Selumetinib shows ‘limited efficacy’ for paediatric tumours with MAPK pathway alterations
By Lynda Williams, medwireNews Reporter
Screening for mitogen-activated protein kinase (MAPK) signalling pathway alterations in children and young adults with cancer or histiocytic disorders is feasible, but targeted therapy with selumetinib showed “limited efficacy” in this population, say the NCI-COG Pediatric MATCH trial investigators.
Carl Allen, from Baylor College of Medicine in Houston, Texas, USA, and co-workers report in the Journal of Clinical Oncology that treatment arm E of the phase 2 study assessed the MEK inhibitor selumetinib in 20 patients aged 1–21 years (median 14 years) who had relapsed or refractory solid tumours, lymphoma or histiocytic disorders.
This included seven patients with high-grade glioma (HGG) and seven with rhabdomyosarcoma, and individual cases of neuroblastoma, yolk sac (endodermal sinus) tumour, malignant peripheral nerve sheath tumour, plexiform neurofibroma, cervical clear cell adenocarcinoma and ovarian mucinous adenocarcinoma.
Overall, 21 actionable mutations were identified, including hotspot mutations in KRAS (n=8), NRAS (n=3) and HRAS (n=1), and inactivating mutations in NF1 (n=7) and BRAF V600E (n=2).
The patients were given selumetinib 25 mg/m2 twice daily to a maximum dose of 75 mg in 28-day cycles for up 2 years or until progression or toxicity, the researchers explain.
Overall, 25% of the patients experienced grade 3 or more severe adverse events possibly or probably related to selumetinib therapy. This included grade 3 uveitis, decreased lymphocyte counts and thromboembolism, grade 4 creatinine phosphokinase elevation, and grade 5 pulmonary embolism.
The investigators describe the clinical activity of selumetinib as “disappointing”, with no objective responses and a 6-month progression-free survival rate of 15%.
Three patients achieved stable disease. These included two patients with HGG carrying NF1 and PTEN or KRAS mutations who received six and 12 cycles of treatment before progression, respectively, and a third patient with plexiform neurofibroma harbouring NF1 and BRCA2 mutations who continued treatment for 13 cycles before discontinuing with dose-limiting toxicity of uveitis.
Allen et al note that responses to selumetinib in children both in the current study and earlier research have been limited to those with tumours that are “less clinically aggressive and molecularly defined almost exclusively by single gene driver mutations in the MAPK pathway.”
The authors conclude that “the Pediatric MATCH data add to the accumulating evidence that targeting RAS-mutated tumors with single MAPK pathway–directed agents is not an effective approach.”
And they suggest that “selumetinib and other MEK inhibitors will require combination with additional molecularly targeted, immunotherapeutic, or cytotoxic agents to achieve optimal efficacy in patients with genomically complex tumors.”
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J Clin Oncol 2022; doi:10.1200/JCO.21.02840