NeoAdjuvant Therapy With Trastuzumab-deruxtecan Versus Chemotherapy+Trastuzumab+Pertuzumab in HER2+ Early Breast Cancer

NCT ID: NCT05704829

Last Updated: 2025-11-19

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 402 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-02-05
• Study Completion Date: 2029-06-30

Brief Summary

ADAPT-HER2-IV will address question of optimal neoadjuvant therapy in patients with less advanced -HER2+ EBC.

ADAPT-HER2-IV is planned as a superiority trial to demonstrate higher pCR rates in both clinically relevant subgroups of low-intermediate risk HER2+ EBC. Moreover, it aims to demonstrate excellent survival in patients treated by T-DXd (with the use of standard chemotherapy at investigator´s decision restricted only to patients with substantial residual tumour burden after T-DXd-treatment).

Detailed Description

As the ADAPT-trials have clearly shown, pCR after 12 weeks of therapy, independent of the specific de-escalated neoadjuvant regimen and independent of further use of systemic chemotherapy, is an independent predictor of excellent prognosis4,19, also in patients treated by an antibody-drug conjugate alone (T-DM1), or in those receiving pertuzumab+trastuzumab+/-weekly paclitaxel.

In contrast to the adjuvant setting, none of the neoadjuvant trials so far has focused on HER2+ patients with a low-intermediate risk profile (e.g., node-negative patients with cT1-2 tumours). The ADAPT-HER2-IV trial aims to close this evidence gap.

Since there is some uncertainty about the optimal treatment duration in intermediate- to high-risk HER2+ EBC (e.g., tumour size >3 cm), we recommend using a longer 18-week taxane-based treatment (+/- carboplatin, at investigator´s decision) due to a large body of evidence for taxane + carboplatin combinations in patients in locally advanced stages.

Antibody-drug conjugates appear to be ideal candidate drugs for a "de-escalated" treatment due to their favourable safety (reduced alopecia, polyneuropathy rates, etc.) and a high efficacy profile (e.g., comparable pCR rates after 18 weeks of T-DM1 and taxane+pertuzumab+trastuzumab in the PREDIX HER2 trial20). Similarly to the classical chemotherapy landscape, optimal duration of antibody-drug conjugate-based neoadjuvant therapy remains unclear. pCR rates of around 40% to 60% were observed after 12 and 18 weeks of T-DM1 treatment (+/-pertuzumab) in the ADAPT TP, KRISTINE and PREDIX HER2 trials in HR+/HER2+ disease21,22. Moreover, long-term survival seem to be comparable between T-DM1+pertuzumab and older chemotherapy-containing regimens (docetaxel+carboplatin+trastuzumab+pertuzumab) despite of higher local progression rates and lower pCR in one study22.

Trastuzumab-deruxtecan (T-DXd) has shown promising activity in a small cohort of metastatic patients, including both HER2+ and HER2-low BC, pre-treated with several lines of therapy. Doi et al. reported overall response rates (ORR) of 58% and a disease control rate of 100% with overall survival at 12 months at in HER2+ disease pre-treated by T-DM1+/-pertuzumab in a late line setting23. T-DXd-therapy was associated with a manageable safety profile. Recently, clearly higher efficacy of T-DXd vs. T-DM1 was shown in second line metastatic breast cancer (MBC) in the DESTINY-03 trial24. Median progression free survival was not reached in T-DM1-arm vs. 6.8 months in the T-DXd-arm. This effect was independent of hormone receptor status, prior pertuzumab treatment, visceral metastases, number of prior therapy lines and presence of brain metastases. ORR was doubled (34.2 vs. 79.7%), favouring the T-DXd arm.

Conditions

HER2-positive Early Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

T-DXd: HER2+ and low-intermediate risk for recurrence

12 weeks T-DXd i.v. in neoadjuvant treatment; pCR dependent T-DXd for 1 year in total in postneoadjuvant treatment

Group Type: EXPERIMENTAL

Trastuzumab deruxtecan

Intervention Type: DRUG

T-DXd i.v.

T-DXd: HER2+ and intermediate-high risk for recurrence

18 weeks T-DXd i.v. in neoadjuvant treatment; pCR dependent T-DXd for 1 year in total in postneoadjuvant treatment

Group Type: EXPERIMENTAL

Trastuzumab deruxtecan

Intervention Type: DRUG

T-DXd i.v.

Control: HER2+ and low-intermediate risk for recurrence

Standard-of-Care-Treatment: 12 weeks PAC+T+P (standard-of-care) in neoadjuvant treatment; pCR dependent SOC chemotherapy +T+/-P or SOC T+/-P for 1 year in total in postneoadjuvant treatment

Group Type: OTHER

Standard-of-Care

Intervention Type: DRUG

Chemotherapy+T+P

Control: HER2+ and intermediate-high risk for recurrence

Standard-of-Care-Treatment: 18 weeks PAC/DOC+Carbo+T+P (standard-of-care) in neoadjuvant treatment; pCR dependent SOC chemotherapy +T+/-P or SOC T+/-P for 1 year in total in postneoadjuvant treatment

Group Type: OTHER

Standard-of-Care

Intervention Type: DRUG

Chemotherapy+T+P

Interventions

Trastuzumab deruxtecan

T-DXd i.v.

Intervention Type: DRUG

Standard-of-Care

Chemotherapy+T+P

Intervention Type: DRUG

Other Intervention Names

ENHERTU; Chemotherapy+T+P

Eligibility Criteria

Inclusion Criteria

Patients eligible for inclusion in this study must meet all the following criteria:

1. Female patients with invasive, untreated HER2+ breast cancer (as assessed by local pathology) maximum 6 weeks before registration (standard-of-care diagnostic biopsy according to current AGO guidelines)

2. Age ≥18 years 3a. Cohort 1: low- to intermediate-risk for recurrence as per investigator´s decision (recommendation: cT1c - cT2 (1 - ≤3cm), cN0; cT1a/b excluded), OR 3b. Cohort 2: intermediate- to high-risk for recurrence as per investigator´s decision (recommendation: cT2 (>3 - ≤5cm), cN0) 3c. Elderly patients (≥ 65 years) may be assigned to any cohort as per investigator's decision

4. Written informed consent 5. LVEF ≥ 50% within 28 days before randomisation 6. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 7. Adequate organ and bone marrow function within 14 days before randomisation 8. Adequate treatment washout period before randomisation (refer to protocol for detailed information) 9. Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential (refer to protocol for detailed information) 10. Female subjects must not donate, or retrieve for their own use, ova from the time of randomisation and throughout the study treatment period, and for at least 7 months after the final study drug administration. (refer to protocol for detailed information)

Exclusion Criteria

Patients eligible for inclusion in this study must not meet any of the following criteria:

1. Non-operable breast cancer including inflammatory breast cancer

2. cT1a/b breast cancer

3. Any previous history of invasive breast cancer

4. Primary malignancies within 5 years, with the exception of adequately resected non-melanoma skin cancer, curatively treated in-situ disease

5. Any evidence for existing metastatic disease (confirmed by CT Thorax/Abdomen, bone scan, or other methods according to clinical practice

6. Previous or concurrent treatment with cytotoxic agents for any reason (except non-oncological reasons)

7. Concurrent treatment with other experimental drugs and participation in another clinical trial with any investigational drug within 30 days prior to study entry

8. Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study/inadequate organ function

9. Reasons indicating risk of poor compliance

10. Woman of child-bearing potential defined as a woman physiologically capable of becoming pregnant, and not using highly effective methods of contraception during the study treatment and for 3 months after stopping the treatment.

11. Use of oral (oestrogen and progesterone), transdermal, injected, or implanted hormonal methods of contraception as well as hormonal replacement therapy.

12. Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results.

13. Patients with a medical history of myocardial infarction (MI) within 6 months before randomisation, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV), Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrolment to rule out MI.

14. Corrected QT interval (QTcF) prolongation to > 470 msec (females) based on average of the screening triplicate12-lead ECG.

15. History of (non-infectious) ILD / pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.

16. Lung criteria: Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder; Any autoimmune, connective tissue or inflammatory disorders (e.g., Rheumatoid arthritis, Sjogren's, sarcoidosis etc.) where there is documented, or a suspicion of pulmonary involvement at the time of randomisation; Prior pneumonectomy (complete); Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals

17. Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients should be tested for HIV prior to randomisation if required by local regulations or ethics committee (EC).

18. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of trastuzumab deruxtecan.

Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IMP.

19. Known allergy or hypersensitivity to study treatment (T-DXd) or any of the study drug excipients.

20. History of severe hypersensitivity reactions to other monoclonal antibodies.

21. Pregnant or breastfeeding female patients, or patients who are planning to become pregnant.

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

West German Study Group

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nadia Harbeck, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

Breast Centre, Dept. Obstetrics & Gynaecology and CCC Munich LMU University Hospital

Sherko Kuemmel, PRof. Dr.

Role: PRINCIPAL_INVESTIGATOR

Breast Centre, Kliniken Essen Mitte Essen

Oleg Gluz, PD Dr.

Role: PRINCIPAL_INVESTIGATOR

Breast Centre, Evang. Bethesda-Hospital Moenchengladbach

Michael Braun, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

Breast Centre Rotkreuzklinikum Munich

Monika Graeser, PD Dr.

Role: PRINCIPAL_INVESTIGATOR

Breast Centre, Evang. Bethesda-Hospital Moenchengladbach

Locations

Klinikum Mittelbaden, Brustzentrum

Baden-Baden, Baden-Wurttemberg, Germany

Praxis für Interdisziplinäre Onkologie und Hämatologie (PIO)

Freiburg im Breisgau, Baden-Wurttemberg, Germany

Universitätsklinikum Tübingen

Tübingen, Baden-Wurttemberg, Germany

Universitätsklinikum Ulm

Ulm, Baden-Wurttemberg, Germany

Hämotologisch onkologische Praxis Heinrich Bangerter Augsburg GbR

Augsburg, Bavaria, Germany

Universitätsklinikum Augsburg / Klinik für Frauenheilkunde und Geburtshilfe

Augsburg, Bavaria, Germany

Breast Center of the University of Munich (LMU) Universitätsfrauenklinik

Munich, Bavaria, Germany

Rotkreuz Klinikum München

Munich, Bavaria, Germany

Klinikum Bremerhaven Reinkenheide

Bremerhaven, City state Bremen, Germany

Universittsklinikum am Klinikum Südstadt

Rostock, ecklenburg-Vorpommerns, Germany

AGAPLESION Markus Krankenhaus Gynäkologie

Frankfurt am Main, Hesse, Germany

Klinikum Frankfurt Höchst GmbH

Frankfurt am Main, Hesse, Germany

Klinikum Kassel

Kassel, Hesse, Germany

Studien GbR Braunschweig

Braunschweig, Lower Saxony, Germany

Niels-Stensen-Kliniken Franziskus-Hospital

Georgsmarienhütte, Lower Saxony, Germany

Ärztehaus am Bahnhofsplatz

Hildesheim, Lower Saxony, Germany

MVZ Klinik Dr. Hancken GmbH

Stade, Lower Saxony, Germany

Uniklinik RWTH Aachen

Aachen, North Rhine-Westphalia, Germany

Onkologische Schwerpunktpraxis Bielefeld

Bielefeld, North Rhine-Westphalia, Germany

St. Elisabeth Krankenhaus GmbH

Cologne, North Rhine-Westphalia, Germany

Kliniken der Stadt Köln GmbH / Brustzentrum Holweide

Cologne, North Rhine-Westphalia, Germany

Kliniken für Frauenheilkunde / Universitätsklinikum Düsseldorf

Düsseldorf, North Rhine-Westphalia, Germany

Luisenkrankenhaus GmbH

Düsseldorf, North Rhine-Westphalia, Germany

Sankt-Antonius-Hospital

Eschweiler, North Rhine-Westphalia, Germany

Kliniken Essen-Mitte, Klinik für Senologie/Interdisziplinäres Brustzentrum

Essen, North Rhine-Westphalia, Germany

Universitätsklinikum Essen, Brustzentrum

Essen, North Rhine-Westphalia, Germany

Onkodok Gütersloh

Gütersloh, North Rhine-Westphalia, Germany

St. Barbara Klinik

Hamm, North Rhine-Westphalia, Germany

Brustzentrum Niederrhein, Johanniter Bethesda Krankenhaus

Mönchengladbach, North Rhine-Westphalia, Germany

MVZ Media Vita am St. Franziskus Hospital

Münster, North Rhine-Westphalia, Germany

Frauenklinik St. Louise-St. Vincenz-KH GmbH

Paderborn, North Rhine-Westphalia, Germany

MKS St. Paulus GmbH

Schwerte, North Rhine-Westphalia, Germany

Praxisnetzwerk Hämatologie und intern. Onkologie

Troisdorf, North Rhine-Westphalia, Germany

Helios-Klinik Wuppertal

Wuppertal, North Rhine-Westphalia, Germany

Klinikum Mutterhaus

Trier, Rhineland-Palatinate, Germany

CaritasKlinikum Saarbrücken St. Theresia

Saarbrücken, Saarland, Germany

Universitätsklinikum Leipzig

Leipzig, Saxony, Germany

Frauenklinik / Brustzentrum am Klinikum Obergölzsch Rodewisch

Rodewisch, Saxony, Germany

UK Schleswig Holstein

Lübeck, Schleswig-Holsteins, Germany

Charite Campus Mitte

Berlin, , Germany

Ev. Waldkrankenhaus Spandau

Berlin, , Germany

Universitätsklinikum Hamburg-Eppendorf / Klinik und Poliklinik für Gynäkologie

Hamburg, , Germany

Brustzentrum am Krankenhaus Jerusalem

Hamburg, , Germany

Countries

Germany

Other Identifiers

WSG-AM12 (ADAPT-HER2-IV)

Identifier Type: -

Identifier Source: org_study_id