Nimotuzumab binds to the extracellular domain of epidermal growth factor receptor (EGFR, HER1, c-ErB1) and inhibits the binding of epidermal growth factor (EGF) and other ligands such as transforming growth factor alfa. The intrinsic properties of Nimotuzumab require bivalent binding (i.e., binding with both antibody arms to two targets simultaneously) for stable attachment to cellular surface, which leads to Nimotuzumab selectively binding to cells that express moderate to high EGFR levels1. The EGFR is a transmembrane glycoprotein that is a member of a family of receptors named HER. EGFR is expressed in cells from all three embryonic layer cells, especially in cells of epithelial origin (Skin, respiratory tract, gastrointestinal tract, urinary tract and liver). In wide diversity of human tumors of epithelial origin like head and neck (SCCHN), non small cell lung cancer (NSCLC), pancreatic, colon, breast, kidney ovarian and bladder carcinomas EGFR is over expressed. It is also over expressed in gliomas. Binding of Nimotuzumab to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased vascular endothelial growth factor production.
In vitro studies using tumor cell lines like A431, MDA-MB-435, U87 and in vivo studies in human tumor xenografted SCID mice have shown that Nimotuzumab has anti-proliferative, anti-angiogenic and proapoptotic activity.
Nimotuzumab administered in combination with concomitant chemotherapy or radiotherapy exhibits nonlinear pharmacokinetics. Following a 30 minute infusion the area under the concentration time curve (AUC) increased in a greater than dose proportional manner as the dose increased from 50 to 400 mg. Nimotuzumab clearance (CL) decreased from 1.08 to 0.34 mL/h/kg as the dose increased from 50 to 200, and at doses >200 mg, it appeared to plateau. The volume of the central compartment (Vc) for Nimotuzumab ranged from 2.3 to 7.2L and the maximal concentration Cmax was 27 to 57 ng/mL for the same dose range. The elimination half life (t1/2ß) ranged from 62.91 to 304.51 hrs for the doses 50 to 400mg.
In the human body, Nimotuzumab is mainly distributed in liver, spleen, heart, kidney and bladder. Liver uptakes most of the Nimotuzumab. Evidence from animal pharmacokinetic study indicates that the concentration of the antibody in tumor is highest at 24 hours after injection.
The immunotoxicity studies in green monkeys consisting of four intra-dermal doses of adjuvanted-Nimotuzumab elicited only sub maximal immunogenic response, suggestive of lesser immunogenecity with non adjuvanted Nimotuzumab.
Immunogenicity [human anti-human antibody (HAHA)] to determine the antiidiotypic response against Nimotuzumab was evaluated in clinical studies at single and multiple doses to a maximum of 2400mg with a follow-up of one year. Out of the 34 patients evaluated only one patient showed a response.
The low anti-idiotypic response is indicative of the humanized nature of the antibody and may also be responsible for the low hypersensitivity reaction. The development of an immunogenic response is dependent on a number of factors like timing of sample collection, sample handling, time of collection, underlying disease and concomitant medication. The incidence of development of antibodies to Nimotuzumab is not conclusive.
The efficacy and safety of Nimotuzumab concurrently with chemotherapy and/or radiotherapy has been studied in two randomized controlled trials (RCT) (229 patients) and two non randomized (53 patients) clinical trials. Safety data from all of these patients were also evaluated.
A randomized multicentric phase II clinical trial enrolled 92 patients to study the addition of Nimotuzumab to two regimens of standard of care namely Radiotherapy (RT) and Chemotherapy (CT) + RT in the management of stage III & stage IVA unresectable head and neck cancer. The two groups were evenly matched with respect to the age, sex, stage of tumor and baseline KPS with no statistical difference between the groups. Patients received Nimotuzumab as 200 mg IV infusion weekly once for 6 weeks. The response to treatment was evaluated at the end of 3 months and 6 months. A total of sixteen patients were not evaluable. 76 patients were evaluable for efficacy analysis.
The objective response rates (ORR) in the different treatment groups were:
| Treatment groups | n=54# | ORR % (p value) |
|---|---|---|
| Nimotuzumab +RT | 13 | 76.47 (0.02) |
| RT | 7 | 36.84 |
| Nimotuzumab +CT+RT | 20 | 100.00 (0.02) |
∗ CT+RT 14 70.00 ♦Nimotuzumab + RT vs RT
Nimotuzumab CT RT vs CT+RT
# 54 patients showed ORR of the 76 evaluable for analysis
Nimotuzumab did not deteriorate the KPS of the patient when it was added to CT+RT and RT. Nimotuzumab when used concurrently with CT and/or RT showed greater Objective Response Rate than the control treatment groups. At 30 months follow up2, the survival rate in Nimotuzumab plus Chemoradiation arm was 69.5% versus 21.7% in chemoradiation alone arm and in Nimotuzumab plus radiotherapy arm was 39.1% versus 21.7% in radiotherapy alone arm. The addition of Nimotuzumab to Chemoradiation resulted in a reduction in risk of death (rrd) by 85% (HR 0.15, p-0.0006) and to RT a 36% rrd (HR0.64, p 0.33) (OS per protocol).
In another randomized, open-labeled multi-centric phase II clinical trial in patients with locally advanced (stage III or IVA-B) nasopharyngeal squamous carcinoma3 137 patients were included out of which 70 were in the study drug (Nimotuzumab) group, and 67 in the control group. Patients in the study drug group received Nimotuzumab in combination with radical radiotherapy, while the control group received radiotherapy alone. Patients received 8 weekly infusions of Nimotuzumab at the dose of 100 mg in combination with radiotherapy. The first infusion was given on the same day patients started radiotherapy and ended simultaneously with the radiotherapy.
Analysis was performed at the end of the treatment, 5 and 17 weeks after the treatment separately. Upon the end of the treatment, the CR (Complete Remission) percentage of study drug group was: 76.56% for primary tumor, 75.00% for lymph node, and 65.63% for overall evaluation; compared with those of control group as 34.85%, 57.58%, and 27.27% respectively. The CR percentages in study drug group were higher than those in control. 5 weeks after the treatment, the CR percentages in study drug group were 90.63% for local tumor, 89.06% for lymph node, and 87.50% for overall evaluation; compared with the control group of 51.52%, 72.73%, and 42.42% respectively. 17 weeks after the treatment, the CR percentages in study drug group were 92.19% for local tumor, 93.75% for lymph node, and 90.63% for overall evaluation, compared with 63.64%, 80.30%, and 51.52% in the control. All differences were statistically significant. The objective response observed at 17 weeks after the treatment was 100% in study drug group and 90.91% in control group. The difference was statistically significant. The mean value of Karnofsky grading of study drug group after treatment was higher than that of control group, which was statistically significant, which indicates that the antibody is helpful to improve the patient life quality. The differences between the patient body weights before and after the treatment were analyzed and the mean value of experimental group was 0.35 kg and that of control group was 0.87 kg and this difference was statistically significant.
A single center phase I/II open-label, nonrandomized, clinical trial was designed to evaluate safety, and efficacy of Nimotuzumab in combination with external beam radiotherapy in 12 advanced EGF-R expressing head and neck cancer (Stages III or IV) patients suitable for radical radiation therapy. Four different treatment cohorts of 3 patients were established. Single doses in the 4 defined cohorts from 50 to 400 mg of Nimotuzumab. Patients received the same dose on a weekly basis for 6 weeks. For the 4 cohorts, total Nimotuzumab cumulative doses were 300, 600, 1200, and 2400 mg. Patients also received either 60 or 66 Gy radiation depending on response from Co 60 sources at 2Gy doses given daily for five days over six weeks. After finishing accrual, the protocol was amended to include five new patients in the two highest dose groups to further evaluate the relationship between the antitumor response and serum antibody levels.
In the first trial section, where 12 patients took the 4 dose levels of Nimotuzumab, 7 patients of the 12 showed ORR (PR or CR), and four subjects showed stable disease and there was tumor progression in 1 case after the combined therapy. In 6 of the 7 responding patients, there was complete remission of the primary tumor and its metastases while 1 patient showed a partial response. Preliminary pharmacokinetic analysis indicated that receptor saturation was achieved above 200 mg.
Overall survival significantly increased after the use of doses of 200 or 400 mg in comparison with lower doses (P=0.03). With a median follow-up from treatment beginning to the closeout date of 45.2 months (range, 41.5 to 48.1months), the median survival for 50 and 100 mg treated patients was 8.60 months, while the median survival of the patients receiving 200 and 400 mg was 44.30 months. The 3-year survival rate was 16.7% for subjects treated with the two lowest doses and 66.7% for the patients treated with 200 and 400 mg. After the protocol was amended to include 10 new patients in 200 and 400 mg groups, finally, 14 (87.5%) of the 16 patients achieved ORR where 11 were CR. The overall mean survival is 22 months; 8 patients remain alive and seven are disease free4.
Another multi-centric nonrandomized study evaluating the safety and efficacy of Nimotuzumab in combination with radiation therapy (RT) in the treatment of patients with locally advanced, unresectable squamous cell carcinoma of the head and neck (SCCHN) was conducted in thirty one subjects. Patients were treated with radiotherapy of 6600 or 7000 cGy in 33 or 35 fractions plus 100 or 200 mg doses of Nimotuzumab once weekly for 6 weeks. The ITT population was defined as all patients who received at least one dose of Nimotuzumab. The evaluable population was defined as all patients who received six doses of Nimotuzumab and reached week 12 evaluations Twentyfour patients were fully evaluable. Of these, 17 (70%) showed complete tumor responses as their best response. In total, thirteen patients completed the study as complete responders. Of the remaining evaluable patients, 3 (12.5%) patients achieved partial responses and then progressed at 24 week, 1(4.9%) patient had stable disease for 3 visits and then progressed. The remaining 3 (12.5%) patients had progressive disease. The mean survival in the ITT population was 829 days. The median survival of the evaluable population is currently 43.4 months.
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