SPRINT: a landmark study in the treatment of NF1 PN1,2

SPRINT Phase 2 Stratum 1 was an open-label, multicenter, single-arm study coordinated with the NCI. This study of 50 pediatric patients with NF1-related inoperable plexiform neurofibromas (PN) that caused significant morbidity was designed to assess the efficacy and safety of Koselugo in reducing the volume of NF1 PN.1,2

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AGE ELIGIBILITY RANGE1,2: 2 to 18 years (N=50)

Median age: 10.2 years (range: 3.5 to 17.4 years)

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DOSING Koselugo (capsules)1,2

25 mg/m2 (BSA) twice daily, approximately 12 hours apart

PRIMARY ENDPOINT: Overall Response Rate (ORR) per REiNS criteria2

ORR was defined as the percentage of patients with complete response (defined as disappearance of the HCP-identified target PN) or confirmed partial response (defined as ≥20% reduction of the HCP-identified target PN).*

  • Duration of response
  • Safety
  • PN-related pain intensity improvement using the

Key inclusion criteria in SPRINT1,2

NF1 with symptomatic, inoperable PN (defined as PN that could not be completely surgically removed without risk for substantial morbidity due to PN location, invasiveness, or high vascularity)

All patients (N=50) had at least 1 clinically significant PN-related morbidity (median number of 3 [range: 1 to 5]) at baseline

Key exclusion criteria in SPRINT3

Evidence of MPNST, an optic glioma, malignant glioma, or other cancer requiring treatment with chemotherapy or radiation therapy

*The target PN was defined as the PN that caused relevant clinical symptoms or complications (PN-related morbidities). Response was confirmed by 3D MRI volumetric analysis at a subsequent assessment within 3 to 6 months.2

Pain intensity of the target PN was self-reported by patients ≥8 years of age using the NRS-11.1

BSA=body surface area; HCP=healthcare provider; MPNST=malignant peripheral nerve sheath tumor; MRI=magnetic resonance imaging; NCI=National Cancer Institute; NF1=neurofibromatosis type 1; NRS-11=Numeric Rating Scale-11; REiNS=Response Evaluation in Neurofibromatosis and Schwannomatosis; 3D=three dimensional.

SPRINT: changing the treatment paradigm

The baseline characteristics of patients in SPRINT reflect the variability of NF1 PN

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Progressive and nonprogressive PN1,4

  • 42% (21/50) of patients had a progressive PN (growth ≥20% within 15 months prior to enrollment)
  • 30% (15/50) of patients had a nonprogressive PN
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Patients with and without past surgeries5

56% of patients had undergone at least 1 prior PN-related or NF1-related surgical procedure

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A range of PN volumes4

Median target PN volume was 487 mL (range: 5 mL to 3820 mL)

Morbidities that were present in ≥20% (N=50) of patients included2,5:

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Visual impairment

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Motor dysfunction

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Airway dysfunction

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Thirty-six patients had evaluable prestudy volumetric MRI data. 28% (14/50) of patients had insufficient PN progression status at baseline.4,5

Koselugo brings targeted MEK inhibition to NF1 PN treatment

Inhibition Graphic

ERK=extracellular signal-regulated kinase; MAPK=mitogen-activated protein kinase; MEK=mitogen-activated protein kinase kinase; NF1=neurofibromatosis type 1; PN=plexiform neurofibromas; RAF=rapidly accelerated fibrosarcoma; RAS=rat sarcoma viral oncogene homolog.



Cardiomyopathy. A decrease in left
ventricular ejection fraction (LVEF) ≥10% below baseline occurred in pediatric
patients who received Koselugo in SPRINT with some experiencing decreased LVEF below the institutional lower limit of normal
(LLN), including one patient with Grade 3. All patients with decreased LVEF were asymptomatic and identified during routine echocardiography. The safety of Koselugo has not been established in patients with a history of impaired LVEF or a baseline ejection fraction that is below the institutional LLN. Assess ejection fraction by echocardiogram prior to initiating treatment, every 3 months during the first year of treatment, every 6 months thereafter, and as clinically indicated. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction. In patients who interrupt Koselugo for decreased LVEF, obtain an echocardiogram or a cardiac MRI every 3 to 6 weeks. Upon resolution of decreased LVEF, obtain an echocardiogram or a cardiac MRI every 2 to 3 months.

Ocular Toxicity. Blurred vision, photophobia, cataracts, and ocular hypertension
occurred. Retinal pigment epithelial detachment (RPED) occurred in the pediatric population during treatment with single agent Koselugo and resulted in permanent discontinuation. Conduct ophthalmic assessments prior to initiating Koselugo, at regular intervals during treatment, and for new or worsening visual changes. Permanently discontinue Koselugo in patients with retinal vein occlusion (RVO). Withhold Koselugo in patients with RPED, conduct ophthalmic assessments every 3 weeks until resolution, and resume Koselugo at a reduced dose.

Gastrointestinal Toxicity. Diarrhea
occurred, including Grade 3. Diarrhea resulting in permanent discontinuation, dose interruption or dose reduction occurred. Advise patients to start an anti-diarrheal agent (eg, loperamide) and to increase fluid intake immediately after the first episode of diarrhea. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction.

Skin Toxicity. Rash occurred in 91% of 74 pediatric patients. The most frequent rashes included dermatitis acneiform (54%), maculopapular rash (39%), and eczema (28%). Grade 3 rash occurred, in addition to rash resulting in dose interruption or dose reduction. Monitor for severe skin rashes. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction.

Increased Creatine Phosphokinase (CPK). Increased CPK occurred, including Grade 3 or 4 resulting in dose reduction. Increased CPK concurrent with myalgia occurred, including one patient who permanently discontinued Koselugo for myalgia. Obtain serum CPK prior to initiating Koselugo, periodically during treatment, and as clinically indicated. If increased CPK occurs, evaluate for rhabdomyolysis or other causes. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction.

Increased Levels of Vitamin E and Risk of Bleeding. Koselugo capsules contain
vitamin E which can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors. Supplemental vitamin E is not recommended if daily vitamin E intake (including the amount of vitamin E in Koselugo and supplement) will exceed the recommended or safe limits due to increased risk of bleeding. An increased risk of bleeding may occur in patients who are coadministered vitamin-K antagonists or anti-platelet antagonists with Koselugo. Monitor for bleeding in these patients and increase international normalized ratio (INR) in patients taking a vitamin-K antagonist. Perform anticoagulant assessments more frequently and adjust the dose of vitamin K antagonists or anti-platelet agents as appropriate.

Embryo-Fetal Toxicity. Based on findings
from animal studies, Koselugo can cause fetal harm when administered during pregnancy. In animal studies, administration of selumetinib to mice during organogenesis caused reduced fetal weight, adverse structural defects, and effects on embryo-fetal survival at approximate exposures >5 times the human exposure at the clinical dose of 25 mg/m2 twice daily. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with Koselugo and for 1 week after the last dose.


Common adverse reactions ≥40% include vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin, musculoskeletal pain, fatigue, pyrexia, acneiform rash, stomatitis, headache, paronychia, and pruritus.


Effect of Other Drugs on Koselugo

Concomitant use of Koselugo with a strong
or moderate CYP3A4 inhibitor or
increased selumetinib plasma concentrations, which may increase the risk of adverse reactions. Avoid coadministration with Koselugo. If coadministration cannot be avoided, reduce Koselugo dosage.

Concomitant use of Koselugo with a strong or moderate CYP3A4 inducer decreased selumetinib plasma concentrations, which may reduce Koselugo efficacy. Avoid concomitant use with Koselugo.


Pregnancy & Lactation. Verify the
pregnancy status of patients of reproductive potential prior to initiating Koselugo. Due to the potential for adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with Koselugo and for 1 week after the last dose.


KOSELUGO is indicated for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN).

To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
1-800-236-9933 or at
https://us-aereporting.astrazeneca.com or FDA at
1-800-FDA-1088 or

Please see full Prescribing Information for Koselugo® (selumetinib).


1. Gross AM, Wolters PL, Dombi E, et al. Selumetinib in children with inoperable plexiform neurofibromas. N Engl J Med. 2020;382(15):1430-1442. doi:10.1056/

2. Koselugo. Package insert. AstraZeneca Pharmaceuticals LP.

3. Gross AM, Wolters PL, Dombi E, et al. Selumetinib in children with inoperable plexiform neurofibromas [protocol]. N Engl J Med.
2020;382(15):1430-1442. doi:10.1056/NEJMoa1912735

4. Gross AM, Wolters PL, Dombi E, et al. Long-term safety and efficacy of selumetinib in children with neurofibromatosis type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas. Neuro Oncol. 2023;25(10):1883-1894. doi:10.1093/

5. Data on File, REF-75729, AstraZeneca Pharmaceuticals LP.

6. Boyd KP, Korf BR, Theos A. Neurofibromatosis type 1. J Am Acad Dermatol. 2009;61(1):1-16. doi:10.1016/