On February 11, 2025, the Food and Drug Administration sanctioned mirdametinib (Gomekli, SpringWorks Therapeutics, Inc.), a kinase inhibitor, for adult and pediatric patients aged 2 years and older diagnosed with neurofibromatosis type 1 (NF1) exhibiting symptomatic plexiform neurofibromas (PN) that are not suitable for complete resection.
Effectiveness and Safety
The efficacy was assessed in ReNeu (NCT03962543), a multicenter, single-arm trial involving 114 patients aged ≥2 years (58 adults, 56 pediatric patients) with symptomatic, inoperable neurofibromatosis type 1-associated plexiform neurofibromas resulting in substantial morbidity.
A non-resectable PN is characterized as a PN that cannot be entirely surgically excised without incurring significant morbidity due to encasement or closeness to critical tissues, invasiveness, or high vascularity.
The primary efficacy outcome measure was the overall response rate (ORR), defined as the proportion of patients exhibiting a complete response (disappearance of the target PN) or a partial response (≥20% reduction in PN volume). Responses were evaluated by a blinded independent central review utilizing volumetric MRI analysis according to the modified Response Evaluation in Neurofibromatosis and Schwannomatosis guidelines, which mandated confirmation of responses within 2 to 6 months during the 24-cycle therapy phase.
The confirmed overall response rate (ORR) was 41% for adults (95% confidence interval: 29, 55) and 52% for the pediatric cohort (95% confidence interval: 38, 65).
The predominant adverse effects (>25%) in adult patients included rash, diarrhea, nausea, musculoskeletal discomfort, vomiting, and exhaustion. The predominant Grade 3 or 4 test anomaly (>2%) was elevated creatine phosphokinase.
The predominant adverse effects (>25%) in pediatric patients included rash, diarrhea, musculoskeletal discomfort, stomach pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea. The predominant Grade 3 or 4 laboratory abnormalities (>2%) were reduced neutrophil count and elevated creatine phosphokinase levels.
Mirdametinib may induce left ventricular dysfunction and ocular damage, which encompasses retinal vascular blockage, retinal pigment epithelial separation, and impaired vision. Mirdametinib should be withheld, dosage adjusted, or totally discontinued depending on the severity of adverse events.
Dr. Nishant Mittal is a highly accomplished researcher with over 13 years of experience in the fields of cardiovascular biology and cancer research. His career is marked by significant contributions to stem cell biology, developmental biology, and innovative research techniques.
Research Highlights
Dr. Mittal's research has focused on several key areas:
1) Cardiovascular Development and Regeneration: He studied coronary vessel development and regeneration using zebrafish models1.
2) Cancer Biology: At Dartmouth College, he developed zebrafish models for studying tumor heterogeneity and clonal evolution in pancreatic cancer.
3) Developmental Biology: His doctoral work at Keio University involved identifying and characterizing medaka fish mutants with cardiovascular defects.
4) Stem Cell Research: He investigated the effects of folic acid on mouse embryonic stem cells and worked on cryopreservation techniques for hematopoietic stem cells.
Publications and Presentations
Dr. Mittal has authored several peer-reviewed publications in reputable journals such as Scientific Reports, Cardiovascular Research, and Disease Models & Mechanisms1. He has also presented his research at numerous international conferences, including the Stanford-Weill Cornell Cardiovascular Research Symposium and the Weinstein Cardiovascular Development Conference.
In summary, Dr. Nishant Mittal is a dedicated and accomplished researcher with a strong track record in cardiovascular and cancer biology, demonstrating expertise in various model systems and a commitment to advancing scientific knowledge through innovative research approaches.
