Initiation criteria for mepolizumab sufficient for determining long-term benefit
medwireNews: Researchers have been unable to find a reliable rule for identifying patients who are likely to benefit from continued long-term mepolizumab treatment for severe eosinophilic asthma.
They found that the initiation criteria of two or more exacerbations in the past year and blood eosinophil counts of 150 cells/µL or more at treatment initiation or 300 cells/µL or more in the previous year “provide the best method” for assessing patient benefit from mepolizumab treatment.
“These criteria create a useful starting rule, which mitigates the utility of any subsequent continuation rule,” say Necdet Gunsoy (GlaxoSmithKline, Uxbridge, UK) and fellow investigators.
The researchers add: “The principle of effective starting rules will continue to emerge with personalized treatment approaches, which will use patient markers to identify and target treatments to those likely to respond.
“Thereafter, decisions about continuation of treatment should perhaps be based on achieving a predefined reduction in longer term exacerbation frequency and/or oral corticosteroid dose; failure to achieve this should prompt a reevaluation of the role of eosinophilic airway inflammation in the pathogenesis of the patients’ events and a new treatment approach.”
The post-hoc analysis included data from the randomized, placebo-controlled DREAM and MENSA studies, which comprised a total of 246 and 547 participants, respectively. Of these, a corresponding 120 and 365 were taking mepolizumab.
Five possible continuation rules were examined, based on values recorded 16 weeks after starting treatment. These included change in blood eosinophil levels from baseline, physician-rated response to treatment, an improvement of 0.5 points or more on The Asthma Control Questionnaire (ACQ-5), an improvement of 80 mL or 10% or more from baseline in prebronchodilator forced expiratory volume in 1 second (FEV1), and no change or a reduction in annualized exacerbations.
These rules were assessed using the placebo-adjusted rate ratio (PARR) and the rate ratio for noncontinuers (RRNC). The first assessed whether the rules could identify patients receiving long-term benefit (reduction of 20% or more in exacerbation rates) beyond that observed among placebo-treated patients, while the second assessed whether patients not meeting the rules still received benefit from treatment compared with placebo-treated patients who do not meet the rules.
Reduction from baseline in blood eosinophil counts met the criteria for a useful tool of 0.8 or less on the PARR and at least 0.8 on the RRNC for the MENSA trial but not the DREAM trial, the team reports in The Journal of Allergy and Clinical Immunology: In Practice.
The small number of patients taking mepolizumab who failed the continuation rule (24 for MENSA and six for DREAM) may have led to high levels of uncertainty, they suggest. The researchers also note that while the rule looked to be useful for patients with blood eosinophil counts below 150 cells/µL, this number would be very small in practice.
Physician-rated responses failed to meet the PARR and RRNC criteria for a suitable continuation rule in both trials, as did the ACQ-5 and FEV1 continuation rules. The primary failure was that patients taking mepolizumab who did not meet the continuation rule still had a reduction in exacerbations compared with patients taking placebo who did not meet the rule.
Reduction in exacerbation frequency was found to be a potentially useful tool in DREAM but not in MENSA. The PARR was 0.60 in both studies, and while the RRNC was 0.92 in DREAM it was 0.79 in MENSA. The study authors point out, however, that a longer period of exacerbation assessment, such as a year, may be more appropriate for determining long-term reductions.
The team acknowledges some limitations to the study, including the fact that the studies were not optimally designed to determine continuation rules, they had limited follow-up, and only a small number of mepolizumab-treated patients did not meet the continuation rules.
By Lucy Piper
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