Major adverse cardiac events (MACE) with immune checkpoint inhibitor (ICI)-based therapies for cancer: A pooled analysis of investigational clinical trials sponsored by the National Cancer Institute Cancer Therapy Evaluation Program (NCI-CTEP) in the United States and Canada.

2508 Background: MACE due to ICIs are infrequent immune-related adverse events (irAEs) that comprise a spectrum of cardiac toxicities with variable manifestations. ICI-related MACE can lead to significant morbidity and mortality, hence the need to better define presentations of MACE and their association with non-cardiac irAEs in ICI-treated patients. Methods: We conducted a retrospective pooled analysis of MACE captured in the serious adverse events reporting database of the NCI-CTEP for NCI-sponsored investigational clinical trials between 6/2015-12/2019. Patients (pts) were eligible if they had been treated with anti-programmed cell death protein-1/programmed death-ligand 1 (anti-PD-[L]1) alone or in combination with additional anti-cancer therapies. Results: A total of 6,925 pts received anti-PD-(L)1-based therapies; 48% (n = 3354) were treated with single-agent anti-PD-(L)1 therapy. Of 6925 pts, 0.6% (n = 40) qualified as ICI-related MACE. Myocarditis accounted for 45% (n = 18/40) of total ICI-MACE. Approximately 77.5% (n = 31/40) of MACE were ≥ grade 3. Multi-system organ involvement with other non-cardiac irAEs was seen in 65% (n = 26/40). Most pts with myocarditis (83%, n = 15/18) had one or more non-cardiac irAEs associated; non-cardiac irAEs were observed in 50% (n = 11/22) of non-myocarditis MACE. Incidence of MACE was higher with anti-PD-(L)1 + targeted therapies vs. anti-PD-(L)1 + anti-CTLA-4 (2.1% vs. 0.09%, p = 0.08). Most of these were non-myocarditis MACE. There was a significantly higher incidence of myocarditis with anti-PD-(L)1-based combinations vs. single-agent anti-PD-(L)1 therapies (0.39%, n = 13/3341 vs. 0.14%, n = 5/3566, p = 0.04. Most pts with myocarditis had been treated with anti-PD-1-based combinations (72%, n = 13/18); the most common combination being anti-PD1+ anti-CTLA-4 (92%, n = 12/13). Pts with myocarditis presented after a median of 2 ICI doses and after a median of 35 days from the initial ICI administration. In pts with myocarditis, a concurrent or preceding history of myositis was present in 53% (n = 8/15). Deaths related to myocarditis were identified in 22.5% (n = 4/18). All four patients who died had concurrent myositis, with three having concurrent transaminitis. Conclusions: Our results represent the first report of a comprehensive pooled analysis of ICI-MACE obtained from NCI CTEP-sponsored investigational clinical trials. Based on our results, increasing patient and prescriber awareness in understanding patterns of ICI-MACE and associated non-cardiac irAEs should be emphasized. Furthermore, better characterization of the risk and patterns of non-myocarditis MACE with the use of anti-PD(L)-1 ICIs concurrently with non-ICI-based anti-cancer therapies is needed.

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