Long-term Phase 3 Results Show Similar Efficacy, Cardiac Safety of SB3 vs Herceptin

The authors of what they say is the largest and longest follow-up study comparing the trastuzumab biosimilar SB3 to the reference product (Herceptin) in HER2-positive breast cancer found “no clinically meaningful difference” between the biosimilar and the reference product.

Trastuzumab is a monoclonal antibody to human epidermal growth factor receptor 2 (HER2) approved by the FDA in 1998. According to the investigators, trastuzumab is the standard of care of patients with HER2-positive breast cancer and HER2-positive advanced gastric cancer “due to its effectiveness and favorable toxicity profile.” However, routine cardiac monitoring is recommended for patients taking trastuzumab, since there is concern about increased risk of cardiac events.

The investigators presented their secondary analysis on efficacy and cardiac safety of a phase 3 equivalence trial that randomized patients with HER2-positive early and locally advanced breast cancer to SB3 or the reference product along with chemotherapy. The original findings from the trial demonstrated equivalent efficacy of SB3 to reference trastuzumab based on the risk ratio of breast pathological complete response (bpCR) rates.

The prespecified secondary analysis aimed to determine whether trastuzumab SB3 had long-term cardiac safety and efficacy comparable to those of the originator after 6 years of follow-up. The primary outcomes were symptomatic congestive heart failure and decreases in left ventricular ejection fraction (LVEF), and secondary outcomes were event-free survival (EFS) and overall survival (OS).

A subset of patients (n = 367; n = 186 treated with the biosimilar; n = 181 with the reference product) from the original trial participated in the treatment-free follow-up portion of the study. The median follow-up duration was 68 months (range, 8.5-78.1 months).

Overall cardiac safety profile of SB3 comparable to that of reference trastuzumab

Median LVEF at baseline was 65% (range, 55%-76%) in patients receiving SB3 and 65% (range, 55%-85%) in patients receiving the reference product, and LVEF changes were “comparable” between groups, the authors said. Clinically significant decreases in LVEF occurred in one patient (0.4%) in the SB3 group and 2 patients (0.7%) in the originator group, all within 2 years of the first trastuzumab administration. No incidences of symptomatic congestive heart failure were reported in either group.

No significant differences in event-free or overall survival between groups

Survival outcomes were investigated in 538 participants, the 367 from the cardiac safety analysis plus an additional 171 patients who were enrolled in the follow-up study after a protocol amendment. Event-free survival (EFS) was comparable between groups, with 54 (20%) patients in the biosimilar group and 67 (25%) patients in the reference product group experiencing events during the follow-up period. Five-year EFS and overall survival (OS) rates were 80% and 93% in the SB3 group and 75% and 85% in the trastuzumab group.

Effect of drift in reference product on survival outcomes

In the original trial, the upper limit of the 95% CI of the difference in risk of bpCR exceeded the upper limit of the predefined equivalence margin. According to the authors, this difference could have been due to the fact that some patients received reference trastuzumab with downward drift in antibody-dependent cell-mediated cytotoxic (ADCC) activity during part of the trial period.

The authors noted that the numerical differences they observed in the follow-up study in 5-year EFS and OS rates were smaller when comparing the biosimilar SB3 to the nondrifted reference product subgroup than the entire reference product group. Also, the drifted reference product subgroup had an increased risk of events compared to the non-drifted reference product group.

Limitations of the study the investigators noted included a lack of racial diversity in patients, premature discontinuation of the study due to COVID-19, unbalanced numbers of patients in drifted and non-drifted groups, and that the survival analyses were not statistically powered.

Reference

Pivot X, Cortés J, Lüftner D, et al. Cardiac safety and efficacy of SB3 trastuzumab biosimilar for ERBB2-positive early breast cancer: secondary analysis of a randomized clinical trial. JAMA Netw Open. 2023;6(4):e235822. doi:10.1001/jamanetworkopen.2023.5822