165MO - Trastuzumab-deruxtecan (T-DXd) in HER2-positive breast cancer patients (pts) with active brain metastases: Primary outcome analysis from the TUXEDO-1 trial

Background

Brain metastases (BM) are a frequent and devastating complication of HER2-positive breast cancer (BC). T-DXd is an antibody-drug conjugate with high activity in pretreated pts but information regarding activity in active BM is limited. Therefore, the prospective, single-arm, phase II TUXEDO-1 trial investigated T-DXd in HER2-positive BC pts with active BM.

Methods

TUXEDO-1 included adult pts with HER2-positive BC and newly diagnosed untreated BM or BM progressing after local therapy, prior exposure to trastuzumab and pertuzumab, and no indication for immediate local therapy. The primary endpoint was intracranial response rate (RR) centrally assessed by Response Assessment in Neuro-Oncology (RANO)-BM criteria. Secondary endpoints consisted of extracranial RR, progression-free survival (PFS), overall survival, safety, and quality-of-life. Based on a Simon’s two-stage design (RR under alternative hypothesis >60%; RR under null hypothesis <26%), a total number of 15 pts were enrolled. The null hypothesis was to be rejected with a type I error rate of 5% and a power of 80% if at least 7 responses were observed.

Results

As of December 29^th, 2021, all 15 pts had received at least one dose of T-DXd (60% progressive BM, 70% prior T-DM1). One patient initially assessed as having parenchymal BM was found to have dural metastasis upon restaging and was excluded from efficacy analyses. In the intention-to-treat population, intracranial RR was 73.3% (11/15) (per protocol population: 78.6% [11/14]). At 11 months median follow-up, PFS was 14 months (95% CI 8.48-19.52); two pts died from disease progression. Main non-haematological toxicities consisted of grade 1/2 fatigue (86.7%), nausea (46.7%), and diarrhoea (26.7%). Dose reductions were required in 9 pts; 4 pts had serious adverse events. Grade 2 interstitial lung disease and a symptomatic drop of left-ventricular ejection fraction were observed in one patient each.

Conclusions

In the TUXEDO-1 study, T-DXd yielded high intracranial response rates. Data suggest that T-DXd achieves significant therapeutic effects in the central nervous system and should thus be further explored in this context.

Clinical trial identification

NCT04752059.

Legal entity responsible for the study

Medical University of Vienna, Department of Medicine 1.

Funding

Daiichi Sankyo.

Disclosure

R. Bartsch: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Daiichi; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Seagen; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Institutional, Funding, Investigator Initiated Trial: Daiichi; Financial Interests, Institutional, Invited Speaker, Drug support for investigator initiated trial: MSD. M. Marhold: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Daiichi; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: MEDmedia; Financial Interests, Personal and Institutional, Other: Amgen; Financial Interests, Personal and Institutional, Other: Novartis; Financial Interests, Personal and Institutional, Other: Pierre Fabre; Financial Interests, Personal and Institutional, Other: Daiichi; Financial Interests, Personal and Institutional, Other: Roche; Financial Interests, Personal and Institutional, Other: Eisai. Z.A. Bago-Horvath: Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal and Institutional, Other: Daiichi. T. Fuereder: Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Invited Speaker: Accord; Financial Interests, Personal, Invited Speaker: Merck Darmstadt; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Merck Darmstadt. C.F. Singer: Financial Interests, Personal, Other, consultancy: Amgen; Financial Interests, Personal, Advisory Board, ADVISORY FUNCTION: NOVARTIS; Financial Interests, Personal, Advisory Board, ADVISORY ROLE: ROCHE; Financial Interests, Personal, Other, STUDY SUPPORT: PFITZER; Financial Interests, Personal, Advisory Board, ADVISORY, SPEAKER HONORARIES, STUDY SUPPORT: ASTRAZENECA; Financial Interests, Personal, Invited Speaker, STUDY COORDINATOR: AMGEN; Non-Financial Interests, Principal Investigator, STUDY: AMGEN; Non-Financial Interests, Principal Investigator, STUDY: ASTRAZENECA; Non-Financial Interests, Project Lead, REGISTER: PFITZER. M. Preusser: Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: GLG; Financial Interests, Personal, Invited Speaker: CMC contrast; Financial Interests, Personal, Invited Speaker: GSK; Financial Interests, Personal, Invited Speaker: Mundipharma; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Other: BMJ journals; Financial Interests, Personal, Writing Engagements: MedMedia; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Invited Speaker: MEDahead; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Tocagen; Financial Interests, Personal, Invited Speaker: Adastra; Financial Interests, Personal, Invited Speaker: Gan & Lee Pharmaceuticals. All other authors have declared no conflicts of interest.