@article{e03b14f31f0d4ea58e339e6784a04ef1,
title = "Safety and Efficacy of Crizotinib in Patients With Advanced or Metastatic ROS1-Rearranged Lung Cancer (EUCROSS): A European Phase II Clinical Trial",
abstract = "Introduction: ROS1 rearrangements are found in 1\% of lung cancer patients. Therapeutic efficacy of crizotinib in this subset has been shown in early phase trials in the United States and East Asia. Here we present data on efficacy and safety of a prospective phase II trial evaluating crizotinib in European ROS1-positive patients (EUCROSS).Patients and Methods: The trial was a multicenter, single-arm phase II trial (Clinicaltrial.gov identifier:NCT02183870). Key eligibility criteria included patients who were 18 years of age or older with advanced/metastatic lung cancer and centrally confirmed ROS1-rearranged lung cancer (fluorescence-in situ hybridization). Treatment included 250 mg crizotinib twice daily. The primary endpoint was investigator-assessed objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors, version 1.1). Key secondary endpoints were progression-free survival (PFS), overall survival, efficacy by independent radiologic review, safety, health-related quality of life, and molecular characterization of tumor tissue.Results: Thirty-four patients received treatment. Four patients were excluded from efficacy analysis. Investigator ORR was 70\% (95\% confidence interval [CI]: 51-85; 21 of 30 patients) and median PFS was 20.0 months (95\% CI: 10.1-not reached). Two patients with ROS1 wild-type sequences assessed by DNA sequencing had progression as best response. CD74-ROS1-positive patients had a trend towards a higher ORR and longer median PFS. TP53-co-mutant patients had a significantly shorter median PFS than wild-type patients (7.0 months, 95\% CI: 1.7-20.0 versus 24.1 months, 95\% CI: 10.1-not reached; p = 0.022). Treatment-related adverse events were documented in 33 of 34 patients (97\%).Conclusions: Crizotinib is highly effective and safe in patients with ROS1-rearranged lung cancer. ROS1-/TP53-co-aberrant patients had a significantly worse outcome compared to TP53 wild-type patients. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.",
keywords = "Lung cancer, Targeted treatment, ROS1, Crizotinib, TP53, ROS1 REARRANGEMENTS, ANAPLASTIC LYMPHOMA, ANTITUMOR-ACTIVITY, KINASE INHIBITION, TARGETING ROS1, ALK, ADENOCARCINOMA, CHEMOTHERAPY, MUTATIONS, FUSIONS",
author = "Sebastian Michels and Bartomeu Massuti and Hans-Ulrich Schildhaus and Jeremy Franklin and Martin Sebastian and Enriqueta Felip and Christian Grohe and Delvys Rodriguez-Abreu and Abdulla, \{Diana S. Y.\} and Helge Bischoff and Christian Brandts and Enric Carcereny and Jesus Corral and Dingemans, \{Anne-Marie C.\} and Eva Pereira and Jana Fassunke and Fischer, \{Rieke N.\} and Masyar Gardizi and Lukas Heukamp and Amelia Insa and Anna Kron and Roopika Menon and Thorsten Persigehl and Martin Reck and Richard Riedel and Rothschild, \{Sacha I.\} and Scheel, \{Andreas H.\} and Matthias Scheffler and Petra Schmalz and Smit, \{Egbert F.\} and Meike Limburg and Mariano Provencio and Niki Karachaliou and Sabine Merkelbach-Bruse and Martin Hellmich and Lucia Nogova and Reinhard Buettner and Rafael Rosell and Juergen Wolf",
note = "Funding Information: Disclosure: Dr. Michels has reveived grants from Pfizer and Novartis; and has received personal fees from Pfizer, Novartis, Roche, and Boehringer Ingelheim. Dr. Massut{\'i} has received personal fees from Roche, Bristol-Myers Squibb, Merck Sharp \& Dohme, Boehringer Ingelheim, and Pfizer. Dr. Schildhaus has received grants from Novartis and Roche; and has received personal fees from ZytoVision, Pfizer, Novartis, and Roche. Dr. Sebastian has received personal fees from Boehringer Ingelheim, Lilly, Pfizer, Novartis, Roche, Astra Zeneca, Bristol-Myers Squibb, Merck Sharp \& Dohme, Takeda, Mediolanum, AbbVie, and Celgene. Dr. Felip has received personal fees from Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, Merck Sharp \& Dohme, Novartis, and Merck. Dr. Abdulla has received personal fees from Pfizer Pharma GmbH, Bristol-Myers Squibb, Boehringer Ingelheim, Novartis, Merck Sharpe \& Dohme, Roche Pharma AG, and Loxo Oncology. Dr. Dingemans has received personal fees from Pfizer. Dr. Gardizi has received grants from Pfizer. Dr. Reck has received personal fees from Bristol-Myers Squibb, Astra Zeneca, Abbott, Boehringer Ingelheim, Celgene, Merck KGaA (EMD), Merck Sharpe \& Dohme, Pfizer, Novartis, and Roche. Dr. Riedel has received personal fees from Boehringer Ingelheim; and has received nonfinancial support from Boehringer Ingelheim, Eli Lilly, and Novartis. Dr. Rothschild is a Medical Advisor for the Federal Committee for Pharmaceutical Products, Federal Office of Public Health (FOPH), Switzerland; and has received honoraria for his institution from Pfizer and Novartis. Dr. Merkelbach-Bruse has received personal fees from Pfizer, Astra Zeneca, Roche, Bristol-Myers Squibb, and Novartis. Dr. Nogova has received grants from Pfizer; and has received personal fees from Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Novartis, and Roche. Dr. Wolf has received personal fees from AbbVie, Astra Zeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, Ignyta, Lilly, Merck Sharp \& Dohme, Novartis, Pfizer, and Roche; and has received research support to his institution from Bristol-Myers Squibb, Merck Sharp \& Dohme, Novartis, and Pfizer. The remaining authors declare no conflict of interest.This trial was supported by Clinical Trials Centre Cologne (CTCC)Medical Faculty, University of Cologne by performing the overall Project Management, Data Base Development, Site Management, Data Monitoring in Germany and Switzerland, and Safety Management and by the Spanish Lung Cancer Group by performing Project Management and Site Monitoring in Spain. The authors thank all the patients and investigators who participated in the trial conduct. Funding Information: Disclosure: Dr. Michels has reveived grants from Pfizer and Novartis; and has received personal fees from Pfizer, Novartis, Roche, and Boehringer Ingelheim. Dr. Massut? has received personal fees from Roche, Bristol-Myers Squibb, Merck Sharp \& Dohme, Boehringer Ingelheim, and Pfizer. Dr. Schildhaus has received grants from Novartis and Roche; and has received personal fees from ZytoVision, Pfizer, Novartis, and Roche. Dr. Sebastian has received personal fees from Boehringer Ingelheim, Lilly, Pfizer, Novartis, Roche, Astra Zeneca, Bristol-Myers Squibb, Merck Sharp \& Dohme, Takeda, Mediolanum, AbbVie, and Celgene. Dr. Felip has received personal fees from Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, Merck Sharp \& Dohme, Novartis, and Merck. Dr. Abdulla has received personal fees from Pfizer Pharma GmbH, Bristol-Myers Squibb, Boehringer Ingelheim, Novartis, Merck Sharpe \& Dohme, Roche Pharma AG, and Loxo Oncology. Dr. Dingemans has received personal fees from Pfizer. Dr. Gardizi has received grants from Pfizer. Dr. Reck has received personal fees from Bristol-Myers Squibb, Astra Zeneca, Abbott, Boehringer Ingelheim, Celgene, Merck KGaA (EMD), Merck Sharpe \& Dohme, Pfizer, Novartis, and Roche. Dr. Riedel has received personal fees from Boehringer Ingelheim; and has received nonfinancial support from Boehringer Ingelheim, Eli Lilly, and Novartis. Dr. Rothschild is a Medical Advisor for the Federal Committee for Pharmaceutical Products, Federal Office of Public Health (FOPH), Switzerland; and has received honoraria for his institution from Pfizer and Novartis. Dr. Merkelbach-Bruse has received personal fees from Pfizer, Astra Zeneca, Roche, Bristol-Myers Squibb, and Novartis. Dr. Nogova has received grants from Pfizer; and has received personal fees from Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Novartis, and Roche. Dr. Wolf has received personal fees from AbbVie, Astra Zeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, Ignyta, Lilly, Merck Sharp \& Dohme, Novartis, Pfizer, and Roche; and has received research support to his institution from Bristol-Myers Squibb, Merck Sharp \& Dohme, Novartis, and Pfizer. The remaining authors declare no conflict of interest.This trial was supported by Clinical Trials Centre Cologne (CTCC) Medical Faculty, University of Cologne by performing the overall Project Management, Data Base Development, Site Management, Data Monitoring in Germany and Switzerland, and Safety Management and by the Spanish Lung Cancer Group by performing Project Management and Site Monitoring in Spain. The authors thank all the patients and investigators who participated in the trial conduct. Disclosure: Dr. Michels has reveived grants from Pfizer and Novartis; and has received personal fees from Pfizer, Novartis, Roche, and Boehringer Ingelheim. Dr. Massut? has received personal fees from Roche, Bristol-Myers Squibb, Merck Sharp \& Dohme, Boehringer Ingelheim, and Pfizer. Dr. Schildhaus has received grants from Novartis and Roche; and has received personal fees from ZytoVision, Pfizer, Novartis, and Roche. Dr. Sebastian has received personal fees from Boehringer Ingelheim, Lilly, Pfizer, Novartis, Roche, Astra Zeneca, Bristol-Myers Squibb, Merck Sharp \& Dohme, Takeda, Mediolanum, AbbVie, and Celgene. Dr. Felip has received personal fees from Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, Merck Sharp \& Dohme, Novartis, and Merck. Dr. Abdulla has received personal fees from Pfizer Pharma GmbH, Bristol-Myers Squibb, Boehringer Ingelheim, Novartis, Merck Sharpe \& Dohme, Roche Pharma AG, and Loxo Oncology. Dr. Dingemans has received personal fees from Pfizer. Dr. Gardizi has received grants from Pfizer. Dr. Reck has received personal fees from Bristol-Myers Squibb, Astra Zeneca, Abbott, Boehringer Ingelheim, Celgene, Merck KGaA (EMD), Merck Sharpe \& Dohme, Pfizer, Novartis, and Roche. Dr. Riedel has received personal fees from Boehringer Ingelheim; and has received nonfinancial support from Boehringer Ingelheim, Eli Lilly, and Novartis. Dr. Rothschild is a Medical Advisor for the Federal Committee for Pharmaceutical Products, Federal Office of Public Health (FOPH), Switzerland; and has received honoraria for his institution from Pfizer and Novartis. Dr. Merkelbach-Bruse has received personal fees from Pfizer, Astra Zeneca, Roche, Bristol-Myers Squibb, and Novartis. Dr. Nogova has received grants from Pfizer; and has received personal fees from Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Novartis, and Roche. Dr. Wolf has received personal fees from AbbVie, Astra Zeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, Ignyta, Lilly, Merck Sharp \& Dohme, Novartis, Pfizer, and Roche; and has received research support to his institution from Bristol-Myers Squibb, Merck Sharp \& Dohme, Novartis, and Pfizer. The remaining authors declare no conflict of interest. Funding Information: This trial was supported by Clinical Trials Centre Cologne (CTCC) Medical Faculty, University of Cologne by performing the overall Project Management , Data Base Development, Site Management, Data Monitoring in Germany and Switzerland, and Safety Management and by the Spanish Lung Cancer Group by performing Project Management and Site Monitoring in Spain. The authors thank all the patients and investigators who participated in the trial conduct. Publisher Copyright: {\textcopyright} 2019 International Association for the Study of Lung Cancer",
year = "2019",
month = jul,
doi = "10.1016/j.jtho.2019.03.020",
language = "English",
volume = "14",
pages = "1266--1276",
journal = "Journal of Thoracic Oncology",
issn = "1556-0864",
publisher = "Elsevier Inc.",
number = "7",
}