Early-Stage, Metastatic Settings Equivalent for Evaluating Biosimilarity

According to findings of a systematic literature review presented at the 2018 ESMO Congress, the neoadjuvant and metastatic breast cancer settings are appropriate areas to evaluate the equivalence of biosimilars and originator products.

Hope S. Rugo, MD

According to findings of a systematic literature review presented at the 2018 ESMO Congress, the neoadjuvant and metastatic breast cancer settings are appropriate areas to evaluate the equivalence of biosimilars and originator products.

The review, presented by lead author Hope S. Rugo, MD, pooled conference abstracts from January 1, 2013, to March 14, 2018 that included the search terms “biosimilar” and “trastuzumab” (Herceptin). 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 Rugo.

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 withTargeted Oncologyduring 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.

TARGETED ONCOLOGY:Could you provide an overview of the comparative review of trastuzumab biosimilars in breast cancer?

Rugo: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.

TARGETED ONCOLOGY:Once you established the equivalent efficacy in these trials, what else did you examine?

Rugo: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.

The other thing that was sort of questioned in publications [was whether] the neoadjuvant setting was the optimal setting to evaluate biosimilarity. We looked at the homogeneity of the patient populations. You had a heterogeneous population drop out for other reasons, but it turns out that both populations were very homogeneous.

In most countries where you would study biosimilars, people don't have access to trastuzumab. That’s the tragedy that we're trying to rectify with biosimilars. The prior exposure to trastuzumab was minuscule in the first-line metastatic trials. Patients were pretty homogeneous in terms of the amount of visceral disease and were offering patients a much longer response duration and PFS than they would have had without trastuzumab.

TARGETED ONCOLOGY:Should guidelines be put into place to formally accept biosimilars in these settings, taking into account the hesitance regarding their use in the United States?

Rugo:There has been a lot of discussion about what defines biosimilars. Continued education is based on regulatory guidelines from the European Medicines Agency, FDA, and World Health Organization. They have allowed a lot of flexibility in terms of identifying the most clinically sensitive setting to study the drug in. Obviously, there are different settings, and it may vary. We don’t need to further define it. The regulatory agencies will give guidance for trial designs moving forward.

It's important that clinicians understand that we don't need to retest every single setting; that's not the whole intent of biosimilars. It's simply a way to test something that isn't a generic in a way that doesn't completely recreate the wheel, but rather based on the success and tolerability of the originator product, makes something more accessible for patients. In fact, having multiple biosimilars is better because there is more competition in price, both with the biosimilars and the originator product.


Rugo H, Curigliano G, Cardoso F, et. al. Settings-based efficacy comparison of trastuzumab biosimilars in breast cancer: a systematic literature review.Ann of Oncol. 2018;29(suppl_8). doi: 10.1093/annonc/mdy272.