First-line immunotherapy for lung cancer with MET exon 14 skipping and the relevance of TP53 mutations

Miriam Blasi¹, Jonas Kuon², Heike Lüders³, Daniel Misch⁴, Diego Kauffmann-Guerrero⁵, Moritz Hilbrandt⁶, Daniel Kazdal⁷, Roger-Fei Falkenstern-Ge⁸, Björn Hackanson⁹, Sebastian Dintner¹⁰, Martin Faehling¹¹, Martina Kirchner¹², Anna-Lena Volckmar¹², Hans-Georg Kopp⁸, Michael Allgäuer¹², Christian Grohé³, Amanda Tufman⁵, Martin Reck¹³, Nikolaj Frost⁶, Albrecht Stenzinger⁷, Michael Thomas¹, Petros Christopoulos¹⁴

Affiliations

¹ Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital and National Center for Tumor Diseases (NCT), NCT Heidelberg, A Partnership Between DKFZ and Heidelberg University Hospital, Germany; Translational Lung Research Center (TLRC) Heidelberg, member of the German Center for Lung Research (DZL), Heidelberg, Germany.
² Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital and National Center for Tumor Diseases (NCT), NCT Heidelberg, A Partnership Between DKFZ and Heidelberg University Hospital, Germany; Translational Lung Research Center (TLRC) Heidelberg, member of the German Center for Lung Research (DZL), Heidelberg, Germany; Lungenklinik Loewenstein, Department of Thoracic Oncology, Loewenstein, Germany.
³ Department of Respiratory Medicine, Evangelische Lungenklinik Berlin, Berlin, Germany.
⁴ Department of Pneumology, Helios Klinikum Emil von Behring, Berlin, Germany.
⁵ Department of Medicine V, University Hospital, LMU Munich, Germany; Comprehensive Pneumology Center Munich (CPC-M), member of the German Center for Lung Research (DZL), Munich, Germany.
⁶ Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
⁷ Translational Lung Research Center (TLRC) Heidelberg, member of the German Center for Lung Research (DZL), Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
⁸ Robert Bosch Centrum für Tumorerkrankungen (RBCT), Stuttgart, Germany.
⁹ Department of Hematology/Oncology, University Medical Center Augsburg, Augsburg, Germany as part of the BZKF (Bavarian Center for Cancer Research) and Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
¹⁰ Pathology, Medical Faculty, University of Augsburg, Augsburg, Germany, part of the Bavarian Cancer Research Center (BZKF), Augsburg, Germany.
¹¹ Klinik für Kardiologie, Angiologie und Pneumologie, Klinikum Esslingen, Germany.
¹² Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
¹³ Department of Pneumology, LungenClinic Großhansdorf, Großhansdorf, Germany; Airway Research Center North (ARCN), member of the German Center for Lung Research (DZL), Großhansdorf, Germany.
¹⁴ Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital and National Center for Tumor Diseases (NCT), NCT Heidelberg, A Partnership Between DKFZ and Heidelberg University Hospital, Germany; Translational Lung Research Center (TLRC) Heidelberg, member of the German Center for Lung Research (DZL), Heidelberg, Germany. Electronic address: Petros.Christopoulos@med.uni-heidelberg.de.

PMID: 38271745
DOI: 10.1016/j.ejca.2024.113556

Free article

First-line immunotherapy for lung cancer with MET exon 14 skipping and the relevance of TP53 mutations

Miriam Blasi et al. Eur J Cancer. 2024 Mar.

Free article

. 2024 Mar:199:113556.

doi: 10.1016/j.ejca.2024.113556. Epub 2024 Jan 17.

Authors

Affiliations

¹ Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital and National Center for Tumor Diseases (NCT), NCT Heidelberg, A Partnership Between DKFZ and Heidelberg University Hospital, Germany; Translational Lung Research Center (TLRC) Heidelberg, member of the German Center for Lung Research (DZL), Heidelberg, Germany.
² Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital and National Center for Tumor Diseases (NCT), NCT Heidelberg, A Partnership Between DKFZ and Heidelberg University Hospital, Germany; Translational Lung Research Center (TLRC) Heidelberg, member of the German Center for Lung Research (DZL), Heidelberg, Germany; Lungenklinik Loewenstein, Department of Thoracic Oncology, Loewenstein, Germany.
³ Department of Respiratory Medicine, Evangelische Lungenklinik Berlin, Berlin, Germany.
⁴ Department of Pneumology, Helios Klinikum Emil von Behring, Berlin, Germany.
⁵ Department of Medicine V, University Hospital, LMU Munich, Germany; Comprehensive Pneumology Center Munich (CPC-M), member of the German Center for Lung Research (DZL), Munich, Germany.
⁶ Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
⁷ Translational Lung Research Center (TLRC) Heidelberg, member of the German Center for Lung Research (DZL), Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
⁸ Robert Bosch Centrum für Tumorerkrankungen (RBCT), Stuttgart, Germany.
⁹ Department of Hematology/Oncology, University Medical Center Augsburg, Augsburg, Germany as part of the BZKF (Bavarian Center for Cancer Research) and Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
¹⁰ Pathology, Medical Faculty, University of Augsburg, Augsburg, Germany, part of the Bavarian Cancer Research Center (BZKF), Augsburg, Germany.
¹¹ Klinik für Kardiologie, Angiologie und Pneumologie, Klinikum Esslingen, Germany.
¹² Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
¹³ Department of Pneumology, LungenClinic Großhansdorf, Großhansdorf, Germany; Airway Research Center North (ARCN), member of the German Center for Lung Research (DZL), Großhansdorf, Germany.
¹⁴ Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital and National Center for Tumor Diseases (NCT), NCT Heidelberg, A Partnership Between DKFZ and Heidelberg University Hospital, Germany; Translational Lung Research Center (TLRC) Heidelberg, member of the German Center for Lung Research (DZL), Heidelberg, Germany. Electronic address: Petros.Christopoulos@med.uni-heidelberg.de.

PMID: 38271745
DOI: 10.1016/j.ejca.2024.113556

Erratum in

Corrigendum to "First-line immunotherapy for lung cancer with MET exon 14 skipping and the relevance of TP53 mutations" [Eur J Cancer 199 (2024) 113556].
Blasi M, Kuon J, Lüders H, Misch D, Kauffmann-Guerrero D, Hilbrandt M, Kazdal D, Falkenstern-Ge RF, Hackanson B, Dintner S, Faehling M, Kirchner M, Volckmar AL, Kopp HG, Allgäuer M, Grohé C, Tufman A, Reck M, Frost N, Stenzinger A, Thomas M, Christopoulos P. Blasi M, et al. Eur J Cancer. 2024 Jul;205:114130. doi: 10.1016/j.ejca.2024.114130. Epub 2024 May 24. Eur J Cancer. 2024. PMID: 38789333 No abstract available.

Abstract

Background: The efficacy of checkpoint inhibitors for non-small cell lung cancer (NSCLC) with MET exon 14 skipping (METΔ14ex) remains controversial.

Materials and methods: 110 consecutive METΔ14ex NSCLC patients receiving first-line chemotherapy (CHT) and/or immunotherapy (IO) in 10 German centers between 2016-2022 were analyzed.

Results: Combined CHT-IO was given to 35/110 (32%) patients, IO alone to 43/110 (39%), and CHT to 32/110 (29%) upfront. Compared to CHT, CHT-IO showed longer progression-free survival (median PFS 6 vs. 2.5 months, p = 0.004), more objective responses (ORR 49% vs. 28%, p = 0.086) and numerically longer overall survival (OS 16 vs. 10 months, p = 0.240). For IO monotherapy, OS (14 vs. 16 months) and duration of response (26 vs. 22 months) were comparable to those of CHT-IO. Primary progressive disease (PD) was more frequent with IO compared to CHT-IO (13/43 vs. 3/35, p = 0.018), particularly for never-smokers (p = 0.041). Higher PD-L1 TPS were not associated with better IO outcomes, but TP53 mutated tumors showed numerically improved ORR (56% vs. 32%, p = 0.088) and PFS (6 vs. 3 months, p = 0.160), as well as longer OS in multivariable analysis (HR=0.54, p = 0.034) compared to their wild-type counterparts. Any second-line treatment was administered to 35/75 (47%) patients, with longer survival for capmatinib or tepotinib compared to crizotinib (PFS 10 vs. 3 months, p = 0.013; OS 16 vs. 13 months, p = 0.270).

Conclusion: CHT-IO is superior to CHT, and IO alone also effective for METΔ14ex NSCLC, especially in the presence of TP53 mutations and independent of PD-L1 expression, but never-smokers are at higher risk of primary PD.

Keywords: Immunotherapy; Lung cancer; Met exon 14 skipping; TP53; Tyrosine kinase inhibitors.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JK: speaker’s honoraria from BMS, AstraZeneca and Pfizer, travel grants from Takeda, advisory board honoraria from Takeda, Roche and AstraZeneca. DM: advisory board/lecture fees from AstraZeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Novartis, Roche, Sanofi and Takeda. DiKa: advisory boards/speaker´s honoraria from BMS, Boehringer-Ingelheim, MSD, Roche, Janssen, Pfizer, AstraZeneca; support for attending meetings from Novartis, Boehringer-Ingelheim. MH: advisory board, speaker’s honoraria and travel grants from Boehringer-Ingelheim. BH: advisory board/lecture fees from AstraZeneca, Boehringer Ingelheim, BMS, MSD, Roche, Pfizer. MF: grants from AstraZeneca, BMS, MSD, and Roche; consulting fees from AstraZeneca, MSD, Roche, BMS; speaker´s honoraria from AstraZeneca, MSD, Roche, BMS. MK: speaker’s honoraria and travel grants from Veracyte Inc. AV: speaker’s honoraria from AstraZeneca. MA: speaker’s honoraria from Boehringer Ingelheim. CG: advisory board/lecture fees from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Takeda, MSD, Novartis, Pfizer, Roche, AbbVie, Tesaro/GSK and Blueprints Medicines. AT: consulting fees from Boehringer Ingelheim, Daiichi, Astra Zeneca, Roche, Pfizer, BMS, MSD, Sanofi, Lilly, Novartis; speaker’s honoraria from Boehringer Ingelheim, Daiichi, Astra Zeneca, Roche, Pfizer, BMS, MSD, Sanofi, Lilly, Novartis; travel grants from Sanofi, Janssen, Daiichi; BMS, MSD, AstraZeneca. MR: advisory board/lecture fees from Amgen, AstraZeneca, BMS, Boehringer, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Samsung. NF: grants from Roche, consulting fees from AbbVie, Amgen, AstraZeneca, BeiGene, Berlinchemie, Boehringer Ingelheim, Bristol Myers&Squibb, Lilly, Merck Sharp&Dohme, Merck, Novartis, Pfizer, Roche, Sanofi, Takeda; support for attending meetings from Amgen, AstraZeneca, BMS, Janssen, Lilly, Takeda. AS: advisory board honoraria from BMS, AstraZeneca, ThermoFisher, Novartis, speaker’s honoraria from BMS, Illumina, AstraZeneca, Novartis, ThermoFisher, MSD, Roche, and research funding from Chugai and BMS. MT: research funding from AstraZeneca, BMS, Merck, Roche, Takeda; speaker’s honoraria from AstraZeneca, Beigene, Novartis, Eli Lilly, BMS, MSD, Roche, Celgene, Takeda, AbbVie, Boehringer Ingelheim, Pfizer, Eli Lilly, MSD, Takeda, Pfizer, Chugai, Daiichi Sankyo, GlaxoSmithKline, Janssen Oncology, Merck, Sanofi and travel grants from AstraZeneca, BMS, MSD, Novartis, Daiichi Sankyo, Janssen Oncology, Lilly, Merck, Pfizer, Roche, Sanofi, Takeda, Boehringer Ingelheim. PC: research funding from AstraZeneca, Amgen, Boehringer Ingelheim, Novartis, Roche, and Takeda, speaker’s honoraria from AstraZeneca, Janssen, Novartis, Roche, Pfizer, Thermo Fisher, Takeda, support for attending meetings from AstraZeneca, Eli Lilly, Daiichi Sankyo, Gilead, Novartis, Pfizer, Takeda, and personal fees for participating to advisory boards from AstraZeneca, Boehringer Ingelheim, Chugai, Pfizer, Novartis, MSD, Takeda and Roche, all outside the submitted work. All other authors have no conflicts of interest to declare.

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First-line immunotherapy for lung cancer with MET exon 14 skipping and the relevance of TP53 mutations

Affiliations

First-line immunotherapy for lung cancer with MET exon 14 skipping and the relevance of TP53 mutations

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

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