Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial

Nadia Harbeck; Eva Ciruelos; Guy Jerusalem; Volkmar Mueller; Naoki Niikura; Giuseppe Viale; Rupert Bartsch; Christian Kurzeder; Michaela J. Higgins; Roisin M. Connolly; Sally Baron-Hay; Maria Gion; Valentina Guarneri; Giampaolo Bianchini; Hans Wildiers; Santiago Escriva-de-Romani; Manoj Prahladan; Helen Bridge; Nataliya Kuptsova-Clarkson; Nana Scotto; Sunil Verma; Nancy U. Lin; Belinda Yeo; Nicole Mccarthy; Amelia Mccartney; Timothy Clay; Nicholas Murray; Andrea Gombos; Joelle Collignon; Eveline De Cuypere; Katarzyna Jerzak; Stephen Chia; Maja Maraldo; Jeanette Ronlev; Eva Brix; Minna Tanner; Johanna Mattson; Riikka Huovinen; Pauline Wimberger; Mattea Reinisch; Hans Tesch; Michael Untch; Peter Fasching; Tjoung-Won Park-Simon; Joke Tio; Michael Braun; Eva Maria Grischke; Frederik Marme; Marion van Mackelenbergh; Et al.; Maaike de Boer

doi:10.1038/s41591-024-03261-7

Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial

Nadia Harbeck^*, Eva Ciruelos, Guy Jerusalem, Volkmar Mueller, Naoki Niikura, Giuseppe Viale, Rupert Bartsch, Christian Kurzeder, Michaela J. Higgins, Roisin M. Connolly, Sally Baron-Hay, Maria Gion, Valentina Guarneri, Giampaolo Bianchini, Hans Wildiers, Santiago Escriva-de-Romani, Manoj Prahladan, Helen Bridge, Nataliya Kuptsova-Clarkson, Nana ScottoSunil Verma, Nancy U. Lin, Belinda Yeo, Nicole Mccarthy, Amelia Mccartney, Timothy Clay, Nicholas Murray, Andrea Gombos, Joelle Collignon, Eveline De Cuypere, Katarzyna Jerzak, Stephen Chia, Maja Maraldo, Jeanette Ronlev, Eva Brix, Minna Tanner, Johanna Mattson, Riikka Huovinen, Pauline Wimberger, Mattea Reinisch, Hans Tesch, Michael Untch, Peter Fasching, Tjoung-Won Park-Simon, Joke Tio, Michael Braun, Eva Maria Grischke, Frederik Marme, Marion van Mackelenbergh, Et al., Maaike de Boer

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2-positive (HER2+) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2+ mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs (n = 263) and no BMs (n = 241)) treated with one or more prior anti-HER2-based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9-67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9-65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5-68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade >= 3: 3%) of patients with BMs and 13% (grade >= 3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2+ mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761.

Original language	English
Article number	967
Pages (from-to)	3717–3727
Number of pages	11
Journal	Nature Medicine
Volume	30
Issue number	12
Early online date	1 Sept 2024
DOIs	https://doi.org/10.1038/s41591-024-03261-7
Publication status	Published - 1 Dec 2024

Keywords

CLINICAL-PRACTICE GUIDELINE
EXPLORATORY ANALYSIS
EMTANSINE T-DM1
CAPECITABINE
RADIOSURGERY
RADIOTHERAPY
EFFICACY
DS-8201A
SOCIETY

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1 Erratum / corrigendum / retractions

Publisher Correction: Publisher Correction: Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial(Nature Medicine, 10.1038/s41591-024-03261-7)
Harbeck, N., Ciruelos, E., Jerusalem, G., Müller, V., Niikura, N., Viale, G., Bartsch, R., Kurzeder, C., Higgins, M. J., Connolly, R. M., Baron-Hay, S., Gión, M., Guarneri, V., Bianchini, G., Wildiers, H., Escrivá-de-Romaní, S., Prahladan, M., Bridge, H., Kuptsova-Clarkson, N. & Scotto, N. & 31 others, Verma, S., Lin, N. U., Anders, C., Hall, P., Zaman, K., Aebi, S., Rossi, L., Klint, L., Killander, F., Schiza, A., del Prado, P. M., González, C. H., Flores, E. G., Sanchez, C. R., López, R. L., Castán, J. C., Borrego, M. R., Marti, M. P. L., Gregori, J. G., Manich, C. S., Losada, M. J. V., Sousa, A. R., Cardoso, F., Simões, J., Duchnowska, R., Jassem, J., Radecka, B., Nowecki, Z., Wysocki, P., de Boer, M. & DESTINY-Breast12 study group, 1 Dec 2024, In: Nature Medicine. 30, 12, p. 3780 1 p., 3780.
Research output: Contribution to journal › Erratum / corrigendum / retractions › Academic

Open Access

Cite this

Harbeck, N., Ciruelos, E., Jerusalem, G., Mueller, V., Niikura, N., Viale, G., Bartsch, R., Kurzeder, C., Higgins, M. J., Connolly, R. M., Baron-Hay, S., Gion, M., Guarneri, V., Bianchini, G., Wildiers, H., Escriva-de-Romani, S., Prahladan, M., Bridge, H., Kuptsova-Clarkson, N., ... de Boer, M. (2024). Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Nature Medicine, 30(12), 3717–3727. Article 967. https://doi.org/10.1038/s41591-024-03261-7

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title = "Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial",

abstract = "Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2-positive (HER2+) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2+ mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs (n = 263) and no BMs (n = 241)) treated with one or more prior anti-HER2-based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9-67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9-65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5-68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade >= 3: 3%) of patients with BMs and 13% (grade >= 3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2+ mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761.",

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author = "Nadia Harbeck and Eva Ciruelos and Guy Jerusalem and Volkmar Mueller and Naoki Niikura and Giuseppe Viale and Rupert Bartsch and Christian Kurzeder and Higgins, {Michaela J.} and Connolly, {Roisin M.} and Sally Baron-Hay and Maria Gion and Valentina Guarneri and Giampaolo Bianchini and Hans Wildiers and Santiago Escriva-de-Romani and Manoj Prahladan and Helen Bridge and Nataliya Kuptsova-Clarkson and Nana Scotto and Sunil Verma and Lin, {Nancy U.} and Belinda Yeo and Nicole Mccarthy and Amelia Mccartney and Timothy Clay and Nicholas Murray and Andrea Gombos and Joelle Collignon and {De Cuypere}, Eveline and Katarzyna Jerzak and Stephen Chia and Maja Maraldo and Jeanette Ronlev and Eva Brix and Minna Tanner and Johanna Mattson and Riikka Huovinen and Pauline Wimberger and Mattea Reinisch and Hans Tesch and Michael Untch and Peter Fasching and Tjoung-Won Park-Simon and Joke Tio and Michael Braun and Grischke, {Eva Maria} and Frederik Marme and {van Mackelenbergh}, Marion and {Et al.} and {de Boer}, Maaike",

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Harbeck, N, Ciruelos, E, Jerusalem, G, Mueller, V, Niikura, N, Viale, G, Bartsch, R, Kurzeder, C, Higgins, MJ, Connolly, RM, Baron-Hay, S, Gion, M, Guarneri, V, Bianchini, G, Wildiers, H, Escriva-de-Romani, S, Prahladan, M, Bridge, H, Kuptsova-Clarkson, N, Scotto, N, Verma, S, Lin, NU, Yeo, B, Mccarthy, N, Mccartney, A, Clay, T, Murray, N, Gombos, A, Collignon, J, De Cuypere, E, Jerzak, K, Chia, S, Maraldo, M, Ronlev, J, Brix, E, Tanner, M, Mattson, J, Huovinen, R, Wimberger, P, Reinisch, M, Tesch, H, Untch, M, Fasching, P, Park-Simon, T-W, Tio, J, Braun, M, Grischke, EM, Marme, F, van Mackelenbergh, M, Et al. & de Boer, M 2024, 'Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial', Nature Medicine, vol. 30, no. 12, 967, pp. 3717–3727. https://doi.org/10.1038/s41591-024-03261-7

TY - JOUR

T1 - Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases

T2 - a phase 3b/4 trial

AU - Harbeck, Nadia

AU - Ciruelos, Eva

AU - Jerusalem, Guy

AU - Mueller, Volkmar

AU - Niikura, Naoki

AU - Viale, Giuseppe

AU - Bartsch, Rupert

AU - Kurzeder, Christian

AU - Higgins, Michaela J.

AU - Connolly, Roisin M.

AU - Baron-Hay, Sally

AU - Gion, Maria

AU - Guarneri, Valentina

AU - Bianchini, Giampaolo

AU - Wildiers, Hans

AU - Escriva-de-Romani, Santiago

AU - Prahladan, Manoj

AU - Bridge, Helen

AU - Kuptsova-Clarkson, Nataliya

AU - Scotto, Nana

AU - Verma, Sunil

AU - Lin, Nancy U.

AU - Yeo, Belinda

AU - Mccarthy, Nicole

AU - Mccartney, Amelia

AU - Clay, Timothy

AU - Murray, Nicholas

AU - Gombos, Andrea

AU - Collignon, Joelle

AU - De Cuypere, Eveline

AU - Jerzak, Katarzyna

AU - Chia, Stephen

AU - Maraldo, Maja

AU - Ronlev, Jeanette

AU - Brix, Eva

AU - Tanner, Minna

AU - Mattson, Johanna

AU - Huovinen, Riikka

AU - Wimberger, Pauline

AU - Reinisch, Mattea

AU - Tesch, Hans

AU - Untch, Michael

AU - Fasching, Peter

AU - Park-Simon, Tjoung-Won

AU - Tio, Joke

AU - Braun, Michael

AU - Grischke, Eva Maria

AU - Marme, Frederik

AU - van Mackelenbergh, Marion

AU - Et al.

AU - de Boer, Maaike

PY - 2024/12/1

Y1 - 2024/12/1

N2 - Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2-positive (HER2+) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2+ mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs (n = 263) and no BMs (n = 241)) treated with one or more prior anti-HER2-based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9-67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9-65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5-68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade >= 3: 3%) of patients with BMs and 13% (grade >= 3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2+ mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761.

AB - Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2-positive (HER2+) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2+ mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs (n = 263) and no BMs (n = 241)) treated with one or more prior anti-HER2-based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9-67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9-65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5-68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade >= 3: 3%) of patients with BMs and 13% (grade >= 3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2+ mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761.

KW - CLINICAL-PRACTICE GUIDELINE

KW - EXPLORATORY ANALYSIS

KW - EMTANSINE T-DM1

KW - CAPECITABINE

KW - RADIOSURGERY

KW - RADIOTHERAPY

KW - EFFICACY

KW - DS-8201A

KW - SOCIETY

U2 - 10.1038/s41591-024-03261-7

DO - 10.1038/s41591-024-03261-7

M3 - Article

SN - 1078-8956

VL - 30

SP - 3717

EP - 3727

JO - Nature Medicine

JF - Nature Medicine

IS - 12

M1 - 967

ER -

Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial

Abstract

Keywords

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Research output

Publisher Correction: Publisher Correction: Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial(Nature Medicine, 10.1038/s41591-024-03261-7)

Cite this