Systemic and Intracranial Efficacy and Safety of Trastuzumab Deruxtecan in Patients with HER2-Mutant Non-Small Cell Lung Cancer across Treatment Lines: Evidence from the TRACER/HERTras Real-World Cohort

Oliver Illini; Anna-Carina Hund; Hans-Georg Kopp; Mor Moskovitz; Giannis Mountzios; Wolfgang M Brueckl; Martin Früh; Marie-Elisabeth Leßmann; Petros Christopoulos; Albrecht Stenzinger; Michael Thomas; Roni Gillis; Nir Peled; Fabian Acker; Alfredo Addeo; Andriani Charpidou; Christian Grohé; Laetitia Mauti; Sacha I Rothschild; Sabine Schmid; Christian Schumann; Damien Urban; Robert Wurm; Simon Ekman; Marcus Skribek; Franziska Glanemann; Marcel Wiesweg; Christoph Jakob Ackermann; Sofia Agelaki; Petra Hoffknecht; Marko Jakopović; Jens Kern; David König; Katharina Kostenzer; Cornelia Kropf-Sanchen; Eckart Laack; David Lang; Laurenz Nagl; Georg Pall; Martin Reck; Waleed Kian; Anna T Allemann; Jürgen Alt; David Araújo; Alexandros Bokas; Fabikan Hannah; Krainer-Jacobs Julie; Christoph Weinlinger; Adrianus Johannes de Langen; Evangelos Georgios Fergadis; Elena Fountzilas; Patrizia Froesch; Nikolaj Frost; Frank Griesinger; Franziska Jordan; Charisios Karanikiotis; Barbara Kiesewetter; Ippokratis Korantzis; Andrea Lopes Machado; Panagiota Economopoulou; Arnold Pilz; Patrick Reimann; Achim Rittmeyer; Akram Saad; Konstantinos Samitas; Karsten Schulmann; Riyaz Shah; Jan Alexander Stratmann; Hossein Taghizadeh; Kai Tammoscheit; Amanda Tufman; Jan-Phillip Weber; Ewald Wöll; Arschang Valipour; Tobias R Overbeck; Maximilian J Hochmair

doi:10.1016/j.jtho.2026.103651

Systemic and Intracranial Efficacy and Safety of Trastuzumab Deruxtecan in Patients with HER2-Mutant Non-Small Cell Lung Cancer across Treatment Lines: Evidence from the TRACER/HERTras Real-World Cohort

Oliver Illini
, Anna-Carina Hund
, Hans-Georg Kopp
, Mor Moskovitz
, Giannis Mountzios
, Wolfgang M Brueckl
, Martin Früh
, Marie-Elisabeth Leßmann
, Petros Christopoulos
, Albrecht Stenzinger
, Michael Thomas
, Roni Gillis
, Nir Peled
, Fabian Acker
, Alfredo Addeo
, Andriani Charpidou
, Christian Grohé
, Laetitia Mauti
, Sacha I Rothschild
, Sabine Schmid

Christian Schumann, Damien Urban, Robert Wurm, Simon Ekman, Marcus Skribek, Franziska Glanemann, Marcel Wiesweg, Christoph Jakob Ackermann, Sofia Agelaki, Petra Hoffknecht, Marko Jakopović, Jens Kern, David König, Katharina Kostenzer, Cornelia Kropf-Sanchen, Eckart Laack, David Lang, Laurenz Nagl, Georg Pall, Martin Reck, Waleed Kian, Anna T Allemann, Jürgen Alt, David Araújo, Alexandros Bokas, Fabikan Hannah, Krainer-Jacobs Julie, Christoph Weinlinger, Adrianus Johannes de Langen, Evangelos Georgios Fergadis, Elena Fountzilas, Patrizia Froesch, Nikolaj Frost, Frank Griesinger, Franziska Jordan, Charisios Karanikiotis, Barbara Kiesewetter, Ippokratis Korantzis, Andrea Lopes Machado, Panagiota Economopoulou, Arnold Pilz, Patrick Reimann, Achim Rittmeyer, Akram Saad, Konstantinos Samitas, Karsten Schulmann, Riyaz Shah, Jan Alexander Stratmann, Hossein Taghizadeh, Kai Tammoscheit, Amanda Tufman, Jan-Phillip Weber, Ewald Wöll, Arschang Valipour, Tobias R Overbeck, Maximilian J Hochmair

Klinische Abteilung für Innere Medizin I (UK St. Pölten)

Publikation: Beitrag in Fachzeitschrift (peer-reviewed) › Artikel in Fachzeitschrift

Abstract

INTRODUCTION: HER2 mutations define a distinct, therapeutically actionable subset of non-small cell lung cancer (NSCLC). Trastuzumab deruxtecan (T-DXd) has demonstrated strong activity in clinical trials, but real-world data are limited.

METHODS: We conducted a retrospective, multinational cohort study of patients with advanced HER2-mutant NSCLC treated with T-DXd outside clinical trials between August 2021 and January 2025 across 68 centers in Europe and Israel. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial efficacy, and safety.

RESULTS: Among 168 patients (median age 62 years; 59% female; 56% never-smokers), the ORR was 54.8% (95%CI, 46.9-62.4) and disease control rate 88.7% (95%CI, 82.9-93.1). Median PFS was 7.2 months (95%CI, 6.2-9.7) and OS 18.3 months (95%CI, 13.3-24.8). Treatment-naïve patients (n=18) achieved an ORR of 72.2% (95%CI, 46.5-90.3) and median OS of 22.1 months (95%CI, 10.0-NE). Patients with measurable brain metastases (n=27) had an intracranial ORR of 74.1% (95%CI, 53.7-88.9), including 25.9% complete responses. Grade ≥3 treatment-related adverse events occurred in 32% of patients. Interstitial lung disease (ILD)/pneumonitis occurred in 14% (four fatal cases) of patients, without consistent predictors.

CONCLUSIONS: In the largest real-world cohort reported to date, T-DXd demonstrated robust systemic and intracranial activity in HER2-mutant NSCLC, including treatment-naïve patients and those with active brain metastases who were largely excluded from prior studies. Toxicity was consistent with previous reports, with ILD remaining the main safety concern. These findings support integration of HER2-targeted therapies into evolving treatment algorithms.

Originalsprache	Englisch
Seiten (von - bis)	103651
Fachzeitschrift	Journal of Thoracic Oncology
DOIs	https://doi.org/10.1016/j.jtho.2026.103651
Publikationsstatus	Angenommen/Im Druck - 24 Feb. 2026

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Illini, O., Hund, A.-C., Kopp, H.-G., Moskovitz, M., Mountzios, G., Brueckl, W. M., Früh, M., Leßmann, M.-E., Christopoulos, P., Stenzinger, A., Thomas, M., Gillis, R., Peled, N., Acker, F., Addeo, A., Charpidou, A., Grohé, C., Mauti, L., Rothschild, S. I., ... Hochmair, M. J. (Angenommen/Im Druck). Systemic and Intracranial Efficacy and Safety of Trastuzumab Deruxtecan in Patients with HER2-Mutant Non-Small Cell Lung Cancer across Treatment Lines: Evidence from the TRACER/HERTras Real-World Cohort. Journal of Thoracic Oncology, 103651. https://doi.org/10.1016/j.jtho.2026.103651

@article{8250ac37b9294eb9bd4747eb66d97b00,

title = "Systemic and Intracranial Efficacy and Safety of Trastuzumab Deruxtecan in Patients with HER2-Mutant Non-Small Cell Lung Cancer across Treatment Lines: Evidence from the TRACER/HERTras Real-World Cohort",

abstract = "INTRODUCTION: HER2 mutations define a distinct, therapeutically actionable subset of non-small cell lung cancer (NSCLC). Trastuzumab deruxtecan (T-DXd) has demonstrated strong activity in clinical trials, but real-world data are limited.METHODS: We conducted a retrospective, multinational cohort study of patients with advanced HER2-mutant NSCLC treated with T-DXd outside clinical trials between August 2021 and January 2025 across 68 centers in Europe and Israel. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial efficacy, and safety.RESULTS: Among 168 patients (median age 62 years; 59\% female; 56\% never-smokers), the ORR was 54.8\% (95\%CI, 46.9-62.4) and disease control rate 88.7\% (95\%CI, 82.9-93.1). Median PFS was 7.2 months (95\%CI, 6.2-9.7) and OS 18.3 months (95\%CI, 13.3-24.8). Treatment-na{\"i}ve patients (n=18) achieved an ORR of 72.2\% (95\%CI, 46.5-90.3) and median OS of 22.1 months (95\%CI, 10.0-NE). Patients with measurable brain metastases (n=27) had an intracranial ORR of 74.1\% (95\%CI, 53.7-88.9), including 25.9\% complete responses. Grade ≥3 treatment-related adverse events occurred in 32\% of patients. Interstitial lung disease (ILD)/pneumonitis occurred in 14\% (four fatal cases) of patients, without consistent predictors.CONCLUSIONS: In the largest real-world cohort reported to date, T-DXd demonstrated robust systemic and intracranial activity in HER2-mutant NSCLC, including treatment-na{\"i}ve patients and those with active brain metastases who were largely excluded from prior studies. Toxicity was consistent with previous reports, with ILD remaining the main safety concern. These findings support integration of HER2-targeted therapies into evolving treatment algorithms.",

author = "Oliver Illini and Anna-Carina Hund and Hans-Georg Kopp and Mor Moskovitz and Giannis Mountzios and Brueckl, \{Wolfgang M\} and Martin Fr{\"u}h and Marie-Elisabeth Le{\ss}mann and Petros Christopoulos and Albrecht Stenzinger and Michael Thomas and Roni Gillis and Nir Peled and Fabian Acker and Alfredo Addeo and Andriani Charpidou and Christian Groh{\'e} and Laetitia Mauti and Rothschild, \{Sacha I\} and Sabine Schmid and Christian Schumann and Damien Urban and Robert Wurm and Simon Ekman and Marcus Skribek and Franziska Glanemann and Marcel Wiesweg and Ackermann, \{Christoph Jakob\} and Sofia Agelaki and Petra Hoffknecht and Marko Jakopovi{\'c} and Jens Kern and David K{\"o}nig and Katharina Kostenzer and Cornelia Kropf-Sanchen and Eckart Laack and David Lang and Laurenz Nagl and Georg Pall and Martin Reck and Waleed Kian and Allemann, \{Anna T\} and J{\"u}rgen Alt and David Ara{\'u}jo and Alexandros Bokas and Fabikan Hannah and Krainer-Jacobs Julie and Christoph Weinlinger and \{de Langen\}, \{Adrianus Johannes\} and Fergadis, \{Evangelos Georgios\} and Elena Fountzilas and Patrizia Froesch and Nikolaj Frost and Frank Griesinger and Franziska Jordan and Charisios Karanikiotis and Barbara Kiesewetter and Ippokratis Korantzis and Machado, \{Andrea Lopes\} and Panagiota Economopoulou and Arnold Pilz and Patrick Reimann and Achim Rittmeyer and Akram Saad and Konstantinos Samitas and Karsten Schulmann and Riyaz Shah and Stratmann, \{Jan Alexander\} and Hossein Taghizadeh and Kai Tammoscheit and Amanda Tufman and Jan-Phillip Weber and Ewald W{\"o}ll and Arschang Valipour and Overbeck, \{Tobias R\} and Hochmair, \{Maximilian J\}",

note = "Copyright {\textcopyright} 2026. Published by Elsevier Inc.",

year = "2026",

month = feb,

day = "24",

doi = "10.1016/j.jtho.2026.103651",

language = "English",

pages = "103651",

journal = "Journal of Thoracic Oncology",

issn = "1556-0864",

publisher = "Elsevier Inc.",

}

Illini, O, Hund, A-C, Kopp, H-G, Moskovitz, M, Mountzios, G, Brueckl, WM, Früh, M, Leßmann, M-E, Christopoulos, P, Stenzinger, A, Thomas, M, Gillis, R, Peled, N, Acker, F, Addeo, A, Charpidou, A, Grohé, C, Mauti, L, Rothschild, SI, Schmid, S, Schumann, C, Urban, D, Wurm, R, Ekman, S, Skribek, M, Glanemann, F, Wiesweg, M, Ackermann, CJ, Agelaki, S, Hoffknecht, P, Jakopović, M, Kern, J, König, D, Kostenzer, K, Kropf-Sanchen, C, Laack, E, Lang, D, Nagl, L, Pall, G, Reck, M, Kian, W, Allemann, AT, Alt, J, Araújo, D, Bokas, A, Hannah, F, Julie, K-J, Weinlinger, C, de Langen, AJ, Fergadis, EG, Fountzilas, E, Froesch, P, Frost, N, Griesinger, F, Jordan, F, Karanikiotis, C, Kiesewetter, B, Korantzis, I, Machado, AL, Economopoulou, P, Pilz, A, Reimann, P, Rittmeyer, A, Saad, A, Samitas, K, Schulmann, K, Shah, R, Stratmann, JA, Taghizadeh, H, Tammoscheit, K, Tufman, A, Weber, J-P, Wöll, E, Valipour, A, Overbeck, TR & Hochmair, MJ 2026, 'Systemic and Intracranial Efficacy and Safety of Trastuzumab Deruxtecan in Patients with HER2-Mutant Non-Small Cell Lung Cancer across Treatment Lines: Evidence from the TRACER/HERTras Real-World Cohort', Journal of Thoracic Oncology, S. 103651. https://doi.org/10.1016/j.jtho.2026.103651

Systemic and Intracranial Efficacy and Safety of Trastuzumab Deruxtecan in Patients with HER2-Mutant Non-Small Cell Lung Cancer across Treatment Lines: Evidence from the TRACER/HERTras Real-World Cohort. / Illini, Oliver; Hund, Anna-Carina; Kopp, Hans-Georg et al.
in: Journal of Thoracic Oncology, 24.02.2026, S. 103651.

Publikation: Beitrag in Fachzeitschrift (peer-reviewed) › Artikel in Fachzeitschrift

TY - JOUR

T1 - Systemic and Intracranial Efficacy and Safety of Trastuzumab Deruxtecan in Patients with HER2-Mutant Non-Small Cell Lung Cancer across Treatment Lines

T2 - Evidence from the TRACER/HERTras Real-World Cohort

AU - Illini, Oliver

AU - Hund, Anna-Carina

AU - Kopp, Hans-Georg

AU - Moskovitz, Mor

AU - Mountzios, Giannis

AU - Brueckl, Wolfgang M

AU - Früh, Martin

AU - Leßmann, Marie-Elisabeth

AU - Christopoulos, Petros

AU - Stenzinger, Albrecht

AU - Thomas, Michael

AU - Gillis, Roni

AU - Peled, Nir

AU - Acker, Fabian

AU - Addeo, Alfredo

AU - Charpidou, Andriani

AU - Grohé, Christian

AU - Mauti, Laetitia

AU - Rothschild, Sacha I

AU - Schmid, Sabine

AU - Schumann, Christian

AU - Urban, Damien

AU - Wurm, Robert

AU - Ekman, Simon

AU - Skribek, Marcus

AU - Glanemann, Franziska

AU - Wiesweg, Marcel

AU - Ackermann, Christoph Jakob

AU - Agelaki, Sofia

AU - Hoffknecht, Petra

AU - Jakopović, Marko

AU - Kern, Jens

AU - König, David

AU - Kostenzer, Katharina

AU - Kropf-Sanchen, Cornelia

AU - Laack, Eckart

AU - Lang, David

AU - Nagl, Laurenz

AU - Pall, Georg

AU - Reck, Martin

AU - Kian, Waleed

AU - Allemann, Anna T

AU - Alt, Jürgen

AU - Araújo, David

AU - Bokas, Alexandros

AU - Hannah, Fabikan

AU - Julie, Krainer-Jacobs

AU - Weinlinger, Christoph

AU - de Langen, Adrianus Johannes

AU - Fergadis, Evangelos Georgios

AU - Fountzilas, Elena

AU - Froesch, Patrizia

AU - Frost, Nikolaj

AU - Griesinger, Frank

AU - Jordan, Franziska

AU - Karanikiotis, Charisios

AU - Kiesewetter, Barbara

AU - Korantzis, Ippokratis

AU - Machado, Andrea Lopes

AU - Economopoulou, Panagiota

AU - Pilz, Arnold

AU - Reimann, Patrick

AU - Rittmeyer, Achim

AU - Saad, Akram

AU - Samitas, Konstantinos

AU - Schulmann, Karsten

AU - Shah, Riyaz

AU - Stratmann, Jan Alexander

AU - Taghizadeh, Hossein

AU - Tammoscheit, Kai

AU - Tufman, Amanda

AU - Weber, Jan-Phillip

AU - Wöll, Ewald

AU - Valipour, Arschang

AU - Overbeck, Tobias R

AU - Hochmair, Maximilian J

PY - 2026/2/24

Y1 - 2026/2/24

N2 - INTRODUCTION: HER2 mutations define a distinct, therapeutically actionable subset of non-small cell lung cancer (NSCLC). Trastuzumab deruxtecan (T-DXd) has demonstrated strong activity in clinical trials, but real-world data are limited.METHODS: We conducted a retrospective, multinational cohort study of patients with advanced HER2-mutant NSCLC treated with T-DXd outside clinical trials between August 2021 and January 2025 across 68 centers in Europe and Israel. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial efficacy, and safety.RESULTS: Among 168 patients (median age 62 years; 59% female; 56% never-smokers), the ORR was 54.8% (95%CI, 46.9-62.4) and disease control rate 88.7% (95%CI, 82.9-93.1). Median PFS was 7.2 months (95%CI, 6.2-9.7) and OS 18.3 months (95%CI, 13.3-24.8). Treatment-naïve patients (n=18) achieved an ORR of 72.2% (95%CI, 46.5-90.3) and median OS of 22.1 months (95%CI, 10.0-NE). Patients with measurable brain metastases (n=27) had an intracranial ORR of 74.1% (95%CI, 53.7-88.9), including 25.9% complete responses. Grade ≥3 treatment-related adverse events occurred in 32% of patients. Interstitial lung disease (ILD)/pneumonitis occurred in 14% (four fatal cases) of patients, without consistent predictors.CONCLUSIONS: In the largest real-world cohort reported to date, T-DXd demonstrated robust systemic and intracranial activity in HER2-mutant NSCLC, including treatment-naïve patients and those with active brain metastases who were largely excluded from prior studies. Toxicity was consistent with previous reports, with ILD remaining the main safety concern. These findings support integration of HER2-targeted therapies into evolving treatment algorithms.

AB - INTRODUCTION: HER2 mutations define a distinct, therapeutically actionable subset of non-small cell lung cancer (NSCLC). Trastuzumab deruxtecan (T-DXd) has demonstrated strong activity in clinical trials, but real-world data are limited.METHODS: We conducted a retrospective, multinational cohort study of patients with advanced HER2-mutant NSCLC treated with T-DXd outside clinical trials between August 2021 and January 2025 across 68 centers in Europe and Israel. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial efficacy, and safety.RESULTS: Among 168 patients (median age 62 years; 59% female; 56% never-smokers), the ORR was 54.8% (95%CI, 46.9-62.4) and disease control rate 88.7% (95%CI, 82.9-93.1). Median PFS was 7.2 months (95%CI, 6.2-9.7) and OS 18.3 months (95%CI, 13.3-24.8). Treatment-naïve patients (n=18) achieved an ORR of 72.2% (95%CI, 46.5-90.3) and median OS of 22.1 months (95%CI, 10.0-NE). Patients with measurable brain metastases (n=27) had an intracranial ORR of 74.1% (95%CI, 53.7-88.9), including 25.9% complete responses. Grade ≥3 treatment-related adverse events occurred in 32% of patients. Interstitial lung disease (ILD)/pneumonitis occurred in 14% (four fatal cases) of patients, without consistent predictors.CONCLUSIONS: In the largest real-world cohort reported to date, T-DXd demonstrated robust systemic and intracranial activity in HER2-mutant NSCLC, including treatment-naïve patients and those with active brain metastases who were largely excluded from prior studies. Toxicity was consistent with previous reports, with ILD remaining the main safety concern. These findings support integration of HER2-targeted therapies into evolving treatment algorithms.

U2 - 10.1016/j.jtho.2026.103651

DO - 10.1016/j.jtho.2026.103651

M3 - Journal article

C2 - 41747890

SN - 1556-0864

SP - 103651

JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

ER -