Samsung Bioepis Data Suggest Clinical Impact From Herceptin Product Quality Drift
Executive Summary
Post hoc data from a long-term safety study of Samsung’s trastuzumab biosimilar and Genentech’s reference product suggest event-free survival rates differ based on a shift in one of Herceptin’s key quality attributes; Genentech said it proactively alerted health authorities when the shift was detected and the evidence does not indicate a clinical impact on patient outcomes.
New data from biosimilar company Samsung Bioepis Co. Ltd. raise questions about potential clinical implications when a reference product’s quality attributes drift over time and highlight the challenges sponsors face when trying to demonstrate high similarity against an inherently variable complex biologic.
Post hoc data come from a long-term cardiac safety study comparing Samsung’s trastuzumab biosimilar Ontruzant (also known as SB3) and Genentech Inc.’s reference product Herceptin. They suggest that breast cancer patients exposed to product from Herceptin lots marked by a shift in a key quality attribute experienced significantly lower event-free survival than patients exposed to lots in which the quality attribute shift was not seen.
The data will be the subject of a poster presentation at the upcoming American Society of Clinical Oncology annual meeting in Chicago.
Downward Shift In ADCC Activity
Samsung’s biosimilar received European Union approval in November 2017 and US approval (as trastuzumab-dttb) in January. It has launched in the EU but not the US.
Samsung currently is conducting a five-year, cardiac safety study of 367 patients with HER2+ early or locally advanced breast cancer in seven countries in Europe and Asia. Patients were eligible for enrollment if they completed Samsung’s Phase III comparative efficacy and safety trial in the neoadjuvant setting that supported the biosimilar’s approval.
ADCC variability for some lots was noted in both the EMA and US FDA reviews of Ontruzant.
According to the study abstract, a marked downward shift in antibody-dependent cell-mediated cytotoxicity (ADCC) activity was observed in Herceptin lots with expiration dates from August 2018 to December 2019. Some of those lots were used in the Phase III comparative efficacy and safety study.
Patients exposed to at least one Herceptin lot with shifted ADCC during neoadjuvant therapy were classified as “exposed,” while patients in the Herceptin arm who never received product from a shifted ADCC lot were categorized as “unexposed.” Event-free survival and overall survival after three years of follow-up were analyzed by ADCC status on a post hoc basis.
Among the 181 patients who received Herceptin, 126 were exposed and 55 were unexposed to shifted ADCC lots. There were 186 patients in the Ontruzant arm.
At a median follow-up duration of 40.8 months and 40.5 months in the Ontruzant and Herceptin arms, respectively, three-year event-free survival rates were 92.5% for Ontruzant, 94.5% in the unexposed Herceptin group, and 82.5% in the exposed arm. Overall survival rates were 97%, 100%, and 90.6%, respectively.
“Exposed was associated with decreased EFS compared to Unexposed (HR 0.14, 95% CI 0.04-0.51, p= 0.003),” the abstract states. “There was a trend of decreased OS in Exposed compared to Unexposed, however, there was no significant difference (HR 0.14, 95% CI 0.02-1.15, p= 0.068).” No difference in event-free survival or overall survival was observed between Ontruzant and the unexposed Herceptin group.
The variability in ADCC activity for some US and EU Herceptin lots was noted in both the European Medicines Agency and US Food and Drug Administration reviews of Ontruzant.
In the Phase III comparative efficacy and safety trial, Ontruzant was associated with a numerically higher breast pathological complete response rate compared to EU Herceptin (51.7% vs. 42%). However, both regulators found that similar efficacy had been established.
In the European public assessment report for Ontruzant, the EMA said it was doubtful “that a small shift as the one observed would have any significant impact in terms of clinical outcomes.”
Genentech: No Clinical Impact
Genentech told the Pink Sheet that when the ADCC shift was first identified, the company proactively alerted health authorities. “Based on our assessments, the evidence does not indicate that the glycan [ADCC] shift had a clinical impact on patient outcomes,” the company said.
“Biologics such as Herceptin are complex medicines because they’re produced from living cells through highly sensitive manufacturing processes. As a result, some batch-to-batch variability within prespecified parameters is expected,” Genentech said.
“We adhere to strict controls and regulatory requirements to ensure that variability between batches is always kept within the boundaries that are approved by the health authorities and, therefore, efficacy and patient safety are not compromised. We rigorously monitor and test our products and processes to ensure patients are receiving high quality medicines.”
Biosimilar sponsor concerns about the challenges of demonstrating analytical similarity due to changes in reference product quality attributes over time contributed to the US FDA’s decision to abandon its earlier recommendation for statistical equivalence testing (see sidebar for story).