Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: AstraZeneca AB, SE-151 85 Södertälje, Sweden
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor
ATC code: L01EE04
Selumetinib is a selective inhibitor of mitogen activated protein kinase kinases 1 and 2 (MEK ½). Selumetinib blocks MEK activity and the RAF-MEK-ERK pathway. Therefore, MEK inhibition can block the proliferation and survival of tumour cells in which the RAF-MEK-ERK pathway is activated.
The efficacy of selumetinib in paediatric and adult NF1-PN patients was evaluated in studies as described below.
The efficacy of Koselugo was evaluated in an open-label, multi-centre, single-arm study (SPRINT) Phase II Stratum 1 of 50 paediatric patients with NF1 inoperable PN that caused significant morbidity. Inoperable PN was defined as a PN that could not be surgically completely removed without risk for substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN. Patients were excluded for the following ocular toxicities: any current or past history of CSR, current or past history of RVO, known intraocular pressure >21 mmHg (or upper limit of normal adjusted by age) or uncontrolled glaucoma. Patients received 25 mg/m² (BSA) twice daily, for 28 days (1 treatment cycle), on a continuous dosing schedule. Treatment was discontinued if a patient was no longer deriving clinical benefit, experienced unacceptable toxicity or PN progression, or at the discretion of the investigator.
The target PN, the PN that caused relevant clinical symptoms or complications (PN-related morbidities), was evaluated for response rate using centrally read volumetric magnetic resonance imaging (MRI) analysis per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria. Tumour response was evaluated at baseline and while on treatment after every 4 cycles for 2 years, and then every 6 cycles.
Patients had target PN MRI volumetric evaluations and clinical outcome assessments, which included functional assessments and patient reported outcomes.
At enrolment, the median age of the patients was 10.2 years (range: 3.5 to 17.4 years), 60% were male and 84% were Caucasian.
The median target PN volume at baseline was 487.5 mL (range: 5.6 - 3820 mL). PN-related morbidities that were present in ≥20% of patients included disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment, and bladder/bowel dysfunction.
The primary efficacy endpoint was objective response rate (ORR), defined as the percentage of patients with complete response (defined as disappearance of the target PN) or confirmed partial response (defined as ≥20% reduction in PN volume, confirmed at a subsequent tumour assessment within 3-6 months), based on National Cancer Institute (NCI) centralised review. Duration of response (DoR) was also evaluated.
Efficacy results are provided based on a data cut-off of March 2021, unless stated otherwise.
Table 6. Efficacy results from SPRINT Phase II Stratum 1:
| Efficacy parameter | SPRINT (N=50) | Objective response ratea,b | |
| Objective response rate, n (%) (95% CI) | 34 (68%) (53.3 - 80.5) | ||
| Complete response | 0 | ||
| Confirmed partial response, n (%)b | 34 (68%) | ||
| Duration of response | |||
| DoR ≥12 months, n (%) | 31 (91.2%) | ||
| DoR ≥24 months, n (%) | 26 (76.5%) | ||
| DoR ≥36 months, n (%) | 21 (61.8%) | ||
CI – confidence interval, DoR – duration of response.
a Responses required confirmation at least 3 months after the criteria for first partial response were met.
b Complete response: disappearance of the target lesion; partial response: decrease in target PN volume by ≥20% compared to baseline.
An independent centralised review of tumour response per REiNS criteria (data cut-off June 2018) resulted in an ORR of 44% (95% CI: 30.0, 58.7).
The median time to onset of response was 7.2 months (range: 3.3 months to 3.2 years). The median (min-max) time to the maximal PN shrinkage from baseline was 15.1 months (range: 3.3 months to 5.2 years). The median DoR from onset of response was not reached; at the time of data cut-off the median follow-up time was 41.3 months. The median time from treatment initiation to disease progression while on treatment was not reached.
At the time of data cut-off or last scan on treatment for patients who had discontinued treatment, 25 (50%) patients remained in confirmed partial response, 1 (2%) had unconfirmed partial responses, 12 (24%) had stable disease and 10 (20%) had progressive disease.
The efficacy of Koselugo in adult patients was evaluated in a Phase III, multicentre, international study that had a parallel, randomised 1:1, double-blind, placebo-controlled, 2 arm design. A total of 145 adult patients were randomised to receive either selumetinib 25 mg/m² (BSA) or placebo twice daily for 12 cycles (28-day cycles). After the end of Cycle 12, placebo patients crossed over to receive open label selumetinib or earlier if disease progression was confirmed by the Independent Central Review (ICR). Treatment was discontinued if a patient was no longer deriving clinical benefit, experienced unacceptable toxicity, patient's decision, if PN progressed, or at the discretion of the investigator.
KOMET study enrolled male and female adult (≥ 18 years of age at enrollment) patients with a diagnosis of NF1 who have symptomatic, inoperable PN; at least one target PN measurable by volumetric MRI analysis; chronic target PN pain score documented for a minimum period (for at least 4 days out of 7 days for at least 2 weeks during the screening period); stable chronic PN pain medication use at time of enrollment.
The target PN, the clinically most relevant PN, which is measurable by volumetric MRI analysis and, if relevant, one additional non-target PN, was evaluated for response rate using centrally read volumetric MRI analysis per REiNS criteria. Tumour response was evaluated at baseline and while on treatment after every 4 cycles for 2 years, and then every 6 cycles. Patients had target and non-target PN MRI volumetric evaluations and clinical outcome assessments.
Demographics and baseline disease characteristics were generally well balanced between the selumetinib and placebo treatment arms. Baseline demographics in the selumetinib and placebo groups were as follows: median age at enrolment was 29 years (range: 18 to 60 years), male (51.7%), White (55.9%), and Asian (31%). The median volume of the target PN was 110.18 mL for the selumetinib group and 221.85 mL for the placebo group. The most common PN related morbidities were pain, motor dysfunction and disfigurement, affecting 23% or more of the patients in both groups. Airway, vision, and bowel/bladder morbidities were less frequent, affecting 4.2% or less of the patients in both the selumetinib and placebo groups.
The primary efficacy endpoint was ORR for selumetinib by the end of Cycle 16. ORR was defined as the percentage of patients with confirmed complete response (disappearance of the target PN, confirmed by consecutive scan within 3–6 months after the first response) or confirmed partial response (target PN volume decrease ≥ 20%, compared to baseline, confirmed by a consecutive scan within 3–6 months after the first response) by the end of Cycle 16 as determined by ICR per REiNS criteria.
At the planned primary analysis, the study met its primary endpoint demonstrating a statistically significant ORR versus placebo. At the time of the final data cut-off (DCO), the median total duration of exposure was 749 days (approximately 25 months) in patients randomized to selumetinib; the median DoR from onset of response was not reached. Efficacy results are presented in Table 7 below.
Table 7. Efficacy results from KOMET:
| Efficacy Parameters | Selumetinib (N=71) | Placebo (N=74) |
| Objective Response Rate by the end o Cycle 16 (ORR)a,b,c | ||
| ORR % (95% CI) | 19.7 (11.2, 30.9) | 5.4 (1.5, 13.3) |
| p valued | 0.0112 | |
| Best objective response (BOR) by the end of Cycle 16, n (%)a,b,c,e | ||
| Confirmed Complete Response | 0 | 0 |
| Confirmed Partial Response | 14 (19.7%) | 4 (5.4%) |
| Time to Response (TTR)a | ||
| Median (95% CI) months | 3.7 (3.61, 11.07) | ND |
| Duration of Response (DOR)f,g,h | ||
| Median (95% CI) months | NR (11.5, NE) | ND |
| Number and percentage remaining in response | ||
| ≥6 months, n (%) | 14 (100%) | ND |
| ≥12 months, n (%) | 9 (64.3%) | ND |
CI – confidence interval, NE – not estimated, NR - not reached, ND – Not determined for placebo treatment arm.
a Results are based on planned primary analysis (DCO: 05 August 2024) which occurred when all the patients had the opportunity to complete Cycle 16.
b Each treatment cycle in the study is of 28 calendar days (Cycle 16 corresponds to approximately 15 months).
c Patients with confirmed complete response or partial response by independent central review (ICR) per REiNS criteria. Response confirmation was by a consecutive scan within 3 to 6 months after the first response as determined by ICR per REiNS criteria.
d 2-sided p-value calculated using Fisher's exact method (alpha of 0.047) by comparison of Selumetinib vs Placebo.
e Complete response: disappearance of the target lesion; Partial Response: decrease in target PN volume by ≥20% compared to baseline; Stable Disease: insufficient volume change from baseline to qualify for either partial response or progressive disease; Progressive Disease: increase in target PN volume by ≥20% compared to baseline or the documented time of best response.
f Duration of Response from date of first documented response (subsequently confirmed) until date of documented progression by ICR per REiNS criteria.
g Calculated using Kaplan-Meier method.
h Calculated for patients randomized to selumetinib arm that achieved a confirmed partial response (cPR) by end of Cycle 16 and including data until the final DCO (17 March 2025, which occurred when all the patients had the opportunity to complete Cycle 24).
This medicinal product has been authorised under a so-called "conditional approval" scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
The pharmacokinetic (PK) parameters in paediatric patients (3 to ≤18 years old) with NF1-PN and in adult patients (≥18 years old) with NF1-PN are comparable.
In the SPRINT Phase II Stratum 1, at the recommended dose of 25 mg/m² twice daily in paediatric patients (3 to <18 years old), the geometric mean (coefficient of variation [CV%]) maximum plasma concentration (Cmax) was 731 (62%) ng/mL and the area under the plasma drug concentration curve (AUC0-12) following the first dose was 2009 (35%) ng·h/mL. Minimal accumulation of ~1.1-fold was observed at steady state upon twice daily dosing.
In the KOMET study, at the recommended dose of 25 mg/m² twice daily in adult patients (≥18 years old), the geometric mean (geometric coefficient of variation [gCV%]) maximum plasma concentration (Cmax) was 789 (47%) ng/mL and the area under the plasma drug concentration curve (AUC0-12) was 2986 (43%) ng·h/mL at steady-state.
Across all ages, the minimal accumulation range was 1.2 to 1.5 following administration of selumetinib.
In paediatric patients (3 to ≤18 years old), at a dose level of 25 mg/m², selumetinib has an apparent oral clearance of 8.8 L/h, mean apparent volume of distribution at steady state of 78 L and mean elimination half-life of ~6.2 hours.
In adult patients (≥18 years old), at a dose level of 25 mg/m², selumetinib has an apparent oral clearance of 14.1 L/h, mean apparent volume of distribution at steady state of 126.1 L and mean elimination half-life of ~9.0 hours.
In healthy adult subjects, the mean absolute oral bioavailability of selumetinib was 62%. Following oral dosing, selumetinib is rapidly absorbed, producing peak steady state plasma concentrations (tmax) between 1-1.5 hours post-dose.
In separate clinical studies, in healthy adult subjects and in adult patients with advanced solid malignancies at a dose of 75 mg, co-administration of selumetinib with a high-fat meal resulted in a mean decrease in Cmax of 50% and 62%, respectively, compared to fasting administration. Selumetinib mean AUC was reduced by 16% and 19%, respectively, and the time to reach maximum concentration (tmax) was delayed by approximately 1.5 to 3 hours (see section 4.2).
In healthy adult subjects at a dose of 50 mg, co-administration of selumetinib with a low-fat meal resulted in 60% lower Cmax when compared to fasting administration. Selumetinib AUC was reduced by 38%, and the time to reach maximum concentration (tmax) was delayed by approximately 0.9 hours (see section 4.2).
In adolescent patients with NF1 and inoperable PN treated with multiple doses of 25 mg/m² bid, co-administration of selumetinib with a low-fat meal resulted in 24% lower Cmax when compared to fasting administration. Selumetinib AUC was reduced by 8%, and tmax was delayed by approximately 0.57 hours (see section 4.2).
A population PK analysis including children and adolescent patients with NF1 and inoperable PN, adult patients with advanced solid malignancies and healthy adult subjects taken from 15 studies showed that concomitant administration of a low or high fat meal resulted in a mean decrease in the exposure (AUC) of selumetinib when compared to fasted administration (23.1% and 20.7%, respectively) which was not considered clinically relevant.
The mean apparent volume of distribution at steady state of selumetinib across 20 to 30 mg/m² ranged from 78 to 171 L in paediatric patients. Comparable values were observed in adult patients across 25 mg/m² and ranged from 40 to 3710 L. These values indicate moderate distribution into tissue.
In vitro plasma protein binding is 98.4% in humans. Selumetinib mostly binds to serum albumin (96.1%) than α-1 acid glycoprotein (<35%).
In vitro, selumetinib undergoes phase 1 metabolic reactions including oxidation of the side chain, N-demethylation, and loss of the side chain to form amide and acid metabolites. CYP3A4 is the predominant isoform responsible for selumetinib oxidative metabolism with CYP2C19, CYP2C9, CYP2E1 and CYP3A5 involved to a lesser extent. In vitro studies indicate that selumetinib also undergoes direct phase 2 metabolic reactions to form glucuronide conjugates principally involving the enzymes UGT1A1 and UGT1A3. Glucuronidation is a significant route of elimination for selumetinib phase 1 metabolites involving several UGT isoforms.
Following oral dosing of 14C-selumetinib to healthy male subjects, unchanged selumetinib (~40% of the radioactivity) with other metabolites including glucuronide of imidazoindazole metabolite (M2; 22%), selumetinib glucuronide (M4; 7%), N-desmethyl selumetinib (M8; 3%), and N-desmethyl carboxylic acid (M11; 4%) accounted for the majority of the circulating radioactivity in human plasma. N-desmethyl selumetinib represents less than 10% of selumetinib levels in human plasma but is approximately 3 to 5 times more potent than the parent compound, contributing to about 21% to 35% of the overall pharmacologic activity.
In vitro, selumetinib is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP2E1. In vitro, selumetinib is not an inducer of CYP1A2 and CYP2B6. Selumetinib is an inducer of CYP3A4 in vitro, this is however not expected to be clinically relevant.
In vitro, selumetinib inhibits UGT1A3, UGT1A4, UGT1A6 and UGT1A9 however these effects are not expected to be clinically relevant.
Based on in vitro studies, selumetinib is a substrate for BCRP and P-gp transporters but is unlikely to be subjected to clinically relevant drug interactions. In vitro studies suggest that selumetinib does not inhibit the breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), OATP1B1, OATP1B3, OCT2, OAT1, MATE1 and MATE2K at the recommended paediatric dose. A clinically relevant effect on the pharmacokinetics of concomitantly administered substrates of OAT3 cannot be excluded.
In healthy adult subjects, following a single oral 75 mg dose of radiolabelled selumetinib, 59% of the dose was recovered in faeces (19% unchanged) while 33% of the administered dose (<1% as parent) was found in urine by 9 days of sample collection.
The exposure of 50 mg oral selumetinib was investigated in adult subjects with normal renal function (N=11) and subjects with ESRD (N=12). The ESRD group showed 16% and 28% lower Cmax and AUC, respectively, with the fraction of unbound selumetinib being 35% higher in ESRD subjects. As a result, the unbound Cmax and AUC ratios were 0.97 and 1.13 in the ESRD group when compared to the group with normal renal function. A small increase, approximately 20% AUC, in the N-desmethyl metabolite to parent ratio was detected in the ESRD group when compared to the normal group. As exposure in ESRD subjects was similar to those with normal renal function, investigations in mild, moderate and severe renally impaired subjects were not performed. Renal impairment is expected to have no meaningful influence on the exposure of selumetinib (see section 4.2).
Adult subjects with normal hepatic function (N=8) and mild hepatic impairment (Child-Pugh A, N=8) were dosed with 50 mg selumetinib, subjects with moderate hepatic impairment (Child-Pugh B, N=8) were administered a 50 or 25 mg dose, and subjects with severe hepatic impairment (Child-Pugh C, N=8) were administered a 20 mg dose. Selumetinib total dose normalised AUC and unbound AUC were 86% and 69% respectively, in mild hepatic impairment patients, compared to the AUC values for subjects with normal hepatic function. Selumetinib exposure (AUC) was higher in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment; the total AUC and unbound AUC values were 159% and 141% (Child-Pugh B) and 157% and 317% (Child-Pugh C), respectively, of subjects with normal hepatic function (see section 4.2). There was a trend of lower protein binding in subjects with severe hepatic impairment although the protein binding remained >99% (see section 4.3).
Following a single-dose, selumetinib exposure appears to be higher in Japanese, non-Japanese-Asian and Indian healthy adult subjects compared to Western adult subjects, however, there is considerable overlap with Western subjects when corrected for body weight or BSA (see section 4.2).
The PK parameters in adult healthy subjects and adult patients with advanced solid malignancies, are similar to those in paediatric patients (3 to ≤18 years old) with NF1.
In adult patients, Cmax and AUC increased dose proportionally over a 25 mg to 100 mg dose range.
Selumetinib was positive in the mouse micronucleus study via an aneugenic mode of action. The free mean exposure (Cmax) at the no observed effect level (NOEL) was approximately 27-times greater than clinical free exposure at the maximum recommended human dose (MRHD) of 25 mg/m².
Selumetinib was not carcinogenic in rats or transgenic mice.
In repeat-dose toxicity studies in mice, rats and monkeys, the main effects seen after selumetinib exposure were in the skin, GI tract and bones. Scabs associated with microscopic erosions and ulceration at a free exposure similar to the clinical exposure (free AUC) at the MRHD were seen in rats. Inflammatory and ulcerative GI tract findings associated with secondary changes in the liver and lymphoreticular system at free exposures approximately 28 times the clinical free exposure at the MRHD were observed in mice. Growth plate (physeal) dysplasia was seen in male rats dosed for up to 3 months with selumetinib at a free exposure 11 times the clinical free exposure at the MRHD. GI findings showed evidence of reversibility following a recovery period. Reversibility for skin toxicities and physeal dysplasia was not evaluated. Vascular engorgement of the corpus cavernosum of the bulbocavernosus muscle were observed in male mice in a 26-week study at a dose of 40 mg/kg/day (28 times the free AUC in humans at the MRHD) leading to significant urinary tract obstruction as well as inflammation and luminal hemorrhage of the urethra leading to early death in male mice.
Developmental and reproduction toxicity studies were conducted in mice. Fertility was not affected in male mice at up to 40 mg/kg/day (corresponding to 22-fold the free AUC in humans at the MRHD). In females, mating performance and fertility were not affected at up to 75 mg/kg/day, but a reversible decrease in the number of live foetuses was observed at this dose level; the NOAEL for effects on reproductive performance was 5 mg/kg/day (approximately 3.5-fold the free AUC in humans at the MRHD). A treatment-related increase in the incidence of external malformations (open eye, cleft palate) was reported in absence of maternal toxicity in embryofoetal development studies at >5 mg/kg/day, and in the pre- and post-natal development study at ≥1 mg/kg/day (corresponding to 0.4-fold the free Cmax in humans at the MRHD). The other treatment related effects observed at non-maternotoxic dose levels in these studies consisted of embryo-lethality and decreased foetal weight at ≥25 mg/kg/day (corresponding to 22-fold the free AUC in humans at the MRHD), reductions in post-natal pup growth and at weaning a lower number of pups met the pupil constriction criterion at 15 mg/kg/day (corresponding to 3.6-fold the free Cmax in humans at the MRHD). Selumetinib and its active metabolite were excreted in the milk of lactating mice at concentrations approximately the same as those in plasma.
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