A Multicenter Phase III Clinical Study and Translational Research on Adaptive Neoadjuvant Therapy of De-escalation and Escalation for HER2-Positive Breast Cancer Based on Multi-Omics Response Evaluation Model

Summary

This study is a phase III clinical trial to explore the efficacy and safety of HER2-positive breast cancer neoadjuvant adaptive therapy compared with standard therapy based on multi-omics data, and to explore a new prediction model for pCR. The trial protocol in this study design has sufficient preliminary basis.

HER2-targeted therapies can significantly improve pCR rates and enhance clinical outcomes in HER2-positive breast cancer patients undergoing neoadjuvant treatment. However, standard neoadjuvant regimens typically involve multiple chemotherapeutic agents, often accompanied by severe adverse reactions. To optimize neoadjuvant strategies, minimize chemotherapy-related toxicities, and maximize the therapeutic advantages of anti-HER2 therapies, research on downstaging chemotherapy regimens has been intensively pursued. The first phase III HELEN-006 study evaluating the efficacy and safety of albumin-bound paclitaxel combined with neoadjuvant chemotherapy (nab-PHP) in HER2-positive breast cancer, led by Professor Liu Zhenzhen's team at Henan Cancer Hospital, was published online in The Lancet Oncology. This landmark study demonstrated that the nab-PHP regimen achieved higher pCR rates and better tolerability compared to the standard TCbHP regimen, charting a new course for downstaging chemotherapy approaches.

In recent years, new anti-HER2 drugs such as pyrotinib, T-DM1, and T-DXd have been continuously developed and launched, achieving good results in the treatment of HER2-positive breast cancer. These advances have changed clinical practice and are recommended in domestic and international guidelines for second-line or later-line treatment of advanced HER2-positive breast cancer. Their efficacy in neoadjuvant therapy is still being explored. The PHEDRA study is a multicenter, double-blind, randomized, controlled phase 3 trial that included a total of 355 patients: 178 in the group receiving docetaxel and trastuzumab combined with pyrotinib (TH+Py), and 177 in the group receiving docetaxel and trastuzumab combined with placebo. The study results show that the pCR rate in the TH+Py group was significantly higher than in the TH+placebo group (41.0% vs. 22.0%, P\<0.0001). The DESTINY-Breast 11 study is an open-label phase III clinical trial designed to investigate the efficacy and safety of neoadjuvant T-DXd monotherapy or T-DXd followed by sequential THP compared with dose-dense doxorubicin and cyclophosphamide followed by sequential THP (ddAC-THP) in patients with high-risk, early-stage HER2+ breast cancer. Patients with locally advanced HER2+ breast cancer, either HR+ or HR-, were randomized in a 1:1:1 ratio to Group A (T-DXd monotherapy), Group B (T-DXd followed by sequential THP), or Group C (ddAC-THP). The primary endpoint is pathological complete response (pCR). Currently, the DESTINY-Breast 011 study is still ongoing. At the 2024 SABCS conference, results were reported from a prospective, randomized, open-label phase II trial of SHR-A1811, a HER2-targeted antibody-drug conjugate, in the neoadjuvant treatment of HER2-positive early breast cancer. The main goal of this study is to assess the efficacy and safety of SHR-A1811 in the neoadjuvant treatment of HER2-positive early breast cancer. Open-label, phase II trial; the primary objective of this study is to explore the efficacy and safety of SHR-A1811 as neoadjuvant therapy in HER2-positive early-stage breast cancer. The pCR rate of SHR-A1811 monotherapy was 63.2% in the overall population, 50.0% in HR+ breast cancer, and 74.5% in HR- breast cancer. Everolimus is an mTOR inhibitor that can suppress the "phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR)" signaling pathway in tumor cells, thereby exerting an anti-cancer effect. In the BOLERO-3 clinical study, for patients with advanced disease who had failed anti-HER2 therapy, adding everolimus to vinorelbine plus trastuzumab prolonged the duration of disease control by about 1.2 months.

Our research group has previously established a nationwide multicenter multi-omics database that includes clinical information, pathological characteristics, and ctDNA data from 958 patients with advanced breast cancer. This has clarified the gene mutation profiles and prognostic features of advanced breast cancers with different molecular subtypes. Subsequently, we further developed a dynamic ctDNA monitoring sample library with 430 cases, tracking gene changes at multiple time points during the treatment of advanced breast cancer patients. By integrating clinical information, pathological features, and other multi-omics data, we comprehensively explored the process of tumor clonal evolution during treatment in patients with advanced breast cancer, providing a solid foundation for the development of efficacy prediction models.

This study is a nationwide, multicenter, prospective, randomized, controlled phase III clinical trial. It aims to compare the efficacy and safety of mu

Conditions

• Patients With HER2-positive Breast Cancer (BC) Suitable for Neoadjuvant Therapy

Interventions

DRUG

The control group

received the TCbHP regimen (docetaxel, carboplatin, trastuzumab, and pertuzumab)

DRUG

Adaptive therapy of de-escalation and escalation based on imaging and molecular analysis for predicting response

At baseline, patients receive the Nab-P+HP regimen (albumin-bound paclitaxel plus trastuzumab and pertuzumab).After one cycle of treatment (C1), ctDNA testing is performed. After two cycles of treatment , radiological evaluation is conducted. If the patient is ctDNA (-) and achieves PR, they continue with the Nab-P+HP regimen . If the patient is ctDNA (-) and non-PR, they receive the TCbHP regimen for two cycles. If the patient is ctDNA (+) and has no mutations in the PI3K/AKT/mTOR (PAM)pathway, they receive the PyroHT regimen (pyrotinib plus trastuzumab and docetaxel) for two cycles. If the patient is ctDNA (+) at baseline or after one treatment cycle and has PAM pathway mutations, they receive the EveroHT regimen (everolimus plus trastuzumab and docetaxel) for two cycles. If the patient achieves PR after C4, they continue with the regimen for another two cycles. If PR is not achieved，the patient switches to ADC or AC+H (anthracycline plus cyclophosphamide plus trastuzumab) regimen

Sponsors & Collaborators

• Cancer Institute and Hospital, Chinese Academy of Medical Sciences

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

70 Years

Sex

FEMALE

Healthy Volunteers

No

Timeline & Regulatory

Start

2025-11-16

Primary Completion

2027-12-31

Completion

2027-12-31