Lorlatinib in pretreated ALK- or ROS1-positive lung cancer and impact of TP53 co-mutations: results from the German early access program

Nikolaj Frost; Petros Christopoulos; Diego Kauffmann-Guerrero; Jan Stratmann; Richard Riedel; Monica Schaefer; Jürgen Alt; Sylvia Gütz; Daniel C Christoph; Eckart Laack; Martin Faehling; Richard Fischer; Klaus Fenchel; Sebastian Haen; Lukas Heukamp; Christian Schulz; Frank Griesinger

doi:10.1177/1758835920980558

Lorlatinib in pretreated ALK- or ROS1-positive lung cancer and impact of TP53 co-mutations: results from the German early access program

Ther Adv Med Oncol. 2021 Feb 9:13:1758835920980558. doi: 10.1177/1758835920980558. eCollection 2021.

Authors

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

Affiliations

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.

Keywords: ALK; NSCLC; ROS1; TP53; brain metastases; early access program; lorlatinib.