Prolonged Use of Nimotuzumab in Children with Central Nervous System Tumors: Safety and Feasibility

Abstract

Primary brain tumors constitute the most frequent solid tumor of childhood. High expression of the epidermal growth factor receptor (EGFR) protein has been associated with tumor progression and enhanced tumorigenicity in adult and children gliomas. Nimotuzumab is a humanized antibody that targets the EGFR and has proven efficacy in adult and children gliomas. To provide a new therapeutic option for patients with active, poor prognosis central nervous system (CNS) tumors and to evaluate the feasibility and safety of long-term nimotuzumab therapy in children with diverse CNS tumors, an expanded access program was launched at the Juan Manuel Marquez hospital. Patients were required to be 18 or younger and have one CNS tumor: low-grade glioma (LGG) or high-grade glioma (HGG), brainstem glioma (BSG), ependymoma or primitive neuroectodermal tumor (PNET), and a Lansky or Karnofsky performance status ≥40. Treatment consisted of weekly nimotuzumab administered at 150 mg/m(2) for 12 weeks, continuing every 14 days in the absence of severe condition worsening or unacceptable toxicity. Nimotuzumab was administered alone or in combination with radiotherapy, chemotherapy, or both, depending on the tumor type, stage, and previous treatment. Eighty-eight patients, 39 with BSG, 25 with HGG, 9 with progressive LGG, 9 with anaplastic ependymomas, and 6 with other tumor types, including PNET, neuroblastoma, meduloblastoma, and thalamic tumors, were treated with the antibody. The mean number of nimotuzumab doses was 36, from 1 to 108. The most frequent adverse events were mild to moderate skin rash, mucositis, vomiting, seizures, hypothermia, hyperthermia, and paleness. One patient had a grade 3 mucositis, while the other had a grade 3 bleeding on surgery. Sixteen children stopped treatment after at least 2 years with stable disease, partial or complete response. All children were able to maintain the best response achieved on treatment after a 3-year interruption. In summary, this study shows the feasibility of very prolonged administration of nimotuzumab together with the lack of rebound effect after treatment cessation.

Cetuximab or nimotuzumab plus intensity-modulated radiotherapy versus cisplatin plus intensity-modulated radiotherapy for stage II-IVb nasopharyngeal carcinoma

“…Specifically, the overall rate of a G3 or G4 reaction can reach 22%, and fatal events related to infusion have also been documented . Compared with the CTX arm, significantly lower frequencies of severe skin reactions, mucositis and hypersensitivity infusion reactions were observed in the NTZ arm, both in the current analysis and in previous studies . This benefit could be attributed to the reduced affinity of NTZ, which results in binding with less avidity, compared to CTX, thus sparing healthy tissues and avoiding severe toxicities.…”

“…24,25 Compared with the CTX arm, significantly lower frequencies of severe skin reactions, mucositis and hypersensitivity infusion reactions were observed in the NTZ arm, both in the current analysis and in previous studies. [26][27][28] This benefit could be attributed to the reduced affinity of NTZ, which results in binding with less avidity, compared to CTX, 29 20 And recently, they further demonstrated addition of cisplatin, fluorouracil and docetaxel (TPF) induction chemotherapy to concurrent chemoradiotherapy could significantly improve failure-free survival in locoregionally Table 4. Interaction between treatment regimen status and other significant prognostic factors and its effect on disease-free survival, distant metastasis-free survival, loco-regional relapse-free survival and overall survival in all eligible 1,837 cases (Continued) advanced NPC.…”

Seizures in Children with Brain Tumours — Epidemiology, Significance, Management, and Outcomes

“…In attempts to reduce tumour progression and prolong survival, newer chemotherapeutic drugs are continuously being tested. Some, like nimotuzumab [205]and bevacizumab [206], both of them antibodies against epithelial growth factor receptors (EGFR), have been demonstrating considerable promise, and this may have implications for which AEDs are best tolerated as interactions and mutual toxicities become clearer. What is evident is that AEDs, in themselves, are usually inadequate to control seizures in most patients with epileptogenic brain tumours.…”

Management of diffuse intrinsic pontine glioma in children: current and future strategies for improving prognosis

“…EGFRvIII expression by immunohistochemistry was observed in approximately half of a small cohort of DIPGs [47], but it remains unclear whether its expression alone harbors any meaningful clinical significance. Several clinical trials continue to investigate the role of EGF receptor (EGFR)-targeting agents in children with DIPG, including monoclonal antibodies (e.g., nimotuzumab [48,49]), small-molecule inhibitors (e.g., erlotinib [10,50]), and EGFRvIII-targeting peptide vaccines [51]. However, the rationale for this approach remains weak given the uncommon findings of EGFR pathway abnormalities in DIPG [5].…”