Selumetinib for Adults with NF1-Associated Inoperable Plexiform Neurofibromas: Results from the KOMET Phase 3 Trial

Highlights

– The KOMET phase 3 trial is the first international randomized, placebo-controlled study evaluating selumetinib in adults with NF1-associated inoperable plexiform neurofibromas (PNs).
– Selumetinib achieved a significantly higher objective response rate (20%) compared to placebo (5%) at 16 cycles, with rapid median response onset (3.7 months).
– No new safety signals were observed; adverse events aligned with established selumetinib profiles.
– Selumetinib showed trends towards pain reduction and decreased analgesic use, although not all secondary endpoints reached statistical significance.

Study Background and Disease Burden

Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder, affecting approximately 1 in 3,000 individuals worldwide. Plexiform neurofibromas (PNs) are complex, often inoperable benign tumors that arise from peripheral nerves, affecting up to half of individuals with NF1. These tumors can cause significant morbidity, including disfigurement, pain, functional impairment, and life-threatening complications due to their infiltrative growth. For adults with symptomatic, inoperable PNs, there has been no globally approved pharmacologic therapy. The unmet need for effective, safe medical treatments in this population is substantial, given the high disease burden and limited surgical options.

Study Design

The KOMET trial (ClinicalTrials.gov NCT04924608) is a multicenter, international, randomized, placebo-controlled, double-blind phase 3 study. Eligible adults (≥18 years) with NF1 and symptomatic, inoperable PNs were randomized 1:1 to receive oral selumetinib (25 mg/m² twice daily) or placebo in 28-day cycles. The study allowed crossover to selumetinib upon radiologically confirmed progression or after 12 cycles. The primary endpoint was objective response rate (ORR), defined as confirmed partial or complete response per independent central review using Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria by cycle 16. Key secondary endpoints included changes in chronic pain intensity (≥3 at baseline) and health-related quality of life (PlexiQoL).

A total of 184 participants were enrolled, with 145 adults randomized (selumetinib n=71; placebo n=74).

Key Findings

Efficacy Outcomes:
– Selumetinib produced an ORR of 20% (14 of 71; 95% CI 11.2–30.9) compared to 5% (4 of 74; 95% CI 1.5–13.3) with placebo by cycle 16 (p=0.011).
– The median time to response was 3.7 months, indicating early onset of tumor shrinkage.
– Reductions in tumor volume were observed as early as cycle 16, corroborated by central radiological review.

Pain and Quality of Life:
– In participants with baseline chronic pain intensity ≥3, selumetinib led to a greater reduction in pain score at cycle 12 compared to placebo (least-squares mean [SE] -2.0 [0.30] vs -1.3 [0.29]); this difference approached but did not reach statistical significance (p=0.070).
– A clinically meaningful improvement in pain from baseline was observed in the selumetinib group.
– The change in PlexiQoL total scores from baseline to cycle 12 was not significantly different between groups (least-squares mean difference [SE] -0.1 [0.59]; 95% CI -1.2 to 1.1).

Safety:
– Adverse events with selumetinib were consistent with its known safety profile. Common events included skin rash, gastrointestinal symptoms (diarrhea, nausea), and elevated creatine phosphokinase.
– No new safety signals or unexpected toxicities were identified.

Expert Commentary

The KOMET study represents a significant advance in the management of NF1-associated inoperable PNs in adults, a population previously lacking any approved therapeutic options. The objective response rate of 20% is clinically meaningful, considering the refractory nature of these tumors and the historical absence of effective systemic treatments. Importantly, the trial confirms the efficacy of MEK inhibition in adult NF1-PN, expanding upon prior evidence established in pediatric populations.

While secondary endpoints such as pain reduction and quality of life showed favorable trends, the lack of statistical significance highlights the complexity of measuring patient-centered outcomes in this heterogeneous disease. Nonetheless, the observed improvements in pain and the reduction in analgesia use are likely to be relevant for clinical practice.

Selumetinib’s safety profile remains predictable, with manageable adverse effects, supporting its use in this chronic disease context. The crossover design ensures ethical access to active treatment, but may dilute long-term between-group differences in quality of life or pain endpoints.

Limitations of the study include the relatively short duration of double-blind follow-up for a chronic disease, the subjective nature of pain assessments, and the restriction to symptomatic, inoperable PNs, which may limit generalizability to broader NF1 populations. Further research should address long-term outcomes, durability of response, and optimal patient selection.

Conclusion

The KOMET phase 3 trial establishes selumetinib as the first effective systemic therapy for adults with NF1 and symptomatic, inoperable plexiform neurofibromas, fulfilling a critical unmet need. The significant objective response rate, rapid onset of action, and manageable safety profile support its adoption into clinical practice. Ongoing observation and future studies will clarify its long-term benefits and patient-centered impact.

References

Chen AP, Coyne GO, Wolters PL, Martin S, Farschtschi S, Blanco I, Chen Z, Darrigo LG Jr, Eoli M, Whittle JR, Nishida Y, Lamarca R, de la Rosa Rodriguez R, Adeyemi A, Herrero I, Llorente N, Diede SJ, Dombi E, Wolkenstein P; KOMET study investigators. Efficacy and safety of selumetinib in adults with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas (KOMET): a multicentre, international, randomised, placebo-controlled, parallel, double-blind, phase 3 study. Lancet. 2025 Jun 21;405(10496):2217-2230. doi: 10.1016/S0140-6736(25)00986-9.