Radiotherapy plus nimotuzumab or placebo in the treatment of high grade glioma patients: results from a randomized, double blind trial

Abstract

BackgroundThe prognosis of patients bearing high grade glioma remains dismal. Epidermal Growth Factor Receptor (EGFR) is well validated as a primary contributor of glioma initiation and progression. Nimotuzumab is a humanized monoclonal antibody that recognizes the EGFR extracellular domain and reaches Central Nervous System tumors, in nonclinical and clinical setting. While it has similar activity when compared to other anti-EGFR antibodies, it does not induce skin toxicity or hypomagnesemia.MethodsA randomized, double blind, multicentric clinical trial was conducted in high grade glioma patients (41 anaplastic astrocytoma and 29 glioblastoma multiforme) that received radiotherapy plus nimotuzumab or placebo. Treatment and placebo groups were well-balanced for the most important prognostic variables. Patients received 6 weekly doses of 200 mg nimotuzumab or placebo together with irradiation as induction therapy. Maintenance treatment was given for 1 year with subsequent doses administered every 3 weeks. The objectives of this study were to assess the comparative overall survival, progression free survival, response rate, immunogenicity and safety.ResultsThe median cumulative dose was 3200 mg of nimotuzumab given over a median number of 16 doses. The combination of nimotuzumab and RT was well-tolerated. The most prevalent related adverse reactions included nausea, fever, tremors, anorexia and hepatic test alteration. No anti-idiotypic response was detected, confirming the antibody low immunogenicity. The mean and median survival time for subjects treated with nimotuzumab was 31.06 and 17.76 vs. 21.07 and 12.63 months for the control group.ConclusionsIn this randomized trial, nimotuzumab showed an excellent safety profile and significant survival benefit in combination with irradiation.Trial registrationCuban National Register for clinical trials (No. 1745) (http://registroclinico.sld.cu/ensayos).

Nimotuzumab in combination with radiotherapy in high grade glioma patients

“…In the phase 2/3 study, the median survival time was 17.24 and 44.56 mo for GBM and AA patients treated with irradiation and the antibody, respectively. 30 Overall, our set of treated and control patients had worse survival compared with the patients from the previous randomized trial. This can be associated with the poor performance status, the reduced number of subjects with gross total resection and the high percent of older patients included in our series, which was performed mainly as part of the phase 4 study with enrollment criteria that were less restrictive.…”

Delineating the functional map of the interaction between nimotuzumab and the epidermal growth factor receptor

“…A recent survey 4 describes three anti-EGFR mAbs as currently marketed for cancer therapy: cetuximab (first approved for clinical use in US and Europe in 2004), panitumumab (approved in 2006 and 2007, respectively), and nimotuzumab (the humanized version of R3 murine mAb 5,6 ), which has been approved in Cuba since 2002 and is marketed in over 20 countries, including Brazil, India and China. Its use is supported by a wide clinical experience, showing efficacy to treat patients with head and neck cancer, 7 high grade glioma 8 and esophageal tumors. 9 Additional clinical trials are being performed.…”

Nimotuzumab en el tratamiento de pacientes con glioma maligno. Comparación entre estudios pre-registro y pos-aprobación.

“…7-9 La cefalea, la ebre y las alteraciones de las enzimas hepáticas fueron los eventos más comunes tanto en los estudios pre-registro 8,9 como en los EPA. 11,12 En cuanto a la aparición de eventos dermatológicos del tipo rash o eritema cutáneo solo de noti caron en los estudios EPA, pero en escasa frecuencia 11,12 ; lo que persiste como distintivo en el per l de seguridad del nimotuzumab, en contraste con otros monoclonales dirigidos al mismo blanco tumoral del EGFR16 y por consiguiente, una ventaja para el manejo de un fármaco, que garantiza una mejor adherencia al tratamiento.…”