Clinical Trial Design With Biosimilars

Bruce A. Feinberg, DO: Hope, ASCO—and Dr. Peter Yu, in particular—has formally stated that as part of the cancer link launch, only 3% of adult cancer patients are participating in clinical trials. Those who are participating are younger, healthier, less diverse, and probably more health literate. The list goes on about how they’re different. You had actually done a clinical trial with a biosimilar. Describe that trial. Then, let’s also get into this question of subsequent real world evidence once that drug becomes available.

Hope S. Rugo, MD: We did a trial looking at a trastuzumab biosimilar from Mylan. The first discussion you have, when you’re looking at a biosimilar that’s for therapeutic purposes for cancer where at least some component of its use is in the curative setting, is, where are you going to test it? The FDA and EMA’s guidance on that has been to use a sensitive indication. They didn’t actually give further guidance than that, which means you sort of look across the board and say, “What is the most sensitive indication?” And then, they also say to use a short-term endpoint. So, if you, for example, reproduced all of the other trials that were done to get the originator product approved, you would have to do progression-free survival, overall survival, or disease-free survival. It would be very costly and time-consuming. You’d never get any of those agents out. Secondary objectives, yes, but not primary. So, those are the 2 main areas of difference in the way we normally think about drug development.

In discussing how we should do that trial, which was some time ago, we didn’t have the FDA guidance on neoadjuvant therapy in breast cancer. We felt like the way that trastuzumab was first approved in the first-line metastatic setting would be most appropriate. We also kept in mind the fact that in the rest of the world, where people don’t have access to trastuzumab, they really don’t have access. So, very few would have been previously exposed to trastuzumab in the early stage setting. It allowed us to get a population that was relatively similar to one where the originator product was tested. So, that was ideal. We could use a short-term endpoint of response rate.

Bruce A. Feinberg, DO: Where was the trial done, in order to meet those requirements?

Hope S. Rugo, MD: We were originally doing the trial outside of the United States, where insurance covered trastuzumab. No one has any reason to participate in that kind of trial—right now, until maybe the patent goes away and there are options—but it was intended to be used in the entire rest of the world—Europe, Africa, and South America, and then in Eastern Europe and in Asia. When we actually went to do those studies, the infrastructure in Africa was very difficult, so that was a difficult place to do the trials. We had very little uptake there, and in South America, there were eventually sites, but there was a small input as well. Eastern Europe—big enthusiasm. People don’t have access to the drug, but these are seasoned investigators who are used to doing clinical trials and can provide much of the curative therapy through clinical trials in many situations. Again, you were talking about a single payer—the situation where the government is paying for people who have low income, but in a very limited sense. Otherwise, people pay out-of-pocket. And then, in many countries like in Asia, where there was tremendous interest, that’s where accrual was.

In Europe, there was initial enthusiasm. But pertuzumab, the second antibody, was approved based on the CLEOPATRA trial—where, if you give trastuzumab and pertuzumab together as first-line treatment for metastatic HER2-positive breast cancer in combination with a taxane, we saw a marked improvement in survival over a year. Then, people wanted to give pertuzumab. But with pertuzumab, there’s no access in the rest of the world, even now. For example, there’s no access to pertuzumab in most of China because of these issues of cost and availability. Who’s paying for it? We couldn’t buy pertuzumab in a trial until patients progressed, since they could stay on that trastuzumab/pertuzumab combination, sometimes, for many years. So, we elected to just move forward with countries where pertuzumab wasn’t available.

It’s an interesting thing. You get a population of patients who range in age and health, and it’s a very different population than what we see in the United States that Dr. Peter Yu was referring to. It’s really a much more diverse population of patients. So, that did give us a more diverse population. And then, we do look at immunogenicity. You have to do this huge preclinical set of studies in order to get to the clinical trial, and then the clinical trial looks at the short-term endpoint of response rate. In HER2-positive disease in breast cancer, which is a little bit different from how you would study bevacizumab in lung cancer, you actually give the chemotherapy and antibody together, and you assess response. But then, the standard of care is to continue the antibodies after stopping the chemotherapy, which patients in many other countries don’t have access to. We said, “That’s the standard of care for us in the United States and in Europe, so that has to be the standard of care for this trial.” So, we continued the antibody until progression in the trial, and then we were able to look at progression-free survival and overall survival over a period of time.

Bruce A. Feinberg, DO: And the results were?

Hope S. Rugo, MD: The results showed that there was no difference in immunogenicity. Actually, it was kind of funny. Going back and looking for the data on immunogenicity of trastuzumab, the originator product, was pretty tough. There was very little immunogenicity in this product, either. It was identical. We looked at toxicity and it was relatively similar. It’s actually interesting that in the randomized trial, unless you have huge numbers of patients, some things can be a little unbalanced. For example, the choice of chemotherapy agent didn’t really make any difference. The institution had to choose paclitaxel or docetaxel. Most institutions outside of the United States will choose docetaxel, because you only have to come in every 3 weeks. That’s an advantage for many people where they’re a far distance from the center. There were a few more patients with bone metastases in the biosimilar arm, so there was a little bit more arthralgia during the treatment. But afterwards, when they were on an antibody alone, the side effects were identical. There were no differences in serious adverse events and no differences in cardiac toxicity, which was really important in this population of patients. And then, of course, our primary endpoint, which was overall response rate, was identical. The EMA and FDA have given guidance on how to look at overall response rates in cancer therapeutics where you either look at the ratio or difference and then you have a range you have to fit into. With both criteria, this biosimilar was identical. It met the criteria for being identical to the reference product.