Similar Effectiveness, Safety of Biosimilar CT-P6 vs Reference Trastuzumab in Retrospective Study

An analysis of retrospective data demonstrated comparable safety and efficacy profiles between CT-P6, a trastuzumab biosimilar, and Herceptin (reference trastuzumab) combined with chemotherapy and pertuzumab.

A retrospective study, published in The Breast, compared the trastuzumab biosimilar CT-P6 to the reference product (Herceptin) in 44 patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer who received trastuzumab therapy alongside chemotherapy and pertuzumab. Similar effectiveness and safety measures were observed in the biosimilar and reference product groups.

In HER2-positive breast cancers, overexpression of the HER2 protein results in an aggressive cancer. The authors wrote that HER2-positive breast cancers “had a poor prognosis until the development and introduction of targeted therapies,” the first of which was trastuzumab.

Trastuzumab is a monoclonal antibody to HER2 that inhibits ligand-independent HER2 signaling. Pertuzumab, another monoclonal antibody to HER2 with a complementary mechanism of action, is often combined with trastuzumab therapy in early HER2-positive breast cancer to “provide a dual blockade of HER2-driven signaling.”

“Scarce” data on the combination of CT-P6 and chemotherapy

CT-P6 is a biosimilar trastuzumab approved by both the European Medicines Agency (EMA) and the FDA for the treatment of HER2-positive early and advanced breast cancer. The investigators aimed to compare CT-P6 to the reference product in combination with pertuzumab, since the clinical trial that established biosimilarity did not combine trastuzumab and pertuzumab, and because “scarce preclinical and clinical data exists about the combination of CT-P6, pertuzumab and chemotherapy.”

The retrospective study was carried out at a single center, where patients with HER2-positive early breast cancer were treated with chemotherapy, pertuzumab, and trastuzumab, either CT-P6 (n = 20) or the reference product (n = 24). The patients were treated just before and just after the approval of the biosimilar, between 2017 and 2020.

Most patients (95.5%) were treated with 4 cycles of doxorubicin plus cyclophosphamide followed by 12 weekly administrations of paclitaxel or nab-paclitaxel with concomitant pertuzumab plus trastuzumab prior to surgery. Two patients, 1 in each group, were treated without anthracyclines.

Response to therapy, safety, and cost

Baseline characteristics were similar between groups, except for age. Patients in the CT-P6 group were younger on average (mean [SD], 48 [4.9] years) than those in the reference group (mean [SD], 60 [11.2] years).

Clinical complete response and pathological complete response rates were similar between groups: 55% and 65% of patients in the biosimilar group achieved a clinical complete response and pathological complete response, compared to 66.7% and 66.7% in the reference product group.

Adverse events were similar between groups. There were no interruptions in treatment.One patient in each group experienced an infusion-related reaction. In 3 cases, 2 in the biosimilar group and 1 in the reference group, grade 3 toxicity related to diarrhea was observed.The dose of paclitaxel, but not trastuzumab or pertuzumab, was reduced in these patients. Left ventricular ejection fraction values were not significantly different between groups at baseline, after cycle 4, or at the end of the neoadjuvant period, suggesting no differences in cardiotoxicity.

The authors reported a reduced treatment cost of €1474 ($1582) per patient for those treated with CT-P6.

Biosimilar CT-P6 and reference trastuzumab “share mechanisms of action” in vitro

In HER2-positive breast cancer, constitutive activation of HER2 drives excessive activation of the mitogen-activated protein kinase and phosphoinositide 3-kinase pathways, thus promoting tumor cell proliferation and survival. The investigators complemented their retrospective study with experiments in 2 HER2-positive breast cancer cell lines.

In the 2 HER2+ cell lines, similar inhibition of proliferation was observed following treatment with either CT-P6 or reference trastuzumab. The combination of the biosimilar or reference product with pertuzumab resulted in a greater inhibition of cell proliferation.

In both HER2+ cell lines, high basal phosphorylation of HER2 and its downstream effectors AKT and ERK1/2 was observed. Both trastuzumab products inhibited phosphorylation of HER2, AKT and ERK1/2 “to a similar degree” when administered alone, according to the investigators. Similar to the cell proliferation results, a stronger reduction in phosphorylation was observed when each trastuzumab product was combined with pertuzumab.

The authors noted an unexpected result, which was a reduction in total HER2 levels following treatment with the biosimilar or reference product alone or combined with pertuzumab. They said this finding suggests “an alternative mechanism of action based on irreversibly binding of anti-HER2 antibodies to the receptor eventually causing its degradation.”

“To mimic the standard of care of neoadjuvant treatment,” the authors treated the HER2+ cells with either the biosimilar or reference product plus pertuzumab and paclitaxel. Similar synergistic effects inhibiting proliferation were observed for CT-P6 and reference trastuzumab.The results of the in vitro experiments, the authors wrote, “are in agreement with those found in the retrospective clinical study.”

The researchers concluded that CT-P6 and reference trastuzumab were similar in effectiveness and safety in the retrospective cohort and that CT-P6 reduced the cost of treatment. Their study, they wrote, is “one of the few real-world studies” showing CT-P6 and the reference product have similar effectiveness and safety profiles when combined with pertuzumab. They added that their in vitro study demonstrated that the biosimilar and reference product “share mechanisms of action consisting of blocking cell proliferation and colony formation through the inhibition of HER2-mediated AKT and ERK1/2, as single agents and in combination with pertuzumab.”


Bernat-Peguera A, Trigueros M, Ferrando-Díez A, et al. Efficacy of CT-P6 (trastuzumab biosimilar) versus reference trastuzumab in combination with pertuzumab in HER2-positive early-stage breast cancer: Preclinical and real-life clinical data. Breast. 2022;62:1-9. doi:10.1016/j.breast.2022.01.007