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WITH UNPRECEDENTED TUMOR RESPONSE IN PEDIATRIC PATIENTS WITH NF1 PN, KOSELUGO IS REDEFINING TREATMENT1

Koselugo is the first and only FDA-approved treatment proven to shrink plexiform neurofibromas (PN)1

KOSELUGO® (selumetinib) Primary Endpoint: Overall Response Rate (ORR)
KOSELUGO® (selumetinib) Primary Endpoint: Overall Response Rate (ORR)
66_percent

66% of patients achieved ≥20% tumor reduction (n=33/50) 95% CI: 51, 79

  • ORR was defined as the percentage of patients with complete response (defined as disappearance of the target PN) or confirmed partial response (defined as a decrease in target PN volume ≥20% from baseline)
  • 33 partial responses were confirmed by 3D MRI volumetric analyses at a subsequent tumor assessment within 3 to 6 months*
  • 82% of patients (n=27/33) had duration of response ≥12 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

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

Onset of Response in SPRINT Trial 3.3 Months- Excellent Response, 7.2 Months-Median Response, 19.2 Months, Latest Response
Onset of Response in SPRINT Trial 3.3 Months- Excellent Response, 7.2 Months-Median Response, 19.2 Months, Latest Response

Based on an AstraZeneca analysis of NCI data2

Percentage Change from Baseline was -27.85% (Range: 2.2% to -54.5%) in Target PN Volume for Each Patient in the SPRINT Study

Best percentage change in target PN volume is the maximum reduction from baseline or the minimum increase from baseline in the absence of a reduction.

Percentage Change from Baseline was -27.85% (Range: 2.2% to -54.5%) in Target PN Volume for Each Patient in the SPRINT Study

Best percentage change in target PN volume is the maximum reduction from baseline or the minimum increase from baseline in the absence of a reduction.

  • The median change in PN volume from baseline was -27.85% (range: 2.2% to -54.5%)2

CI=confidence interval; MRI=magnetic resonance imaging; NCI=National Cancer Institute; NF1=neurofibromatosis type 1; REiNS=Response Evaluation in Neurofibromatosis and Schwannomatosis.

Review the SPRINT Study Design.

PATIENT PN VOLUME RESPONSE OVER TIME

Based on an AstraZeneca analysis of NCI data2

SPRINT Phase ll Study – Percentage Change in Target PN Volume, 88% were Exposed to KOSELUGO® (selumetinib) for ≥12 Months and 66% were Exposed for ≥2 years
SPRINT Phase ll Study – Percentage Change in Target PN Volume, 88% were Exposed to KOSELUGO® (selumetinib) for ≥12 Months and 66% were Exposed for ≥2 years
SPRINT Phase ll Study – Percentage Change in Target PN Volume, 88% were Exposed to KOSELUGO® (selumetinib) for ≥12 Months and 66% were Exposed for ≥2 years
  • The median time to onset of response was 7.2 months (range: 3.3 months to 1.6 years)1
  • Of patients in the SPRINT study (N=50), 88% were exposed to Koselugo for ≥12 months and 66% were exposed for ≥2 years1

ONSET AND DURATION OF RESPONSE (DOR)

Time to Onset of Tumor Response was 7.2 Months Among Patients Meeting the Primary Endpoint
Time to Onset of Tumor Response was 7.2 Months Among Patients Meeting the Primary Endpoint

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

Of the patients who had a partial response, 82% had DOR ≥12 months (n=27/33)1

Estimated Probability of Remaining in Response Based on Analysis of SPRINT DOR Data using Kaplan-Meier Method
Estimated Probability of Remaining in Response Based on Analysis of SPRINT DOR Data using Kaplan-Meier Method
Estimated Probability of Remaining in Response Based on Analysis of SPRINT DOR Data using Kaplan-Meier Method

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.2

†Dots represent censored observations.

‡A cycle was defined as 28 days.

§4 patients were censored not due to progression.

BID=twice daily.

Review the SPRINT Study Design.

EXPLORATORY ENDPOINT FROM THE SPRINT STUDY

Limitations of data

PN-related pain intensity improvement was an exploratory endpoint in the SPRINT study. However, these data were limited by several factors:

  • Limited sample size||
  • Open-label, single-arm nature of the SPRINT study
  • Limitations of the instrument used to evaluate data in the selected pediatric patient population (NRS-11)
Adjusted Mean Change Baseline of NRS-11 Physician Selected Target Tumor Pain Score in Pre-cycle Assessment
Adjusted Mean Change Baseline of NRS-11 Physician Selected Target Tumor Pain Score in Pre-cycle Assessment
Adjusted Mean Change Baseline of NRS-11 Physician Selected Target Tumor Pain Score in Pre-cycle Assessment

Patients aged 8 to 18 years at enrollment completed self-reported measures of the NRS-112

  • In total, 24 patients completed NRS-11 assessments for physician-selected target tumor pain, at baseline and at the pre-cycle 13 visit
  • Overall, the median score for target tumor pain intensity at baseline and pre-cycle 13 were:
    • Median score (range) at baseline (n=26): 2.5 (0 to 10)
    • Median score (range) at pre-cycle 13 (n=24): 0 (0 to 7)
  • Of the 24 patients with physician-selected target tumor scores who completed both baseline and pre-cycle 13 assessments:
    • 12 (50%) patients showed improvement of ≥2 points (CMT)**
    • Of the 12 (50%) patients who showed no change, 10 patients had a pain score of 0 or 1 at baseline and therefore had no possibility to improve by 2 points or more
    • No patients showed deterioration at pre-cycle 13

ll34 patients were expected to complete the NRS-11 based on age alone (≥8 years old), but only 26 patients had baseline NRS-11 physician-selected target tumor scores. One patient had severe cognitive impairment and was non-verbal, so the NRS-11 was not administered to him. The remaining patients missing the score had no baseline data for physician-selected target tumor, since they either: 1) were administered the first version that did not contain this item, and their self-selected tumor did not match the physician-selected tumor, or 2) they did not complete the physician-selected target tumor question in the second version (ie, did not indicate whether self-selected tumor was the same as physician-selected target tumor).2

Pain intensity was measured by the NRS-11, consisting of 4 questions scored on a scale of 0=no pain to 10=worst pain you can imagine. Of the 4 items in the NRS-11, this section focuses on physician-selected target tumor (target PN) pain. It is important to note that 8 patients performed their baseline evaluations using an earlier version of the NRS-11, which did not yet include the physician-selected target tumor pain item. Target tumor data for these 8 patients are only summarized if the location of the self-selected and physician-selected target tumor was the same.2

#2 patients had a baseline score but no pre-cycle 13 scores, as both had dropped out of treatment prior to that visit.2

**A decrease of 2 points on the NRS-11 was considered the CMT for this study population, as this was reported in several studies in other populations and was also supported by the CMTs evaluated based on the distribution-based approach.2

CMT=clinically meaningful threshold; FAS=full analysis set; MMRM=mixed model repeated measures; NRS-11=Numeric Rating Scale-11.

Some patients had reduction in pain intensity without increased use of pain medication

  • 14 patients with a baseline pain score of ≥2 had a reduction in pain intensity without increased analgesic use
  • Pain palliation occurred within 2 to 4 months of treatment

Pain palliation was evaluated on the basis of 2 components:

  • Reduction in pain intensity score
  • Stability or reduction in analgesic use

Review the SPRINT Study Design.

Review the safety
profile of Koselugo

IMPORTANT SAFETY INFORMATION

Cardiomyopathy. A decrease in left ventricular ejection fraction (LVEF) ≥10% below baseline occurred in 23% of 74 pediatric patients who received Koselugo in SPRINT. Four percent of patients experienced decreased LVEF below the institutional lower limit of normal (LLN). Grade 3 decreased LVEF occurred in one patient and resulted in dose reduction. All patients with decreased LVEF were asymptomatic and identified during routine echocardiography. Decreased LVEF resolved in 71% of these patients. Decreased LVEF resulting in permanent discontinuation of Koselugo occurred in a pediatric population with NF1 in an expanded access program. 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 in 15% of 74 pediatric patients receiving Koselugo in SPRINT. Blurred vision resulted in dose interruption in 2.7% of patients. Ocular toxicity resolved in 82% of 11 patients. 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. For other ocular toxicities, withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction.

Gastrointestinal Toxicity. Diarrhea occurred in 77% of 74 pediatric patients who received Koselugo in SPRINT, including Grade 3 in 15% of patients. Diarrhea resulting in permanent discontinuation occurred in 1.4% of patients. Diarrhea resulting in dose interruption or dose reduction occurred in 15% and 1.4% of patients, respectively. The median time to first onset of diarrhea was 17 days, and the median duration was 2 days.

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 who received Koselugo in SPRINT. The most frequent rashes included dermatitis acneiform (54%), maculopapular rash (39%), and eczema (28%). Grade 3 rash occurred in 8% of patients. Rash resulted in dose interruption in 11% of patients and dose reduction in 4% of patients. 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 in 76% of 74 pediatric patients who received Koselugo in SPRINT, including Grade 3 or 4 in 9% of patients. Increased CPK resulted in dose reduction in 7% of patients. Increased CPK concurrent with myalgia occurred in 8% of patients, 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 patients 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 (10 mg capsules contain 32 mg vitamin E as the excipient, D-alpha-tocopheryl polyethylene glycol 1000 succinate [TPGS], while Koselugo 25 mg capsules contain 36 mg vitamin E as TPGS). Vitamin E can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors. Daily vitamin E intake that exceeds the recommended or safe limits may increase the risk of bleeding. 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.

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) monitoring 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 to a pregnant woman. 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 pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Koselugo and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Koselugo and for 1 week after the last dose.

Breastfeeding. Due to the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with Koselugo and for 1 week after the last dose.

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 of strong or moderate CYP3A4 inhibitors or fluconazole with Koselugo. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole 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 of strong or moderate CYP3A4 inducers with Koselugo.

The most common adverse reactions ≥40% are: vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin, musculoskeletal pain, fatigue, pyrexia, acneiform rash, stomatitis, headache, paronychia, and pruritus.

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).


Please see complete Prescribing Information, including Patient Information.

You may report side effects related to AstraZeneca products by clicking here.

IMPORTANT SAFETY INFORMATION

Cardiomyopathy. A decrease in left ventricular ejection fraction (LVEF) ≥10% below baseline occurred in 23% of 74 pediatric patients who received Koselugo in SPRINT. Four percent of patients experienced decreased LVEF below the institutional lower limit of normal (LLN). Grade 3 decreased LVEF occurred in one patient and resulted in dose reduction. All patients with decreased LVEF were asymptomatic and identified during routine echocardiography. Decreased LVEF resolved in 71% of these patients. Decreased LVEF resulting in permanent discontinuation of Koselugo occurred in a pediatric population with NF1 in an expanded access program. 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 in 15% of 74 pediatric patients receiving Koselugo in SPRINT. Blurred vision resulted in dose interruption in 2.7% of patients. Ocular toxicity resolved in 82% of 11 patients. 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. For other ocular toxicities, withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction.

Gastrointestinal Toxicity. Diarrhea occurred in 77% of 74 pediatric patients who received Koselugo in SPRINT, including Grade 3 in 15% of patients. Diarrhea resulting in permanent discontinuation occurred in 1.4% of patients. Diarrhea resulting in dose interruption or dose reduction occurred in 15% and 1.4% of patients, respectively. The median time to first onset of diarrhea was 17 days, and the median duration was 2 days.

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 who received Koselugo in SPRINT. The most frequent rashes included dermatitis acneiform (54%), maculopapular rash (39%), and eczema (28%). Grade 3 rash occurred in 8% of patients. Rash resulted in dose interruption in 11% of patients and dose reduction in 4% of patients. 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 in 76% of 74 pediatric patients who received Koselugo in SPRINT, including Grade 3 or 4 in 9% of patients. Increased CPK resulted in dose reduction in 7% of patients. Increased CPK concurrent with myalgia occurred in 8% of patients, 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 patients 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 (10 mg capsules contain 32 mg vitamin E as the excipient, D-alpha-tocopheryl polyethylene glycol 1000 succinate [TPGS], while Koselugo 25 mg capsules contain 36 mg vitamin E as TPGS). Vitamin E can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors. Daily vitamin E intake that exceeds the recommended or safe limits may increase the risk of bleeding. 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.

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) monitoring 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 to a pregnant woman. 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 pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Koselugo and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Koselugo and for 1 week after the last dose.

Breastfeeding. Due to the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with Koselugo and for 1 week after the last dose.

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 of strong or moderate CYP3A4 inhibitors or fluconazole with Koselugo. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole 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 of strong or moderate CYP3A4 inducers with Koselugo.

The most common adverse reactions ≥40% are: vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin, musculoskeletal pain, fatigue, pyrexia, acneiform rash, stomatitis, headache, paronychia, and pruritus.

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).


Please see complete Prescribing Information, including Patient Information.

You may report side effects related to AstraZeneca products by clicking here.

References: 1. Koselugo [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2021. 2. Data on File, REF-75729, AstraZeneca Pharmaceuticals LP.

References: 1. Korf BR, Rubenstein AE. Neurofibromatosis: A Handbook for Patients, Families, and Health Care Professionals. New York, NY: Thieme Medical Publishers; 2005. 2. Anderson JL, Gutmann DH. Neurofibromatosis type 1. In: Islam MP, Roach SE, eds. Neurocutaneous Syndromes. Waltham, MA: Elsevier B.V.; 2015:75-86. Handbook of Clinical Neurology. 3rd series; vol 132. 3. Data on File, REF-75729, AstraZeneca Pharmaceuticals LP. 4. Gross AM, Singh G, Akshintala S, et al. Association of plexiform neurofibroma volume changes and development of clinical morbidities in neurofibromatosis 1. Neuro Oncol. 2018;20(12):1643-1651. 5. Wolters PL, Burns KM, Martin S, et al. Pain interference in youth with neurofibromatosis type 1 and plexiform neurofibromas and relation to disease severity, social-emotional functioning, and quality of life. Am J Med Genet A. 2015;167A(9):2103-2113. 6. Needle MN, Cnaan A, Dattilo J, et al. Prognostic signs in the surgical management of plexiform neurofibroma: the Children's Hospital of Philadelphia experience, 1974-1994. J Pediatr. 1997;131(5):678-682.

References: 1. Data on File, REF-75729, AstraZeneca Pharmaceuticals LP. 2. Koselugo [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2021. 3. Dombi E, Ardern-Holmes SL, Babovic-Vuksanovic D, et al. Recommendations for imaging tumor response in neurofibromatosis clinical trials. Neurology. 2013;81(suppl 1):S33-S40. 4. Blakeley JO, Plotkin SR. Therapeutic advances for the tumors associated with neurofibromatosis type 1, type 2, and schwannomatosis. Neuro Oncol. 2016;18(5):624-638. 5. Yap YS, McPherson JR, Ong CK, et al. The NF1 gene revisited—from bench to bedside. Oncotarget. 2014;5(15):5873-5892.

References: 1. Koselugo [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2021. 2. Data on File, REF-75729, AstraZeneca Pharmaceuticals LP.

References: 1. Koselugo. Package insert. AstraZeneca Pharmaceuticals LP; 2021. 2. Data on File, REF-75729, AstraZeneca Pharmaceuticals LP.

References: 1. Koselugo [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2021. 2. Data on File, REF-75730, AstraZeneca Pharmaceuticals LP. 3. Data on File, REF-70330, AstraZeneca Pharmaceuticals LP. 4. Data on File, REF-75729, AstraZeneca Pharmaceuticals LP.