Hope S. Rugo, MD
Early-stage and metastatic breast cancer are appropriate settings to test the equivalence of biosimilars and originator products, according to a systematic literature review presented at the 2018 ESMO Congress.
The review pooled conference abstracts that included the search terms “biosimilar” and “trastuzumab” (Herceptin) from January 1, 2013, to March 14, 2018. Eight phase III clinical trials for 6 investigational biosimilars were reviewed after selection for studies with sufficient comparative clinical efficacy results.
“We felt that by looking in great detail at the results and the way the studies were done, that both the neoadjuvant and metastatic settings were equally good settings to evaluate biosimilarity and that both could be used to extrapolate the use of biosimilars in other settings with other combinations, and other diseases like gastric cancer,” said Hope S. Rugo, MD, lead author of the review.
Half of the trials were done in the neoadjuvant setting while half were done in the metastatic setting, with respective endpoints of primary efficacy outcome/pathologic complete response (pCR) and primary efficacy outcome/overall response rate (ORR).
All investigational biosimilars demonstrated clinical equivalence to reference trastuzumab whether they were tested in the early-stage or metastatic setting. Moreover, the trastuzumab biosimilars CT-P6 and PF-05280014 demonstrated equivalence in both the neoadjuvant and metastatic settings.
In an interview with OncLive®
during the 2018 ESMO Congress, Rugo, professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, discussed this analysis of trastuzumab biosimilars in breast cancer.
OncLive: Could you provide an overview of the comparative review of trastuzumab biosimilars in breast cancer?
: We had a poster looking at the different biosimilar trials. We were interested in looking at whether or not there was any evidence that one setting was preferable to study biosimilarity. We looked specifically at the biosimilar trastuzumab trials compared with the originator. There has been some discussion that you may have better response if you look at the biosimilar trastuzumab agents in the neoadjuvant setting versus the first-line metastatic setting.
The regulatory guidance for looking at biosimilars is to choose a very sensitive indication and a short-term endpoint. The idea is you don't want to be doing these huge studies looking at progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). In lung cancer, bevacizumab (Avastin) was combined with chemotherapy for 6 cycles, and that was it.
In breast cancer, we give trastuzumab over time. In the study, we put all of the trials with published results together. The requirements for biosimilarity are looking at these short-term endpoints, either response in the metastatic setting or pCR in the neoadjuvant setting. Then, we looked at the hazard ratio. Basically, they all showed incredible similarity. They all met the criteria. The intervals that were allowed were fairly narrow and quite similar.
Once you established the equivalent efficacy in these trials, what else did you examine?
We looked at safety information. It was very similar across the different subsets. Then, we looked at other endpoints that you can evaluate. In the neoadjuvant trials, they're able to look at pCR. Most of the trials administer trastuzumab or the originator biosimilar in stock for 1 year, so the entire exposure is 1 year regardless of what the adjuvant study is. Only one of the trials is looking at longer-term DFS; that was added as an endpoint once patients got to the 1-year mark. Presumably, they'll have most of those people evaluated for 5 years. That is really good, but we don't have that endpoint yet.
For the metastatic setting, you have the advantage of giving chemotherapy [in combination with an] antibody and then stop treatment. We stopped at 24 weeks for our biosimilar trial. Then you continue the antibody afterwards, so you either continue the originator or the biosimilar until disease progression. The patient’s exposure to the drug is much longer in terms of safety evaluation because it's a shorter-term endpoint. Then, we look at PFS and of course OS after a specified number of events.
In our biosimilar trial, we were able to show that the ORR at 24 weeks correlated very highly with 48-week PFS, which is great. This means these short-term endpoints correlate even in the metastatic setting.