Expert: Consider Oral Chemotherapies for Pediatric Patients With Low-Grade Gliomas

Although there are some important considerations for oral chemotherapies in pediatric patients with low-grade gliomas (LGGs), oral formulations can offer effective treatments in this unique patient population, according to a session at the Hematology/Oncology Pharmacy Association virtual 2021 conference.

Gliomas are the second most common childhood malignancy and the most common solid tumor in children, said presenter Kate Reichert, PharmD, BCPPS, a pediatric oncology clinical pharmacy specialist at Memorial Sloan Kettering. LGGs account for approximately 40% of all central nervous system (CNS) tumors for children under 18 years of age, and they have a wide range of histologic subtypes.

Generalizing symptoms are secondary to increased intracranial pressure from obstruction of the ventricles and can include headaches, lethargy, nausea, and vomiting, while localizing symptoms vary. Surgical resection is the mainstay of therapy and may be curative when a total resection is possible, whereas chemotherapy is utilized for incompletely resected, unresectable, or progressive pediatric LGGs with varying response rates, according to Reichert.

She said the most common chemotherapy regimen for pediatric patients with LGGs is carboplatin and vincristine, although vinblastine monotherapy has recently been extensively used. Radiation used to be a first-line therapy but has fallen out of favor because of documented risks of radiotherapy in the developing brain, according to Reichert.

The presentation reviewed 3 chemotherapies for this patient population: selumetinib, trametinib, and dabrafenib. All 3 have shown encouraging results in clinical trials.

Selumetinib is a potent, selective oral non-ATP-competitive small molecule inhibitor of MEK1/2 and was approved by the FDA in 2020 for pediatric patients aged 2 years and older for the treatment of neurofibromatosis type 1 (NF1) with symptomatic, inoperable plexiform neurofibromas. Selumetinib must be given on an empty stomach and swallowed whole, which Reichert noted can be a challenge in young children.

In a clinical trial of selumetinib in pediatric patients with BRAF-aberrant or NF1-associated recurrent, refractory, or progressive LGG, investigators found that selumetinib is active with the potential to be an alternative to standard chemotherapy. The findings led to the development of 2 Children’s Oncology Group (COG) phase 3 studies comparing selumetinib to standard chemotherapy in newly diagnosed pediatric LGG.

Precautions with selumetinib include bleeding risk, cardiomyopathy, CPK elevations, rash, diarrhea, ocular toxicity, and hepatic impairment. Reichert said there are currently a trio of phase 3 trials investigating its use.

Next, Reichert discussed trametinib and its potential for pediatric patients with LGGs. It is a reversible, highly selective allosteric inhibitor of MEK1/2 activation and kinase activity, and is FDA-approved for several adult indications. Findings from a retrospective, multi-center, centrally reviewed study by Selt F et al showed a 100% disease control rate with 6 partial responses, 2 minor responses, and 10 patients with stable disease.

The study had a median treatment time of 12.5 months and adverse effects (AEs) occurred in 89% of patients, with 44% experiencing severe AEs. Most of the AEs were skin rash and paronychia, Reichert said. Like selumetinib, trametinib must be administered on an empty stomach and should be administered at the same time each day. Notably, it may also enhance the AEs of dabrafenib.

Finally, Reichert said dabrafenib seems to be well-tolerated and is showing promising results in clinical trials. It is a potent, selective inhibitor of some mutated forms of the protein kinase BRAF V600 mutations and is FDA-approved for several adult indications, both as a monotherapy and combination therapy.

Research published by Hargave et al evaluated the safety, tolerability, and clinical activity of dabrafenib in pediatric patients with advanced BRAF V600 mutation-positive solid tumors. Of the 32 patients with pediatric LGG, 15 were continuing treatment at the data cutoff. They had an overall response rate of 44% and a 1-year progression-free survival rate of 85%. Fatigue was the most common treatment-related AE, and grade 3 or 4 AEs were reported in 9 patients.

It should be administered on an empty stomach with doses approximately 12 hours apart. When given in combination with trametinib, Reichert said the once-daily dose of trametinib should be taken at the same time each day with either the morning or evening dose of dabrafenib. Precautions for dabrafenib include febrile reactions, hemorrhage, hyperglycemia, malignancy, uveitis, and venous thromboembolism.

With any oral chemotherapy option, Reichert said it is important to consider the available formulations and their various administration schedules. Practitioners are hoping for approved oral formulations that are easier for children, although Reichert said medical professionals can contact manufacturers for dissolution information if necessary. More mature clinical trial data will also be interesting in the future, to see whether any AEs differ between pediatric patients and adults, although they seem to be well-tolerated so far in children, according to Reichert.

REFERENCE

Reichert K. Oral Chemotherapy for Pediatric Low-Grade Gliomas. Presented at: Hematology/Oncology Pharmacy Association 2021 Virtual Conference; April 14, 2021. Accessed April 14, 2021.