Furthermore, the 3-year overall survival (OS) rate was 89.4% among patients who received drifted trastuzumab and 100% among patients who received non-drifted trastuzumab — a difference that theoretically could be associated with a higher likelihood of death for those who were in the drifted product cohort — but the difference lacked significance (HR, 7.96; 95% CI, 0.95-67.00).The EFS and OS rates were not significantly different between patients who received SB3 and patients who received non-drifted trastuzumab.5
The extension study also revealed that ADCC status was significantly associated with EFS (HR, 2.62; 95% CI, 1.46–4.49; P =.0012), suggesting that the trastuzumab drift may have indirectly impacted EFS.5
A coauthor on the extension study, Dr Lyman, said the reason “everyone” is not “all over” these findings is the fact that this was a retrospective subset analysis; these types of studies (and any conclusions drawn from them) are subject to a higher risk of bias than some other studies that use a more controlled design.
The phase 3 trial initially concluded with 380 patients in the biosimilar group and 384 in the reference trastuzumab group, but only about half agreed to participate in the extension study: 186 in the biosimilar group and 181 in the reference trastuzumab group.5
As a result, Dr Rugo said, “You can’t say definitively that [that] shift in trastuzumab results in a difference in EFS.” Dr Lyman expressed a similar view, adding that it’s unknown whether any patient was harmed as a result of being administered medications from the drifted lots.
The FDA declined to comment on the extension study, saying that the agency does not generally comment on “third-party” studies.
A Genentech spokesperson told Cancer Therapy Advisor that when the “glycan shift” was first identified, Genentech “proactively alerted health authorities” and the investigations conducted by the health authorities concluded that “the new data [do] not provide evidence that indicates a clinically relevant impact on patient outcomes.”
Although the drifted trastuzumab appears to have been restored, Dr Lyman views this event as a “wake-up call” to industry, regulators, clinicians, and patients that these stakeholders can’t let their guard down. He added, “We need to keep a very close eye on these products over time.”
Given the low likelihood that these findings will be confirmed in another study, Dr Rugo stressed that there should be “continuous” analytic evaluations of trastuzumab products to make sure that they align with the expected standards. In fact, in light of their findings, Samsung recommends that the quality profile of the reference product be monitored throughout the “entire” period of biosimilar development.2
“The most critical thing is now we’re all more aware that [product drift] isn’t just theoretical,” said Dr Lyman. “This can happen in reality and in a situation where you’re treating patients to cure them, to eradicate a disease like HER2-positive early-stage breast cancer.”
Disclosures: Dr Rugo reported having received funding from Genentech, the manufacturer of trastuzumab. Dr Lyman reported having initially received payment from Samsung for consulting on the initial trial findings. He was not paid for his contributions to the extension study.
- 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 treated with neoadjuvant therapy for human epidermal growth factor receptor 2-positive early breast cancer. J Clin Oncol. 2018;36(10):968-974.
- Kim S, Song J, Park S, et al. Drifts in ADCC-related quality attributes of Herceptin®: Impact on development of a trastuzumab biosimilar. MAbs. 2017;9(4):704-714.
- Lyman GH, Zon R, Harvey RD, and Schilsky RL. Rationale, opportunities, and reality of biosimilar medications. N Engl J Med. 2018;378(21):2036-2044.
- Samsung Bioepis. US FDA approves Ontuzant® (trastuzumab-dttb), Samsung Bioepis’ first oncology medicine in the United States [news release]. Incheon, Korea: Samsung Bioepis Co., Ltd. Published January 21, 2019. Accessed November 22, 2019.
- 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.