Hear from NF1-PN experts
Actor portrayal.
Clinical perspectives in NF1-PN
The videos below feature NF1 experts Dr. Nghiemphu and Dr. Moertel discussing NF1-PN and clinical data from the ReNeu trial for GOMEKLI, as well as case studies of actual patients who were treated with GOMEKLI.
Clinical Management of NF1-PN
Drs. Nghiemphu and Moertel discuss the unmet needs and challenges in managing patients with NF1-PN and factors to consider when determining treatment options.
[Text onscreen]
GOMEKLI logo.
Episode #1: Clinical Management of NF1-PN
The first FDA-approved treatment for both adult and pediatric patients aged ≥2 years with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas (PN) not amenable to complete resection.
[Dr Nghiemphu]
My name is Dr Phioanh Leia Nghiemphu, and I'm a neuro-oncologist and the director of the UCLA Neurofibromatosis and Schwannomatosis Clinic.
I'm happy to share today that I also have Dr Moertel, one of the lead investigators of the ReNeu study.
[Dr Moertel]
My name is Dr Christopher Moertel.
I'm a neuro-oncologist and I serve as professor of pediatrics at the University of Minnesota School of Medicine, and I'm the medical director of the Comprehensive Neurofibromatosis Clinic at the University of Minnesota Masonic Children's Hospital.
[Dr Nghiemphu]
I'd like to have a brief discussion with Dr Moertel about unmet needs and the clinical management of NF1-PN in our practices.
How we treat symptomatic patients with NF1-PN is always evolving. So, in your opinion, Dr Moertel, what factors are the most important when determining management options for a patient with NF1-PN that is symptomatic and has been deemed in need of intervention?
Do these factors differ between pediatric and adult patients? And, if yes, how do they differ?
[Dr Moertel]
Determining the management of patients with NF1-PN is multifactorial, as you know, as it involves considerations of several treatment options to reduce or prevent the morbidities associated with PNs.
When deciding whether or not surgery is appropriate, factors that should be considered include the size and location of the tumor and amenability to resection.
Up to approximately 85% of PNs are not amenable to complete resection.
Additionally, many patients experience postoperative tumor regrowth, pain, and complications of the surgery.
When selecting a systemic treatment, contraindications or preexisting conditions, the age of the patient, and a patient's ability to swallow pills are considerations.
[Dr Nghiemphu]
What are some of the challenges in managing this disease in your patients?
[Dr Moertel]
Well, as we just mentioned, the rate of PN regrowth after partial, or even complete, resection is one of the many challenges of surgery.
[Dr Moertel, voiceover only]
For systemic treatment, until now, there was no FDA-approved option to treat adult patients with NF1-PN or for individuals who have difficulty swallowing intact capsules. And that's a lot of people in my practice.
Until now, treatment options for adults were limited to surgery or off-label therapies.
[Dr Moertel]
Having an FDA-approved treatment option for adults is a great step forward.
Dr Nghiemphu, is it important to address the symptomatic plexiform neurofibromas in a timely manner? And, if so, can you explain why it's important?
[Dr Nghiemphu]
Yes, the clinical manifestation of NF1 can start soon after birth and continue throughout childhood and adulthood.
These manifestations can affect the skeletal system, the skin, and the central nervous system. And NF1-PNs, which can occur at any time throughout life, can be debilitating.
[Dr Nghiemphu, voiceover only]
They are associated with significant morbidities, such as pain, disfigurement, compression of internal organs, and impaired physical function.
The most rapid growth of NF1-PNs usually occurs among those aged 5 years or younger. However, although some patients may experience slow PN regrowth, clinical morbidities often persist and can have a detrimental impact.
[Dr Moertel]
Dr Nghiemphu, of the symptoms experienced with plexiform neurofibromas that you see, what are the most common among your patients?
[Dr Nghiemphu]
For many of my patients, pain can interfere with daily functioning, and the disfigurement can have a substantial effect on their lives.
Reducing the size of PNs may help address these morbidities.
[Dr Moertel, voiceover only]
I would like to review the highlights of the Important Safety Information.
GOMEKLI can cause ocular toxicity, including retinal vein occlusion, retinal pigment epithelium detachment, and blurred vision.
Conduct comprehensive ophthalmic assessments prior to initiating GOMEKLI, at regular intervals during treatment, and to evaluate any new or worsening visual changes.
Follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
GOMEKLI can cause left ventricular dysfunction.
It can occur in patients who are treated with GOMEKLI.
Before initiating GOMEKLI, assess ejection fraction by echocardiogram and monitor ejection fraction every 3 months during the first year and then as clinically indicated. Withhold, reduce the dose of, or discontinue GOMEKLI, depending on the severity of the adverse reaction.
GOMEKLI can cause dermatologic adverse reactions, including rash.
The most frequent rashes include dermatitis acneiform, rash, eczema, maculo-papular rash, and pustular rash.
Initiate supportive care at first signs of dermatologic adverse reactions and follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
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.
Because of the potential for adverse reactions in breastfed children, women should be advised not to breastfeed during treatment with GOMEKLI and for 1 week after the last dose.
Advise females of reproductive potential to use effective contraception during treatment with GOMEKLI and for 6 weeks after the last dose.
Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of GOMEKLI.
GOMEKLI logo.
Episode #1: Clinical Management of NF1-PN
The first FDA-approved treatment for both adult and pediatric patients aged ≥2 years with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas (PN) not amenable to complete resection.
[Dr Nghiemphu]
My name is Dr Phioanh Leia Nghiemphu, and I'm a neuro-oncologist and the director of the UCLA Neurofibromatosis and Schwannomatosis Clinic.
I'm happy to share today that I also have Dr Moertel, one of the lead investigators of the ReNeu study.
[Dr Moertel]
My name is Dr Christopher Moertel.
I'm a neuro-oncologist and I serve as professor of pediatrics at the University of Minnesota School of Medicine, and I'm the medical director of the Comprehensive Neurofibromatosis Clinic at the University of Minnesota Masonic Children's Hospital.
[Dr Nghiemphu]
I'd like to have a brief discussion with Dr Moertel about unmet needs and the clinical management of NF1-PN in our practices.
How we treat symptomatic patients with NF1-PN is always evolving. So, in your opinion, Dr Moertel, what factors are the most important when determining management options for a patient with NF1-PN that is symptomatic and has been deemed in need of intervention?
Do these factors differ between pediatric and adult patients? And, if yes, how do they differ?
[Dr Moertel]
Determining the management of patients with NF1-PN is multifactorial, as you know, as it involves considerations of several treatment options to reduce or prevent the morbidities associated with PNs.
When deciding whether or not surgery is appropriate, factors that should be considered include the size and location of the tumor and amenability to resection.
Up to approximately 85% of PNs are not amenable to complete resection.
Additionally, many patients experience postoperative tumor regrowth, pain, and complications of the surgery.
When selecting a systemic treatment, contraindications or preexisting conditions, the age of the patient, and a patient's ability to swallow pills are considerations.
[Dr Nghiemphu]
What are some of the challenges in managing this disease in your patients?
[Dr Moertel]
Well, as we just mentioned, the rate of PN regrowth after partial, or even complete, resection is one of the many challenges of surgery.
[Dr Moertel, voiceover only]
For systemic treatment, until now, there was no FDA-approved option to treat adult patients with NF1-PN or for individuals who have difficulty swallowing intact capsules. And that's a lot of people in my practice.
Until now, treatment options for adults were limited to surgery or off-label therapies.
[Dr Moertel]
Having an FDA-approved treatment option for adults is a great step forward.
Dr Nghiemphu, is it important to address the symptomatic plexiform neurofibromas in a timely manner? And, if so, can you explain why it's important?
[Dr Nghiemphu]
Yes, the clinical manifestation of NF1 can start soon after birth and continue throughout childhood and adulthood.
These manifestations can affect the skeletal system, the skin, and the central nervous system. And NF1-PNs, which can occur at any time throughout life, can be debilitating.
[Dr Nghiemphu, voiceover only]
They are associated with significant morbidities, such as pain, disfigurement, compression of internal organs, and impaired physical function.
The most rapid growth of NF1-PNs usually occurs among those aged 5 years or younger. However, although some patients may experience slow PN regrowth, clinical morbidities often persist and can have a detrimental impact.
[Dr Moertel]
Dr Nghiemphu, of the symptoms experienced with plexiform neurofibromas that you see, what are the most common among your patients?
[Dr Nghiemphu]
For many of my patients, pain can interfere with daily functioning, and the disfigurement can have a substantial effect on their lives.
Reducing the size of PNs may help address these morbidities.
[Dr Moertel, voiceover only]
I would like to review the highlights of the Important Safety Information.
GOMEKLI can cause ocular toxicity, including retinal vein occlusion, retinal pigment epithelium detachment, and blurred vision.
Conduct comprehensive ophthalmic assessments prior to initiating GOMEKLI, at regular intervals during treatment, and to evaluate any new or worsening visual changes.
Follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
GOMEKLI can cause left ventricular dysfunction.
It can occur in patients who are treated with GOMEKLI.
Before initiating GOMEKLI, assess ejection fraction by echocardiogram and monitor ejection fraction every 3 months during the first year and then as clinically indicated. Withhold, reduce the dose of, or discontinue GOMEKLI, depending on the severity of the adverse reaction.
GOMEKLI can cause dermatologic adverse reactions, including rash.
The most frequent rashes include dermatitis acneiform, rash, eczema, maculo-papular rash, and pustular rash.
Initiate supportive care at first signs of dermatologic adverse reactions and follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
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.
Because of the potential for adverse reactions in breastfed children, women should be advised not to breastfeed during treatment with GOMEKLI and for 1 week after the last dose.
Advise females of reproductive potential to use effective contraception during treatment with GOMEKLI and for 6 weeks after the last dose.
Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of GOMEKLI.
Clinical Overview in Adults and Case-Based Insights
Drs. Nghiemphu and Moertel review the ReNeu efficacy and safety results and present 2 case studies of adult patients who were treated with GOMEKLI.
[Text onscreen]
GOMEKLI logo.
Episode #2: Clinical Overview in Adults and Case-Based Insights
[Dr Nghiemphu]
My name is Dr Phioanh Leia Nghiemphu, and I'm a neuro-oncologist and the director of the UCLA Neurofibromatosis and Schwannomatosis Clinic.
I'm happy to share today that I also have Dr Moertel, one of the lead investigators of the ReNeu study.
[Dr Moertel]
My name is Dr Christopher Moertel.
I'm a neuro-oncologist and I serve as professor of pediatrics at the University of Minnesota School of Medicine, and I'm the medical director of the Comprehensive Neurofibromatosis Clinic at the University of Minnesota Masonic Children's Hospital.
[Dr Nghiemphu]
GOMEKLI is the first FDA-approved treatment for both adult and pediatric patients 2 years of age and older with NF1 who have symptomatic PNs not amenable to complete resection.
At this time, I'd like to pass things over to Dr Moertel, who will give an overview of the ReNeu study for GOMEKLI.
[Dr Moertel]
Thank you!
I'm thrilled to be sharing an overview of the pivotal trial that led to the approval of GOMEKLI.
ReNeu is one of the largest multicenter studies to date of patients with NF1 plexiform neurofibromas.
The efficacy and safety of GOMEKLI were assessed in 114 adult and pediatric patients aged 2 years and older with plexiform neurofibromas causing significant morbidity.
ReNeu was a multicenter, single-arm, phase 2b study with a treatment phase of approximately 22 months, and an optional long-term follow-up treatment phase for those patients who chose to continue treatment with GOMEKLI and a 30-day safety follow-up after treatment discontinuation.
Patients received GOMEKLI based on body surface area at a dosage of 2 mg/m2 orally twice daily on a 3-weeks-on and 1-week-off schedule.
The maximum daily dose of GOMEKLI was 4 mg twice daily.
In both cohorts, the majority of the adult and pediatric patients who completed the treatment phase, with or without a confirmed overall response, chose to remain on GOMEKLI during the long-term follow-up. 84% of adult patients and 85% of pediatric patients made this choice.
The primary endpoint was confirmed overall response rate, which was defined as the proportion of patients with complete response, that is disappearance of the target plexiform neurofibroma, or partial response, a 20% or greater reduction on magnetic resonance imaging of the target PN volume, from baseline to Cycle 24.
That's the treatment phase, and this was assessed by blinded independent central review on 2 or more consecutive scans within 2 to 6 months.
One of the key features of the ReNeu study was that all responses were assessed by blinded independent central review, and MRIs were reviewed by 2 independent radiologists—concordance in response categorization between reviewers was actually very high.
In this study, the secondary endpoints consisted of safety, tolerability, duration of response, and the change from baseline at prespecified Cycle 13 in patient-reported outcomes, or PROs, of worst tumor pain severity, pain interference, and health-related quality of life.
Dr Nghiemphu, I'll turn it over to you to present the efficacy data for the adults in the ReNeu study.
[Dr Nghiemphu]
During the treatment phase, 41% of adult patients who were treated with GOMEKLI achieved a confirmed overall response by REiNS criteria.
Based on a post hoc exploratory analysis, among those patients who achieved a confirmed overall response, 62% achieved a deep response, so that's defined as greater than 50% reduction in the target PN volume from baseline.
This waterfall plot depicts the best percentage change from baseline in tumor volume in adult patients who were treated with GOMEKLI. This was a prespecified exploratory endpoint in the trial.
The teal bars represent adult patients who had a confirmed overall response. The white bars represented nonresponders who had a best overall response of stable disease or progressive disease.
Adults treated with GOMEKLI saw a 41% median reduction in volume of target PNs, and many achieved notable depths of response, with maximum best change being to 90%.
Furthermore, based on a post hoc subgroup analysis, patients who achieved a deep response had a longer median duration of treatment than those who did not achieve a deep response. The median duration of treatment for patients with a deep response was 37 months compared to 26 months for those with just a 20% to 50% reduction in PN volume.
This swimmer plot shows the treatment duration for each patient. Of the 50 evaluable adult patients, 24 had a partial response and 26 had a best response of stable disease.
Note that stable disease and progressive disease were exploratory endpoints, and data should be interpreted with caution, as ReNeu is a single-arm trial.
88% of confirmed overall responders maintained a response for 12 months or more. The median duration of response has not been reached, as the majority of responders are still experiencing a response.
Almost half of the patients, 46%, had an onset of response at the first assessment around Cycle 5, which was approximately 4 months, and the median time to the first response was 7.8 months.
This safety table represents adverse reactions seen in 20% or more of patients.
The most common adverse reactions occurring in greater than 25% of adult patients were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue.
The majority of adverse reactions were mild to moderate, and there were low rates of severe, Grade 3 or 4, adverse reactions.
For your reference, and to ensure that you and your patients are provided with the support needed, SpringWorks will have a Dosing and Adverse Reaction Management Guide available. This resource includes information on how to manage some of the most common dermatologic and GI side effects, as well as additional information on other adverse reactions.
In the adult cohort, 31% of patients had a dose interruption, and 17% had a dose reduction due to an adverse reaction.
The most common adverse reactions that required dose interruptions were left ventricular dysfunction and COVID-19. Adverse reactions that required dose reductions included rash.
Additionally, 22% of adult patients permanently discontinued GOMEKLI due to rash, diarrhea, nausea, abdominal pain, alopecia, dry skin, left ventricular dysfunction, cough, wheezing, COVID-19, peripheral swelling, retinal vein occlusion, dizziness, and vomiting.
Prior to initiating GOMEKLI, conduct a comprehensive ophthalmic assessment, assess ejection fraction by echocardiogram, and verify the pregnancy status of females of reproductive potential.
During treatment, monitor ejection fraction every 3 months during the first year, and then as clinically indicated. Conduct comprehensive ophthalmic assessment at regular intervals.
Laboratory abnormalities that worsen from baseline and occurred in 15% or more of patients are shown on this slide.
The most common laboratory abnormality was increased CPK. In addition, decreased neutrophil count was also a commonly observed laboratory abnormality in children.
It is recommended to conduct lab tests prior to initiating treatment and at regular intervals during treatment.
So, now we would like to share case studies of patients who were treated with GOMEKLI in the ReNeu clinical trial.
Before we begin, I would like to note that the profile presented is based on an actual patient who was treated with GOMEKLI. Identifiers have been changed. Every patient's experience is unique and individual results may vary.
The case I will be sharing with you is an 18-year-old female with a painful plexiform neurofibroma in the right breast.
The patient has skin changes and symptoms since birth, but imaging at the age of 12 ultimately led to the diagnosis of NF1.
She is a college student and is active in the NF community.
She presented with multiple PNs, one of which was growing and also was painful.
The tumor first presented when she was around 16 or 17 as a small nodule that grew over the course of a year.
The tumor was not amenable to resection really, because a mastectomy would have been required. The PN diffused through the right breast and involved much of the skin surface.
As you can see from the image here, the PN is evident by the hyperintense white areas on MRI, and there's a nodule on the inside and thickened white areas over the skin.
Her primary symptoms were hyperesthesia, or extreme sensitivity due to the diffuse PN all over her breast; pain; skin discoloration; and misshapen breasts.
For this patient, daily living was quite a challenge, and different-sized breasts made getting dressed and bra sizing very difficult for her.
Wearing clothing was painful due to skin irritation from fabric contact, and she was concerned about just living with misshapen breasts.
Her parents were very involved with her care and came to appointments with her.
She has been taking over-the-counter pain medications and, because of her age, her care team consisted of a pediatric oncologist who helped her in the transition to adult care.
She was enrolled in the ReNeu clinical trial at 18, as she had a painful PN that was not able to be resected.
As I mentioned before, this would have required mastectomy.
She received the capsule at 4 mg twice a day.
The results from the trial for this patient are shown here. These are MRI images shown on the slides are 2D visuals and do not capture the total volumetric changes observed.
These were images I provided, but additional images may have been utilized during the trial to assess full volumetrics.
The patient achieved a confirmed overall response with a best target volume reduction from baseline of 84%.
Her adverse reactions included mild nausea and vomiting; mild rash, which was managed with doxycycline and clindamycin ointment on the face; and intermittent erythematous rash and itchiness, which were managed with clobetasol lotion.
During Cycle 4, she did have some mild alopecia that emerged. It was treated but did not resolve.
The patient now feels her appearance has improved and is managing her medication and medical diary.
As a result of the tumor volume reduction, wearing a bra and clothing is more comfortable, as irritation from fabric touching her skin has decreased.
The tumor volume reduction has remained durable, and her PN remains stable.
She also reconsented and is now participating in the long-term follow-up of ReNeu.
[Dr Moertel]
This case I'm about to show you is regarding a 69-year-old male with a large plexiform neurofibroma in the head and neck region.
The patient has been a social drinker and smoker since his teenage years, and he, his mother, and his sister have a history of stroke.
He has no family history of NF1.
He was referred by his primary care physician for stabbing pain in the right side of his jaw and hearing loss, or muffled hearing.
Magnetic resonance imaging (MRI) scans confirmed a large walnut-sized plexiform neurofibroma.
The progressing PN was diffused around his neck and penetrated into the neck muscles, so it was not amenable to resection.
It also extended into the muscles of his jaw and occluded his ear canal.
His pain was waking him up and he was unable to function with what he referred to as his stabbing pain.
The patient was taking over-the-counter medications for pain and his care team consisted of a primary care physician, a dermatologist, an ophthalmologist, and myself.
He enrolled in the ReNeu clinical trial and received the capsule formulation of GOMEKLI dosed at 4 mg twice daily.
Results from the trial are shown here.
MRI images shown on the slide, again, are 2D visuals and do not capture the total volumetric changes observed.
These were the images I provided, but additional images may have been utilized during the trial to assess full volumetrics.
The patient achieved a confirmed overall response with a best target tumor volume reduction from baseline of approximately 73%. As a result of this tumor reduction, hearing and symptoms improved.
He did have adverse reactions.
Adverse reactions included a rash on the scalp, for which he was referred to a dermatologist for oral and topical treatment, and at a follow-up visit, his skin was clearer.
He also had mild asymptomatic CPK increase.
The patient opted to reconsent and participated in the long-term follow-up phase of the ReNeu clinical trial, but he discontinued at Cycle 44 after a recurrent stroke unrelated to his treatment.
The patient resumed his art, published a book that he wrote and illustrated, 14 months though, after discontinuing treatment, his symptoms have started to come back.
[Dr Moertel, voiceover only]
I would like to review the highlights of the Important Safety Information.
GOMEKLI can cause ocular toxicity, including retinal vein occlusion, retinal pigment epithelium detachment, and blurred vision.
Conduct comprehensive ophthalmic assessments prior to initiating GOMEKLI, at regular intervals during treatment, and to evaluate any new or worsening visual changes. Follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
GOMEKLI can cause left ventricular dysfunction. It can occur in patients who are treated with GOMEKLI. Before initiating GOMEKLI, assess ejection fraction by echocardiogram and monitor ejection fraction every 3 months during the first year and then as clinically indicated. Withhold, reduce the dose of, or discontinue GOMEKLI, depending on the severity of the adverse reaction.
GOMEKLI can cause dermatologic adverse reactions, including rash.
The most frequent rashes include dermatitis acneiform, rash, eczema, maculo-papular rash, and pustular rash.
Initiate supportive care at first signs of dermatologic adverse reactions and follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
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.
Because of the potential for adverse reactions in breastfed children, women should be advised not to breastfeed during treatment with GOMEKLI and for 1 week after the last dose.
Advise females of reproductive potential to use effective contraception during treatment with GOMEKLI and for 6 weeks after the last dose.
Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of GOMEKLI.
GOMEKLI logo.
Episode #2: Clinical Overview in Adults and Case-Based Insights
[Dr Nghiemphu]
My name is Dr Phioanh Leia Nghiemphu, and I'm a neuro-oncologist and the director of the UCLA Neurofibromatosis and Schwannomatosis Clinic.
I'm happy to share today that I also have Dr Moertel, one of the lead investigators of the ReNeu study.
[Dr Moertel]
My name is Dr Christopher Moertel.
I'm a neuro-oncologist and I serve as professor of pediatrics at the University of Minnesota School of Medicine, and I'm the medical director of the Comprehensive Neurofibromatosis Clinic at the University of Minnesota Masonic Children's Hospital.
[Dr Nghiemphu]
GOMEKLI is the first FDA-approved treatment for both adult and pediatric patients 2 years of age and older with NF1 who have symptomatic PNs not amenable to complete resection.
At this time, I'd like to pass things over to Dr Moertel, who will give an overview of the ReNeu study for GOMEKLI.
[Dr Moertel]
Thank you!
I'm thrilled to be sharing an overview of the pivotal trial that led to the approval of GOMEKLI.
ReNeu is one of the largest multicenter studies to date of patients with NF1 plexiform neurofibromas.
The efficacy and safety of GOMEKLI were assessed in 114 adult and pediatric patients aged 2 years and older with plexiform neurofibromas causing significant morbidity.
ReNeu was a multicenter, single-arm, phase 2b study with a treatment phase of approximately 22 months, and an optional long-term follow-up treatment phase for those patients who chose to continue treatment with GOMEKLI and a 30-day safety follow-up after treatment discontinuation.
Patients received GOMEKLI based on body surface area at a dosage of 2 mg/m2 orally twice daily on a 3-weeks-on and 1-week-off schedule.
The maximum daily dose of GOMEKLI was 4 mg twice daily.
In both cohorts, the majority of the adult and pediatric patients who completed the treatment phase, with or without a confirmed overall response, chose to remain on GOMEKLI during the long-term follow-up. 84% of adult patients and 85% of pediatric patients made this choice.
The primary endpoint was confirmed overall response rate, which was defined as the proportion of patients with complete response, that is disappearance of the target plexiform neurofibroma, or partial response, a 20% or greater reduction on magnetic resonance imaging of the target PN volume, from baseline to Cycle 24.
That's the treatment phase, and this was assessed by blinded independent central review on 2 or more consecutive scans within 2 to 6 months.
One of the key features of the ReNeu study was that all responses were assessed by blinded independent central review, and MRIs were reviewed by 2 independent radiologists—concordance in response categorization between reviewers was actually very high.
In this study, the secondary endpoints consisted of safety, tolerability, duration of response, and the change from baseline at prespecified Cycle 13 in patient-reported outcomes, or PROs, of worst tumor pain severity, pain interference, and health-related quality of life.
Dr Nghiemphu, I'll turn it over to you to present the efficacy data for the adults in the ReNeu study.
[Dr Nghiemphu]
During the treatment phase, 41% of adult patients who were treated with GOMEKLI achieved a confirmed overall response by REiNS criteria.
Based on a post hoc exploratory analysis, among those patients who achieved a confirmed overall response, 62% achieved a deep response, so that's defined as greater than 50% reduction in the target PN volume from baseline.
This waterfall plot depicts the best percentage change from baseline in tumor volume in adult patients who were treated with GOMEKLI. This was a prespecified exploratory endpoint in the trial.
The teal bars represent adult patients who had a confirmed overall response. The white bars represented nonresponders who had a best overall response of stable disease or progressive disease.
Adults treated with GOMEKLI saw a 41% median reduction in volume of target PNs, and many achieved notable depths of response, with maximum best change being to 90%.
Furthermore, based on a post hoc subgroup analysis, patients who achieved a deep response had a longer median duration of treatment than those who did not achieve a deep response. The median duration of treatment for patients with a deep response was 37 months compared to 26 months for those with just a 20% to 50% reduction in PN volume.
This swimmer plot shows the treatment duration for each patient. Of the 50 evaluable adult patients, 24 had a partial response and 26 had a best response of stable disease.
Note that stable disease and progressive disease were exploratory endpoints, and data should be interpreted with caution, as ReNeu is a single-arm trial.
88% of confirmed overall responders maintained a response for 12 months or more. The median duration of response has not been reached, as the majority of responders are still experiencing a response.
Almost half of the patients, 46%, had an onset of response at the first assessment around Cycle 5, which was approximately 4 months, and the median time to the first response was 7.8 months.
This safety table represents adverse reactions seen in 20% or more of patients.
The most common adverse reactions occurring in greater than 25% of adult patients were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue.
The majority of adverse reactions were mild to moderate, and there were low rates of severe, Grade 3 or 4, adverse reactions.
For your reference, and to ensure that you and your patients are provided with the support needed, SpringWorks will have a Dosing and Adverse Reaction Management Guide available. This resource includes information on how to manage some of the most common dermatologic and GI side effects, as well as additional information on other adverse reactions.
In the adult cohort, 31% of patients had a dose interruption, and 17% had a dose reduction due to an adverse reaction.
The most common adverse reactions that required dose interruptions were left ventricular dysfunction and COVID-19. Adverse reactions that required dose reductions included rash.
Additionally, 22% of adult patients permanently discontinued GOMEKLI due to rash, diarrhea, nausea, abdominal pain, alopecia, dry skin, left ventricular dysfunction, cough, wheezing, COVID-19, peripheral swelling, retinal vein occlusion, dizziness, and vomiting.
Prior to initiating GOMEKLI, conduct a comprehensive ophthalmic assessment, assess ejection fraction by echocardiogram, and verify the pregnancy status of females of reproductive potential.
During treatment, monitor ejection fraction every 3 months during the first year, and then as clinically indicated. Conduct comprehensive ophthalmic assessment at regular intervals.
Laboratory abnormalities that worsen from baseline and occurred in 15% or more of patients are shown on this slide.
The most common laboratory abnormality was increased CPK. In addition, decreased neutrophil count was also a commonly observed laboratory abnormality in children.
It is recommended to conduct lab tests prior to initiating treatment and at regular intervals during treatment.
So, now we would like to share case studies of patients who were treated with GOMEKLI in the ReNeu clinical trial.
Before we begin, I would like to note that the profile presented is based on an actual patient who was treated with GOMEKLI. Identifiers have been changed. Every patient's experience is unique and individual results may vary.
The case I will be sharing with you is an 18-year-old female with a painful plexiform neurofibroma in the right breast.
The patient has skin changes and symptoms since birth, but imaging at the age of 12 ultimately led to the diagnosis of NF1.
She is a college student and is active in the NF community.
She presented with multiple PNs, one of which was growing and also was painful.
The tumor first presented when she was around 16 or 17 as a small nodule that grew over the course of a year.
The tumor was not amenable to resection really, because a mastectomy would have been required. The PN diffused through the right breast and involved much of the skin surface.
As you can see from the image here, the PN is evident by the hyperintense white areas on MRI, and there's a nodule on the inside and thickened white areas over the skin.
Her primary symptoms were hyperesthesia, or extreme sensitivity due to the diffuse PN all over her breast; pain; skin discoloration; and misshapen breasts.
For this patient, daily living was quite a challenge, and different-sized breasts made getting dressed and bra sizing very difficult for her.
Wearing clothing was painful due to skin irritation from fabric contact, and she was concerned about just living with misshapen breasts.
Her parents were very involved with her care and came to appointments with her.
She has been taking over-the-counter pain medications and, because of her age, her care team consisted of a pediatric oncologist who helped her in the transition to adult care.
She was enrolled in the ReNeu clinical trial at 18, as she had a painful PN that was not able to be resected.
As I mentioned before, this would have required mastectomy.
She received the capsule at 4 mg twice a day.
The results from the trial for this patient are shown here. These are MRI images shown on the slides are 2D visuals and do not capture the total volumetric changes observed.
These were images I provided, but additional images may have been utilized during the trial to assess full volumetrics.
The patient achieved a confirmed overall response with a best target volume reduction from baseline of 84%.
Her adverse reactions included mild nausea and vomiting; mild rash, which was managed with doxycycline and clindamycin ointment on the face; and intermittent erythematous rash and itchiness, which were managed with clobetasol lotion.
During Cycle 4, she did have some mild alopecia that emerged. It was treated but did not resolve.
The patient now feels her appearance has improved and is managing her medication and medical diary.
As a result of the tumor volume reduction, wearing a bra and clothing is more comfortable, as irritation from fabric touching her skin has decreased.
The tumor volume reduction has remained durable, and her PN remains stable.
She also reconsented and is now participating in the long-term follow-up of ReNeu.
[Dr Moertel]
This case I'm about to show you is regarding a 69-year-old male with a large plexiform neurofibroma in the head and neck region.
The patient has been a social drinker and smoker since his teenage years, and he, his mother, and his sister have a history of stroke.
He has no family history of NF1.
He was referred by his primary care physician for stabbing pain in the right side of his jaw and hearing loss, or muffled hearing.
Magnetic resonance imaging (MRI) scans confirmed a large walnut-sized plexiform neurofibroma.
The progressing PN was diffused around his neck and penetrated into the neck muscles, so it was not amenable to resection.
It also extended into the muscles of his jaw and occluded his ear canal.
His pain was waking him up and he was unable to function with what he referred to as his stabbing pain.
The patient was taking over-the-counter medications for pain and his care team consisted of a primary care physician, a dermatologist, an ophthalmologist, and myself.
He enrolled in the ReNeu clinical trial and received the capsule formulation of GOMEKLI dosed at 4 mg twice daily.
Results from the trial are shown here.
MRI images shown on the slide, again, are 2D visuals and do not capture the total volumetric changes observed.
These were the images I provided, but additional images may have been utilized during the trial to assess full volumetrics.
The patient achieved a confirmed overall response with a best target tumor volume reduction from baseline of approximately 73%. As a result of this tumor reduction, hearing and symptoms improved.
He did have adverse reactions.
Adverse reactions included a rash on the scalp, for which he was referred to a dermatologist for oral and topical treatment, and at a follow-up visit, his skin was clearer.
He also had mild asymptomatic CPK increase.
The patient opted to reconsent and participated in the long-term follow-up phase of the ReNeu clinical trial, but he discontinued at Cycle 44 after a recurrent stroke unrelated to his treatment.
The patient resumed his art, published a book that he wrote and illustrated, 14 months though, after discontinuing treatment, his symptoms have started to come back.
[Dr Moertel, voiceover only]
I would like to review the highlights of the Important Safety Information.
GOMEKLI can cause ocular toxicity, including retinal vein occlusion, retinal pigment epithelium detachment, and blurred vision.
Conduct comprehensive ophthalmic assessments prior to initiating GOMEKLI, at regular intervals during treatment, and to evaluate any new or worsening visual changes. Follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
GOMEKLI can cause left ventricular dysfunction. It can occur in patients who are treated with GOMEKLI. Before initiating GOMEKLI, assess ejection fraction by echocardiogram and monitor ejection fraction every 3 months during the first year and then as clinically indicated. Withhold, reduce the dose of, or discontinue GOMEKLI, depending on the severity of the adverse reaction.
GOMEKLI can cause dermatologic adverse reactions, including rash.
The most frequent rashes include dermatitis acneiform, rash, eczema, maculo-papular rash, and pustular rash.
Initiate supportive care at first signs of dermatologic adverse reactions and follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
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.
Because of the potential for adverse reactions in breastfed children, women should be advised not to breastfeed during treatment with GOMEKLI and for 1 week after the last dose.
Advise females of reproductive potential to use effective contraception during treatment with GOMEKLI and for 6 weeks after the last dose.
Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of GOMEKLI.
Clinical Overview in Children and Case-Based Insights
Drs. Nghiemphu and Moertel review the ReNeu efficacy and safety results and present a case study of a pediatric patient who was treated with GOMEKLI.
[Text onscreen]
GOMEKLI logo.
Episode #3: Clinical Overview in Children and Case-Based Insights
[Dr Nghiemphu]
My name is Dr Phioanh Leia Nghiemphu, and I'm a neuro-oncologist and the director of the UCLA Neurofibromatosis and Schwannomatosis Clinic.
I'm happy to share today that I also have Dr Moertel, one of the lead investigators of the ReNeu study.
[Dr Moertel]
My name is Dr Christopher Moertel.
I'm a neuro-oncologist and I serve as professor of pediatrics at the University of Minnesota School of Medicine, and I'm the medical director of the Comprehensive Neurofibromatosis Clinic at the University of Minnesota Masonic Children's Hospital.
[Dr Nghiemphu]
GOMEKLI is the first FDA-approved treatment for both adult and pediatric patients 2 years of age and older with NF1 who have symptomatic PNs not amenable to complete resection.
At this time, I'd like to pass things over to Dr Moertel who will give an overview of the ReNeu study for GOMEKLI.
[Dr Moertel]
Thank you!
I'm thrilled to be sharing an overview of the pivotal trial that led to the approval of GOMEKLI.
ReNeu is one of the largest multicenter studies to date of patients with NF1 plexiform neurofibromas.
The efficacy and safety of GOMEKLI were assessed in 114 adult and pediatric patients aged 2 years and older with plexiform neurofibromas causing significant morbidity.
ReNeu was a multicenter, single-arm, phase 2b study with a treatment phase of approximately 22 months, and an optional long-term follow-up treatment phase for those patients who chose to continue treatment with GOMEKLI and a 30-day safety follow-up after treatment discontinuation.
Patients received GOMEKLI based on a body surface area at a dosage of 2 mg/m2 orally twice daily on a 3-weeks-on and 1-week-off schedule.
The maximum daily dose of GOMEKLI was 4 mg twice daily.
In both cohorts, the majority of the adult and pediatric patients who completed the treatment phase, with or without a confirmed overall response, chose to remain on GOMEKLI during the long-term follow-up. 84% of adult patients and 85% of pediatric patients made this choice.
The primary endpoint was confirmed overall response rate, which was defined as the proportion of patients with complete response, that is disappearance of the target plexiform neurofibroma, or partial response, a 20% or greater reduction on magnetic resonance imaging of the target PN volume, from baseline to Cycle 24.
That's the treatment phase, and this was assessed by blinded independent central review on 2 or more consecutive scans within 2 to 6 months.
One of the key features of the ReNeu study was that all responses were assessed by blinded independent central review, and MRIs were reviewed by 2 independent radiologists—concordance in response categorization between reviewers was actually very high.
In this study, the secondary endpoints consisted of safety, tolerability, duration of response, and the change from baseline at prespecified Cycle 13 in patient-reported outcomes, or PROs, of worst tumor pain severity, pain interference, and health-related quality of life.
During the treatment phase, 52% of pediatric patients who were treated with GOMEKLI achieved a confirmed overall response by REiNS criteria.
Based on a post hoc exploratory analysis, among those patients who achieved a confirmed overall response, 52% achieved a deep response, defined as greater than 50% reduction in target PN volume from baseline.
This waterfall plot depicts the best percentage change from baseline in tumor volume in pediatric patients who were treated with GOMEKLI.
This was a prespecified exploratory endpoint in the trial.
The gold bars represent pediatric patients who had a confirmed overall response. The white bars represent nonresponders who had a best overall response of stable disease or, in some cases, progressive disease.
Children treated with GOMEKLI saw a 42% median reduction in volume of target PNs, and many achieved notable depths of response, with the maximum best change being 91%.
Furthermore, based on a post hoc analysis of a subgroup, patients who achieved a deep response had a longer median duration of treatment than those who did not achieve a deep response. The median duration of treatment for patients with a deep response was 27 months compared with 25 months for those with a 20% to 50% reduction in plexiform tumor volume.
The swimmer plot shows the treatment duration for each pediatric patient.
Of the 51 evaluable pediatric patients, 29 had a partial response and 22 had a best response of stable disease.
Note that stable disease and progressive disease were exploratory endpoints, and data should be interpreted with caution, as ReNeu is a single-arm trial.
90% of confirmed overall responders maintained a response for 12 months or more.
The median duration of response has not yet been reached, as the majority of responders are still experiencing response.
Almost half of the patients, 45%, had an onset of response at the first on-treatment assessment at Cycle 5, about 4 months, and the median time to first response was 7.9 months.
Now, I'll pass it back to Dr Nghiemphu, who will review the safety profile of GOMEKLI.
[Dr Nghiemphu]
This safety table represents adverse reactions seen in 20% or more of patients.
The most common adverse reactions occurring in greater than 25% of pediatric patients were rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea.
The majority of adverse reactions were mild to moderate, and there were low rates of severe, Grade 3 or 4, adverse reactions.
For your reference, and to ensure that you and your patients are provided with the support needed, SpringWorks will have a Dosing and Adverse Reaction Management Guide available. This resource includes information on how to manage some of the most common dermatologic and GI side effects, as well as additional information on other adverse reactions.
In the pediatric cohort, 30% of patients had a dose interruption, and 13% had a dose reduction due to an adverse reaction. The most common adverse reaction that required dose interruption was COVID-19. Adverse reactions that required dose reductions included rash and decreased neutrophil count.
Additionally, 9% of pediatric patients permanently discontinued treatment due to urticaria, rash, abdominal pain, constipation, and diarrhea.
Prior to initiating GOMEKLI, conduct a comprehensive ophthalmic assessment, assess ejection fraction by echocardiogram, and verify the pregnancy status of females of reproductive potential.
During treatment, monitor ejection fraction every 3 months during the first year, and then as clinically indicated. Conduct comprehensive ophthalmic assessments at regular intervals.
Laboratory abnormalities that worsened from baseline and occurred in 15% or more of patients are shown on this slide.
The most common laboratory abnormality was increased CPK. In addition, decreased neutrophil count was also a commonly observed laboratory abnormality in children.
It is recommended to conduct lab tests prior to initiating treatment and at regular intervals during treatment.
[Dr Moertel]
This case I would like to share with you is that of a 7-year-old patient with a large abdominal plexiform neurofibroma.
This patient had no family history of NF and was diagnosed with NF1 as an infant.
The patient presented with a grapefruit-sized abdominal plexiform neurofibroma that extended into his left groin.
The patient did not have any prior surgeries and was counseled actually against resection because of the large and invasive size of the tumor, the risk of regrowth, and risk of permanent damage from the surgery.
The PN caused him significant pain that interfered with his daily activities.
He had difficulty walking and was not able to run.
Although he wanted to play sports, such as football, he didn't because the risk of being hit in the abdomen was too great.
He could not sit for long periods due to discomfort from the location of the tumor, which made school difficult, and he was awakened at night frequently by pain.
The patient was using over-the counter medications and minimizing his activities, unfortunately, to manage his pain. His care team consisted of a primary care physician, a dermatologist, nurse coordinators, and myself.
He enrolled in the ReNeu clinical trial and received the capsule formulation of GOMEKLI dosed at 2 mg twice daily.
Results from the trial are shown here. MRI images are 2-dimensional and do not capture the total volumetric changes observed.
These were the images I provided, but additional images may have been utilized during the trial to assess full volumetrics.
The patient achieved a confirmed overall response with a best target tumor reduction from baseline of approximately 50%.
As a result of the tumor volume reduction, symptoms have improved.
Adverse reactions during therapy included mild diarrhea; vomiting; mild rash, for which skin creams and bleach baths were recommended; and 1 event of asymptomatic Grade 2 left ventricular ejection fraction, which decreased/improved in the long-term follow-up phase.
He also experienced moderate headaches during the off-treatment week from time to time.
The patient enjoys now attending baseball and hockey events and is now prioritizing academic and social activities.
He opted to reconsent and is participating in the long-term follow-up arm of the ReNeu clinical trial.
This patient remains on GOMEKLI to this day.
[Dr Moertel, voiceover only]
I would like to review the highlights of the Important Safety Information.
GOMEKLI can cause ocular toxicity, including retinal vein occlusion, retinal pigment epithelium detachment, and blurred vision.
Conduct comprehensive ophthalmic assessments prior to initiating GOMEKLI, at regular intervals during treatment, and to evaluate any new or worsening visual changes. Follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
GOMEKLI can cause left ventricular dysfunction. It can occur in patients who are treated with GOMEKLI.
Before initiating GOMEKLI, assess ejection fraction by echocardiogram and monitor ejection fraction every 3 months during the first year and then as clinically indicated. Withhold, reduce the dose of, or discontinue GOMEKLI, depending on the severity of the adverse reaction.
GOMEKLI can cause dermatologic adverse reactions, including rash. The most frequent rashes include dermatitis acneiform, rash, eczema, maculo-papular rash, and pustular rash.
Initiate supportive care at first signs of dermatologic adverse reactions and follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
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.
Because of the potential for adverse reactions in breastfed children, women should be advised not to breastfeed during treatment with GOMEKLI and for 1 week after the last dose.
Advise females of reproductive potential to use effective contraception during treatment with GOMEKLI and for 6 weeks after the last dose.
Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of GOMEKLI.
GOMEKLI logo.
Episode #3: Clinical Overview in Children and Case-Based Insights
[Dr Nghiemphu]
My name is Dr Phioanh Leia Nghiemphu, and I'm a neuro-oncologist and the director of the UCLA Neurofibromatosis and Schwannomatosis Clinic.
I'm happy to share today that I also have Dr Moertel, one of the lead investigators of the ReNeu study.
[Dr Moertel]
My name is Dr Christopher Moertel.
I'm a neuro-oncologist and I serve as professor of pediatrics at the University of Minnesota School of Medicine, and I'm the medical director of the Comprehensive Neurofibromatosis Clinic at the University of Minnesota Masonic Children's Hospital.
[Dr Nghiemphu]
GOMEKLI is the first FDA-approved treatment for both adult and pediatric patients 2 years of age and older with NF1 who have symptomatic PNs not amenable to complete resection.
At this time, I'd like to pass things over to Dr Moertel who will give an overview of the ReNeu study for GOMEKLI.
[Dr Moertel]
Thank you!
I'm thrilled to be sharing an overview of the pivotal trial that led to the approval of GOMEKLI.
ReNeu is one of the largest multicenter studies to date of patients with NF1 plexiform neurofibromas.
The efficacy and safety of GOMEKLI were assessed in 114 adult and pediatric patients aged 2 years and older with plexiform neurofibromas causing significant morbidity.
ReNeu was a multicenter, single-arm, phase 2b study with a treatment phase of approximately 22 months, and an optional long-term follow-up treatment phase for those patients who chose to continue treatment with GOMEKLI and a 30-day safety follow-up after treatment discontinuation.
Patients received GOMEKLI based on a body surface area at a dosage of 2 mg/m2 orally twice daily on a 3-weeks-on and 1-week-off schedule.
The maximum daily dose of GOMEKLI was 4 mg twice daily.
In both cohorts, the majority of the adult and pediatric patients who completed the treatment phase, with or without a confirmed overall response, chose to remain on GOMEKLI during the long-term follow-up. 84% of adult patients and 85% of pediatric patients made this choice.
The primary endpoint was confirmed overall response rate, which was defined as the proportion of patients with complete response, that is disappearance of the target plexiform neurofibroma, or partial response, a 20% or greater reduction on magnetic resonance imaging of the target PN volume, from baseline to Cycle 24.
That's the treatment phase, and this was assessed by blinded independent central review on 2 or more consecutive scans within 2 to 6 months.
One of the key features of the ReNeu study was that all responses were assessed by blinded independent central review, and MRIs were reviewed by 2 independent radiologists—concordance in response categorization between reviewers was actually very high.
In this study, the secondary endpoints consisted of safety, tolerability, duration of response, and the change from baseline at prespecified Cycle 13 in patient-reported outcomes, or PROs, of worst tumor pain severity, pain interference, and health-related quality of life.
During the treatment phase, 52% of pediatric patients who were treated with GOMEKLI achieved a confirmed overall response by REiNS criteria.
Based on a post hoc exploratory analysis, among those patients who achieved a confirmed overall response, 52% achieved a deep response, defined as greater than 50% reduction in target PN volume from baseline.
This waterfall plot depicts the best percentage change from baseline in tumor volume in pediatric patients who were treated with GOMEKLI.
This was a prespecified exploratory endpoint in the trial.
The gold bars represent pediatric patients who had a confirmed overall response. The white bars represent nonresponders who had a best overall response of stable disease or, in some cases, progressive disease.
Children treated with GOMEKLI saw a 42% median reduction in volume of target PNs, and many achieved notable depths of response, with the maximum best change being 91%.
Furthermore, based on a post hoc analysis of a subgroup, patients who achieved a deep response had a longer median duration of treatment than those who did not achieve a deep response. The median duration of treatment for patients with a deep response was 27 months compared with 25 months for those with a 20% to 50% reduction in plexiform tumor volume.
The swimmer plot shows the treatment duration for each pediatric patient.
Of the 51 evaluable pediatric patients, 29 had a partial response and 22 had a best response of stable disease.
Note that stable disease and progressive disease were exploratory endpoints, and data should be interpreted with caution, as ReNeu is a single-arm trial.
90% of confirmed overall responders maintained a response for 12 months or more.
The median duration of response has not yet been reached, as the majority of responders are still experiencing response.
Almost half of the patients, 45%, had an onset of response at the first on-treatment assessment at Cycle 5, about 4 months, and the median time to first response was 7.9 months.
Now, I'll pass it back to Dr Nghiemphu, who will review the safety profile of GOMEKLI.
[Dr Nghiemphu]
This safety table represents adverse reactions seen in 20% or more of patients.
The most common adverse reactions occurring in greater than 25% of pediatric patients were rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea.
The majority of adverse reactions were mild to moderate, and there were low rates of severe, Grade 3 or 4, adverse reactions.
For your reference, and to ensure that you and your patients are provided with the support needed, SpringWorks will have a Dosing and Adverse Reaction Management Guide available. This resource includes information on how to manage some of the most common dermatologic and GI side effects, as well as additional information on other adverse reactions.
In the pediatric cohort, 30% of patients had a dose interruption, and 13% had a dose reduction due to an adverse reaction. The most common adverse reaction that required dose interruption was COVID-19. Adverse reactions that required dose reductions included rash and decreased neutrophil count.
Additionally, 9% of pediatric patients permanently discontinued treatment due to urticaria, rash, abdominal pain, constipation, and diarrhea.
Prior to initiating GOMEKLI, conduct a comprehensive ophthalmic assessment, assess ejection fraction by echocardiogram, and verify the pregnancy status of females of reproductive potential.
During treatment, monitor ejection fraction every 3 months during the first year, and then as clinically indicated. Conduct comprehensive ophthalmic assessments at regular intervals.
Laboratory abnormalities that worsened from baseline and occurred in 15% or more of patients are shown on this slide.
The most common laboratory abnormality was increased CPK. In addition, decreased neutrophil count was also a commonly observed laboratory abnormality in children.
It is recommended to conduct lab tests prior to initiating treatment and at regular intervals during treatment.
[Dr Moertel]
This case I would like to share with you is that of a 7-year-old patient with a large abdominal plexiform neurofibroma.
This patient had no family history of NF and was diagnosed with NF1 as an infant.
The patient presented with a grapefruit-sized abdominal plexiform neurofibroma that extended into his left groin.
The patient did not have any prior surgeries and was counseled actually against resection because of the large and invasive size of the tumor, the risk of regrowth, and risk of permanent damage from the surgery.
The PN caused him significant pain that interfered with his daily activities.
He had difficulty walking and was not able to run.
Although he wanted to play sports, such as football, he didn't because the risk of being hit in the abdomen was too great.
He could not sit for long periods due to discomfort from the location of the tumor, which made school difficult, and he was awakened at night frequently by pain.
The patient was using over-the counter medications and minimizing his activities, unfortunately, to manage his pain. His care team consisted of a primary care physician, a dermatologist, nurse coordinators, and myself.
He enrolled in the ReNeu clinical trial and received the capsule formulation of GOMEKLI dosed at 2 mg twice daily.
Results from the trial are shown here. MRI images are 2-dimensional and do not capture the total volumetric changes observed.
These were the images I provided, but additional images may have been utilized during the trial to assess full volumetrics.
The patient achieved a confirmed overall response with a best target tumor reduction from baseline of approximately 50%.
As a result of the tumor volume reduction, symptoms have improved.
Adverse reactions during therapy included mild diarrhea; vomiting; mild rash, for which skin creams and bleach baths were recommended; and 1 event of asymptomatic Grade 2 left ventricular ejection fraction, which decreased/improved in the long-term follow-up phase.
He also experienced moderate headaches during the off-treatment week from time to time.
The patient enjoys now attending baseball and hockey events and is now prioritizing academic and social activities.
He opted to reconsent and is participating in the long-term follow-up arm of the ReNeu clinical trial.
This patient remains on GOMEKLI to this day.
[Dr Moertel, voiceover only]
I would like to review the highlights of the Important Safety Information.
GOMEKLI can cause ocular toxicity, including retinal vein occlusion, retinal pigment epithelium detachment, and blurred vision.
Conduct comprehensive ophthalmic assessments prior to initiating GOMEKLI, at regular intervals during treatment, and to evaluate any new or worsening visual changes. Follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
GOMEKLI can cause left ventricular dysfunction. It can occur in patients who are treated with GOMEKLI.
Before initiating GOMEKLI, assess ejection fraction by echocardiogram and monitor ejection fraction every 3 months during the first year and then as clinically indicated. Withhold, reduce the dose of, or discontinue GOMEKLI, depending on the severity of the adverse reaction.
GOMEKLI can cause dermatologic adverse reactions, including rash. The most frequent rashes include dermatitis acneiform, rash, eczema, maculo-papular rash, and pustular rash.
Initiate supportive care at first signs of dermatologic adverse reactions and follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
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.
Because of the potential for adverse reactions in breastfed children, women should be advised not to breastfeed during treatment with GOMEKLI and for 1 week after the last dose.
Advise females of reproductive potential to use effective contraception during treatment with GOMEKLI and for 6 weeks after the last dose.
Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of GOMEKLI.
Safety Profile and Adverse Reaction Management
Drs. Nghiemphu and Moertel review the safety profile of GOMEKLI and discuss adverse reaction management strategies from their own clinical practice and the ReNeu trial.
[Text onscreen]
GOMEKLI logo.
Episode #4 Safety Profile and Adverse Reaction Management
[Dr Nghiemphu]
My name is Dr Phioanh Leia Nghiemphu, and I'm a neuro-oncologist and the director of the UCLA Neurofibromatosis and Schwannomatosis Clinic.
I'm happy to share today that I also have Dr Moertel, one of the lead investigators of the ReNeu study.
[Dr Moertel]
My name is Dr Christopher Moertel.
I'm a neuro-oncologist and I serve as professor of pediatrics at the University of Minnesota School of Medicine, and I'm the medical director of the Comprehensive Neurofibromatosis Clinic at the University of Minnesota Masonic Children's Hospital.
[Dr Nghiemphu]
GOMEKLI is the first FDA-approved treatment for both adult and pediatric patients 2 years of age and older with NF1 who have symptomatic PNs not amenable to complete resection.
This safety table represents adverse reactions seen in 20% or more of patients.
The most common adverse reactions occurring in greater than 25% of adult patients were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue.
The most common adverse reactions occurring in greater than 25% of pediatric patients were rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea.
The majority of adverse reactions were mild to moderate, and there were low rates of severe, Grade 3 or 4, adverse reactions. For your reference, and to ensure that you and your patients are provided with the support needed, SpringWorks will have a Dosing and Adverse Reaction Management Guide available. This resource includes information on how to manage some of the most common dermatologic and GI side effects, as well as additional information on other adverse reactions.
In the adult cohort, 31% of patients had a dose interruption, and 17% had a dose reduction due to an adverse reaction.
The most common adverse reactions that required dose interruptions were left ventricular dysfunction and COVID-19. Adverse reactions that required dose reductions included rash.
Additionally, 22% of adult patients permanently discontinued GOMEKLI due to rash, diarrhea, nausea, abdominal pain, alopecia, dry skin, left ventricular dysfunction, cough, wheezing, COVID-19, peripheral swelling, retinal vein occlusion, dizziness, and vomiting.
In the pediatric cohort, 30% of patients had a dose interruption, and 13% had a dose reduction due to an adverse reaction. The most common adverse reaction that required dose interruption was COVID-19. Adverse reactions that required dose reductions included rash and decreased neutrophil count.
Additionally, 9% of pediatric patients permanently discontinued treatment due to urticaria, rash, abdominal pain, constipation, and diarrhea.
Prior to initiating GOMEKLI, conduct a comprehensive ophthalmic assessment, assess ejection fraction by echocardiogram, and verify the pregnancy status of females of reproductive potential.
During treatment, monitor ejection fraction every 3 months during the first year, and then as clinically indicated. Conduct comprehensive ophthalmic assessment at regular intervals.
Laboratory abnormalities that worsened from baseline and occurred in 15% or more of patients are shown on this slide.
In adults and children, the most common laboratory abnormality was increased CPK. In addition, decreased neutrophil count was also a commonly observed laboratory abnormality in children.
It is recommended to conduct lab tests prior to initiating treatment and at regular intervals.
[Dr Moertel]
Now, I'd like to have a discussion with Dr Nghiemphu around management of adverse reactions.
This is important for ensuring that patients can stay on therapy.
Dr Nghiemphu, in the patient cohort in which you were involved in the ReNeu study, how did you manage skin adverse reactions?
[Dr Nghiemphu]
My patients were able to manage through the skin adverse reactions, and this is an important part of MEK inhibitor therapy.
Of the patients who had skin adverse reactions, the majority experienced the first onset pretty early in Cycle 1.
For intolerable Grade 2 or Grade 3 reactions, you should withhold GOMEKLI until Grade 1 or less, and then resume GOMEKLI at a reduced dose.
For Grade 3 or 4 dermatitis acneiform or nonacneiform rash, you should also withhold GOMEKLI until Grade 1 or lower, and then resume GOMEKLI at a reduced dose.
I provided some general guidance, including hygienic skin care practices such as the use of mild cleansers and hypoallergenic moisturizers at least twice a day to prevent dry skin and to avoid agents such as retinoids that could dry out the skin.
In addition, I have seen that proactive management can help a lot with this.
There were some recommendations presented at the Society of Neuro-Oncology Conference last year.
Not every clinician has easy access to a dermatologist, so it’s important to have some management strategies in house.
Dr Moertel, in a patient cohort in which you were involved in the ReNeu study, how did you manage the gastrointestinal adverse reactions?
[Dr Moertel]
For intolerable Grade 2 or Grade 3 reactions, you should withhold GOMEKLI until Grade 1 or less, and then resume GOMEKLI at a reduced dose.
For Grade 4 reactions, consider discontinuing GOMEKLI altogether.
For managing GI adverse reactions, I followed the guidance from the study protocol, which says to consider the good-old BRAT diet, which consists of bananas, rice, applesauce, and toast or just plain pasta.
Also avoid fried, spicy, or fatty foods, and increase fluid intake.
For noninfectious diarrhea, I used loperamide.
[Dr Moertel, voice over only]
I would like to review the highlights of the Important Safety Information.
GOMEKLI can cause ocular toxicity, including retinal vein occlusion, retinal pigment epithelium detachment, and blurred vision.
Conduct comprehensive ophthalmic assessments prior to initiating GOMEKLI, at regular intervals during treatment, and to evaluate any new or worsening visual changes. Follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
GOMEKLI can cause left ventricular dysfunction. It can occur in patients who are treated with GOMEKLI. Before initiating GOMEKLI, assess ejection fraction by echocardiogram and monitor ejection fraction every 3 months during the first year, and then as clinically indicated. Withhold, reduce the dose of, or discontinue GOMEKLI, depending on the severity of the adverse reaction.
GOMEKLI can cause dermatologic adverse reactions, including rash.
The most frequent rashes include dermatitis acneiform, rash, eczema, maculo-papular rash, and pustular rash.
Initiate supportive care at first signs of dermatologic adverse reactions and follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
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.
Because of the potential for adverse reactions in breastfed children, women should be advised not to breastfeed during treatment with GOMEKLI and for 1 week after the last dose.
Advise females of reproductive potential to use effective contraception during treatment with GOMEKLI and for 6 weeks after the last dose.
Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of GOMEKLI.
GOMEKLI logo.
Episode #4 Safety Profile and Adverse Reaction Management
[Dr Nghiemphu]
My name is Dr Phioanh Leia Nghiemphu, and I'm a neuro-oncologist and the director of the UCLA Neurofibromatosis and Schwannomatosis Clinic.
I'm happy to share today that I also have Dr Moertel, one of the lead investigators of the ReNeu study.
[Dr Moertel]
My name is Dr Christopher Moertel.
I'm a neuro-oncologist and I serve as professor of pediatrics at the University of Minnesota School of Medicine, and I'm the medical director of the Comprehensive Neurofibromatosis Clinic at the University of Minnesota Masonic Children's Hospital.
[Dr Nghiemphu]
GOMEKLI is the first FDA-approved treatment for both adult and pediatric patients 2 years of age and older with NF1 who have symptomatic PNs not amenable to complete resection.
This safety table represents adverse reactions seen in 20% or more of patients.
The most common adverse reactions occurring in greater than 25% of adult patients were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue.
The most common adverse reactions occurring in greater than 25% of pediatric patients were rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea.
The majority of adverse reactions were mild to moderate, and there were low rates of severe, Grade 3 or 4, adverse reactions. For your reference, and to ensure that you and your patients are provided with the support needed, SpringWorks will have a Dosing and Adverse Reaction Management Guide available. This resource includes information on how to manage some of the most common dermatologic and GI side effects, as well as additional information on other adverse reactions.
In the adult cohort, 31% of patients had a dose interruption, and 17% had a dose reduction due to an adverse reaction.
The most common adverse reactions that required dose interruptions were left ventricular dysfunction and COVID-19. Adverse reactions that required dose reductions included rash.
Additionally, 22% of adult patients permanently discontinued GOMEKLI due to rash, diarrhea, nausea, abdominal pain, alopecia, dry skin, left ventricular dysfunction, cough, wheezing, COVID-19, peripheral swelling, retinal vein occlusion, dizziness, and vomiting.
In the pediatric cohort, 30% of patients had a dose interruption, and 13% had a dose reduction due to an adverse reaction. The most common adverse reaction that required dose interruption was COVID-19. Adverse reactions that required dose reductions included rash and decreased neutrophil count.
Additionally, 9% of pediatric patients permanently discontinued treatment due to urticaria, rash, abdominal pain, constipation, and diarrhea.
Prior to initiating GOMEKLI, conduct a comprehensive ophthalmic assessment, assess ejection fraction by echocardiogram, and verify the pregnancy status of females of reproductive potential.
During treatment, monitor ejection fraction every 3 months during the first year, and then as clinically indicated. Conduct comprehensive ophthalmic assessment at regular intervals.
Laboratory abnormalities that worsened from baseline and occurred in 15% or more of patients are shown on this slide.
In adults and children, the most common laboratory abnormality was increased CPK. In addition, decreased neutrophil count was also a commonly observed laboratory abnormality in children.
It is recommended to conduct lab tests prior to initiating treatment and at regular intervals.
[Dr Moertel]
Now, I'd like to have a discussion with Dr Nghiemphu around management of adverse reactions.
This is important for ensuring that patients can stay on therapy.
Dr Nghiemphu, in the patient cohort in which you were involved in the ReNeu study, how did you manage skin adverse reactions?
[Dr Nghiemphu]
My patients were able to manage through the skin adverse reactions, and this is an important part of MEK inhibitor therapy.
Of the patients who had skin adverse reactions, the majority experienced the first onset pretty early in Cycle 1.
For intolerable Grade 2 or Grade 3 reactions, you should withhold GOMEKLI until Grade 1 or less, and then resume GOMEKLI at a reduced dose.
For Grade 3 or 4 dermatitis acneiform or nonacneiform rash, you should also withhold GOMEKLI until Grade 1 or lower, and then resume GOMEKLI at a reduced dose.
I provided some general guidance, including hygienic skin care practices such as the use of mild cleansers and hypoallergenic moisturizers at least twice a day to prevent dry skin and to avoid agents such as retinoids that could dry out the skin.
In addition, I have seen that proactive management can help a lot with this.
There were some recommendations presented at the Society of Neuro-Oncology Conference last year.
Not every clinician has easy access to a dermatologist, so it’s important to have some management strategies in house.
Dr Moertel, in a patient cohort in which you were involved in the ReNeu study, how did you manage the gastrointestinal adverse reactions?
[Dr Moertel]
For intolerable Grade 2 or Grade 3 reactions, you should withhold GOMEKLI until Grade 1 or less, and then resume GOMEKLI at a reduced dose.
For Grade 4 reactions, consider discontinuing GOMEKLI altogether.
For managing GI adverse reactions, I followed the guidance from the study protocol, which says to consider the good-old BRAT diet, which consists of bananas, rice, applesauce, and toast or just plain pasta.
Also avoid fried, spicy, or fatty foods, and increase fluid intake.
For noninfectious diarrhea, I used loperamide.
[Dr Moertel, voice over only]
I would like to review the highlights of the Important Safety Information.
GOMEKLI can cause ocular toxicity, including retinal vein occlusion, retinal pigment epithelium detachment, and blurred vision.
Conduct comprehensive ophthalmic assessments prior to initiating GOMEKLI, at regular intervals during treatment, and to evaluate any new or worsening visual changes. Follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
GOMEKLI can cause left ventricular dysfunction. It can occur in patients who are treated with GOMEKLI. Before initiating GOMEKLI, assess ejection fraction by echocardiogram and monitor ejection fraction every 3 months during the first year, and then as clinically indicated. Withhold, reduce the dose of, or discontinue GOMEKLI, depending on the severity of the adverse reaction.
GOMEKLI can cause dermatologic adverse reactions, including rash.
The most frequent rashes include dermatitis acneiform, rash, eczema, maculo-papular rash, and pustular rash.
Initiate supportive care at first signs of dermatologic adverse reactions and follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
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.
Because of the potential for adverse reactions in breastfed children, women should be advised not to breastfeed during treatment with GOMEKLI and for 1 week after the last dose.
Advise females of reproductive potential to use effective contraception during treatment with GOMEKLI and for 6 weeks after the last dose.
Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of GOMEKLI.
Dosing and Administration
Dr. Moertel discusses the dosing and administration of GOMEKLI, the first FDA-approved treatment option for NF1-PN that is available as a dispersible tablet for patients who have difficulty swallowing.1-3
[Text onscreen]
GOMEKLI logo.
Episode #5 GOMEKLI Dosing and Administration
[Dr Moertel]
Hi, my name is Dr Christopher Moertel.
I'm a neuro-oncologist and I serve as a professor of pediatrics at the University of Minnesota School of Medicine, and the medical director of the Comprehensive Neurofibromatosis Clinic at the University of Minnesota Masonic Children's Hospital.
GOMEKLI is the first treatment approved for both adults and children aged 2 years and older with NF1 who have symptomatic plexiform neurofibromas not amenable to complete resection.
Now, let's discuss the dosing and administration of GOMEKLI.
GOMEKLI has a dosing schedule of 3 weeks on and 1 week off.
Dosing is based on BSA, and should be dosed at 2 mg/m2.
The maximum dosage of GOMEKLI is 4 mg orally twice daily.
You can see here to the left of the slide the various dosing recommendations for different BSA ranges.
Underneath the top-left table and to the right are tables from the Prescribing Information that provide recommendations around dose reductions and dose modifications to address adverse reactions.
Until now, there was no FDA–approved option for children and adults who have difficulty swallowing capsules.
Now, GOMEKLI is the first treatment option available as a dispersible tablet, and it may be taken with or without food.
Instruct patients that tablets can be swallowed whole or dispersed in drinking water and administered orally as a liquid.
This option may be beneficial for patients who are not able to swallow whole tablets.
GOMEKLI can also be taken as capsules, which must be swallowed whole.
Advise patients not to open them, break them, or chew the capsules.
The capsules come in 2-mg and 1-mg strengths, and the dispersible tablets come in a 1-mg strength.
[Dr Moertel, voiceover only]
I would like to review the highlights of the Important Safety Information.
GOMEKLI can cause ocular toxicity, including retinal vein occlusion, retinal pigment epithelium detachment, and blurred vision.
Conduct comprehensive ophthalmic assessments prior to initiating GOMEKLI, at regular intervals during treatment, and to evaluate any new or worsening visual changes. Follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
GOMEKLI can cause left ventricular dysfunction.
It can occur in patients who are treated with GOMEKLI.
Before initiating GOMEKLI, assess ejection fraction by echocardiogram and monitor ejection fraction every 3 months during the first year and then as clinically indicated. Withhold, reduce the dose of, or discontinue GOMEKLI, depending on the severity of the adverse reaction.
GOMEKLI can cause dermatologic adverse reactions, including rash.
The most frequent rashes include dermatitis acneiform, rash, eczema, maculo-papular rash, and pustular rash.
Initiate supportive care at first signs of dermatologic adverse reactions and follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
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.
Because of the potential for adverse reactions in breastfed children, women should be advised not to breastfeed during treatment with GOMEKLI and for 1 week after the last dose.
Advise females of reproductive potential to use effective contraception during treatment with GOMEKLI and for 6 weeks after the last dose.
Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of GOMEKLI.
GOMEKLI logo.
Episode #5 GOMEKLI Dosing and Administration
[Dr Moertel]
Hi, my name is Dr Christopher Moertel.
I'm a neuro-oncologist and I serve as a professor of pediatrics at the University of Minnesota School of Medicine, and the medical director of the Comprehensive Neurofibromatosis Clinic at the University of Minnesota Masonic Children's Hospital.
GOMEKLI is the first treatment approved for both adults and children aged 2 years and older with NF1 who have symptomatic plexiform neurofibromas not amenable to complete resection.
Now, let's discuss the dosing and administration of GOMEKLI.
GOMEKLI has a dosing schedule of 3 weeks on and 1 week off.
Dosing is based on BSA, and should be dosed at 2 mg/m2.
The maximum dosage of GOMEKLI is 4 mg orally twice daily.
You can see here to the left of the slide the various dosing recommendations for different BSA ranges.
Underneath the top-left table and to the right are tables from the Prescribing Information that provide recommendations around dose reductions and dose modifications to address adverse reactions.
Until now, there was no FDA–approved option for children and adults who have difficulty swallowing capsules.
Now, GOMEKLI is the first treatment option available as a dispersible tablet, and it may be taken with or without food.
Instruct patients that tablets can be swallowed whole or dispersed in drinking water and administered orally as a liquid.
This option may be beneficial for patients who are not able to swallow whole tablets.
GOMEKLI can also be taken as capsules, which must be swallowed whole.
Advise patients not to open them, break them, or chew the capsules.
The capsules come in 2-mg and 1-mg strengths, and the dispersible tablets come in a 1-mg strength.
[Dr Moertel, voiceover only]
I would like to review the highlights of the Important Safety Information.
GOMEKLI can cause ocular toxicity, including retinal vein occlusion, retinal pigment epithelium detachment, and blurred vision.
Conduct comprehensive ophthalmic assessments prior to initiating GOMEKLI, at regular intervals during treatment, and to evaluate any new or worsening visual changes. Follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
GOMEKLI can cause left ventricular dysfunction.
It can occur in patients who are treated with GOMEKLI.
Before initiating GOMEKLI, assess ejection fraction by echocardiogram and monitor ejection fraction every 3 months during the first year and then as clinically indicated. Withhold, reduce the dose of, or discontinue GOMEKLI, depending on the severity of the adverse reaction.
GOMEKLI can cause dermatologic adverse reactions, including rash.
The most frequent rashes include dermatitis acneiform, rash, eczema, maculo-papular rash, and pustular rash.
Initiate supportive care at first signs of dermatologic adverse reactions and follow the dose modification or discontinuation guidance from the Prescribing Information as needed.
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.
Because of the potential for adverse reactions in breastfed children, women should be advised not to breastfeed during treatment with GOMEKLI and for 1 week after the last dose.
Advise females of reproductive potential to use effective contraception during treatment with GOMEKLI and for 6 weeks after the last dose.
Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of GOMEKLI.
Clinical Management of NF1-PN
Clinical Overview in Adults and Case-Based Insights
Clinical Overview in Children and Case-Based Insights
Safety Profile and Adverse Reaction Management
Dosing and Administration
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
Verify the pregnancy status of patients of reproductive potential prior to initiating GOMEKLI. Due to the potential for adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with GOMEKLI and for 1 week after the last dose.
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.
To report SUSPECTED ADVERSE REACTIONS, contact SpringWorks Therapeutics Inc. at 1-888-400-7989 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please click here for full Prescribing Information, including Patient Information and Instructions for Use.
References
- GOMEKLI. Prescribing Information. SpringWorks Therapeutics, Inc.
- Rapado F, Simo R, Small M. Neurofibromatosis type 1 of the head and neck: dilemmas in management. J Laryngol Otol. 2001;115(2):151-154.
- Yoo HK, Porteous A, Ng A, et al. Impact of neurofibromatosis type 1 with plexiform neurofibromas on the health-related quality of life and work productivity of adult patients and caregivers in the UK: a cross-sectional survey. BMC Neurology. 2023;23(1):419.