Koselugo is the FIRST FDA-approved treatment proven to shrink NF1 PN in pediatric patients1,2

Primary endpoint: Overall response rate1*

Greater than or equal to 20% PN reduction

ORR was 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 tumor assessment within 3 to 6 months).1†

An independent centralized review (ICR) of tumor response per REiNS criteria resulted in an ORR of 44% (95% CI: 30, 59).1

*DCO June 2018.1

†33 partial responses were confirmed by 3D MRI volumetric analyses at a subsequent tumor assessment within 3 to 6 months. The ORR assessment was conducted by a single NCI reviewer who was a SPRINT investigator and who evaluated all PN imaging from patients enrolled at all trial sites.1

MOA=mechanism of action; PN=plexiform neurofibromas.

Substantial reduction in PN volume1,2‖

Based on an AstraZeneca analysis of NCI data5

Chart: Best percentage change from baseline in PN volume per patient, showing -27.9% as the median best percentage change in PN volume from baseline

‡The most recent response at each patient’s last restaging visit prior to DCO was 50% (n=25) with confirmed partial response, 24% (n=12) with stable disease, 22% (n=11) with progressive disease, and 4% (n=2) unevaluable.4,6

§Stable disease was defined as <20% change in PN volume from baseline, and progressive disease was defined as >20% increase from baseline, or from best response if there was a prior partial response.4,6

‖Koselugo is the first FDA-approved therapy for pediatric patients with NF1 who have symptomatic inoperable PN.1,2

DCO June 2018.5

See study design

Secondary endpoint: Duration of response1#

After over 3 years of treatment, the median duration of response was not reached.1**

Duration of response: 79% (26/33) of patients maintained response at 24 months, and 64% (21/33) maintained response at 36 months

DOR was defined as the time from the pre-cycle volumetric MRI assessment of the first documented response (which was subsequently confirmed) until the pre-cycle volumetric MRI assessment of documented progression.6

#DCO March 2021.1

**Median DOR was not reached (95% CI: 41.2 months, NE).1

††DCO February 2021. This information is from the SPRINT long-term follow-up study.4

CI=confidence interval; DCO=data cutoff; DOR=duration of response; FDA=Food and Drug Administration; MRI=magnetic resonance imaging; NCI=National Cancer Institute; NE=not evaluable; NF1=neurofibromatosis type 1; ORR=overall response rate; REiNS=Response Evaluation in Neurofibromatosis and Schwannomatosis; 3D=three dimensional.

See study design

Real patient case: Evidence of the benefits of Koselugo

Review the initial presentation, point of referral, advanced imaging, and results of a real-world Koselugo patient case study.

Initial presentation:

  • Stridor (noisy breathing)
  • History of URIs, likely secondary to airway deviation
  • Frequent need for oral steroids

URI=upper respiratory infection.

Referred to hematologist/
oncologist by pediatrician because of:

  • Café-au-lait macules and axillary freckling, suggestive of NF1
  • Prominence on the right cheek and left neck suggestive of PN

Advanced imaging showed:

  • PN extending from right mandible to the left brachial plexus/left upper extremity and left lung

Before Koselugo

Patient case study: MRI showing results before and after treatment with Koselugo

After Koselugo

Patient case study: MRI showing results before and after treatment with Koselugo
Individual results may vary. Patient images courtesy of D Van Mater, MD.

Patient results with Koselugo treatment:

  • Received very well with mild side effects, including dry skin (managed with lotion) and lightening of hair color
  • Shrinkage of the mandibular lesion and reduction in airway deviation
  • Improvement in stridor symptoms—no longer requires steroids for URIs

Long-term response in PN volume

Based on an AstraZeneca analysis of NCI data7

Percent change in target PN volume, individual patient data over time, SPRINT Phase 2 Stratum 17‡‡

Chart: Percent change in target PN volume over the long-term, showing that a majority of patients continued to see response

‡‡DCO March 2021.7

See study design
Shield icon

Koselugo delivered a strong response with evidence from long-term data1,7§§

View the long-term safety profile here.

See Koselugo safety

§§At DCO June 2018, 66% (33/50) achieved ≥20% tumor reduction. A subsequent long-term follow-up study was included (DCO February 2021).1,4

Evident response with a median time to onset of 7.2 months in patients with NF1 PN1||||

Estimated DOR based on SPRINT data using the Kaplan-Meier method6¶¶

Kaplan-Meier curve showing estimated duration of response. Probability of remaining in response is greater than 60% almost 6 years after first response

Median progression-free survival was not reached in SPRINT Phase 2 Stratum 1.6##***

IIIIThe median time to onset of response was 7.2 months. One more patient achieved ≥20% PN shrinkage after 1.6 years.1

¶¶DCO: March 2021 where there were 34 responders, compared to the 33 responders at the June 2018 DCO.5,7

##Progression-free survival (PFS) was calculated as the number of cycles of treatment until disease progression or censoring at the time of coming off treatment or most recent restaging evaluation.6

***PFS had a DCO of March 2021 and was calculated using Kaplan-Meier method.1,6

BID=twice daily.

See study design

Secondary outcome variable: Onset of response‡‡‡

Time to onset of response among patients who responded to Koselugo5

Timeline showing median onset of response at 7.2 months. 97% of patients experienced response by 11 months, and 100% of patients experienced response by 22.1 months.

†††The median time to onset of response was 7.2 months (range: 3.3 months to 1.6 years).1

‡‡‡DCO June 2018.5

§§§A cycle was defined as 28 days.6

See study design

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

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.

ADVERSE REACTIONS

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.

DRUG INTERACTIONS

Effect of Other Drugs on Koselugo

Concomitant use of Koselugo with a strong
or moderate CYP3A4 inhibitor or
fluconazole 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.

SPECIAL POPULATIONS

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.

INDICATION

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 www.fda.gov/
medwatch.

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

References:

1. Koselugo. Package insert. AstraZeneca Pharmaceuticals LP.

2. Koselugo (selumetinib) approved in US
for paediatric patients with neurofibromatosis type 1 plexiform neurofibromas. AstraZeneca. April 13, 2020. Accessed December 4, 2023. https://www.astrazeneca.com/media-centre/press-releases/2020/koselugo-selumetinib-approved-in-us-for-paediatric-patients-with-neurofibromatosis-type-1-plexiform-neurofibromas.html#

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

4. Gross AM, Dombi E, Wolters PL, 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/
neuonc/noad086

5. Data on File, REF-36657, AstraZeneca Pharmaceuticals LP.

6. Data on File, REF-36656, AstraZeneca Pharmaceuticals LP.