Nikolaj Frost1, Petros Christopoulos2, Diego Kauffmann-Guerrero3, Jan Stratmann4, Richard Riedel5, Monica Schaefer6, Jürgen Alt7, Sylvia Gütz8, Daniel C Christoph9, Eckart Laack10, Martin Faehling11, Richard Fischer12, Klaus Fenchel13, Sebastian Haen14, Lukas Heukamp15, Christian Schulz16, Frank Griesinger17. 1. Department of Infectious Diseases and Respiratory Medicine, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, D-13353, Germany Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Infectious Diseases and Pulmonary Medicine, Berlin, Germany. 2. Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany, and Translational Research Center Heidelberg, Member of the German Center for Lung Research (DZL). 3. Division of Respiratory Medicine and Thoracic Oncology, Department of Internal Medicine V University of Munich (LMU), Thoracic Oncology Centre Munich (TOM), Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Bayern, Germany. 4. Department of Internal Medicine II, University Clinic of Frankfurt, Frankfurt, Germany. 5. Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany. 6. HELIOS Klinikum Emil-von-Behring, Lungenklinik Heckeshorn, Berlin, Germany. 7. Department of Internal Medicine III (Hematology, Oncology, Pneumology), University Medical Center Mainz, Mainz, Germany. 8. Department of Respiratory Medicine and Cardiology, Evangelisches Diakonissenkrankenhaus Leipzig, Leipzig, Germany. 9. Department of Hematology and Oncology, Evang. Kliniken Essen-Mitte, Essen, Germany. 10. Hämato-Onkologie Hamburg, Hamburg, Germany. 11. Department of Cardiology, Angiology and Pneumonology, Klinikum Esslingen, Esslingen, Germany. 12. Onkologie Dreiländereck, Lörrach, Germany. 13. Private Practice for Hematology and Oncology, Saalfeld, Germany. 14. Department of Hematology and Oncology, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. 15. Institute for Hematopathology, Hamburg, Germany. 16. Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany. 17. Department Internal Medicine-Oncology, Pius Hospital, Oldenburg, Germany.
Abstract
INTRODUCTION: We report on the results of the German early access program (EAP) with the third-generation ALK- and ROS1-inhibitor lorlatinib. PATIENTS AND METHODS: Patients with documented treatment failure of all approved ALK/ROS1-specific therapies or with resistance mutations not covered by approved inhibitors or leptomeningeal carcinomatosis were enrolled and analyzed. RESULTS: In total, 52 patients were included [median age 57 years (range 32-81), 54% female, 62% never smokers, 98% adenocarcinoma]; 71% and 29% were ALK- and ROS1-positive, respectively. G1202R and G2032R resistance mutations prior to treatment with lorlatinib were observed in 10 of 26 evaluable patients (39%), 11 of 39 patients showed TP53 mutations (28%). Thirty-six patients (69%) had active brain metastases (BM) and nine (17%) leptomeningeal carcinomatosis when entering the EAP. Median number of prior specific TKIs was 3 (range 1-4). Median duration of treatment, progression-free survival (PFS), response rate and time to treatment failure were 10.4 months, 8.0 months, 54% and 13.0 months. Calculated 12-, 18- and 24-months survival rates were 65, 54 and 47%, overall survival since primary diagnosis (OS2) reached 79.6 months. TP53 mutations were associated with a substantially reduced PFS (3.7 versus 10.8 month, HR 3.3, p = 0.003) and were also identified as a strong prognostic biomarker (HR for OS2 3.0 p = 0.02). Neither prior treatments with second-generation TKIs nor BM had a significant influence on PFS and OS. CONCLUSIONS: Our data from real-life practice demonstrate the efficacy of lorlatinib in mostly heavily pretreated patients, providing a clinically meaningful option for patients with resistance mutations not covered by other targeted therapies and those with BM or leptomeningeal carcinomatosis.
INTRODUCTION: We report on the results of the German early access program (EAP) with the third-generation ALK- and ROS1-inhibitor lorlatinib. PATIENTS AND METHODS: Patients with documented treatment failure of all approved ALK/ROS1-specific therapies or with resistance mutations not covered by approved inhibitors or leptomeningeal carcinomatosis were enrolled and analyzed. RESULTS: In total, 52 patients were included [median age 57 years (range 32-81), 54% female, 62% never smokers, 98% adenocarcinoma]; 71% and 29% were ALK- and ROS1-positive, respectively. G1202R and G2032R resistance mutations prior to treatment with lorlatinib were observed in 10 of 26 evaluable patients (39%), 11 of 39 patients showed TP53 mutations (28%). Thirty-six patients (69%) had active brain metastases (BM) and nine (17%) leptomeningeal carcinomatosis when entering the EAP. Median number of prior specific TKIs was 3 (range 1-4). Median duration of treatment, progression-free survival (PFS), response rate and time to treatment failure were 10.4 months, 8.0 months, 54% and 13.0 months. Calculated 12-, 18- and 24-months survival rates were 65, 54 and 47%, overall survival since primary diagnosis (OS2) reached 79.6 months. TP53 mutations were associated with a substantially reduced PFS (3.7 versus 10.8 month, HR 3.3, p = 0.003) and were also identified as a strong prognostic biomarker (HR for OS2 3.0 p = 0.02). Neither prior treatments with second-generation TKIs nor BM had a significant influence on PFS and OS. CONCLUSIONS: Our data from real-life practice demonstrate the efficacy of lorlatinib in mostly heavily pretreated patients, providing a clinically meaningful option for patients with resistance mutations not covered by other targeted therapies and those with BM or leptomeningeal carcinomatosis.
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