Summary Basis of Decision for Kanjinti

 

The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in support of the indications being sought, and therefore clinical trials are not required to support each indication.

For biosimilars, the purpose of the clinical program is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The degree of similarity at the quality level determines the scope and the breadth of the required clinical data. The clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.

Comparative Pharmacokinetic Studies

Trastuzumab, the medicinal ingredient in Kanjinti and Herceptin, is a humanized recombinant immunoglobulin G1 (IgG1) antibody directed against the human epidermal growth factor receptor 2 (HER2). The HER2 protein, which promotes cell growth, is overexpressed in approximately 25%‑30% of cases of primary breast cancer. The binding of trastuzumab to HER2 inhibits ligand‑independent HER2 signalling, which in turn inhibits the proliferation of cells overexpressing HER2. Additionally, trastuzumab is a potent mediator of antibody‑dependent cell‑mediated cytotoxicity (ADCC).

The comparative pharmacokinetics of Kanjinti and Herceptin were assessed primarily in Study 20130119. Supportive pharmacokinetic data were also obtained through Study 20120283, the comparative clinical efficacy and safety study.

Study 20130119 compared the pharmacokinetics of Kanjinti, Herceptin authorized in the European Union (EU‑sourced Herceptin; the official reference biologic drug), and Herceptin authorized in the United States (US‑sourced Herceptin). This study was conducted in 157 healthy male subjects, who were randomized to receive a 6 mg/kg intravenous infusion of one of the three investigational drugs. The ratios of Test/Reference with respect to exposure and peak concentration were fully contained within prespecified margins, indicating pharmacokinetic similarity between Kanjinti, EU‑sourced Herceptin, and US‑sourced Herceptin. Treatment‑emergent adverse events were reported in 84.0%, 75.0%, and 78.2% of subjects in the Kanjinti, US‑sourced Herceptin, and EU‑sourced Herceptin treatment groups, respectively. No new safety signals were observed in subjects who received Kanjinti.

The design and outcomes of Study 20120283 are described in detail in the Comparative Clinical Efficacy and Safety section. Serum samples were collected from all randomized patients prior to each dose of their assigned investigational drug (pre‑dose or trough samples), and post‑infusion serum samples were collected from a subset of patients. The geometric mean trough serum concentrations increased with each subsequent visit in each treatment group in the neoadjuvant phase, and concentrations were consistent between groups during the treatment period.

For further details, please refer to the Kanjinti Product Monograph, approved by Health Canada and available through the Drug Product Database.

Comparative Clinical Efficacy and Safety

The comparative Phase III study 20120283 demonstrated that there are no clinically meaningful differences between Kanjinti and Herceptin, with respect to clinical efficacy and safety. Herceptin sourced from the European Union was the official reference biologic drug used in this study, and is hereafter referred to as Herceptin. Several major issues were identified during the review of this study, resulting in the issuance of a Notice of Non‑Compliance (NON) for this submission. The sponsor filed a response to the NON (R/NON), which was considered satisfactory. A Notice of Compliance (NOC) was subsequently issued for Kanjinti.

Study 20120283 was a randomized, multicentre, double‑blind, and active‑controlled trial, conducted in 725 female patients with HER2‑positive early breast cancer. The study included a run‑in chemotherapy phase, a neoadjuvant phase, and an adjuvant phase.

In the run‑in chemotherapy phase, patients were treated with epirubicin and cyclophosphamide every three weeks, for four cycles of treatment.

In the neoadjuvant phase, patients were randomized to receive either Kanjinti (number of patients [n] = 364) or Herceptin (n = 361), at a loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg, along with 175 mg/m² paclitaxel every three weeks, for four cycles of treatment. An alternative dosage regimen for paclitaxel, 80 mg/m2 administered once weekly for 12 cycles of treatment, was permitted in regions where it is the local standard of care. Surgery (lumpectomy or mastectomy with sentinel lymph node dissection or axillary lymph node dissection) was completed three to seven weeks after administration of the last dose of the investigational product in the neoadjuvant phase.

In the adjuvant phase, patients received a 6 mg/kg dose of their assigned investigational drug every three weeks, for up to one year from the first day of study drug administration in the neoadjuvant phase.

The co‑primary efficacy endpoints of this study were the risk difference and risk ratio of the pathologic complete response (pCR) in breast tissue and axillary lymph nodes sampled during surgery. The pCR was defined as the absence of invasive tumour cells in the breast tissue and in axillary lymph nodes, regardless of residual ductal carcinoma in situ.

The primary efficacy analysis was based on the pCR assessed by local laboratories in the pCR evaluable population (358 patients treated with Kanjinti and 338 with Herceptin). This population was defined as all randomized patients who had received any amount of investigational product, had undergone surgery, and had a non‑missing evaluable pCR assessment from the local laboratory.

Statistical equivalence was tested first on the risk difference of the pCR between Kanjinti and Herceptin. If the results of this test fell within a predefined margin, indicating equivalence, then the equivalence of the risk ratio of the pCR was to be tested between Kanjinti and Herceptin.

The pCR rates were 48% for Kanjinti and 40.5% for Herceptin. The risk difference of the pCR was 7.3% (90% confidence interval [CI]: 1.2%, 13.4%). Based on the results of this primary analysis, the upper bound of the 90% CI (13.4%) did not fall within the prespecified equivalence margin of ‑13% to 13%. Therefore, equivalence between Kanjinti and Herceptin was not demonstrated. This finding and other uncertainties resulting from this study contributed to the issuance of a NON.

In the R/NON, the sponsor demonstrated that this initial result was unlikely due to issues specific to Kanjinti. A sensitivity analysis was conducted to address the issues identified with the primary analysis, and was based on pCR assessed by a central laboratory on the intent‑to‑treat (ITT) population. These results have shown that the 95% CI of the risk difference of the pCR was fully contained within the prespecified margins, which demonstrates equivalence. Additionally, the antibody‑dependent cell‑mediated cytotoxicity (ADCC) activity of Herceptin drifts over time, and has been documented in scientific literature. This drift might have contributed to the failure of the risk difference of the pCR to meet the prespecified upper bound of the equivalence margins in the primary analysis. The concerns which led to the issuance of the NON have been appropriately addressed and are considered resolved.

The safety analysis population for the neoadjuvant phase included all patients who received any amount of either Kanjinti (n = 364) or Herceptin (n = 361). In the adjuvant phase, the safety analysis population was focused on two treatment arms: patients who received Kanjinti (n = 349) and patients who received Herceptin (n = 171) through both the neoadjuvant and adjuvant phases.

In general, the exposure to Kanjinti and Herceptin was similar between the treatment arms in both phases, as was the exposure to the chemotherapeutic agent paclitaxel in the neoadjuvant phase.

In the neoadjuvant phase, comparable values were observed in the Kanjinti and Herceptin treatment arms with respect to the incidence of treatment‑emergent adverse events (TEAEs; 80.2% and 79.5% for the Kanjinti and Herceptin, respectively), Grade 3 or higher adverse events (14.8% and 14.1%), and adverse events leading to discontinuation (0.8% and 0.6%). The most frequently observed adverse events, each with an incidence of 5% or higher, were arthralgia, asthenia, neutropenia, peripheral neuropathy, anemia, myalgia, peripheral sensory neuropathy, diarrhea, leukopenia, nausea, alopecia, paresthesia, and bone pain. Treatment‑emergent events of interest were more common in patients treated with Kanjinti than with Herceptin (43.1% and 40.7%, respectively). These included cardiac failure, febrile neutropenia, infusion‑related reactions, and infections and infestations.

In the adjuvant phase, higher incidences of TEAEs, treatment‑emergent events of interest, and adverse events leading to discontinuation were observed in patients treated with Kanjinti than in those treated with Herceptin. Grade 3 or higher adverse events were also more common in patients who received Kanjinti in the neoadjuvant and adjuvant phases (7.7%) than in patients who received Herceptin in both phases (5.8%). After adjustments for exposure, incidence rates of most adverse events, falling under several system organ classes, remained higher in patients treated with Kanjinti than in those treated with Herceptin. However, the detailed analysis of the incidences of adverse events of interest (AEOI) of Grade 3 or higher is considered the most relevant and informative safety information. It indicated that there were no clinically meaningful differences, and no new safety signals were detected from the study. Furthermore, among the patients who received Herceptin with low ADCC activities, the incidence of adverse events is slightly lower. This might have contributed to the relative higher incidence of some adverse events reported for patients treated with Kanjinti.

As with Herceptin, the major identified safety concerns identified for Kanjinti include the risk of medication error (possible confusion with trastuzumab emtansine), cardiotoxicity, infusion reactions, pulmonary toxicity, and embryo‑fetal toxicity. These issues have been addressed in the Serious Warnings and Precautions box of the Product Monograph for Kanjinti, as is found in the Product Monograph for Herceptin.

The patient population in the comparative efficacy and safety study does not correspond to an indication authorized in Canada for trastuzumab, the medicinal ingredient in Kanjinti and Herceptin. In the context of a clinical trial, the patient population (patients with early breast cancer in the neoadjuvant setting) is recognized as a sensitive model for demonstrating comparative efficacy and safety. To avoid implying that Kanjinti is indicated for use in the neoadjuvant setting, the following statement was added to the Product Monograph: "The treatment of early breast cancer patients with trastuzumab in the neoadjuvant setting is a model for assessing comparative clinical safety and efficacy; however, it is not an authorized indication in Canada."

Upon review of the R/NON, the safety profile of Kanjinti is considered to be comparable to that which has been established for the reference biologic drug, Herceptin. The identified safety concerns are addressed in the Serious Warnings and Precautions Box and the Warnings and Precautions section of the Product Monograph for Kanjinti, as they are in the Product Monograph for Herceptin.

For more information, refer to the Kanjinti Product Monograph, approved by Health Canada and available through the Drug Product Database.

Comparative Immunogenicity

Treatment with any therapeutic protein is naturally accompanied by the risk of immunogenicity (the development of anti‑drug antibodies [ADAs]). The immunogenicity of Kanjinti was compared to that of Herceptin in Study 20120283. In the neoadjuvant setting, ADAs were detected in 0.6% of patients in the Kanjinti treatment arm and 1.4% of patients in the Herceptin treatment arm, regardless of baseline levels. In the adjuvant setting, ADAs were detected in <1% of patients who received Kanjinti in both the neoadjuvant and adjuvant phases, and in 1.2% of patients who received Herceptin in both the neoadjuvant and adjuvant phases, regardless of baseline levels. Neutralizing antibodies were not detected in patients positive for ADAs. In Study 20130119, the comparative pharmacokinetics study, the results of the assessment for ADA binding at pre‑dose and end of study time points were negative in all subjects.

Indications

Kanjinti is considered to be biosimilar to Herceptin, the reference biologic drug, which is authorized and marketed in Canada for several indications and clinical uses. The specific diseases for which Herceptin is authorized are early breast cancer, metastatic breast cancer, and metastatic gastric cancer.

Within this drug submission, the sponsor requested the authorization of Kanjinti for all but one of the indications that are currently authorized for Herceptin. The indication of Herceptin in combination with Perjeta (pertuzumab) and docetaxel, for untreated HER2‑positive metastatic breast cancer was not requested in the submission filed for Kanjinti.

Similarity between Kanjinti and Herceptin was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug, and therefore clinical trials are not required to support each indication.

The indications have been authorized based on demonstrated similarity between Kanjinti and Herceptin in structural and functional, non‑clinical and clinical studies. In addition, a scientific rationale taking into consideration the mechanism of action, pharmacological effect, pathophysiological mechanisms of the diseases involved, safety profile, dosage regimen, and clinical experience with the reference biologic drug Herceptin, was provided and was considered in line with Health Canada's biosimilar guidance document.