HERTHENA-Breast03: A phase 2, randomized, open-label study evaluating neoadjuvant patritumab deruxtecan + pembrolizumab before or after pembrolizumab + chemotherapy for early-stage TNBC or HR-low+/HER2− breast cancer.

Background:

The standard of care for patients with high-risk, early-stage TNBC is neoadjuvant pembrolizumab (pembro) + chemotherapy followed by adjuvant pembro. Patients with HR-low+/HER2− breast cancer may also be treated per recommendations for TNBC. There is a need for improved neoadjuvant therapy to increase the rate of pCR, as patients who do not achieve pCR have a high risk of recurrence, and to reduce risk of long-term toxicities associated with cyclophosphamide and anthracyclines. HER3 is frequently expressed in breast cancer and implicated in drug resistance. Patritumab deruxtecan (HER3-DXd) is an antibody-drug conjugate comprising a fully human anti-HER3 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor (DXd) via a stable tetrapeptide-based linker that is selectively cleaved within tumor cells. This phase 2 study (NCT06797635) will evaluate neoadjuvant HER3-DXd + pembro before or after carboplatin + paclitaxel + pembro for early-stage TNBC or HR-low+/HER2− breast cancer.

Methods:

Eligible participants (pts) are adults (≥18 y) with untreated, locally advanced nonmetastatic (AJCC stage cT1c, N1–N2 or cT2–cT4, N0–N2) TNBC or HR-low+/HER2− breast cancer. Pts (N ≥10 and ≤30) in part 1 of the study (safety lead-in) will receive neoadjuvant HER3-DXd + pembro followed by carboplatin + paclitaxel + pembro (Table) then surgery. DLT evaluation and dose finding for HER3-DXd (three dose levels of 5.6 mg/kg Q3W, 4.8 mg/kg Q3W and 3.2 mg/kg Q3W) during cycle 1 of neoadjuvant HER3-DXd + pembro will be performed in part 1 to determine an acceptable dose of HER3-DXd for part 2. Pts (N ~342) in part 2 will be randomly assigned 1:1:1 to arm A, B or C (Table) for neoadjuvant treatment. Randomization will be stratified by cancer type (TNBC vs HR-low+/HER2−) and, in the TNBC subgroup, PD-L1 status (combined positive score ≥10 vs <10), overall stage (II vs III) and HER3 expression (low vs high). After neoadjuvant treatment, pts will undergo surgery (with postoperative radiotherapy if clinically indicated) and receive adjuvant pembro 400 mg Q6W for 5 cycles. Pts with residual disease may receive additional adjuvant treatment of physician’s choice. Primary endpoints are safety (part 1 and 2) and pCR (ypT0/Tis ypN0) (part 2). Enrollment is ongoing.

 

Neoadjuvant cycles 1-4

Neoadjuvant cycles 5-8

Part 1
Arm A

HER3-DXd 5.6 or 4.8 or 3.2 mg/kg Q3W + pembroa

Carboplatinb + paclitaxelc + pembroa

Part 2
Arm A

HER3-DXd (selected dose from Part 1) + pembroa

Carboplatinb+ paclitaxelc + pembroa

Part 2 Arm B

Carboplatinb + paclitaxelc + pembroa

HER3-DXd (selected dose from Part 1) + pembroa

Part 2 Arm C

Carboplatinb + paclitaxelc + pembroa

Doxorubicind OR epirubicine + cyclophosphamidef + pembroa
a200 mg Q3W; bAUC 1.5 mg/mL/min QW; c80 mg/m2 QW; d60 mg/m2 Q3W; e90 mg/m2 Q3W; f600 mg/m2 Q3W.

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Author Details

Joyce O'Shaughnessy

Joyce O'Shaughnessy

Baylor University Medical Center, Texas Oncology, Dallas, TX and Sarah Cannon Research Institute, Dallas, TX

Abstract Details

Meeting

2025 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Breast Cancer—Local/Regional/Adjuvant

Track

Breast Cancer

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Abstract Disclosure