Mirdametinib Achieves 87% Response Rate in Pediatric Low-Grade Glioma Phase 1/2 Trial
核心洞察
Mirdametinib demonstrated an 87% overall response rate in children and young adults with recurrent or progressive low-grade glioma with MAPK (搜索) pathway activation in the SJ901 trial.
The recommended phase 2 dose was established at 3 mg/m² twice daily, with only one dose-limiting toxicity observed among 12 patients at this dose level.
The oral MEK (搜索) inhibitor showed acceptable safety with manageable side effects, and 83% of patients remained on or completed therapy at median follow-up of 23.9 months.
Mirdametinib (Gomekli) demonstrated remarkable clinical activity in children, adolescents, and young adults with recurrent or progressive low-grade glioma, achieving an 87% overall response rate in the phase 1/2 SJ901 trial presented at the 2025 Society for Neuro-Oncology Annual Meeting. The oral MEK (搜索) inhibitor showed particular promise in patients with biopsy-proven MAPK (搜索) pathway activation who had not received prior MEK inhibitor therapy.
Strong Efficacy Signals Across Response Categories
At a data cutoff of September 23, 2025, the trial demonstrated impressive response rates across multiple categories using Response Assessment in Pediatric Low-Grade Glioma radiological response criteria. The 87% overall response rate included minor response or better in 87% of patients, partial response or better in 55%, major response or better in 26%, and complete response in 6% of patients.
The median time to achieve minor response or better was 6 months, while the median time to partial response or better extended to 10.7 months. Notably, efficacy varied by dose level, with 36% of patients achieving responses at 2.0 mg/m² or 2.5 mg/m² doses, compared to 46% of those receiving the higher 3.0 mg/m² dose.
"Patients [had] more than 50% reductions in the size of their tumor, which some of these tumors are quite large and are causing a lot of debilitating deficits in our patient population," said Dr. Giles W. Robinson, director of the Division of Neuro-Oncology at St. Jude Children's Research Hospital. "When we see that [reduction], we also see that these patients are incredibly thriving."
Recommended Phase 2 Dose Established
The trial successfully identified 3.0 mg/m² twice daily as the recommended phase 2 dose based on safety and efficacy data. This determination was supported by the finding that only one patient out of 12 who received mirdametinib at this dose level experienced a dose-limiting toxicity, specifically grade 3 thrombocytopenia.
"We are very excited about the preliminary efficacy," said lead study author Dr. Anna Vinitsky, an associate member of St. Jude Faculty at St. Jude Children's Research Hospital.
Manageable Safety Profile
The safety profile proved acceptable, with treatment-related adverse events leading to dose reductions in 34% of patients and treatment discontinuations in only 6% of cases. The most significant adverse events requiring dose reductions included grade 3 weight gain in 8 patients, grade 4 elevated creatine phosphokinase levels in 2 patients, grade 3 elevated alanine aminotransferase levels in 1 patient, and decreased platelet counts in 1 patient.
Treatment discontinuations were rare, occurring in only two patients due to intolerable grade 2 rash and grade 4 elevated CPK levels. Notably, three patients experienced asymptomatic grade 2 decreased left ventricular ejection fraction to less than 50%, but all cases resolved spontaneously. Importantly, investigators reported no retinal toxicities of any grade.
"We're quite thrilled that patients are tolerating the drug well," Robinson noted. "They have some of the more customary AEs we see with MEK (搜索) inhibitors, which are rashes, paronychia, or ingrown toenails. But these are relatively minor [AEs] that the patients learn to manage, or parents learn to manage for the patients."
Patient Population and Treatment Duration
Between June 2021 and September 2025, the trial enrolled 35 patients across phase 1, phase 1 expansion, and phase 2 cohort 2 portions. The median age at diagnosis was 8.3 years, with 54% male and 77% White patients. Primary diagnoses included pilocytic astrocytoma (83%), diffuse glioma (6%), diffuse leptomeningeal glioneuronal tumor (3%), glioneuronal tumor (3%), and low-grade glioma not otherwise specified (6%).
MAPK (搜索) gene abnormalities were distributed across BRAF (搜索) (65%), FGFR1 (搜索) (17%), MYB (搜索) (3%), NF1 (9%), and RAF1 (搜索) (6%). At a median follow-up of 23.9 months, 83% of patients had completed or remained on therapy, with only 17% discontinuing due to progression (4 patients) or toxicity (2 patients).
Addressing Unmet Medical Need
The rationale for investigating mirdametinib in pediatric low-grade glioma stems from limitations of existing MEK (搜索) inhibitors, which often have limited blood-brain barrier penetration and lack oral formulations suitable for pediatric patients. Mirdametinib addresses these challenges as an oral, selective, small-molecule MEK inhibitor that can penetrate the blood-brain barrier and is available in a dispersible tablet formulation more amenable for young children and patients who have difficulty swallowing pills.
The drug received FDA approval in February 2025 for treating adult and pediatric patients at least 2 years of age with neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection.
Future Directions
The trial continues to enroll patients in additional cohorts, with cohorts 1 and 3 of the phase 2 portion enrolling newly diagnosed patients and those previously treated with MEK (搜索) inhibition, respectively. Researchers plan to share continued results as data from the patient cohort mature.
"We would love to see this drug become a standard therapy in LGG," Robinson concluded. "That is the direction we're heading [in]. There needs to be more studies in looking at how does this drug fare with other MEK (搜索) inhibitors, and how does it fare in comparison with what we consider standard of care? But to be honest, [from] treating patients and seeing patients in the clinic thriving on this therapy, it feels like they're doing much better than what we've seen with standard chemotherapies. We are encouraged that this will become one of the therapies of the future for LGG."