open-label, platform study exploring the safety, tolerability, and antitumor activity of T-DXd ± other anticancer agents in HER2+ mBC. 1L T-DXd ± P recently showed encouraging clinical activity and safety profiles consistent with previous reports. D, an anti-PD-L1 antibody, has shown efficacy in combination with T-DXd in HER2-low, hormone receptor (HR)–negative mBC. As part of the DESTINY-Breast07 final analysis, here we report the dose-expansion phase for T-DXd + D as a 1L treatment in HER2+ mBC. Methods: Pts had locally assessed HER2+ (IHC 3+ or IHC 2+/ISH+) mBC. A disease-free interval of ≥12 months (mo) from (neo)adjuvant therapy was required; no prior therapy for mBC was allowed. Pts were stratified by HR (positive vs negative), disease (recurrent vs de novo), and PD-L1 status (positive vs negative; positive defined as ≥1% IHC). Pts received T-DXd 5.4 mg/kg IV, in combination with D 1120 mg IV, every 3 weeks. Primary endpoints were safety and tolerability; secondary endpoints included confirmed ORR (cORR), duration of response (DOR) and progression-free survival (PFS) per RECIST 1.1 by investigator, time to progression on subsequent therapy or death (PFS2) by investigator, and overall survival (OS). Results: At data cutoff (DCO) (January 31, 2025), 64 pts were randomized to the T-DXd + D module, and 63 received treatment. Median follow up was 30.1 mo; median total treatment duration was 26.7 mo for T-DXd and 24.6 mo for D. Efficacy results are given in the Table. The most common adverse events (AEs) were nausea (79.4%), vomiting (46.0%), neutropenia (46.0% by grouped term [GT]), anemia (44.4% by GT), and fatigue (38.1%). Grade ≥3 AEs occurred in 58.7% (n=37/63) and serious AEs in 30.2% (n=19/63) of pts. There were two deaths due to AEs (3.2%): one pt with neutropenia and septic shock and one pt with sepsis. Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis events occurred in 11 (17.5%; Grade 1, n=1; Grade 2, n=8; Grade 3, n=2) pts. Additional data by subgroups (stratification factors and biomarkers) will be presented. Conclusions: Encouraging clinical activity was seen for T-DXd + D as a 1L treatment for HER2+ mBC. Safety profiles were consistent with the known profiles for each therapy, with no fatal ILD events. These promising results provide a rationale for further investigation of this treatment combination. Clinical trial information: NCT04538742 . T-DXd + D (n=64) cORR (80% CI), % 82.8 (75.2, 88.8) mDOR* (Q1–Q3), mo 36.1 (23.3, NE) mPFS* (80% CI), mo 37.7 (35.1, NE) PFS rate at 24 mo (80% CI), % 75.5 (67.2, 82.0) mOS (80% CI), mo NE (NE, NE) mPFS2 (80% CI), mo NE (NE, NE) *Most pts were censored at DCO; m, median; NE, not evaluable; Q, quartile.