Introduction: Rare cases of early-onset pulmonary events (EOPEs) occurring within days of the start of administration of brigatinib have been reported (incidence 3%-6% with use of the recommended dose of 90 mg for 7 days and then a 180-mg step-up dosing regimen). Current prescribing information suggests dose interruption and then dose reduction for grade 1 or 2 events and discontinuation for recurrent or higher grade events. However, clinical experience suggests that alternative strategies exist to safely maintain dosing. Methods: Case vignettes illustrating different EOPE clinical scenarios were assembled; they included (1) successful treatment through the initial EOPE, (2) successful rechallenge after the EOPE, (3) successful rechallenge after the EOPE with utilization of a shallower step-up regimen, and (4) unsuccessful rechallenge. Results: Rapid tolerization to EOPEs within 5 to 8 days may occur with continued dosing, suggesting that dose interruption could be avoided with close observation and temporary supportive care (including supplemental oxygen). If dose interruption occurs, restarting administration of brigatinib at 30 mg, followed by dose increases in 30-mg increments every 3 days to the full dose as tolerated ("shallow step-up dosing") may maximize safety during rechallenge. As compromised baseline respiratory function may increase the rate of clinically apparent EOPEs, proactive use of shallow step-up dosing could be considered in select cases. Conclusions: Clinically apparent EOPEs are a rare complication of brigatinib. They occur within days of starting administration of the drug, with rapid tolerization possible during continued dosing. Adapting the EOPE nomenclature to include the word transient (TEOPE) may further clinician and patient understanding in distinguishing these events from the pneumonitis seen with other tyrosine kinase inhibitors. Improved education and appropriate supportive care and dosing should allow more patients to maximally and safely benefit from brigatinib.
Introduction:
Cardiotoxicity with immune checkpoint inhibitor (ICI) treatment has predominantly focused on myocarditis, which has been estimated to affect ~1% of treated patients. To contextualize myocarditis risk in relation to other cardiovascular (CV) events, we explored reporting of myocarditis, heart failure, arterial and venous thrombotic events in ICI-treated cancer patients.
Methods:
Data from adults treated with ICI between January 2011 and April 2019 were extracted by the University of Colorado enterprise health data warehouse which draws from electronic medical records and claims data. Medical conditions were determined by International Classification of Diseases (ICD) code; analyses was descriptive.
Results:
Among 1813 ICI-treated patients, mean age (SD) was 62.5 (13.5 years), 41% were women, 90% were white, 6% Hispanic, 2% black, 1% Asian, <1% American Indian/Alaskan native or native Hawaiian/Pacific islander and 1% multiple race. Prior to ICI initiation, 48% had hypertension, 16% diabetes, 11% were current smokers, 46% former smokers, 11% had estimated glomerular filtration rate <60 ml/min/1.73m
2
and 17% reported prior coronary revascularization. The most commonly treated malignancies were melanoma (40%) and lung cancer (31%). 47% of patients received pembrolizumab and 42% received nivolumab, the most often administered ICIs during this time period. Both before and after ICI administration, venous thromboembolism (VTE) and heart failure were the most frequently reported CV events (Figure). After initiation of ICI, myocardial infarction (MI) and stroke were reported for 54 (3.0%) and 73 (4.0%) patients, respectively. Myocarditis was more common after ICI than before ICI initiation (1 vs 9 patients [0.1%vs 0.5%]) but was infrequent compared with other CV events.
Conclusions:
Arterial and venous thrombotic events and heart failure were much more common than myocarditis in patients treated with ICI.
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