A manageable safety profile in children and adolescents
Actor portrayal.
The majority of adverse reactions in ReNeu were mild to moderate1
Adverse reactions (≥20%) in pediatric patients who received GOMEKLI (n=56)1
All grades
Grade 3 or 4*
Skin and subcutaneous tissue disorders
Rash†
Gastrointestinal disorders
55%
5%
Nausea
27%
0%
Vomiting
39%
0%
Abdominal pain§
39%
4%
Stomatitis∥
20%
0%
Musculoskeletal pain¶
General disorders and administration site conditions
Pyrexia
20%
0%
COVID-19#
25%
0%
Paronychia
32%
0%
Upper respiratory tract infection
23%
0%
Nervous system disorders
Headache**
34%
2%
Left ventricular dysfunction
27%
2%
Respiratory, thoracic, and mediastinal disorders
Cough††
21%
0%
No treatment-related serious adverse reactions were observed in pediatric patients.1
GOMEKLI has no contraindications.1
*All reactions were Grade 3 except one fatal case of COVID-19 in an adult.
†Rash includes dermatitis acneiform, eczema, maculo-papular rash, pustular rash, dermatitis, erythematous rash, palmar-plantar erythrodysesthesia syndrome, exfoliative rash, skin exfoliation, pruritic rash, papule, papular rash, and macular rash.
‡Diarrhea includes frequent bowel movements.
§Abdominal pain includes upper abdominal pain, gastrointestinal pain, and abdominal discomfort.
ǁStomatitis includes mouth ulceration and aphthous ulcer.
¶Musculoskeletal pain includes noncardiac chest pain, back pain, pain in extremity, neck pain, musculoskeletal chest pain, myalgia, arthralgia, and bone pain.
#Includes one fatal case in an adult.
††Cough includes upper-airway cough syndrome.
Laboratory abnormalities
Select laboratory abnormalities (≥15%) that worsened from baseline in pediatric patients who received GOMEKLI in ReNeu (n=56)1,‡‡,§§
All grades
Grade 3 or 4ǁǁ
Chemistry
Increased creatine phosphokinase
59%
5%
Increased triglycerides
45%
0%
Decreased glucose
36%
2%
Decreased calcium¶¶
20%
0%
Increased creatinine
30%
0%
Increased cholesterol
16%
0%
Increased alkaline phosphatase
29%
0%
Decreased bicarbonate
21%
0%
aminotransferase (ALT)
21%
0%
Hematology
Decreased hemoglobin
29%
0%
Decreased leukocytes
40%
0%
Decreased neutrophils
31%
11%
Increased lymphocytes
27%
0%
‡‡The denominator used to calculate the rate varied from 55 to 56 based on the number of patients with a baseline value and at least 1 posttreatment value.
§§Graded per NCI-CTCAE version 5.0.
ǁǁNo Grade 5 laboratory abnormalities were reported in the ReNeu study.
¶¶Calcium corrected for albumin (mmol/L).
CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute.
Additional information on select adverse reactions
- Rash (all grades) was reported in 73% of pediatric patients and 4% had Grade 3 rash1
- Rash includes dermatitis acneiform, eczema, maculo-papular rash, pustular rash, dermatitis, erythematous rash, palmar-plantar erythrodysesthesia syndrome, exfoliative rash, skin exfoliation, pruritic rash, papule, papular rash, and macular rash1
- Dermatitis acneiform occurred with a higher frequency in patients aged 12 to 17 years than in those aged 2 to 11 years. Nonacneiform rash occurred with a higher frequency in patients aged 2 to 11 years than in those aged 12 to 17 years1
- Supportive care should be initiated at first signs of dermatologic adverse reactions. GOMEKLI should be withheld, dose reduced, or permanently discontinued based on severity of adverse reaction1
- The GI adverse reactions reported in ≥20% of patients in the pediatric cohort were diarrhea (55%), vomiting (39%), abdominal pain (39%), nausea (27%), and stomatitis (20%)1
- There were no cases of Grade ≥3 vomiting, nausea, or stomatitis; 5% of patients had Grade 3 diarrhea and 4% had Grade 3 abdominal pain1
Diarrhea
55% (17/31)
Nausea
Vomiting
55% (12/22)
Abdominal pain
55% (12/22)
GI=gastrointestinal.
- 1 patient in the pediatric cohort of ReNeu reported blurred vision3
- Conduct comprehensive ophthalmic assessments prior to initiating GOMEKLI, at regular intervals during treatment, and to evaluate any new or worsening visual changes such as blurred vision. Continue, withhold, reduce the dose, or permanently discontinue GOMEKLI based on severity of adverse reaction1
- GOMEKLI has not been studied in patients with a history of clinically significant cardiac disease or left ventricular ejection fraction (LVEF) <55% prior to initiation of treatment1
-
Decreased LVEF of 10% to <20% occurred in 25% of pediatric patients treated with GOMEKLI and decreased LVEF of ≥20% occurred in 1.8% of patients1
- Of the patients with decreased LVEF, 1 patient (1.8%) required dose interruption of GOMEKLI
- The median time to first onset of decreased LVEF was 132 days1
- No cases of cardiac failure were reported in the pediatric cohort2
- Assess ejection fraction by echocardiogram prior to initiating treatment, every 3 months during the first year, then as clinically indicated thereafter. Withhold, reduce dose, or permanently discontinue GOMEKLI based on severity of adverse reaction1
- 32% of pediatric patients experienced paronychia; none of these reactions were Grade ≥31
Managing adverse reactions
Dose interruption, reduction, and discontinuation due to adverse reactions1
of patients had a dose interruption
of patients had a dose reduction
Adverse reactions that required dose interruption in ≥5% of patients included COVID-19. Adverse reactions that required dose reduction in ≥3% of patients included rash and decreased neutrophil count.
permanently discontinued treatment
Adverse reactions that required permanent discontinuation of GOMEKLI in ≥1% of patients were urticaria, rash, abdominal pain, constipation, and diarrhea.
Dosing designed with patient needs in mind
GOMEKLI has 2 dosing formulations to help more patients.1
Indication
GOMEKLI (mirdametinib) is indicated for the treatment of adult and pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas (PN) not amenable to complete resection.
Important Safety Information
Warnings and Precautions
Ocular Toxicity: GOMEKLI can cause ocular toxicity including retinal vein occlusion (RVO), retinal pigment epithelium detachment (RPED), and blurred vision. In the adult pooled safety population, ocular toxicity occurred in 28% of patients treated with GOMEKLI: 21% were Grade 1, 5% were Grade 2 and 1.3% were Grade 3. RVO occurred in 2.7%, RPED occurred in 1.3%, and blurred vision occurred in 9% of adult patients. In the pediatric pooled safety population, ocular toxicity occurred in 19% of patients: 17% were Grade 1 and 1.7% were Grade 2. Conduct comprehensive ophthalmic assessments prior to initiating GOMEKLI, at regular intervals during treatment, and to evaluate any new or worsening visual changes such as blurred vision. Continue, withhold, reduce the dose, or permanently discontinue GOMEKLI as clinically indicated.
Left Ventricular Dysfunction: GOMEKLI can cause left ventricular dysfunction. GOMEKLI has not been studied in patients with a history of clinically significant cardiac disease or LVEF <55% prior to initiation of treatment. In the ReNeu study, decreased LVEF of 10 to <20% occurred in 16% of adult patients treated with GOMEKLI. Five patients (9%) required dose interruption, one patient (1.7%) required a dose reduction, and one patient required permanent discontinuation of GOMEKLI. The median time to first onset of decreased LVEF in adult patients was 70 days. Decreased LVEF of 10 to <20% occurred in 25%, and decreased LVEF of ≥20% occurred in 1.8% of pediatric patients treated with GOMEKLI. One patient (1.8%) required dose interruption of GOMEKLI. The median time to first onset of decreased LVEF in pediatric patients was 132 days. All patients with decreased LVEF were identified during routine echocardiography, and decreased LVEF resolved in 75% of patients. Before initiating GOMEKLI, assess ejection fraction (EF) by echocardiogram. Monitor EF every 3 months during the first year and then as clinically indicated. Withhold, reduce the dose, or permanently discontinue GOMEKLI based on severity of adverse reaction.
Dermatologic Adverse Reactions: GOMEKLI can cause dermatologic adverse reactions including rash. The most frequent rashes included dermatitis acneiform, rash, eczema, maculo-papular rash and pustular rash. In the pooled adult safety population, rash occurred in 92% of patients treated with GOMEKLI (37% were Grade 2 and 8% were Grade 3) and resulted in permanent discontinuation in 11% of patients. In the pooled pediatric safety population, rash occurred in 72% of patients treated with GOMEKLI (22% were Grade 2 and 3.4% were Grade 3) and resulted in permanent discontinuation in 3.4% of patients. Initiate supportive care at first signs of dermatologic adverse reactions. Withhold, reduce the dose, or permanently discontinue GOMEKLI based on severity of adverse reaction.
Embryo-Fetal Toxicity: GOMEKLI can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to the initiation of GOMEKLI. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Also advise patients to use effective contraception during treatment with GOMEKLI and for 6 weeks after the last dose (females) or 3 months after the last dose (males).Adverse Reactions
The most common adverse reactions (>25%) in adult patients were rash (90%), diarrhea (59%), nausea (52%), musculoskeletal pain (41%), vomiting (38%), and fatigue (29%). Serious adverse reactions occurred in 17% of adult patients who received GOMEKLI. The most common Grade 3 or 4 laboratory abnormality (>2%) was increased creatine phosphokinase.
The most common adverse reactions (>25%) in pediatric patients were rash (73%), diarrhea (55%), musculoskeletal pain (41%), abdominal pain (39%), vomiting (39%), headache (34%), paronychia (32%), left ventricular dysfunction (27%), and nausea (27%). Serious adverse reactions occurred in 14% of pediatric patients who received GOMEKLI. The most common Grade 3 or 4 laboratory abnormalities (>2%) were decreased neutrophil count and increased creatine phosphokinase.Use in Specific Populations
Indication
References
- GOMEKLI. Prescribing Information. SpringWorks Therapeutics, Inc.
- Data on file: SpringWorks Therapeutics, Inc.
- Moertel CL, Hirbe AC, Shuhaiber HH, et al. ReNeu: a pivotal, phase IIb trial of mirdametinib in adults and children with symptomatic neurofibromatosis type 1-associated plexiform neurofibroma. J Clin Oncol. Published online November 8, 2024. doi.org/10.1200/JCO.24.01034