Zuhera Mechanism of Action

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies. ATC code: L01XC03.
Pharmacology: Pharmacodynamics: Mechanism of Action: The humanised monoclonal IgG1 antibody Trastuzumab is produced by recombinant DNA technology; and contains complementarity-determining regions from a mouse antibody (anti-p185) specific for the extracellular domain of the human epidermal growth factor receptor 2 protein (HER2), along with human framework sequences.
The HER2 receptor becomes constitutive instead of inducible in tumour cells. This is a result of increased cell surface expression/overexpression of HER2 protein caused by HER2 gene amplification. Overexpression is seen in 25% to 30% of primary breast cancers and in 6.8% to 42.6% gastric cancers.
Studies showed that amplification or overexpression of HER2 correlates with shorter disease-free survival.
Trastuzumab binds to sub-domain IV, a juxta-membrane region of HER2's extracellular domain, with high affinity and specificity. This binding inhibits ligand-independent HER2 signalling and prevents the proteolytic cleavage of its extracellular domain, an activation mechanism of HER2.
In in vitro assays and in animals, Trastuzumab is reported to have inhibited proliferation of human tumour cells overexpressing HER2. Trastuzumab also preferentially mediates antibody-dependent cell-mediated cytotoxicity (ADCC) on tumour cells overexpressing HER2.
Clinical Efficacy: The clinical efficacy of Zuhera plus docetaxel was assessed in a randomised, double-blind, comparative phase 3 study in patients with HER2-positive metastatic breast cancer (MBC) without prior chemotherapy. There were no relevant differences between Zuhera and trastuzumab with regard to overall response rate, clinical benefit rate and progression-free survival rate (at 24 weeks) in MBC.
As a part of global clinical development, the clinical efficacy of Trastuzumab of Biocon plus docetaxel/paclitaxel was assessed in a multicenter, double-blind, randomized, parallel-group, phase III study in MBC patients. There were no relevant differences between Trastuzumab of Biocon and trastuzumab (Herceptin) with regard to overall response rate, progression-free survival and overall survival at 48 weeks.
The following data for clinical efficacy in various patient populations treated with trastuzumab is summarized from publicly available information.
Clinical Trials For Herceptin: Metastatic Breast Cancer (MBC): The following regimens were evaluated in clinical studies with trastuzumab (Herceptin): Trastuzumab (Herceptin) monotherapy (in MBC patients with tumours overexpressing HER2 who had failed 1 chemotherapy regimens for metastatic disease).
First-line combination therapy: Trastuzumab (Herceptin) with paclitaxel (in MBC patients with tumours overexpressing HER2 who had previously received anthracycline-based adjuvant chemotherapy); Trastuzumab (Herceptin) with an anthracycline (doxorubicin or epirubicin) plus cyclophosphamide (AC; in MBC patients with tumours overexpressing HER2 who had never received an anthracycline); Trastuzumab (Herceptin) with docetaxel (in HER2-positive MBC patients); Trastuzumab (Herceptin) with anastrozole (in hormone-receptor-positive MBC patients with tumours overexpressing HER2).
The following results were obtained in trials conducted with trastuzumab: Trastuzumab (Herceptin) monotherapy (second- or third-line) produced an objective response rate of 15%, and a median duration of survival of 13 months; in women with MBC overexpressing HER2.
First-line combination therapy: Trastuzumab (Herceptin) and paclitaxel in women with HER2-overexpressing MBC tumours prolonged the median time to disease progression significantly (compared with paclitaxel alone); and increased the tumour response and one-year survival rate. There was an increase of 3.9 months in median time to disease progression relative to paclitaxel alone (6.9 months for combination treatment vs. 3.0 months); Trastuzumab (Herceptin) plus anthracycline plus cyclophosphamide prolonged median time to disease progression, compared to that in the patients treated with only an anthracycline and cyclophosphamide (7.8 months, versus 6.1 months; p<0.001); Trastuzumab (Herceptin) and docetaxel in HER2-positive MBC patients significantly increased overall response rate (61%, versus 34% for docetaxel alone); and prolonged median time to disease progression by 5.6 months; and median overall survival was significantly increased (31.2 months, versus 22.7 months for docetaxel alone); Trastuzumab (Herceptin) and anastrozole in HER2-overexpressing, hormone-receptor- (i.e., oestrogen-receptor and/or progesterone-receptor)-positive MBC patients. In the trastuzumab (Herceptin) plus anastrozole arm, progression-free survival was double; 4.8 months versus 2.4 months for anastrozole alone. In addition, partial response (20.3% versus 6.8%), clinical benefit rate (42.7% versus 27.9%), time to progression (4.8 months versus 2.4 months), and median overall survival (extended by 4.6 months in the combination arm) were also improved. Time to response and duration of response were not different for the groups. After disease progression 70% of the patients in the anastrozole-alone arm crossed over to a trastuzumab (Herceptin) -containing regimen. Though there was no statistically significant difference; 52% of trastuzumab (Herceptin) plus anastrozole patients survived for at least 2 years; versus 45% of the anastrozole-alone patients.
Early Breast Cancer (EBC): Neoadjuvant and adjuvant trastuzumab (Herceptin) were evaluated in patients with HER2-positive locally advanced or inflammatory breast cancer. In this phase 3, multicentre, open-label, randomized trial, patients were randomly assigned (1:1) to receive neoadjuvant trastuzumab (Herceptin) plus chemotherapy followed by adjuvant trastuzumab (Herceptin) for 1 year or the same neoadjuvant chemotherapy alone. 5-year event-free survival was achieved by more patients in the trastuzumab (Herceptin) plus chemotherapy group than the patients in the chemotherapy alone group (58% versus 43%; hazard ratio=0.64, 95% confidence interval [CI] 0.44-0.93; p=0.016).
A separate trial compared 2-year adjuvant trastuzumab (Herceptin) treatment with 1-year adjuvant trastuzumab (Herceptin) treatment in patients with HER2-positive early breast cancer. In this multicentre, randomised, open-label, phase 3 trial, patients were randomly assigned (1:1:1) to three groups: 2-year trastuzumab (Herceptin), 1-year trastuzumab (Herceptin) and observation. Patients received trastuzumab (Herceptin) following surgery and adjuvant and/or neoadjuvant chemotherapy, with or without radiation therapy. There was no significant difference in the primary endpoint, disease-free survival, between 1-year and 2-year trastuzumab (Herceptin) groups (hazard ratio=0.99, 95% CI 0.85-1.14; p=0.86). Despite crossover of 52% patients from the observation group to trastuzumab (Herceptin) therapy, 1-year trastuzumab (Herceptin) treatment was more beneficial than the observation group with respect to disease-free survival (hazard ratio=0.76, 95% CI 0.67-0.86, p<0.0001) and overall survival (hazard ratio=0.76, 95% CI 0.65-0.88; p=0.0005).
Long-term implications of adjuvant trastuzumab (Herceptin) treatment in patients with HER2-positive invasive breast cancer were evaluated in a joint analysis of two phase 3, randomised trials. In both trials, patients were randomly assigned to doxorubicin plus cyclophosphamide followed by paclitaxel with or without trastuzumab (Herceptin). At a median follow-up of 3.9 years, there was more statistically significant reduction in disease-free survival event rate in the trastuzumab (Herceptin) group compared to the control group (p<0.001).
A randomized, multicentre, phase 3 study assessed the efficacy and safety of a new non-anthracycline regimen with trastuzumab (Herceptin) in patients with HER2-positive early breast cancer. Patients were randomly assigned to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (Herceptin) (AC-T plus trastuzumab (Herceptin)) or docetaxel and carboplatin plus 52 weeks of trastuzumab (Herceptin) (TCH). The estimated disease-free survival rate at 5 years was better in the trastuzumab (Herceptin) groups (84% in AC-T plus trastuzumab (Herceptin), 81% in TCH) compared to the AC-T group (75%).
The rates of congestive heart failure (CHF) and cardiac dysfunction were significantly higher in the AC-T plus trastuzumab (Herceptin) group than in the TCH group (CHF, 2.0% vs. 0.4% for the two groups, respectively; >10% relative loss of left ventricular ejection fraction (LVEF), 18.6% vs. 9.4%; both comparisons, p<0.001).
Metastatic Gastric Cancer: A randomised, open-label, multicentre, phase 3 study assessed the effect of first-line trastuzumab (Herceptin) in combination with chemotherapy (fluoropyrimidine and cisplatin) versus chemotherapy alone in patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. Patients were randomly assigned (1:1) to receive trastuzumab (Herceptin) in combination with chemotherapy (capecitabine or 5-fluorouracil [5-FU] plus cisplatin) or chemotherapy alone. The median overall survival, the primary endpoint, was longer in the trastuzumab (Herceptin) plus chemotherapy group compared to the chemotherapy alone group (13.8 [95% CI: 12-16] versus 11.1 months [95% CI: 10-13]; hazard ratio=0.74, 95% CI 0.60-0.91; p=0.0046). Rates of overall grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 [6%]) did not differ between groups.
Immunogenicity: Out of 903 patients that were evaluated, 1 patient was reported to have developed detectable anti trastuzumab (Herceptin) antibodies; but had no allergic symptoms.
Pharmacokinetics: A randomised, double-blind, parallel-group, comparative clinical study in patients with HER2-positive metastatic breast cancer showed that the pharmacokinetic profile of Zuhera was similar to that of Trastuzumab after single- and multi-dose intravenous infusions.
As a part of global clinical development, two phase 1 studies 1) Single-center, single-dose, 2-period, randomized, double-blind, cross-over study and 2) Single-center, randomized, double-blind, three-arm, parallel-group study were conducted in normal healthy volunteers. Both studies showed that pharmacokinetic profile of Trastuzumab of Biocon was similar to that of Trastuzumab (Herceptin). In addition, a multicenter, double-blind, randomized, parallel-group, phase III study showed that pharmacokinetic, efficacy, safety and immunogenicity profiles of Trastuzumab of Biocon was similar to Trastuzumab (Herceptin) in patients with HER2-positive metastatic breast cancer (MBC).
The following data for pharmacokinetics in various patient populations treated with Trastuzumab is summarized from publicly available information.
Breast Cancer: Clinical Trials for Herceptin: A population pharmacokinetics method was used to model steady-state pharmacokinetics in metastatic breast cancer patients (given 4 mg/kg Trastuzumab [loading], followed by 2 mg/kg weekly [maintenance]); in phase 1, phase 2 and pivotal phase 3 clinical trials. Table 1 shows steady-state values. (See Table 1.)

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Patients with early breast cancer were administered an initial loading dose of 8 mg/kg followed by a three weekly maintenance dose of 6 mg/kg for 1 year. The steady state mean maximum concentration (C_max) was 225 μg/mL and mean minimum concentration (C_min) was 68.9 μg/mL at day 21 of cycle 18, the last cycle of treatment for 1 year of treatment.
The pharmacokinetics do not appear to be affected by concomitant anthracycline/cyclophosphamide or paclitaxel chemotherapy, or concomitant anastrozole.
Metastatic Gastric Cancer: Clinical Trials for Herceptin: A two compartment nonlinear population pharmacokinetic model was used to estimate the steady state pharmacokinetics in advanced gastric cancer patients (given 8 mg/kg trastuzumab [loading], followed by 6 mg/kg 3-weekly [maintenance]); in a phase 3 trial. At very low serum concentrations (below 10 μg/mL), non-linear clearance is 7-fold higher than linear clearance. At high serum concentrations, linear clearance dominates and the half-life is approximately 26 days. The mean predicted steady-state area under the concentration-time curve (AUC), over a period of 3 weeks at steady state, is approximately 1213 mg day/L, and the median steady-state C_max and C_min are approximately 132 mg/L and 27.6 mg/L, respectively.
Pharmacokinetics in Special Populations: Clinical Trials for Herceptin: The pharmacokinetics of trastuzumab have not been studied specifically in elderly patients, patients with renal impairment, or patients with hepatic impairment. However, in the trials conducted with trastuzumab, distribution and elimination were not noted to be affected by age and renal impairment (see Dosage & Administration).
Toxicology: Preclinical Safety Data: Nonclinical studies (conventional toxicity studies) on Zuhera did not indicate any special hazard for humans. During conventional single- and repeat-dose toxicity studies of Zuhera in mice and rabbits, no clinically relevant adverse events were observed at the highest dose levels tested. Local tolerance was also evaluated in these toxicity studies, and no clinically relevant effects were observed.
As a part of global nonclinical development, nonclinical studies (conventional toxicity studies) on Trastuzumab of Biocon did not indicate any special hazard for humans. During conventional single- and repeat-dose toxicity studies of Trastuzumab of Biocon in mice and rabbits, no clinically relevant adverse events were observed at the highest dose levels tested. Local tolerance was also evaluated in these toxicity studies, and no clinically relevant effects were observed. Two comparative nonclinical studies undertaken in cynomolgus monkeys showed that the pharmacokinetic and toxicokinetic profile of Trastuzumab of Biocon was similar to that of trastuzumab (Herceptin).