The irreversible proteasome inhibitor carfilzomib (Kyprolis, Onyx Pharmaceuticals), approved for previously treated multiple myeloma (MM), is associated with a clinically relevant risk for adverse cardiovascular events, including high-grade cardiovascular adverse events (CVAEs), reveals the first meta-analysis of trials that examined the issues.
“Since its approval in 2012, there have been increasing reports of carfilzomib-associated CVAE, including heart failure, severe hypertension, cardiac arrhythmias, ischemic events, and cardiac arrest,” Adam Waxman, MD, Abramson Cancer Center, University of Pennsylvania, Philadelphia, and colleagues write.
To ascertain the frequency at which these adverse events (AEs) occur, they conducted a systematic review and meta-analysis of 24 prospective clinical trials involving a total of 2594 patients.
“Our study demonstrates a rate of high-grade CVAE approximately twice as high among patients receiving carfilzomib compared with noncarfilzomib-receiving controls,” the investigators conclude.
“This is of particular importance given that the MM patient population is at an elevated baseline risk of CVAE, underscoring the importance of delineating the cardiovascular risk of therapies for MM,” they add.
“It is critical that clinicians caring for patients with MM be aware of early signs of CVAE and promptly refer such patients for additional evaluation and to hold carfilzomib,” the investigators emphasize.
The study was published online December 28, 2017, in JAMA Oncology
Details of the Findings
The systematic review and meta-analysis included 24 prospective clinical trials, which varied with respect to the numbers of patients treated, the phase of the trial (1 to 3), the number of prior lines of treatment, the maximum dose of carfilzomib used, and the components of accompanying chemotherapies.
“High-grade CVAE data was available for all 24 included studies whereas all-grade CVAE data was available in 22 studies,” the investigators observe. As Dr Waxman explained in an email, in most published cancer trials, “all-grade” AEs include any event, whereas “high-grade” AEs typically include any AE that is of grade 3 or higher. That is the distinction the investigators used for the current meta-analysis.
“On pooling the data…summary all-grade and high-grade CVAE rates were 18.1% and 8.2%, respectively,” the team reports.
The percentage of patients who experienced either a high-grade or any-grade CVAE varied depending on the event, but congestive heart failure and hypertension were the most common.
Table. Estimated Risk for All-Grade and High-Grade CVAEs Seen in Association With Carfilzomib vs Noncarfilzomib Regimens
| All-Grade CVAEs | Grade ≥3 CVAEs | |
|---|---|---|
| All events | 18.1% (P < .001) | 8.2% (P < .001) |
| Heart failure | 3.1% (P < .001) | 2.5% (P < .001 |
| Hypertension | 12.2% (P < .001) | 4.3% (P < .001) |
| Arrhythmia | 2.4% (P = .004) | 0.8% P < .001) |
| Ischemia | 1.8% (P < .001) | 0.8% (P < .001) |
| Cardiac arrest | NA | 0.0% |
The team also found that approximately one quarter of patients treated with carfilzomib developed dyspnea, and another one quarter developed edema ( P < .001 for both endpoints), although rates of dyspnea and edema of grade 3 or higher rate were much lower.
“We found that the phase of trial and the dose of carfilzomib were both significantly associated with high rates of high-grade CVAE,” the researchers observe.
For example, the rate of high-grade CVAE recorded in phase 1 trials of carfilzomib were low, at 2.3%, whereas rates climbed to 9.5% for phase 2 and phase 3 trials (P = .02).
Similarly, carfilzomib doses of less than 45 mg/m2 were associated with a lower rate of high-grade CVAEs, at 6.4%, whereas for doses of 45 mg/m2 or greater, the rate was 11.9% (P = .02).
The median age of patients did not affect CVAE rates, regardless of the number of lines of prior therapy or whether their disease was newly diagnosed or not.
Neither duration of exposure to carfilzomib nor infusion rates had a bearing on CVAE rates.
Pivotal Randomized Trials
The investigators calculated the relative risk of a patient developing a CVAE in the three pivotal clinical trials of carfilzomib in which patients received either the experimental proteasome inhibitor or a noncarfilzomib control regimen.
“For high-grade CVAE, receipt of carfilzomib was associated with a greater than 2-fold increase in risk (P < .001),” the investigators report. “Results for all-grade CVAE were similar, with a summary relative risk of 1.8 (P < .001),” they add.
When the authors excluded hypertension, which is the most common CVAE, the summary relative risk for high-grade events was 2.6 for groups receiving carfilzomib compared with noncarfilzomib control patients (P = .002); the risk for all-grade events was 1.9 (P = .02).
Hence, the study shows a rate of high-grade CVAE approximately twice as high among patients receiving carfilzomib compared with noncarfilzomib-receiving control patients, the team concludes.
Highly Individualized Question
Asked by Medscape Medical News whether potential CVAEs associated with carfilzomib are worth risking when treating patients with the drug, Dr Waxman said this is always going to be a highly individualized question that each physician has to determine for each patient.
“Carfilzomib is an efficacious drug for the treatment of multiple myeloma, with demonstrated overall and progression-free survival benefits in the randomized ASPIRE and ENDEAVOR trials, so its value in the treatment of the disease should not be understated,” Dr Waxman observed.
“So the drug should probably be used at some point in the treatment of most patients with multiple myeloma,” he added.
Moreover, many of the reported AEs seen in association with carfilzomib are reversible, and this fact should be factored into any risk-benefit discussion about whether or not to use the drug.
“There are no strict cardiac contraindications for the use of carfilzomib,” Dr Waxman emphasized.
“However, it is important to note that patients with New York Heart Association class III or IV heart failure, recent myocardial infarction, and some other cardiac diseases were excluded from clinical trials, so it may be prudent to use the drug with a high degree of caution in such patients,” he suggested.
The US Food and Drug Administration has required that the package insert include a list of potential cardiac AEs, including cardiac arrest, heart failure, and myocardial ischemia.
In Dr Waxman’s view, this labeling is adequate, “given the clinical evidence that we currently have available,” he said.
Dr Waxman has disclosed no relevant financial relationships.
JAMA Oncol. Published online December 28, 2017. Abstract
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