Timely intervention critical for major cardiac events after immune checkpoint therapy
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CHICAGO — Patients and prescribers should be more aware of the potential for major adverse cardiac events after immune checkpoint inhibitor-based therapy, according to retrospective study results presented at ASCO Annual Meeting.
The association between immune major adverse cardiac events (MACE) and noncardiac immune-related adverse events highlights the importance of a multidisciplinary management approach, researchers emphasized.
“To the best of our knowledge, this is the first-ever pooled analysis of immune checkpoint inhibitor clinical trials evaluating major adverse cardiac events,” Abdul Rafeh Naqash, MD, assistant professor in the early phase division of Stephenson Cancer Center at University of Oklahoma, said during a presentation. “These findings have important management implications, as more and more patients are being treated with anti-pD-1/PD-l1 combinations.”
Background and methods
Although rare, MACE can manifest in various ways among patients treated with immune checkpoint inhibitors. These events can result in considerable morbidity or death.
More work is needed to better define presentation of these events and their potential relationship with noncardiac immune-related adverse events among patients treated with immune checkpoint inhibitors, according to study background.
Naqash and colleagues performed a retrospective pooled analysis of MACE captured in the NCI-Cancer Therapy Evaluation Program’s serious adverse events reporting database.
The analysis included patients treated with anti-PD-1/-PD-L1 therapy alone or in combination with other anticancer therapies as part of NCI-sponsored investigational clinical trials in the United States and Canada between June 2015 and December 2019.
The analysis included 6,925 patients. Slightly less than half (48%) received single-agent anti-PD-1/PD-L1 therapy. The remainder received those agents as part of combination therapy.
Results
Forty patients (0.6%; median age, 68.5 years; 60% men) developed immune checkpoint inhibitor-related MACE.
The most common malignancies in this group included melanoma (37.5%), genitourinary cancer (16%), gastrointestinal cancer (12.5%), gynecologic cancer (7.5%), lymphoma (5%) and lung cancer (5%).
Median time to MACE from initial immune checkpoint inhibitor administration was approximately 28 days.
Researchers characterized the majority (77.5%) of MACE as grade 3 or higher (grade 3, 50%; grade 4, 20%; grade 5, 7.5%).
Myocarditis accounted for nearly half (45%; n = 18) of MACE, occurring a median two doses after immune checkpoint inhibitor administration. The majority (78%) of cases were grade 3 or higher.
Seventy-two percent of patients with myocarditis had been treated with anti-PD-1/PD-L1-based combination regimens, the most common of which included an anti-CTLA-4 inhibitor (92%).
Researchers reported four myocarditis-related deaths. All four of these individuals had concurrent myositis and three had concurrent transaminitis.
Nonmyocarditis MACE included dysrhythmias, cardiomyopathy, pericardial disorders, acute coronary syndrome and cardiac arrest.
More than half (65%) of patients who developed MACE experienced multisystem organ involvement with other noncardiac immune-related adverse events, the two most common being myositis (27.5%) and transaminitis (25%).
Nearly all patients (92.5%) with MACE required hospitalization and 30% required ICU admission.
Most patients (83%) with myocarditis experienced at least one noncardiac immune-related adverse event, and 50% of those with non-myocarditis MACE developed noncardiac immune-related adverse events.
Forty percent of those who developed MACE received single-agent PD-1/PD-L1 agent therapy, and 60% had received anti-PD-1/PD-L1 in combination with other therapies.
MACE occurred more frequently among patients treated with anti-PD-1/PD-L1 plus targeted therapies (2.1%) than anti-PD-1/PD-L1 plus anti-CTLA-4 therapies (0.9%), anti-PD-1/PD-L1 plus chemotherapy (0.83%) or single-agent anti-PD-1/PD-L1 (0.47%).
Next steps
Immune checkpoint inhibitor-related MACE has heterogeneous presentation and often is associated with poor prognosis, Naqash said.
“This makes timely identification and intervention critical,” Naqash said. “We also saw complex noncardiac immune-related adverse events present concurrently, which makes incorporation of a multidisciplinary approach consisting of cardiologists, oncologists, internists and other subspecialists essential in the management of these patients. In addition, the type of combination therapy may influence MACE risk and incidence, which suggests better characterization of MACE with anti-PD-1/PD-L1-based combination therapies is required.”
Perspective
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Igor Puzanov, MD, MSCI, FACP
Increased use of immune checkpoint inhibitors to treat more patients with multiple types of cancer leads us to find rare, important and potentially serious toxicities. Cardiac toxicities are one of the most serious, and they can be life threatening.
Fulminant myocarditis associated with the use of checkpoint inhibitors was first described in our paper published in The New England Journal of Medicine in 2016. At that time, two of our patients treated with combination anti-PD-1 and anti-CTLA-4 inhibitors died of cardiomyositis. It wasn’t known until then because if you don’t look for it, you miss it. So we realized this could be important and fatal but, at that time, we didn’t know how prevalent it was.
Our group at Roswell Park Comprehensive Cancer Center published results of a retrospective study of cardiac toxicities in Journal for ImmunoTherapy of Cancer that looked at over 1,000 patients. The incidence of major cardiac adverse events was similar — 0.5% to 0.6% — to what Naqash and colleagues reported in their study. Not surprisingly, combination therapy seemed to be more toxic than single-agent therapy, but combination therapies are here to stay.
The study by Naqash and colleagues adds more robust data to the literature, and it is encouraging to me — even though it is hard to compare between trials — that the mortality reported in this abstract seems to be lower than previously described (22% vs 40% to 50%). That may be a case of the clinical community becoming more experienced managing these patients and detecting cardiac events earlier.
Weekly troponin monitoring at the initial time period (6 to 8 weeks) of checkpoint inhibitor therapy is still controversial. The guidelines say “consider.” We do it at Roswell Park because it is a very simple weekly test, and the results from our paper published in 2021 suggest that the events can be detected and therapy started earlier, thus outweighing the cost and inconvenience of additional workup needed.
The feedback from patients has been positive and the weekly monitoring was well-received by them. They do appreciate the effort to detect the potentially fatal toxicity early.
There are two important next steps. One is better therapy in addition to steroids. A randomized, multicenter trial is under way to compare high-dose steroids vs. high-dose steroids with abatacept (Orencia, Bristol Myers Squibb), with a group at Massachusetts General Hospital leading that study. Second is early detection using wearables (eg, an Apple iWatch). Connecting patients remotely enables us to compare their physical activity and heart rate. A certain level of heart rate increase without accompanying activity may raise suspicion for early toxicity. This is a new era with remote monitoring and patient-reported symptoms.
The bottom line is, this study confirms the importance of cardiac side effects from checkpoint inhibitors. More work is required.
References:
Johnson DB et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1609214.
Puzanov I, et al. J Immunother Cancer. 2021;doi:10.1136/jitc-2021-002553.
Perspective
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Namrata (Neena) Vijayvergia, MD
Anecdotes can sometimes scare us and give us the wrong perspective of a particular disease. However, anecdotes are not science. Until you study something in a research setting and a controlled environment, you don’t know for sure.
Immunotherapeutic drugs have changed the course of how we treat patients, but the risk for myocarditis or other serious side effects can be a detriment. Information like this from a large database allows us to educate our patients, and we can feel better about treating them thanks to this important work.
The 0.6% incidence of immune checkpoint inhibitor-related MACE is very comforting. I haven’t personally seen a patient with cardiac side effects from these drugs, but that doesn’t mean these events don’t happen. Seeing such a low number in a very big population of patients from NCI studies give us a real good picture of the landscape.
Myocarditis is inflammation in the heart. If you have an immune system that is revved up, it would be revved up everywhere, so it makes sense that patients with myocarditis would have other immune-related adverse events. Whether this is a cause or effect of what else is happening in the rest of the body is hard to tease out. However, we have learned that when patients have multiple immune-related adverse events, we should look for cardiac events, too.
The knowledge that these drugs are safe — and a deeper understanding of the potential side effects — makes us more empowered to look for these effects and treat them effectively. I will feel much better talking to my patients about their risk now that I have a concrete number to give them. These are retrospective data, so it will be important to replicate these findings in other large data sets. More work is needed, and that will only increase our confidence. However, someone using this drug for the first time should feel much more comfortable doing so based on data like this.
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Naqash AR, et al. Abstract 2508. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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