Patients with HER2-positive early or locally advanced breast cancer who were exposed to reference trastuzumab lots with a marked downward shift in antibody-dependent cell-mediated cytotoxicity (ADCC) had worse outcomes than those not exposed to at least 1 shifted ADCC lot or those treated with its biosimilar.
Mark Pegram, MD
Patients with HER2-positive early or locally advanced breast cancer who were exposed to reference trastuzumab (Herceptin) lots with a marked downward shift in antibody-dependent cell-mediated cytotoxicity (ADCC) had worse outcomes than those not exposed to at least 1 shifted ADCC lot or those treated with its biosimilar (SB3).
In a posthoc analysis of patients treated for 12 months with reference trastuzumab or its biosimilar SB3, long-term follow-up of patients exposed to at least 1 shifted lot demonstrated worse event-free survival (EFS) at 2 years (92.5%) compared with both those not exposed to a lot with a shift in ADCC (98.2%) and those treated with SB3 (96.72%),1 reported Mark D. Pegram, MD, director of the Breast Oncology Program, Stanford Comprehensive Cancer Institute, and colleagues at the 2018 San Antonio Breast Cancer Symposium.
With a median follow-up from initiation of study treatment of 30.1 months in the SB3 arm and 30.2 months in the arm randomized to the reference product, the difference in EFS between unexposed and exposed patients was significant (HR 0.07, P = .0137), representing a 93% reduction in the risk of disease progression/recurrence or death in unexposed patients, Pegram et al wrote in their poster presentation. At 2 years, 4.3% of patients receiving SB3, 1.8% of unexposed reference trastuzumab patients, and 9.5% of exposed reference trastuzumab patients had recurrence after surgery. There was no difference in EFS between patients in the SB3 arm and those in the unexposed reference trastuzumab arm (HR 1.19; P = .8376).
SB3 was approved by the European Commission as a biosimilar of reference trastuzumab on the basis of an equivalent breast pathologic complete response rate and comparable EFS and overall survival (OS) between SB3 and the reference product.
Upon monitoring quality attributes of trastuzumab for the development of SB3,2 multiple lots of reference trastuzumab with expiratory dates up to July 2018 demonstrated a high degree of consistency for all the tested properties. However, a marked downward shift in ADCC was observed in trastuzumab lots with expiry dates from August 2018 to December 2019. Some of these lots were used in the study to demonstrate bioequivalence of SB3, noted Pegram and co-investigators.
The authors of that report, Kim et al, wrote that, “considering that ADCC is one of the clinically relevant mechanisms of action for trastuzumab, the levels of %afucose and %high mannose should be tightly monitored as critical quality attributes for biosimilar development of trastuzumab.” The levels of afucosyl (%afucose) and the high-mannose forms (%high mannose) of N-glycans correlate with ADCC and FcγRIIIa binding activities.
The long-term follow-up set presented here included 367 patients, 186 of the original 437 patients who were treated with SB3 and 181 of the 438 enrolled in the reference trastuzumab arm. Within the reference trastuzumab arm, 55 were not exposed to the lots with reduced ADCC and 126 patients were exposed. The study enrolled patients with HER2-positive early or locally advanced breast cancer who were randomly assigned to receive SB3 or reference trastuzumab in the neoadjuvant setting concurrently with chemotherapy. Patients then underwent surgery followed by adjuvant SB3 or reference trastuzumab.
The OS rate was 100% at both 1 and 2 years in patients randomized to SB3 and was 100% at 1 year and 99.42% at 2 years in those assigned to reference trastuzumab. Exposed patients in the trastuzumab arm had an OS rate of 100% at 1 year and 99.1% at 2 years.
“Although this exploratory analysis is limited in that it does not have sufficient power due to limited sample size and number of events, level of exposure is not defined, and follow-up is short, these results suggest a possible impact of ADCC on EFS or OS. Further long-term results will follow,” Pegram et al concluded.