Proven results in children 
and adolescents*

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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.

[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.