Regulatory Decision Summary for Koselugo

The efficacy of Koselugo was evaluated in an open-label, multi-centre, single-arm study (pivotal SPRINT Phase II - Stratum 1), in 50 children with Neurofibromatosis Type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (NF1-PN). Patients received the recommended dose of Koselugo 25 mg/m² orally twice daily. The primary endpoint was Objective Response Rate (ORR). The ORR (≥20% reduction in target PN volume from baseline) was 66.0% (95% CI: 51, 79), assessed by the National Cancers Institute (NCI) central analysis using REiNS criteria.

The pivotal data indicated that reduction in target plexiform neurofibroma (PN) volume with Koselugo occurred after 4 cycles in almost all patients. For patients who achieved a confirmed response, the median time to response was 7.5 cycles. After 12 and 16 cycles, the estimated proportion of patients remaining in response based on Kaplan-Meier analysis was 100% and 96% (95% CI 76, 99), respectively. The median duration of response (DoR) from onset of response was not reached; at the time of data cut-off, the median follow-up time was 22.1 months. There was a trend toward an association between reduction in tumor volume and durable improvement in clinical outcomes, such as PN-related functional impairment, pain intensity, and disfigurement.

The safety of Koselugo monotherapy was evaluated in a pooled population of 74 pediatric patients treated with 20-30 mg/m² twice daily in SPRINT (Phase I and II). The median total duration of exposure in SPRINT was 28 months (range: <1 – 71 months).

In SPRINT Phase II - Stratum 1, 50 children received the recommended dose of Koselugo 25 mg/m² twice daily for over 2 years. The most common adverse reactions of any grade (incidence ≥20%) were vomiting, rash, blood creatine phosphokinase increase, diarrhea, nausea, dry skin, asthenic events, pyrexia, acneiform rash, hypoalbuminemia, stomatitis, aspartate aminotransferase increased, paronychia, hemoglobin decreased, ALT increased, hair changes, blood creatinine increased and ejection fraction decreased.

In the pediatric pool (SPRINT phase I and II), 73/74 (98.6%) patients had at least 1 adverse event (AE). Approximately 68% of patients had a Grade ≥3 AE, and 23% of patients experienced a serious adverse event (SAE). However, the incidence of AEs resulting in discontinuation was 12%. The SAEs reported in 2 patients were anemia, blood creatine phosphokinase increased, diarrhea, hypoxia, and pyrexia; all other SAEs were reported in 1 (1.4%) patient. Adverse reactions resulting in discontinuation of selumetinib included paronychia, peripheral nerve sheath tumour malignant, diarrhoea, skin ulcer, acute kidney injury, blood creatinine increased, gastro-oesophageal reflux disease, stomatitis, nausea, and weight increased. Dose interruptions as a result of adverse reactions occurred in 80% of patients while dose reductions occurred in 24% of patients, and those occurring in more than 5% of patients included vomiting, paronychia, diarrhea, nausea, abdominal pain, rash, skin infection, influenza-like illness, pyrexia and weight gain. No deaths were reported on study treatment or during the 30-day follow-up period.

Within the target population for the proposed indication, Koselugo benefits include clinically meaningful sustained reduction in the volume of PN associated with improved clinical outcomes. The well-characterized safety profile of Koselugo is consistent with the safety profile of MEK inhibitors, and has been appropriately labelled for both class effects of the drug and adverse reactions observed in the pediatric population.

The benefits-risks profile of Koselugo is deemed to be favorable in the proposed indication.

For more information on Health Canada's decision, please view the Summary Basis of Decision.