Rudolf M Huber1, Karin H Hansen2, Luis Paz-Ares Rodríguez3, Howard L West4, Karen L Reckamp5, Natasha B Leighl6, Marcello Tiseo7, Egbert F Smit8, Dong-Wan Kim9, Scott N Gettinger10, Maximilian J Hochmair11, Sang-We Kim12, Corey J Langer13, Myung-Ju Ahn14, Edward S Kim15, David Kerstein16, Harry J M Groen17, D Ross Camidge18. 1. Division of Respiratory Medicine and Thoracic Oncology, Department of Medicine V, University Hospital of Munich, Thoracic Oncology Centre Munich, German Centre for Lung Research, Munich, Bavaria, Germany. Electronic address: Huber@med.uni-muenchen.de. 2. Department of Clinical Oncology, Odense University Hospital, Odense, Denmark. 3. Medical Oncology Department, University Hospital "12 de Octubre," Madrid, Spain. 4. Thoracic Oncology Program, Swedish Cancer Institute, Seattle, Washington. 5. Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, California. 6. Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. 7. Medical Oncology Unit, University Hospital of Parma, Parma, Italy. 8. Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, the Netherlands. 9. Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. 10. Yale Cancer Center, New Haven, Connecticut. 11. Department of Respiratory and Critical Care Medicine, Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Vienna, Austria. 12. Department of Oncology, Asan Medical Center, Seoul, South Korea. 13. University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania. 14. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 15. Levine Cancer Institute, Atrium Health, Charlotte, North Carolina. 16. Millennium Pharmaceuticals, Inc. (wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachusetts. 17. University of Groningen and University Medical Center Groningen, Groningen, the Netherlands. 18. University of Colorado Cancer Center, Aurora, Colorado.
Abstract
INTRODUCTION: We report updated data from a phase 2 randomized study evaluating brigatinib in crizotinib-refractory anaplastic lymphoma kinase-positive NSCLC. METHODS: Patients were randomized 1:1 to take either oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (arm B), stratified by central nervous system (CNS) metastases and best response to crizotinib. The primary end point was investigator-assessed confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included independent review committee (IRC)-assessed progression-free survival (PFS), intracranial PFS (iPFS), and overall survival (OS). Exploratory analyses included CNS versus ex-CNS target lesion response and correlation of depth of response with PFS and OS. RESULTS: Among 222 randomized patients (112 and 110 in arms A and B, respectively), 59 (27%) remained on brigatinib at analysis (median follow-up: 19.6 versus 24.3 months). At baseline, 71% and 67% had brain lesions among A and B arms, respectively. Investigator-assessed confirmed objective response rate was 46% versus 56%. Median IRC-assessed PFS was 9.2 months (95% confidence interval: 7.4-12.8) versus 16.7 months (11.6-21.4). Median OS was 29.5 months (18.2-not reached) versus 34.1 months (27.7-not reached). IRC-confirmed intracranial objective response rate in patients with measurable baseline brain lesions was 50% (13 of 26) versus 67% (12 of 18); median duration of intracranial response was 9.4 versus 16.6 months. IRC-assessed iPFS was 12.8 versus 18.4 months. Across arms, median IRC-assessed PFS was 1.9, 5.5, 11.1, 16.7, and 15.6 months for patients with no, 1%-25%, 26%-50%, 51%-75%, and 76%-100% target lesion shrinkage, respectively. No new safety findings were observed with longer follow-up. CONCLUSIONS: Brigatinib (180 mg once daily with lead-in) continues to demonstrate robust PFS, long iPFS and duration of intracranial response, and high intracranial objective response rate in crizotinib-refractory patients. Depth of response may be an important end point to capture in future targeted therapy trials.
INTRODUCTION: We report updated data from a phase 2 randomized study evaluating brigatinib in crizotinib-refractory anaplastic lymphoma kinase-positive NSCLC. METHODS: Patients were randomized 1:1 to take either oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (arm B), stratified by central nervous system (CNS) metastases and best response to crizotinib. The primary end point was investigator-assessed confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included independent review committee (IRC)-assessed progression-free survival (PFS), intracranial PFS (iPFS), and overall survival (OS). Exploratory analyses included CNS versus ex-CNS target lesion response and correlation of depth of response with PFS and OS. RESULTS: Among 222 randomized patients (112 and 110 in arms A and B, respectively), 59 (27%) remained on brigatinib at analysis (median follow-up: 19.6 versus 24.3 months). At baseline, 71% and 67% had brain lesions among A and B arms, respectively. Investigator-assessed confirmed objective response rate was 46% versus 56%. Median IRC-assessed PFS was 9.2 months (95% confidence interval: 7.4-12.8) versus 16.7 months (11.6-21.4). Median OS was 29.5 months (18.2-not reached) versus 34.1 months (27.7-not reached). IRC-confirmed intracranial objective response rate in patients with measurable baseline brain lesions was 50% (13 of 26) versus 67% (12 of 18); median duration of intracranial response was 9.4 versus 16.6 months. IRC-assessed iPFS was 12.8 versus 18.4 months. Across arms, median IRC-assessed PFS was 1.9, 5.5, 11.1, 16.7, and 15.6 months for patients with no, 1%-25%, 26%-50%, 51%-75%, and 76%-100% target lesion shrinkage, respectively. No new safety findings were observed with longer follow-up. CONCLUSIONS: Brigatinib (180 mg once daily with lead-in) continues to demonstrate robust PFS, long iPFS and duration of intracranial response, and high intracranial objective response rate in crizotinib-refractory patients. Depth of response may be an important end point to capture in future targeted therapy trials.
Authors: Flávia Melo Cunha de Pinho Pessoa; Caio Bezerra Machado; Emerson Lucena da Silva; Laudreísa da Costa Pantoja; Rodrigo Monteiro Ribeiro; Maria Elisabete Amaral de Moraes; Manoel Odorico de Moraes Filho; Raquel Carvalho Montenegro; André Salim Khayat; Caroline Aquino Moreira-Nunes Journal: Int J Mol Sci Date: 2022-03-30 Impact factor: 5.923
Authors: F Guisier; N Piton; M Bellefleur; N Delberghe; G Avenel; E Angot; O Vittecoq; M Ould-Slimane; H Morisse-Pradier; M Salaun; L Thiberville Journal: BMC Cancer Date: 2020-01-06 Impact factor: 4.430