In Extension Study, Patients Exposed to ADCC-Shifted Lots of Reference Trastuzumab Had Lower EFS Rate

When Samsung Bioepis’ trastuzumab biosimilar, SB3 (Ontruzant), gained regulatory approval in multiple highly regulated markets, it did so on the strength of a data package including evidence from a phase 3 study in patients with HER2-positive early breast cancer. Later, it became apparent that some of the patients who received the reference product in the phase 3 study had been exposed to lots of Herceptin with a marked shift in relative antibody-dependent cell-mediated cytotoxicity (ADCC) activity.
Kelly Davio
August 22, 2019
When Samsung Bioepis’ trastuzumab biosimilar, SB3 (Ontruzant), gained regulatory approval in multiple highly regulated markets, it did so on the strength of a data package including evidence from a phase 3 study in patients with HER2-positive early breast cancer.

In the study, in which patients received either the biosimilar or the reference Herceptin, the prespecified equivalence margin, in terms of in terms of breast pathologic complete response (bpCR) rate, was plus or minus 13% (95% CI of the difference). The adjusted difference was 10.70% (95% CI, 4.13%-17.26%), with the lower margin contained within and the upper margin outside of the predefined equivalence margin.1 A similar trend was observed in total pathologic complete response rate.

Later, it became apparent that some of the patients who received the reference product in the phase 3 study had been exposed to lots of Herceptin—with expiry dates from August 2018 to December 2019—that had been subject to a significant product shift. During development of the biosimilar, Samsung Bioepis’ researchers found that there were 2 marked changes that impacted N-glycan profile, FcγRIIIa binding activity, and relative antibody-dependent cell-mediated cytotoxicity (ADCC) activity.2

Recently, data were presented at the American Society of Clinical Oncology Annual Meeting 2019 that analyzed survival of patients by their treatment’s ADCC status. The researchers in this study found that patients treated with the impacted lots of Herceptin had significantly lower event-free survival (EFS) than those who were not exposed.3

Now, researchers are reporting 3-year findings from a long-term extension of the main phase 3 study that investigated cardiac safety and efficacy of the biosimilar versus the reference. According to the study, while cardiotoxicity was rare, EFS was higher with the biosimilar than with the affected lots of the reference, suggesting once again that reduced ADCC activity was a contributing factor.4  

In the ongoing extension, in which 186 patients in the biosimilar arm and 181 patients in the reference arm were enrolled, the primary outcome was the incidence of symptomatic congestive heart failure and the incidence of an asymptomatic significant left ventricular ejection fraction (LVEF) decrease. EFS and overall survival (OS) were secondary outcomes.

The researchers found no reports of symptomatic congestive heart failure in either arm. Three asymptomatic significant LVEF decreases were reported, with 1 in the biosimilar arm and 2 in the reference arm. No other cardiac-related events, including cardiac death, were reported.

In terms of efficacy, the 3-year EFS rate was 91.9% versus 85.2% in the reference arm. The 3-year OS rate was 97.0% in the biosimilar arm and 92.9% in the reference arm. Cox proportional hazards regression models with backward elimination showed that ADCC activity and bpCR were associated with EFS at the 0.1 significance level.

In total, 55 patients were exposed to the affected lots of the reference, and 126 were treated with the reference and were not exposed, during the neoadjuvant period. The percentage of patients with events was significantly higher among the exposed patients (20.6%) than among the unexposed reference-treated patients (9.1%).

Three-year EFS was 81.7% in the exposed group and 92.7% in the unexposed group (meanwhile, there was no significant difference in EFS between the biosimilar group and the unexposed reference group).

A higher percentage of deaths was observed in the exposed group (9.5%) versus the unexposed group (1.8%); the 3-year OS rate was 89.4% in the exposed group versus 100% in the unexposed group (OS was comparable between the biosimilar group and the unexposed reference group).

Trends similar to those shown in the neoadjuvant setting were observed during the entire treatment period.

The authors write that “This report is limited in that it does not have sufficient power to test the hypothesis of a relationship between ADCC activity and EFS,” but conclude that their data support a relationship between ADCC activity and clinical outcomes.

References
1. Pivot X, Bondarenko I, Nowecki Z, et al. Phase III, randomized, double-blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients with neoadjuvant therapy for human epidermal growth factor receptor 2–positive early breast cancer. J Clin Oncol. 2018;36(1):968-974. doi: 10.1200/JCO.2017.74.0126.

2. Lee JH, Paek K, Moon JH, Ham S, Song J, Kim S. Biological characterization of SB3, a trastuzumab biosimilar, and the influence of changes in reference product characteristics on the similarity assessment [published online June 12, 2019]. BioDrugs. doi: 0.1007/s40259-019-00362-5.

3. Pivot X, Pegram MD, Cortes J, et al. Evaluation of survival by ADCC status: Subgroup analysis of SB3 (Trastuzumab Biosimilar) and reference trastuzumab in patients with HER2-positive early breast cancer at three-year follow-up. Presented at: American Society of Clinical Oncology Annual Meeting 2019; May 31-June 4, 2019; Chicago, IL. Abstract 580.

4. Pivot X, Pegram M, Cortes J, et al. Three-year follow-up from a phase 3 study of SB3 (a trastuzumab biosimilar) versus reference trastuzumab in the neoadjuvant setting for human epidermal growth factor receptor 2–positive breast cancer. Eur J Cancer. 2019;120:1-9. doi: 10.1016/j.ejca.2019.07.015.

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