Terry L Ng1, Amber Johnson2, Raphael A Nemenoff2, Elena Hsieh3, Andrea Abeyta Osypuk4, Adrie van Bokhoven4, Howard Li5, D Ross Camidge6, Erin L Schenk6. 1. Division of Medical Oncology, University of Ottawa, Ottawa, Ontario, Canada; Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Electronic address: teng@toh.ca. 2. Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. 3. Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Division of Allergy and Immunology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado. 4. Pathology Shared Resource, Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. 5. Department of Medicine, University of Colorado, Aurora, Colorado; Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia. 6. Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Abstract
INTRODUCTION: Symptomatic early onset pulmonary events (EOPEs) were observed in 3% to 6% of patients within 1 week of starting brigatinib at 90 mg daily for 7 days followed by 180 mg daily. We conducted a prospective observational cohort study to measure pulmonary function changes on initiating brigatinib. METHODS: Patients initiating brigatinib were eligible. Pulmonary function test (PFT) with diffusing capacity for carbon monoxide (DLCO), Borg dyspnea scale, six-minute walk test, and blood draw for cytometry by time-of-flight were performed at baseline, day 2, and day 8 plus or minus day 15 of brigatinib. The primary end point was the incidence of PFT-defined EOPEs, prespecified as greater than or equal to 20% DLCO reduction from baseline. An interim analysis was performed owing to a higher than expected incidence of DLCO reduction. RESULTS: A total of 90% (nine of 10) experienced DLCO reduction with the nadir occurring on day 2 or day 8. Median DLCO nadir was -13.33% from baseline (range: -34.44 to -5.00). Three participants met the PFT-defined EOPE criteria. All patients, including these three, were asymptomatic, none required brigatinib interruption or dose reduction, and all patients escalated to 180 mg without further issues. Despite continued dosing, by day 15, all assessed patients experienced DLCO recovery. Dyspnea and six-minute walk test results did not correlate with DLCO changes. Patients with a PFT-defined EOPE had significantly higher levels of activated neutrophils at baseline and day 8. CONCLUSIONS: DLCO reduction occurred in 90% during the first 8 days of brigatinib dosing without any related symptoms. DLCO improved in all six patients assessed at day 15 despite continued dosing and dose escalation. Pretreatment levels of neutrophil activation should be explored as a biomarker for developing EOPEs.
INTRODUCTION: Symptomatic early onset pulmonary events (EOPEs) were observed in 3% to 6% of patients within 1 week of starting brigatinib at 90 mg daily for 7 days followed by 180 mg daily. We conducted a prospective observational cohort study to measure pulmonary function changes on initiating brigatinib. METHODS: Patients initiating brigatinib were eligible. Pulmonary function test (PFT) with diffusing capacity for carbon monoxide (DLCO), Borg dyspnea scale, six-minute walk test, and blood draw for cytometry by time-of-flight were performed at baseline, day 2, and day 8 plus or minus day 15 of brigatinib. The primary end point was the incidence of PFT-defined EOPEs, prespecified as greater than or equal to 20% DLCO reduction from baseline. An interim analysis was performed owing to a higher than expected incidence of DLCO reduction. RESULTS: A total of 90% (nine of 10) experienced DLCO reduction with the nadir occurring on day 2 or day 8. Median DLCO nadir was -13.33% from baseline (range: -34.44 to -5.00). Three participants met the PFT-defined EOPE criteria. All patients, including these three, were asymptomatic, none required brigatinib interruption or dose reduction, and all patients escalated to 180 mg without further issues. Despite continued dosing, by day 15, all assessed patients experienced DLCO recovery. Dyspnea and six-minute walk test results did not correlate with DLCO changes. Patients with a PFT-defined EOPE had significantly higher levels of activated neutrophils at baseline and day 8. CONCLUSIONS: DLCO reduction occurred in 90% during the first 8 days of brigatinib dosing without any related symptoms. DLCO improved in all six patients assessed at day 15 despite continued dosing and dose escalation. Pretreatment levels of neutrophil activation should be explored as a biomarker for developing EOPEs.
Authors: Sofie Van Gassen; Britt Callebaut; Mary J Van Helden; Bart N Lambrecht; Piet Demeester; Tom Dhaene; Yvan Saeys Journal: Cytometry A Date: 2015-01-08 Impact factor: 4.355
Authors: I C Gleadhill; R A Wise; S A Schonfeld; P P Scott; T Guarnieri; J H Levine; L S Griffith; E P Veltri Journal: Am J Med Date: 1989-01 Impact factor: 4.965
Authors: Scott N Gettinger; Lyudmila A Bazhenova; Corey J Langer; Ravi Salgia; Kathryn A Gold; Rafael Rosell; Alice T Shaw; Glen J Weiss; Meera Tugnait; Narayana I Narasimhan; David J Dorer; David Kerstein; Victor M Rivera; Timothy Clackson; Frank G Haluska; David Ross Camidge Journal: Lancet Oncol Date: 2016-11-08 Impact factor: 41.316
Authors: Nandini Krishnamoorthy; David N Douda; Thayse R Brüggemann; Isabell Ricklefs; Melody G Duvall; Raja-Elie E Abdulnour; Kimberly Martinod; Luciana Tavares; Xiao Wang; Manuela Cernadas; Elliot Israel; David T Mauger; Eugene R Bleecker; Mario Castro; Serpil C Erzurum; Benjamin M Gaston; Nizar N Jarjour; Sally Wenzel; Eleanor Dunican; John V Fahy; Daniel Irimia; Denisa D Wagner; Bruce D Levy Journal: Sci Immunol Date: 2018-08-03
Authors: Thomas K Wright; Peter G Gibson; Jodie L Simpson; Vanessa M McDonald; Lisa G Wood; Katherine J Baines Journal: Respirology Date: 2016-01-25 Impact factor: 6.424
Authors: Terry L Ng; Narayana Narasimhan; Neeraj Gupta; Karthik Venkatakrishnan; David Kerstein; D Ross Camidge Journal: J Thorac Oncol Date: 2020-03-03 Impact factor: 15.609
Authors: El-Ad David Amir; Brian Lee; Paul Badoual; Martin Gordon; Xinzheng V Guo; Miriam Merad; Adeeb H Rahman Journal: Front Immunol Date: 2019-06-11 Impact factor: 7.561
Authors: Ronald P Schuyler; Conner Jackson; Josselyn E Garcia-Perez; Ryan M Baxter; Sidney Ogolla; Rosemary Rochford; Debashis Ghosh; Pratyaydipta Rudra; Elena W Y Hsieh Journal: Front Immunol Date: 2019-10-15 Impact factor: 7.561