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Brief Title: NeoAdjuvant Therapy With Trastuzumab-deruxtecan Versus Chemotherapy+Trastuzumab+Pertuzumab in HER2+ Early Breast Cancer
Official Title: NeoAdjuvant Dynamic Marker - Adjusted Personalized Therapy Comparing Trastuzumab-deruxtecan Versus Pacli-/Docetaxel+Carboplatin+Trastuzumab+Pertuzumab in HER2+ Early Breast Cancer
Study ID: NCT05704829
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.
Minimum Age: 18 Years
Eligible Ages: ADULT, OLDER_ADULT
Sex: FEMALE
Healthy Volunteers: No
Breast Center of the University of Munich (LMU) Universitätsfrauenklinik, Munich, Bavaria, Germany
Rotkreuz Klinikum München, Muenchen, Bayern, Germany
Niels-Stensen-Kliniken Franziskus-Hospital, Georgsmarienhütte, Niedersachsen, Germany
Kliniken Essen-Mitte, Klinik für Senologie/Interdisziplinäres Brustzentrum, Essen, NRW, Germany
Brustzentrum Niederrhein, Johanniter Bethesda Krankenhaus, Moenchengladbach, NRW, Germany
Klinikum Mittelbaden, Brustzentrum, Baden-Baden, , Germany
Onkologische Schwerpunktpraxis Bielefeld, Bielefeld, , Germany
Universitätsklinikum Essen, Burstzentrum, Essen, , Germany
Onkodok Gütersloh, Gütersloh, , Germany
Brustzentrum am Krankenhaus Jerusalem, Hamburg, , Germany
St. Barbara Klinik, Hamm, , Germany
Helios-Klinik Wuppertal, Wuppertal, , Germany
Name: Nadia Harbeck, Prof. Dr.
Affiliation: Breast Centre, Dept. Obstetrics & Gynaecology and CCC Munich LMU University Hospital
Role: PRINCIPAL_INVESTIGATOR
Name: Sherko Kuemmel, PRof. Dr.
Affiliation: Breast Centre, Kliniken Essen Mitte Essen
Role: PRINCIPAL_INVESTIGATOR
Name: Oleg Gluz, PD Dr.
Affiliation: Breast Centre, Evang. Bethesda-Hospital Moenchengladbach
Role: PRINCIPAL_INVESTIGATOR
Name: Michael Braun, Prof. Dr.
Affiliation: Breast Centre Rotkreuzklinikum Munich
Role: PRINCIPAL_INVESTIGATOR
Name: Monika Graeser, PD Dr.
Affiliation: Breast Centre, Evang. Bethesda-Hospital Moenchengladbach
Role: PRINCIPAL_INVESTIGATOR