Small cell transformation in EGFR-mutated non-small cell lung cancer: DLL3 expression and efficacy of immune checkpoint inhibitors or tyrosine kinase inhibitors combined with chemotherapy

Felix Carl Saalfeld; Johanna Möller; Petros Christopoulos; Carina Wenzel; Anna Rasokat; Xuejun Alice Wang; Ioannis Vathiotis; David König; Oliver Illini; Christian Grohé; Marcel Wiesweg; Claas Wesseler; Christoph Schubart; Natalie Pelusi; Gernot Rohde; Tobias R Overbeck; Jutta Kirfel; Jürgen Alt; Diego Kauffmann-Guerrero; Frank Griesinger; Jonas Kulhavy; Michael Allgäuer; Anna Klimova; Maret Schütz; Daniela E Aust; Maximilian J Hochmair; Sacha I Rothschild; Konstantinos N Syrigos; Rajwanth Veluswamy; Sebastian Michels; Albrecht Stenzinger; Korinna Jöhrens; Martin Wermke

doi:10.1016/j.ejca.2024.115065

Small cell transformation in EGFR-mutated non-small cell lung cancer: DLL3 expression and efficacy of immune checkpoint inhibitors or tyrosine kinase inhibitors combined with chemotherapy

Eur J Cancer. 2024 Dec:213:115065. doi: 10.1016/j.ejca.2024.115065. Epub 2024 Oct 12.

Authors

Felix Carl Saalfeld¹, Johanna Möller², Petros Christopoulos³, Carina Wenzel⁴, Anna Rasokat⁵, Xuejun Alice Wang⁶, Ioannis Vathiotis⁷, David König⁸, Oliver Illini⁹, Christian Grohé¹⁰, Marcel Wiesweg¹¹, Claas Wesseler¹², Christoph Schubart¹³, Natalie Pelusi¹⁴, Gernot Rohde¹⁵, Tobias R Overbeck¹⁶, Jutta Kirfel¹⁷, Jürgen Alt¹⁸, Diego Kauffmann-Guerrero¹⁹, Frank Griesinger²⁰, Jonas Kulhavy²¹, Michael Allgäuer²², Anna Klimova²³, Maret Schütz⁴, Daniela E Aust⁴, Maximilian J Hochmair⁹, Sacha I Rothschild²⁴, Konstantinos N Syrigos⁷, Rajwanth Veluswamy⁶, Sebastian Michels⁵, Albrecht Stenzinger²⁵, Korinna Jöhrens²⁶, Martin Wermke²⁷

Affiliations

¹ Clinic for Internal Medicine I, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany; National Center for Tumor Diseases, Dresden, Germany; National Network Genomic Medicine Lung Cancer (nNGM), Germany.
² Clinic for Internal Medicine I, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany; National Center for Tumor Diseases, Dresden, Germany.
³ Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center for Lung Research (DZL), Heidelberg, Germany; National Network Genomic Medicine Lung Cancer (nNGM), Germany.
⁴ National Center for Tumor Diseases, Dresden, Germany; Department for Pathology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany; National Network Genomic Medicine Lung Cancer (nNGM), Germany.
⁵ Lung Cancer Group Cologne, Department I for Internal Medicine and Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany; National Network Genomic Medicine Lung Cancer (nNGM), Germany.
⁶ Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
⁷ Third Department of Internal Medicine, Sotiria Hospital, National, and Kapodistrian University of Athens, Athens, Greece.
⁸ Division of Medical Oncology, University Hospital Basel, Basel, Switzerland.
⁹ Department of Respiratory and Critical Care Medicine, Klinik Floridsdorf, Vienna Healthcare Group, Vienna, Austria; Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Vienna, Austria.
¹⁰ Department of Respiratory Diseases - ELK, Lindenberger Weg 27, 13125 Berlin, Germany; National Network Genomic Medicine Lung Cancer (nNGM), Germany.
¹¹ West German Cancer Center, Department of Medical Oncology, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; National Network Genomic Medicine Lung Cancer (nNGM), Germany.
¹² Department of Pneumology, Asklepios Tumorzentrum Hamburg, Klinikum Harburg, Hamburg, Germany.
¹³ Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; National Network Genomic Medicine Lung Cancer (nNGM), Germany.
¹⁴ Institute of Pathology, University Hospital, University of Bonn, Venusberg-Campus 1, Gebäude 62, 53127 Bonn, Germany; National Network Genomic Medicine Lung Cancer (nNGM), Germany.
¹⁵ Goethe University Frankfurt, University Hospital, Medical Clinic I, Department of Respiratory Medicine, Frankfurt/Main, Germany.
¹⁶ Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen University, Göttingen, Germany; National Network Genomic Medicine Lung Cancer (nNGM), Germany.
¹⁷ Institute of Pathology, UKSH Campus Lübeck, University Hospital Schleswig-Holstein, Ratzenburger Allee 160, Haus V50, 23538 Lübeck, Germany; National Network Genomic Medicine Lung Cancer (nNGM), Germany.
¹⁸ Department of Hematology and Medical Oncology, University Medical Center Mainz, Mainz, Germany; National Network Genomic Medicine Lung Cancer (nNGM), Germany.
¹⁹ Division of Respiratory Medicine and Thoracic Oncology, Department of Medicine V, Thoracic Oncology Center Munich, University Hospital, University of Munich (LMU), Germany; National Network Genomic Medicine Lung Cancer (nNGM), Germany.
²⁰ Department of Hematology and Oncology, Pius Hospital, University Medicine Oldenburg, Oldenburg, Germany; National Network Genomic Medicine Lung Cancer (nNGM), Germany.
²¹ Translational Oncology/Early Clinical Trial Unit (ECTU), Bavarian Cancer Research Center, National Center for Tumor Diseases, Comprehensive Cancer Center Mainfranken and University Hospital Würzburg, Würzburg, Germany; National Network Genomic Medicine Lung Cancer (nNGM), Germany.
²² Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany; National Network Genomic Medicine Lung Cancer (nNGM), Germany.
²³ Core Unit for Data Management and Analytics, National Center for Tumor Diseases, Dresden, Germany.
²⁴ Cantonal Hospital Baden, Department Internal Medicine, Center of Oncology & Hematology, Baden, Switzerland.
²⁵ Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center for Lung Research (DZL), Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany; National Network Genomic Medicine Lung Cancer (nNGM), Germany.
²⁶ National Center for Tumor Diseases, Dresden, Germany; Department for Pathology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany; Department for Pathology, Klinikum Chemnitz gGmbH, Chemnitz, Germany.
²⁷ Clinic for Internal Medicine I, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany; National Center for Tumor Diseases, Dresden, Germany; National Network Genomic Medicine Lung Cancer (nNGM), Germany. Electronic address: [email protected].

PMID: 39423775
DOI: 10.1016/j.ejca.2024.115065

Abstract

Introduction: Small cell transformation (SCT) is a typical mechanism of adaptive resistance to third generation epidermal growth factor receptor inhibitors (EGFRi) which have become the standard of care for EGFR-driven non-small cell lung cancer (EGFR+ NSCLC). Little is known about the optimal management of SCT patients. This study aimed to compare outcomes under platinum/etoposide chemotherapy alone (chemo) or in combination with EGFR inhibitors (EGFRi+chemo) or immune checkpoint inhibitors (ICI+chemo). In addition, DLL3 expression was explored as potential novel therapeutic target.

Methods: We conducted a retrospective study on patients with EGFR+ NSCLC and SCT treated at 19 centers in Europe and the United States. A total of 47 patients were included of whom 17 received chemo, 20 ICI+chemo, and 10 EGFRi+chemo. We analyzed DLL3 expression by immunohistochemistry.

Results: In the entire cohort, median overall survival (OS) from start of first SCT therapy was 11 months (95 % confidence interval [95 %CI] 9.1-12.9) and median progression-free survival (PFS) was 5 months (95 %CI 4.2-5.8). Median PFS was similar in all three groups (chemo and ICI+chemo 4 months, EGFRi+chemo 6 months), and 12-months PFS was 12 % (95 %CI 2 %-31 %), 13 % (95 %CI 0 %-43 %), and 0 % for ICI+chemo, EGFRi+chemo, and chemo, respectively. Median OS in the ICI+chemo group was 13 months (95 %CI 5.5-20.5) compared to 10 months (95 %CI 7.6-12.4) with chemo and EGFRi+chemo (95 %CI 8.1-11.9), respectively. Before and after SCT, 0 % and 93 % of tumors were DLL3-positive.

Conclusions: Our results suggest that ICI+chemo and DLL3-targeting agents are worth further exploration in EGFR+ NSCLC undergoing SCT.

Presented elsewhere: Part of this work has been presented at ESMO annual meeting in Madrid, Spain in October 2023 (Poster 1336 P).

Keywords: DLL3; EGFR mutation; Immune checkpoint inhibitor; Non-small cell lung cancer; Small cell transformation.

Publication types

Multicenter Study

MeSH terms

Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
Carcinoma, Non-Small-Cell Lung* / drug therapy
Carcinoma, Non-Small-Cell Lung* / genetics
Carcinoma, Non-Small-Cell Lung* / metabolism
Carcinoma, Non-Small-Cell Lung* / mortality
Carcinoma, Non-Small-Cell Lung* / pathology
Cell Transformation, Neoplastic / genetics
ErbB Receptors* / genetics
ErbB Receptors* / metabolism
Female
Humans
Immune Checkpoint Inhibitors* / therapeutic use
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Lung Neoplasms* / mortality
Lung Neoplasms* / pathology
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism
Middle Aged
Mutation*
Progression-Free Survival
Protein Kinase Inhibitors / therapeutic use
Retrospective Studies
Tyrosine Kinase Inhibitors

Substances

ErbB Receptors
DLL3 protein, human
Immune Checkpoint Inhibitors
EGFR protein, human
Intracellular Signaling Peptides and Proteins
Protein Kinase Inhibitors
Membrane Proteins
Tyrosine Kinase Inhibitors