Correction to: Results of nimotuzumab and vinorelbine, radiation and re-irradiation for diffuse pontine glioma in childhood.

The therapeutic experience reported in the paper was conceived after the use of nimotuzumab and radiotherapy (BSCPED-05 international multicentric trial, EUDRACT 2005-003100-11) in 2009 when we decided to explore the activity of the same combination plus vinorelbine (see the paper for the rationale).

A randomised, open label phase III trial with nimotuzumab, an anti-epidermal growth factor receptor monoclonal antibody in the treatment of newly diagnosed adult glioblastoma.

PURPOSE: A randomised, open label phase III trial was conducted to evaluate efficacy of nimotuzumab, a monoclonal antibody against epidermal growth factor receptor (EGF-R) added to standard therapy for newly diagnosed glioblastoma. PATIENTS AND METHODS: 149 glioblastoma patients stratified as with or without residual tumour were randomly assigned to receive either intravenous nimotuzumab 400mg weekly added to standard radiochemotherapy followed by 400mg biweekly after twelve weeks or standard radiochemotherapy. Progression status after 52 weeks (12moPFS) and progression-free survival (PFS) based on Macdonald criteria were co-primary and overall survival (OS), toxicity and quality of life secondary end-points. RESULTS: 142 patients were evaluated for efficacy (per protocol cohort). 12 moPFS was 25.6% in the experimental arm and 20.3% in the control group. In residual tumour patients (n=81) median PFS was 5.6 versus 4.0 months, (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.55-1.37), for patients without residual tumour (n=61) it was 10.6 versus 9.9 months, (HR, 1.01; 95% CI, 0.57-1.77). Median OS in patients with residual tumour was 19.5 versus 16.7 months, (HR, 0.90; 95% CI, 0.52-1.57; P=0.7061), for patients without 23.3 versus 21.0 months (HR, 0.77; 95% CI, 0.41-1.44; P=0.4068). A small cohort of MGMT non-methylated patients with residual tumour showed PFS of 6.2 versus 4.0 months (HR, 0.77; 95% CI, 0.35-1.67; P=0.4997) and OS of 19.0 versus 13.8 months (HR, 0.66; 95% CI, 0.27-1.64; P=0.3648). EGF-R amplification did not correlate with clinical efficacy of nimotuzumab. Nimotuzumab was well tolerated. CONCLUSION: This study, albeit negative, contains hypothesis generating signals supporting evaluation of correlative, efficacy-predicting tumour parameters for nimotuzumab in the treatment of glioblastoma.

Results of nimotuzumab and vinorelbine, radiation and re-irradiation for diffuse pontine glioma in childhood.

Radiotherapy is the only treatment definitely indicated for diffuse pontine gliomas (DIPG). Findings on the role of EGFR signaling in the onset of childhood DIPG prompted the use of nimotuzumab, an anti-EGFR monoclonal antibody. Assuming a potential synergy with both radiotherapy and vinorelbine, a pilot phase 2 protocol was launched that combined nimotuzumab with concomitant radiation and vinorelbine. An amendment in July 2011 introduced re-irradiation at relapse. The primary endpoint for first-line treatment was objective response rate (CR + PR + SD) according to the RECIST. This report concerns the outcome of this strategy as a whole. Vinorelbine 20 mg/m(2) was administered weekly, with nimotuzumab 150 mg/m(2) in the first 12 weeks of treatment; radiotherapy was delivered from weeks 3 to 9, for a total dose of 54 Gy. Vinorelbine 25 mg/m(2) and nimotuzumab were given every other week thereafter until the tumor progressed or for up to 2 years. Re-irradiation consisted of 19.8 Gy, fractionated over 11 days. Baseline and latest MRIs were assessed blindly by an outside neuroradiologist. Twenty five children (mean age 7.4 years) were enrolled as of August 2009 (median follow-up 29 months). A response was observed in 24/25 patients (96 %). The nimotuzumab/vinorelbine combination was very well tolerated, with no acute side-effects. Eleven of 16 locally-relapsing patients were re-irradiated. One-year PFS and OS rates were 30 ± 10 % and 76 ± 9 %, respectively; 2-year OS was 27 ± 9 %; the median PFS and OS were 8.5 and 15 months, respectively. This strategy generated interesting results and warrants further investigation.

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

BACKGROUND: The 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. METHODS: A 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. RESULTS: The 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. CONCLUSIONS: In this randomized trial, nimotuzumab showed an excellent safety profile and significant survival benefit in combination with irradiation. TRIAL REGISTRATION: Cuban National Register for clinical trials (No. 1745) (http://registroclinico.sld.cu/ensayos).

Nimotuzumab treatment of malignant gliomas.

INTRODUCTION: In spite of new alkylating medication and recently accumulated knowledge about genomics, the prognosis of malignant gliomas remains poor. The introduction of single substances interfering with tumour proliferation dynamics has been disappointing and the lessons learned indicate that a complicated network of proliferation needs time consuming, in-depth analysis in order to more specifically treat now distinguishable subgroups of a disease, which too long was thought of as a uniform entity. AREAS COVERED: The clinical trials using the EGFR antibody nimotuzumab in the treatment of malignant gliomas are reviewed. Pending conformation in future studies the antibody might be part of the treatment of MGMT-negative, EGFR-amplified, not completely resected gliomas of adulthood and juvenile DIPG (pontine gliomas). Upcoming genomic results of the different tumour entities may suggest certain combination partners of the antibody. Recent studies of nimotuzumab indicate the reason for the lack of toxicity, which is the most attractive argument for its clinical use besides modest efficacy. EXPERT OPINION: We await the final results on the use of the antibody together with vinorelbine and radiation therapy for the therapy of DIPG. Adult patients with MGMT-negative, EGFR amplified, not totally resected GBM may also profit from this combination therapy. TK-inhibitors combined with the antibody and irradiation may be an option for a therapeutic trial in paediatric patients.