Batch Variation in Trastuzumab Study Affects Outcomes

June 8, 2020
Tony Hagen

Tony Hagen is senior managing editor for The Center for Biosimilars®.

Downward “drift” in batches of reference trastuzumab shed more light on the importance of antibody-dependent cell-mediated cytotoxicity on survival, investigators reported at ASCO20 Virtual, the annual meeting of the American Society of Clinical Oncology.

An extension study of a trastuzumab biosimilar (SB3, Ontruzant) versus reference trastuzumab (TRZ) supports a hypothesis that a downward "drift" in antibody-dependent cell-mediated cytotoxicity (ADCC) contributed to lower event-free survival (EFS) and overall survival (OS), according to data presented at ASCO20 Virtual, the annual meeting of the American Society of Clinical Oncology.

The study, an extension of a phase 3 trial, assessed long-term cardiac safety and efficacy in patients with HER2-positive early or locally advanced breast cancer treated with biosimilar or TRZ.

Significance of ADCC

Of 25 TRZ product lots used in the original study (N = 875), 13 were classified as having a drift in ADCC activity, and the remainder were considered to have ADCC activity in the normal range. Investigators in this study had previously observed that ADCC appears to correlate with EFS.

“ADCC is thought to be an important contributor to the efficacy of trastuzumab, and amplification of ADCC activity could be a promising area of research,” the investigators noted in the October 2019 report.

In the extension study, 367 patients were enrolled from the main study after completing neoadjuvant-adjuvant therapy, 187 on the SB3 arm and 181 on 1 of 2 reference product arms: nondrifted TRZ (n = 55) and drifted TRZ (n = 126).

The investigators reported that the incidence of asymptomatic significant left ventricular ejection fraction (LVEF) decrease was comparable between the biosimilar and TRZ groups. “All of the patients recovered with LVEF above 50%.” There were no instances of congestive heart failure, cardiac death, or other significant cardiac conditions during the follow-up.

Further, there was no statistically significant difference in EFS or OS between SB3 and TRZ. The 4-year EFS rates for SB3 and TRZ were 83.4% and 80.7% (HR, 0.77; 95% CI, 0.47-1.27), respectively; and the 4-year OS rates were 94.4% and 89.6% (HR, 0.53; 95% CI, 0.24-1.16).

Drift Divergence

With regard to EFS between SB3 and nondrifted TRZ, an ad-hoc analysis revealed no difference (HR, 1.60; 95% CI, 0.58-4.40; P = .362). There also was no difference in OS between SB3 and nondrafted TRZ (HR, 0.97; 95% CI, 0.11-8.50; P = .975).

However, between drifted TRZ and nondrifted TRZ, differences were observed for EFS (HR, 5.50; 95% CI, 1.81-16.65; P = .003) and OS (HR, 15.35; 95% CI, 1.78-132.69; P = .013).

The Investigators concluded that “comparable long-term cardiac safety and survival at the 4-year follow-up supports biosimilarity between SB3 and TRZ,” but “ad-hoc analysis results by ADCC status suggest a possible correlation between ADCC and clinical efficacy,” meriting further study.

For further biosimilars coverage of ASCO20 Virtual, click here.

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