Immune checkpoint inhibitors (ICIs) have dramatically improved clinical outcomes in multiple cancer types and are increasingly being used in earlier disease settings and in combination.1 However, high-grade, immune-related adverse events (irAEs) can occur. Recently, fulminant cases of ICI myocarditis have been reported,2–4 but the characteristics, timing, and outcomes of this new clinical entity are unknown. Here we use VigiBase (http://www.vigiaccess.org/),5 the World Health Organization (WHO) database of individual safety case reports, to identify 101 cases of severe myocarditis following treatment with ICIs. We observed early onset of symptoms, frequent deaths, and dramatically increased reporting in 2017.
Patients had a wide spectrum of age (median=69; range=20–90), cancer types (most commonly melanoma and lung cancer), and geographic location (Table). Three-fourths of patients were not reported to receive concomitant cardiovascular or diabetic medications. Most patients (57%) received anti-PD-1 monotherapy, whereas 27% received combination anti-PD-1/PD-L1 + anti-CTLA-4.
Table:
Characteristics of patients with immune checkpoint inhibitor associated myocarditis (n=101)
| Characteristic | Percent (%) |
|---|---|
| Male gender | 66 |
| Cancer | |
| Melanoma | 40 |
| NSCLC | 30 |
| Renal | 7 |
| Other* | 23 |
| Region reporting | |
| Americas | 54 |
| Europe | 33 |
| Asia | 11 |
| Oceania | 3 |
| Concomitant medications | |
| Aspirin | 11 |
| Statin | 11 |
| Beta blocker | 7 |
| ACE/ARB | 12 |
| Diabetes medication | 9 |
| No CV/Diabetes medications | 75 |
| Regimen | |
| Anti-PD-1 monotherapy | |
| - Nivolumab | 43 |
| - Pembrolizumab | 15 |
| Anti-PD-L1 monotherapy# | 3 |
| Anti-CTLA-4 (Ipilimumab) monotherapy | 5 |
| Combination anti-PD-1/PD-L1 + anti-CTLA-4 | 27 |
| Combination anti-PD-1/PD-L1 + other agents** | 8 |
| Timing (median, range) | 27 days (5–155) |
| Concurrent irAEs | |
| Myositis/rhabdomyolysis | 25 |
| Myasthenia gravis | 10 |
| Colitis | 4 |
| Severe cutaneous events† | 4 |
| Other‡ | 5 |
| Fatal outcome | 46 |
| Reporting year | |
| 2010 – 2014 | 3 |
| 2015 | 6 |
| 2016 | 15 |
| 2017 (through Dec. 6) | 76 |
NSCLC: non-small cell lung cancer; irAEs: immune-related adverse events; CV: cardiovascular
Other includes urothelial carcinoma (n=4), mesothelioma (n=3), merkel cell carcinoma (n=3), small cell lung cancer (n=2), hepatocellular carcinoma, thymoma, cholangiocarcinoma, pancreatic adenocarcinoma, colon cancer, and hematologic malignancy (n=1 each).
Atezolizumab, durvalumab, and avelumab;
Includes chemotherapy (n=3), vascular-angiogenesis growth factor inhibitors (n=3), and other investigational agents (n=2).
Includes Stevens-Johnson Syndrome (n=2), bullous pemphigus (n=1) and skin necrosis (n=1).
Includes encephalitis, pneumonitis, hypophysitis, hepatitis, and rheumatoid arthritis flare.
Dosing information was available in 59 patients; 64% received only 1–2 doses before myocarditis onset. The precise timing of myocarditis onset in relation to ICI initiation was available in 33 patients. Of these, the median onset was 27 days (range 5–155 days) with 76% occurring in the first six weeks. Further, concurrent severe irAEs occurred in 42%, most commonly myositis (25%) and myasthenia gravis (11%). Among all cases, death occurred in 46 (46%). Fatality rates were higher with combination anti-PD-1/PD-L1 plus anti-CTLA-4 than with anti-PD-1/PD-L1 monotherapy (67% vs. 36%, p=0.008). Deaths also occurred in 3 of 5 patients with ipilimumab monotherapy associated myocarditis.
Notably, we observed a dramatic increase in reporting incidence over time (76%; n=77 in 2017 thus far). We speculate that this is due to an increased usage of ICIs, as well as heightened recognition of this new clinical entity.2 We highlight the high mortality rate with severe ICI myocarditis which is more frequent with combination PD-1/CTLA-4 blockade, but can also occur with monotherapy. Myocarditis was observed across ICI regimens although it remains too early to determine whether the incidence differs between anti-PD1 and anti-PD-L1 agents. Further, this condition occurs early during therapy and across cancer types. We were unable to capture co-morbidities in this population but relatively few patients were reported as receiving concurrent cardiovascular or diabetes medications. While ICI associated myocarditis has been reported as individual cases, this analysis is the first comprehensive series to report its clinical features.
Acknowledgements:
The supplied data come from a variety of sources. The likelihood of a causal relationship is not the same in all reports. The information does not represent the opinion of the World Health Organization.
This study was supported by The Cancer ITMO of the French National Alliance for Life and Health Sciences (AVIESAN): “Plan Cancer 2014–2019,” by NIH/NCI K23 CA204726, and by the James C. Bradford Jr. Melanoma Fund.
Footnotes
Conflicts of interest: JM has served as a consultant to Novartis, Pfizer, Bristol Myers Squibb, Pharmacyclics, Regeneron, Daiichi Sankyo, and Heat Biologics. DBJ serves on advisory boards for Bristol Myers Squibb, Genoptix, Incyte, Merck, and Novartis.
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