Neoadjuvant trastuzumab deruxtecan alone or followed by paclitaxel, trastuzumab, and pertuzumab for high-risk HER2-positive early breast cancer (DESTINY-Breast11): a randomised, open-label, multicentre, phase III trial.

DESTINY-Breast11 assessed efficacy and safety of neoadjuvant trastuzumab deruxtecan (T-DXd) alone or followed by paclitaxel + trastuzumab + pertuzumab (THP) versus dose-dense doxorubicin + cyclophosphamide (ddAC) followed by THP for high-risk (≥cT3cN0 or cT0-4cN1-3) HER2-positive disease.

DESTINY-Breast11评估了新辅助曲妥珠单抗德曲妥珠单抗（T-DXd）单独使用或随后使用紫杉醇加曲妥珠单抗加帕妥珠单抗（THP）与密集剂量多柔比星加环磷酰胺（ddAC）随后使用THP治疗高风险（≥cT3cN0或cT0-4cN1-3）HER2阳性疾病的疗效和安全性。

patients_and_methods

This open-label, phase III trial (147 sites, 18 countries) randomised adults 1 : 1 : 1 to T-DXd (×8 cycles), T-DXd-THP (4 + 4 cycles), or ddAC-THP (4 + 4 cycles).

这项开放标签的III期临床试验（147个研究地点，涉及18个国家）按照1:1:1的比例随机将成人患者分配至T-DXd组（×8个周期）、T-DXd-THP组（4+4个周期）或ddAC-THP组（4+4个周期）。

T-DXd-alone arm enrolment closed early following the Independent Data Monitoring Committee recommendation.

在独立数据监测委员会的建议后，T-DXd单药治疗组的招募提前结束。

The primary endpoint was pathological complete response (pCR; ypT0/is ypN0; intent-to-treat population).

主要终点是病理完全缓解（pCR; ypT0/is ypN0; 意向治疗人群）

Secondary endpoints included event-free survival (EFS; intent-to-treat population) and safety (safety analysis set).

次要终点包括无事件生存（EFS; 意向治疗人群）和安全性（安全性分析集）

Results

Between 25 October 2021 and 12 March 2025, 286 (T-DXd), 321 (T-DXd-THP), and 320 (ddAC-THP) female patients were randomised. pCR rates were 43.0% (T-DXd, n = 123), 67.3% (T-DXd-THP, n = 216), and 56.3% (ddAC-THP, n = 180).

在2021年10月25日至2025年3月12日期间，共有286名（T-DXd组）、321名（T-DXd-THP组）和320名（ddAC-THP组）女性患者被随机分配。pCR（病理完全缓解）率分别为43.0%（T-DXd组，n=123）、67.3%（T-DXd-THP组，n=216）和56.3%（ddAC-THP组，n=180）。

T-DXd-THP versus ddAC-THP absolute pCR rate difference was 11.2% [95% confidence interval(CI), 4.0% to 18.3%, P = 0.003], with benefit in hormone receptor (HR)-positive [61.4% (n/N = 145/236) versus 52.3% (n/N = 123/235); difference in pCR (ΔpCR) 9.1% (95% CI 0.2% to 17.9%)] and HR-negative [83.1% (n/N = 69/83) versus 67.1% (n/N = 57/85); ΔpCR 16.1% (95% CI 3.0% to 28.8%)] subgroups.

T-DXd-THP与ddAC-THP组的绝对pCR率差异为11.2% [95%置信区间（CI），4.0%至18.3%，P = 0.003]，在激素受体（HR）阳性亚组中，T-DXd-THP组的pCR率为61.4%（n/N = 145/236），而ddAC-THP组为52.3%（n/N = 123/235）；pCR差异（ΔpCR）为9.1%（95% CI 0.2%至17.9%）。在HR阴性亚组中，T-DXd-THP组的pCR率为83.1%（n/N = 69/83），而ddAC-THP组为67.1%（n/N = 57/85）；pCR差异（ΔpCR）为16.1%（95% CI 3.0%至28.8%）。

Median EFS (T-DXd-THP versus ddAC-THP, maturity 4.5%) hazard ratiowas 0.56 (95% CI 0.26 to 1.17).

中位无进展生存期（T-DXd-THP与ddAC-THP相比，成熟度为4.5%）的风险比为0.56（95%置信区间0.26至1.17）。

Grade ≥3 adverse events (AE; T-DXd, 22.6% (n = 64); T-DXd-THP, 37.5% (n = 120); ddAC-THP, 55.8% (n = 174)], serious AE [T-DXd, 10.2% (n = 29); T-DXd-THP, 10.6% (n = 34); ddAC-THP, 20.2% (n = 63)], and all-grade left-ventricular dysfunction [T-DXd, 0.7% (n = 2); T-DXd-THP, 1.3% (n = 4); ddAC-THP, 6.1% (n = 19)] rates were lower for T-DXd and T-DXd-THP than ddAC-THP.

3级或更高级别的不良事件（AE；T-DXd，22.6%（n=64）；T-DXd-THP，37.5%（n=120）；ddAC-THP，55.8%（n=174）），严重不良事件（T-DXd，10.2%（n=29）；T-DXd-THP，10.6%（n=34）；ddAC-THP，20.2%（n=63）），以及所有级别的左心室功能障碍（T-DXd，0.7%（n=2）；T-DXd-THP，1.3%（n=4）；ddAC-THP，6.1%（n=19））的发生率对于T-DXd和T-DXd-THP均低于ddAC-THP。

All-grade adjudicated drug-related interstitial lung disease/pneumonitis rates were low and similar across arms [T-DXd, 4.9% (n = 14); T-DXd-THP, 4.4% (n = 14); ddAC-THP, 5.1% (n = 16)].

所有级别的药物相关间质性肺病/肺炎的发生率较低且各组相似 [T-DXd组，4.9% (n = 14)；T-DXd-THP组，4.4% (n = 14)；ddAC-THP组，5.1% (n = 16)]。

Three treatment-related deaths occurred [T-DXd-THP, 0.3% (n = 1); ddAC-THP, 0.6% (n = 2)].

发生了三例与治疗相关的死亡事件 [T-DXd-THP组，0.3% (n = 1)；ddAC-THP组，0.6% (n = 2)]。

Conclusions

Neoadjuvant T-DXd-THP demonstrated statistically significant and clinically meaningful pCR benefit and improved safety versus ddAC-THP.

新辅助T-DXd-THP与ddAC-THP相比，显示出统计学上显著且具有临床意义的病理完全缓解（pCR）优势，并改善了安全性。