In a phase IIb trial (ReNeu) reported in the Journal of Clinical Oncology, Moertel et al found that the CNS-penetrant small molecule MEK1/2 inhibitor mirdametinib showed activity in adults and children with symptomatic neurofibromatosis type 1-associated plexiform neurofibroma (NF1-PN).
Study Details
In the U.S. multicenter study, 58 adults (≥ 18 years) and 56 children (2–17 years), enrolled between October 2019 and December 2021, received mirdametinib capsules or tablets for oral suspension at 2 mg/m2 twice daily (maximum 4 mg twice daily) in a 3-weeks-on/1-week-off schedule for up to 24 cycles. The primary outcome measure was confirmed objective response rate, defined as the proportion of patients with at least 20% reduction of target PN volume from baseline on consecutive scans during the 24-cycle treatment phase, as assessed by blinded independent central review of volumetric magnetic resonance imaging.
Key Findings
Objective response was observed in 24 of 58 adults (41%, 95% confidence interval [CI] = 29%–55%). Median duration of response was not reached; all objective responses remained durable at data cutoff, with 18 (75%) responses persisting for at least 12 months. Objective response was observed in 29 of 56 children (52%, 95% CI = 38%–65%). Median duration of response was not reached; all objective responses remained durable at data cutoff, with 22 responses (76%) persisting for at least 12 months.
Median target PN volumetric best response was −41% (range = −90% to 13%) among adults and −42% (range = −91% to 48%) in children.
Both adults and children reported significant and clinically meaningful improvements in patient- or parent proxy–reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life that were observed early and sustained during treatment.
The most common treatment-related adverse events of any grade were dermatitis acneiform (78%), diarrhea (48%), and nausea (36%) in adults and dermatitis acneiform (43%), diarrhea (38%), and paronychia (30%) in children. Grade ≥ 3 treatment-related adverse events occurred in 16% of adults (most commonly dermatitis acneiform [9%]) and in 25% of children (most commonly decreased neutrophils [9%] and increased creatine phosphokinase [7%]).
The investigators concluded: “In ReNeu, the largest multicenter NF1-PN trial reported to date, mirdametinib treatment demonstrated significant confirmed [objective response rates] by blinded independent central review, deep and durable PN volume reductions, and early, sustained, and clinically meaningful improvement in pain and [health-related quality of life]. Mirdametinib was well tolerated in adults and children.”
Christopher L. Moertel, MD, of the University of Minnesota, Minneapolis, is the corresponding author of the Journal of Clinical Oncology article.
Disclosure: The study was supported by SpringWorks Therapeutics, Inc. For full disclosures of the study authors, visit ascopubs.org.
