Polyclonal on- and off-target resistance mutations in an EML4-ALK positive non-small cell lung cancer patient under ALK inhibition

// Marcel Kemper 1 , 2 , * , Georg Evers 1 , 2 , * , Arik Bernard Schulze 1 , 2 , Jan Sperveslage 3 , Christoph Schülke 4 , Georg Lenz 1 , 2 , Thomas Herold 5 , Wolfgang Hartmann 3 , Hans-Ulrich Schildhaus 2 , 5 , # and Annalen Bleckmann 1 , 2 , 6 , # 1 Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Muenster, 48149 Muenster, Germany 2 West German Cancer Center, Sites Muenster & Essen, 45147 Essen, Germany 3 Gerhard-Domagk-Institute of Pathology, University Hospital Muenster, 48149 Muenster, Germany 4 Institute of Clinical Radiology, University Hospital Muenster, 48149 Muenster, Germany 5 Institute of Pathology, University Hospital Essen, 45147 Essen, Germany 6 Department of Hematology/Medical Oncology, University Medical Center Goettingen, 37075 Goettingen, Germany * Authors share first authorship # Authors share last authorship Correspondence to: Annalen Bleckmann, email: annalen.bleckmann@ukmuenster.de Keywords: NSCLC; resistance mutations; ALK; KRAS; ALK inhibitors Received: June 25, 2021 Accepted: August 18, 2021 Published: September 14, 2021 Copyright: © 2021 Kemper et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Treatment of advanced stage anaplastic lymphoma kinase ( ALK ) positive non-small cell lung cancer (NSCLC) with ALK tyrosine kinase inhibitors (TKIs) has been shown to be superior to standard platinum-based chemotherapy. However, secondary progress of disease frequently occurs under ALK inhibitor treatment. The clinical impact of re-biopsies for treatment decisions beyond secondary progress is, however, still under debate. Here, we report on two novel subsequent polyclonal on- and off-target resistance mutations in a patient with ALK -fused NSCLC under ALK inhibitor treatment. A 63-year-old male patient with an advanced stage EML4-ALK fused pulmonary adenocarcinoma was initially successfully treated with the second-generation ALK inhibitor alectinib and upon progressions subsequently with brigatinib, lorlatinib and chemoimmunotherapy (CIT). Progress to alectinib was associated with a so far undescribed ALK mutation (p.A1200_G1201delinsW) which was, however, tractable by brigatinib. An off-target KRAS -mutation (p.Q61K) occurred in association with subsequent progression under second-line TKI treatment. Third-line lorlatinib showed limited efficacy but chemoimmunotherapy resulted in disappearance of the KRAS mutant clone and clinical tumor control for another eight months. In conclusion, we suggest molecular profiling of progressive tumor disease also for ALK -positive NSCLC to personalize treatment in a subgroup of ALK -positive patients.