PURPOSE Major adverse cardiac events (MACEs) because of immune checkpoint inhibitors (ICIs) are infrequent immune-related adverse events (irAEs) that comprise a spectrum of cardiac toxicities with variable manifestations. ICI-related MACEs can lead to significant morbidity and mortality, hence the need to better define presentations of MACEs and their association with noncardiac irAEs in ICI-treated patients. METHODS We conducted a retrospective pooled analysis of MACE captured in the serious adverse events reporting database of the National Cancer Institute–Cancer Therapy Evaluation Program for National Cancer Institute–sponsored investigational clinical trials between June 2015 and December 2019. Patients were eligible if they had been treated with anti–programmed cell death protein-1 (anti–PD-1)/programmed cell death-ligand 1 (anti–PD-L1) alone or with additional anticancer therapies. RESULTS A total of 6,925 participants received anti–PD-(L)1-based therapies; 48% (n = 3,354) were treated with single-agent anti–PD-(L)1 therapy. Of 6,925 patients, 0.6% (n = 40) qualified as ICI-related MACE, with 77.5% (n = 31 of 40) being ≥ grade 3. Myocarditis accounted for 45% (n = 18 of 40) of total ICI-MACEs. Concurrent multisystem involvement with other noncardiac irAEs was seen in 65% (n = 26 of 40). Most patients with myocarditis (83%, n = 15 of 18) had one or more noncardiac irAEs associated. Incidence of MACE was higher with anti–PD-(L)1 + targeted therapies compared with anti–PD-(L)1 + anti–cytotoxic T-cell lymphocyte-4 combinations (2.1% v 0.9%, P = .08). There was a higher incidence of myocarditis with anti–PD-(L)1-based combination therapies versus single-agent anti–PD-(L)1 therapies (0.36%, n = 13 of 3,571 v 0.15%, n = 5 of 3,354, P = .08). Deaths related to myocarditis were identified in 22.5% (n = 4 of 18). All four patients who died had concurrent myositis. CONCLUSION Increasing patient and prescriber awareness in understanding patterns of ICI-MACE and associated noncardiac irAEs should be emphasized. Better characterization of the risk of MACE with the concurrent use of non–ICI-based anticancer therapies with anti–PD-(L)1 treatments is needed.

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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.