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Background: There is growing recognition of the risk of cardiovascular (CV) events, particularly myocarditis, in the context of immune checkpoint inhibitor (ICI) therapy; however, true event rates in real-world populations and in the background of CV disease remain uncertain. Objectives: The authors sought to determine CV event occurrence in ICI-treated patients and assess the accuracy of diagnosis by International Classification of Diseases (ICD) code compared with adjudication using established definitions and full-source documentation review. Methods: Electronic medical record extraction identified potential CV events in ICI-treated patients in the University of Colorado Health system. Two cardiologists independently adjudicated events using standardized definitions. Agreement between ICD codes and adjudicated diagnoses was assessed using the kappa statistic. Results: The cohort comprised 1,813 ICI-treated patients with a mean follow-up of 4.6 ± 3.4 years (3.2 ± 3.2 years pre-ICI and 1.4 ± 1.4 years post-ICI). Venous thromboembolic events (VTEs) were the most common event, occurring in 11.4% of patients pre-ICI and 11.3% post-ICI therapy. Post-ICI therapy, the crude rates of myocardial infarction (MI), heart failure, and stroke were 3.0%, 2.8%, and 1.6%, respectively. Six patients (0.3%) developed myocarditis post-ICI. Agreement between the ICD code and adjudication was greater for VTE (κ = 0.82; 95% CI: 0.79-0.85) and MI (κ = 0.74; 95% CI: 0.66-0.82) and worse for myocarditis (κ = 0.50; 95% CI: 0.20-0.80) and heart failure (κ = 0.47; 95% CI: 0.40-0.54). Conclusions: ICD codes correlated well with adjudicated events for VTE and MI, but correlation was worse for heart failure and myocarditis. Adjudication with standardized definitions can enhance the understanding of the incidence of CV events related to ICI therapy.
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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.