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Clinical Trial
. 2024 Dec 5;26(12):2305-2315.
doi: 10.1093/neuonc/noae123.

Final outcome analysis from the phase II TUXEDO-1 trial of trastuzumab-deruxtecan in HER2-positive breast cancer patients with active brain metastases

Rupert Bartsch  1 , Anna Sophie Berghoff  1 , Julia Furtner  2   3 , Maximilian Marhold  1 , Elisabeth Sophie Bergen  1 , Sophie Roider-Schur  4 , Maximilian Johannes Mair  1 , Angelika Martina Starzer  1 , Heidrun Forstner  1 , Beate Rottenmanner  1 , Marie-Bernadette Aretin  5 , Karin Dieckmann  6 , Zsuzsanna Bago-Horvath  7 , Helmuth Haslacher  8 , Georg Widhalm  9 , Aysegül Ilhan-Mutlu  1 , Christoph Minichsdorfer  1 , Thorsten Fuereder  1 , Thomas Szekeres  8 , Leopold Oehler  2 , Birgit Gruenberger  10 , Georg Pfeiler  11 , Christian Singer  11 , Ansgar Weltermann  12 , Luzia Berchtold  13   1 , Matthias Preusser  1
Affiliations
Clinical Trial

Final outcome analysis from the phase II TUXEDO-1 trial of trastuzumab-deruxtecan in HER2-positive breast cancer patients with active brain metastases

Rupert Bartsch et al. Neuro Oncol. .

Abstract

Background: Brain metastases (BM) are a devastating complication of HER2-positive metastatic breast cancer (BC) and treatment strategies providing optimized local and systemic disease control are urgently required. The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) and overall survival (OS) over trastuzumab emtansine but data regarding intracranial activity is limited. In the primary outcome analysis of TUXEDO-1, a high intracranial response rate (RR) was reported with T-DXd. Here, we report the final PFS and OS results.

Patients and methods: TUXEDO-1 accrued adult patients with HER2-positive BC and active BM (newly diagnosed or progressing) without indication for immediate local therapy. The primary endpoint was intracranial RR; secondary endpoints included PFS, OS, safety, quality-of-life (QoL), and neurocognitive function. PFS and OS were estimated with the Kaplan-Meier method and analyzed in the per-protocol population.

Results: At 26.5 months median follow-up, median PFS was 21 months (95% CI: 13.3-n.r.) and median OS was not reached (95% CI: 22.2-n.r.). With longer follow-ups, no new safety signals were observed. The most common grade 3 adverse event was fatigue (20%). Grade 2 interstitial lung disease and a grade 3 symptomatic drop of left-ventricular ejection fraction were observed in one patient each. QoL was maintained over the treatment period.

Conclusions: T-DXd yielded prolonged intra- and extracranial disease control in patients with active HER2-positive BC BM in line with results from the pivotal trials. These results support the concept of antibody-drug-conjugates as systemic therapy for active BM.

Keywords: HER2-positive; brain metastases; breast cancer; trastuzumab deruxtecan.

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Conflict of interest statement

Rupert Bartsch has received lecture honoraria and advisory fees from Astra Zeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Gruenenthal, MSD, Novartis, Pfizer, Pierre-Fabre, Roche, Seagen, and Stemline and research support from Daiichi Sankyo and MSD. Anna Sophie Berghoff has received research support from Daiichi Sankyo, Roche and honoraria for lectures, consultation or advisory board participation from Roche Bristol-Meyers Squibb, Merck, Daiichi Sankyo, AstraZeneca, CeCaVa, Seagen, Alexion, Servier as well as travel support from Roche, Amgen and AbbVie. Julia Furtner has received honoraria for lectures and consultations from Novartis, Seagen, Sanova. Maximilian Marhold has received honoraria for lectures, writing, advisory board participation and consultation from Roche, Gilead, Eli Lilly, Novartis, Astra Zeneca, Daiichi Sankyo, Pfizer, MSD and Medmedia as well as travel support from Amgen, Gilead, Roche, Novartis, Pierre Fabre, MSD, Daiichi Sankyo and Eisai. Maximilian Mair has received research funding from Bristol-Myers Squibb and travel support from Pierre Fabre. Angelika Martina Starzer has received travel support from MSD, Eli Lilly and PharmaMar and lecture honoraria from Astra Zeneca. Zsuzsanna Bago-Horvath has received lecture honoraria from Daiichi Sankyo, Astra Zeneca, and MSD and served on advisory boards for Astra Zeneca, MSD, and Stemline. Aysegül Ilhan-Mutlu has received lecture honoraria from Eli Lilly, Servier, BMS, MSD, Astellas and Daiichi Sankyo, consulting honoraria from Astellas, MSD, Amgen and Astra Zeneca, has served on advisory boards for MSD, Servier, Daiichi Sankyo, BMS and Astellas and has received travel support from BMS, Roche, Eli Lilly and Daiichi Sankyo. Christoph Minichsdorfer has received honoraria from Boehringer Ingelheim, MSD, Merck, Amgen, and Sandoz and travel support from MSD and Merck Darmstadt. Thosten Fuereder has received honoraria from Merck Darmstatdt, MSD, Bristol-Myers Squibb, Roche, Böhringer Ingelheim, Astra Zeneca, Sanofi, Pfizer, Amgen, Takeda, Janssen, Invios, Eli Lilly. Birgit Gruenberger has received honoraria from Astra Zeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, MSD, Pfizer, Pierre Fabre, Sanofi, and Servier; travel support from Merck, MSD, and Roche; and honoraria for participation in an advisory board from Bayer, Eli Lilly, MSD, Pfizer, and Roche. Georg Pfeiler has received honoraria and from Pfizer, Daiichi, Seagen, MSD, Menarini, Merck, Roche, Eli Lilly, Novartis, Astra Zeneca, Gilead, and Accord. Christian Singer has received speaking honoraria, travel grants, financial or nonfinancial support, study support, and unrestricted grants from: Novartis, Astra Zeneca, Amgen, Daiichi-Sanyko, Gilead, Seagen, Science, Seattle Genetics, Pierre-Fabre, Roche, and Myriad. Matthias Preusser has received grants and research support from Böhringer Ingelheim, Bristol-Myers Squibb, Roche, Daiichi Sankyo, MSD, Novocure, GlaxoSmithKline, and AbbVie and honoraria or consultation fees from Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group, CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, MSD, and Tocagen. All other authors have no potential conflicts of interest to disclose.

Figures

Figure 1.
Figure 1.
Consort diagram.
Figure 2.
Figure 2.
Progression-free survival (A) and overall survival (B).
Figure 3.
Figure 3.
Serum S100 levels (µg/L) at baseline, cycle 4, and progression.
See this image and copyright information in PMC

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