Petros Christopoulos1,2, Farastuk Bozorgmehr1,2, Lena Brückner1,2, Inn Chung1,2, Johannes Krisam3, Marc A Schneider2,4, Albrecht Stenzinger2,5, Regina Eickhoff6, Daniel W Mueller6, Michael Thomas7,8. 1. Department of Thoracic Oncology, Thoraxklinik at University Hospital of Heidelberg, Röntgenstraße 1, 69126, Heidelberg, Germany. 2. Translational Lung Research Center Heidelberg TLRCH, Member of the German Center for Lung Research DZL, Im Neuenheimer Feld 156, 69120, Heidelberg, Germany. 3. University Hospital of Heidelberg, Institute of Medical Biometry and Informatics, Im Neuenheimer Feld 130.3, 69120, Heidelberg, Germany. 4. Translational Research Unit (STF), Thoraxklinik at University Hospital of Heidelberg, Röntgenstraße 1, 69126, Heidelberg, Germany. 5. University of Heidelberg, Institute of Pathology, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany. 6. Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Steinbacher Hohl 2-26, 60488, Frankfurt am Main, Germany. 7. Department of Thoracic Oncology, Thoraxklinik at University Hospital of Heidelberg, Röntgenstraße 1, 69126, Heidelberg, Germany. michael.thomas@med.uni-heidelberg.de. 8. Translational Lung Research Center Heidelberg TLRCH, Member of the German Center for Lung Research DZL, Im Neuenheimer Feld 156, 69120, Heidelberg, Germany. michael.thomas@med.uni-heidelberg.de.
Abstract
BACKGROUND: Availability of potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) has pushed the median survival of ALK+ non-smallcell lung cancer (NSCLC) patients to over five years. In particular, second-generation ALK TKI have demonstrated superiority compared to the first-generation compound crizotinib and are meanwhile standard first-line treatment. However, clinical courses of individual patients vary widely, with secondary development of drug resistance and intracranial progression remaining important problems. While these limitations highlight the need for better disease monitoring and additional therapeutic tools, molecular tumor features are increasingly recognized as crucial determinants of clinical outcome. This trial aims to optimize management of ALK+ NSCLC by analyzing the efficacy of second-generation ALK inhibitors in conjunction with deep longitudinal phenotyping across two treatment lines. METHODS/ DESIGN: In this exploratory prospective phase II clinical trial, newly diagnosed ALK+ NSCLC patients will be randomized into two treatment arms, stratified by presence of brain metastases and ECOG performance status: brigatinib (experimental arm) vs. any other approved second-generation ALK TKI. Tumor tissue and blood samples will be collected for biomarker analysis at the beginning and throughout the study period to investigate baseline molecular tumor properties and analyze the development of acquired drug resistance. In addition, participating investigators and patients will have the possibility of fast-track molecular tumor and ctDNA profiling at the time of disease progression using state-of-the-art next-generation sequencing (NGS), in order to support decisions regarding next-line therapy. DISCUSSION: Besides supporting therapeutic decisions for enrolled patients, the ABP trial primarily aims to deepen the understanding of the underlying biology and facilitate development of a framework for individualized management of ALK+ NSCLC according to molecular features. Patients with low molecular risk and the perspective of a "chronic disease" will be distinguished from "high-risk" cases, molecular properties of which will be utilized to elaborate improved methods of non-invasive monitoring and novel preclinical models in order to advance therapeutic strategies. TRIAL REGISTRATION: Clinicaltrials.gov , NCT04318938. Registered March 182,020, https://www.clinicaltrials.gov/ct2/show/NCT04318938 Eudra-CT, 2019-001828-36. Registered September 302,019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-001828-36.
RCT Entities:
BACKGROUND: Availability of potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) has pushed the median survival of ALK+ non-smallcell lung cancer (NSCLC) patients to over five years. In particular, second-generation ALK TKI have demonstrated superiority compared to the first-generation compound crizotinib and are meanwhile standard first-line treatment. However, clinical courses of individual patients vary widely, with secondary development of drug resistance and intracranial progression remaining important problems. While these limitations highlight the need for better disease monitoring and additional therapeutic tools, molecular tumor features are increasingly recognized as crucial determinants of clinical outcome. This trial aims to optimize management of ALK+ NSCLC by analyzing the efficacy of second-generation ALK inhibitors in conjunction with deep longitudinal phenotyping across two treatment lines. METHODS/ DESIGN: In this exploratory prospective phase II clinical trial, newly diagnosed ALK+ NSCLCpatients will be randomized into two treatment arms, stratified by presence of brain metastases and ECOG performance status: brigatinib (experimental arm) vs. any other approved second-generation ALK TKI. Tumor tissue and blood samples will be collected for biomarker analysis at the beginning and throughout the study period to investigate baseline molecular tumor properties and analyze the development of acquired drug resistance. In addition, participating investigators and patients will have the possibility of fast-track molecular tumor and ctDNA profiling at the time of disease progression using state-of-the-art next-generation sequencing (NGS), in order to support decisions regarding next-line therapy. DISCUSSION: Besides supporting therapeutic decisions for enrolled patients, the ABP trial primarily aims to deepen the understanding of the underlying biology and facilitate development of a framework for individualized management of ALK+ NSCLC according to molecular features. Patients with low molecular risk and the perspective of a "chronic disease" will be distinguished from "high-risk" cases, molecular properties of which will be utilized to elaborate improved methods of non-invasive monitoring and novel preclinical models in order to advance therapeutic strategies. TRIAL REGISTRATION: Clinicaltrials.gov , NCT04318938. Registered March 182,020, https://www.clinicaltrials.gov/ct2/show/NCT04318938 Eudra-CT, 2019-001828-36. Registered September 302,019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-001828-36.
Authors: Emilio Francesco Giunta; Alessio Signori; Howard Jack West; Giulio Metro; Alex Friedlaender; Kaushal Parikh; Giuseppe Luigi Banna; Alfredo Addeo Journal: Front Oncol Date: 2022-06-14 Impact factor: 5.738