COMMENTARY

Trastuzumab Biosimilar: An Understudy Waits in the Wings

Kathy D. Miller, MD; Hope S. Rugo, MD

Disclosures

June 22, 2016

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Kathy D. Miller, MD: Hi. I'm Kathy Miller, professor of medicine at the Indiana University School of Medicine in Indianapolis, Indiana. Welcome to Medscape Oncology Insights, coming to you from the floor of the 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO).

The Would-be Trastuzumab Biosimilar

Dr Miller: Back in 1998, trastuzumab redefined the treatment of HER2-positive breast cancer. At this meeting, we hear the first results from a study looking at a trastuzumab biosimilar. The question is, will that redefine treatment in the same way that its predecessor did? Here to talk to me about this new treatment option is Dr Hope Rugo, professor of medicine at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center in San Francisco, California. Welcome, Hope.

Hope S. Rugo, MD: Thanks.

Dr Miller: First let's talk about definitions. We are familiar with generic drugs, both oral and intravenous compounds. How is a biosimilar different from a generic drug?

A Brief Biography of Biosimilars

Dr Rugo: That is a great question. When I started working on this, I had to understand that myself. Why do you just get generic letrozole but you can't get generic biologic agents? The bottom line is that these agents are quite different. The generic agents that we are used to are usually simple chemicals with a low molecular weight. You just have a similar structure and you're okay. You meet certain purity evaluations and you can put your drug on the market without ever demonstrating similar efficacy.

Dr Miller: So, there is a simple chemical structure, a chemist sees the structure and figures out how to make it, you show that you've made the same chemical, and you meet the purity and manufacturing standards. That's all you need?

Dr Rugo: That's all you need. For example, the generic hormone therapies that our patients are on come from all over the world. That certainly allows for a degree of competition, which is not a bad thing in terms of pricing, but there are uncertainties. Some of our patients say that they like the pink one but not the blue one. We don't know about that.

Biosimilars, alternatively, are high-molecular-weight, complex chemicals. The idea behind these agents is that they are very complicated and the structures need to be similar. You need to have similar physical characteristics and purity evaluation. And because they are so complex and of high molecular weight, the regulatory agency said that it's going to be very hard to know whether these drugs are the same; and that would mean that the original compound, the so-called reference product, will be the only drug that is ever on the market. We'll create a set of standards and regulatory guidance for getting these agents into the market after the patent life for the reference product has run out. That's where we get into biosimilars. These are biologic agents, complex chemicals of high molecular weight, and we have a set of guidelines that we need to meet that are set forth by regulatory agencies in the United States and Europe in order to have a biosimilar. These are referred to as proposed biosimilars.

Dr Miller: Generic letrozole is chemically the same as Femara®, the patented letrozole, but these are not exactly the same chemical compound. Do the guidelines require that they show similar activity, that they have the same effect on the body?

They have to show similar activity but with short-term measures of activity.

Dr Rugo: They have to show similar activity but with short-term measures of activity. For example, if you required that every new trastuzumab, bevacizumab, and rituximab—the three therapeutic biosimilars that are being tested now—show survival benefits in the same population, they would be as expensive as the reference product, and you would get nowhere because it would cost so much money and take so many years.

The efficacy requirements are: Where you have seen the biggest efficacy [in the reference product], you show [in the proposed biosimilar] a response rate, a difference in response, or a ratio of response that is similar, depending on the regulatory group. That allows you to say, "I need similar physical characteristics, so the structure has to be pretty similar." You show similar purity and you do preclinical animal models that show that you're not seeing more toxicity. Then you show similar pharmacokinetics and pharmacodynamics in healthy volunteers.

What is interesting about trastuzumab is that as it has been manufactured—and this is true for most reference products that are biologic agents—it has changed a little bit. The manufacturing process changes, but you don't go back and do the study all over again, right? You assume that it's the same. What the US Food and Drug Administration (FDA) said is that you can't just test your biosimilar against the US trastuzumab; you have to test it against the EU trastuzumab, too. They actually had to do a whole other study, which is a poster here at ASCO,[1] comparing the EU trastuzumab and the US trastuzumab with the biosimilar with pharmacokinetic and pharmacodynamic testing.

The trastuzumab that you get today might not be identical to the trastuzumab that you administered to a patient in 1998.

Dr Miller: That is a fascinating comment that I want to make sure our listeners heard. Because these are such complex chemicals, as the manufacturing process evolves—maybe because they need to move to a new place or make the manufacturing process more efficient—the trastuzumab that you get today might not be identical to the trastuzumab that you administered to a patient in 1998.

Dr Rugo: That is absolutely the case. They are not even "maybe the same"; they are not the same. It's similar in terms of the physical characteristics, the purity, and all of those things that we're talking about, but they don't have to reprove the efficacy.

How Similar Is the Biosimilar?

Dr Miller: What do we know now about the trastuzumab biosimilar? You've been working to meet those requirements. Are we at the point where the efficacy bar, at least in terms of response rate or progression, has been met?

Dr Rugo: Yes. We're presenting the data from the HERITAGE study[2] at this meeting. It's the first set of data that has the 24-week primary endpoint overall response rate. The trial was designed to randomly assign patients who had treatment-naive HER2-positive metastatic breast cancer to receive either the branded Herceptin® or the proposed biosimilar, Myl-1401O—not an easy name, but it's a proposed trastuzumab biosimilar. Then they got a taxane. The choice of taxane was by institution; about three quarters of the institutions chose docetaxel and about a quarter chose paclitaxel.

The study was done all around the world in countries that don't have easy access to Herceptin. Patients received the standard treatment in this setting, and they received chemotherapy for eight cycles. Those who had stable or responding disease were allowed to drop the chemotherapy to reduce toxicity and continue on just the antibody alone. The primary endpoint is overall response rate at 24 weeks, and then, of course, we're following patients for progression-free survival. We showed identical overall response-rates at 24 weeks.

The FDA wanted to see the ratio of overall response, and the European Medicines Agency (EMA) wanted to see the difference. They set a narrow range of efficacy equivalence so that it has to be within that range, and both of the results were well within the range.

Dr Miller: That's the other tricky thing that we need to pay close attention to: designing a study to show that two treatments are the same. Statistically, it's exceeding difficult. You need really large numbers. So in this case, the goal is to show that the biosimilar is similar. The question for the regulatory authorities and for us, as we think about using these biosimilars, is: How similar is similar enough to know that you're not short-changing patients or that a difference might be important?

Dr Rugo: Absolutely. I do think that the overall response rate being so similar is very encouraging. Of course, we also want to see progression-free survival (PFS). At the 24-week endpoint, PFS by hazard ratio was identical, but it's still early. We hope to be presenting the 48-week PFS data at an upcoming meeting.

Will Biosimilars Drive Costs Down?

Dr Miller: This is exciting for patients around the world where generic trastuzumab has not existed or where the branded Herceptin is either unavailable or unaffordable. We have to deal with costs in the United States as well. Is this the sort of thing that could give competition, that might drive prices lower for all of us?

That is certainly the hope—that the availability of alternate trastuzumabs, bevacizumabs, or rituximabs will, when the patents run out, foster competition and lower prices.

Dr Rugo: That is certainly the hope—that the availability of alternate trastuzumabs, bevacizumabs, or rituximabs will, when the patents run out (which in the United States is not until 2019 for trastuzumab), foster competition and lower prices. Prices are always higher in the United States, even compared with Canada. It remains to be seen how it will work in the United States. With generic aromatase inhibitors, our insurers have determined which agents our patients get, and I think that it will be very similar with these biologic agents, too.

Many people ask me if I can be sure that safety is the same [between the biosimilar and trastuzumab]. We did look at safety, and it was identical. Cardiac function was also identical. However, the regulatory agencies also want you to do pharmacokinetics, which were the same, and immunogenicity assays. That was interesting to me. I hadn't really thought about it with Herceptin, because we knew early on that it wasn't immunogenic. The anti-drug antibody rate is about 2.5% for both compounds, which is really very interesting to me. For safety, India has different regulatory criteria than the United States, Europe, and many parts of Asia, so the drug has been used for a couple of years in India. There are a lot of safety data, which have all been reported as pharmacovigilance to the regulatory agencies.

Dr Miller: Fascinating work, with bigger implications globally than it might initially seem when you just think about how you could get Herceptin from a different supplier.

Dr Rugo: Yes, I think so.

Lessons From a Negative Vaccine Study

Dr Miller: You mentioned immunogenicity, and I notice that you're reporting a randomized study[3] of a vaccine at this meeting. You are one of the few breast cancer specialists who is also trained as an immunologist. I know that this has been a longtime passion of yours. There has been huge enthusiasm about immunotherapy over the past year or so. This study didn't work. It didn't meet its primary endpoint. Can you tell us about this vaccine study and what we might learn from it even though it didn't meet its primary endpoint?

Dr Rugo: I think that we can learn a lot. This was a vaccine study, so it's different from giving a checkpoint inhibitor, for example, although we are still learning a lot about the use of checkpoint inhibition and other immunologic therapies in breast cancer, which isn't such an immunogenic disease.

It's a carbohydrate-based vaccine. Breast cancer and most epithelial malignancies have abnormal glycosylation, which is fascinating. It sets them apart from other cells, so it has been a target. There was a previous vaccine called Theratope [4] that used this type of hypothesis. This is a vaccine against Globo-H, which is a very commonly expressed carbohydrate antigen that is carried by keyhole limpet hemocyanin (KLH), the carrier protein. What we know is that these carrier proteins aren't very immunogenic, so they are given with an adjuvant from a tree that is very potent and stimulates the immune response.

Patients who had either responded or had stable disease were randomly assigned to receive hormone therapy or chemotherapy. About three quarters of the patients were enrolled in Asia because this is a company based in Taiwan.

No Difference in PFS, But...

Dr Rugo: What we found was that there was no difference in the primary endpoint PFS between the two arms, but patients in the treatment arm who mounted an IgG or IgM immune response to Globo-H, which was the antigen, seemed to do better. We looked at the IgG response to Globo-H, and those who achieved a titer of at least 1:160 against Globo-H anytime during their treatment had the best PFS. The patients who were treated who never had an immune response, which was about half of them, had the worst PFS.

Dr Miller: What portion of patients developed an immune response? By what other measures—such as extent of disease, prior treatment, age, liver function studies, serum protein—did they seem to be healthier that might explain their ability to mount an immune response?

If you could augment the immune response using an immune agonist—maybe a checkpoint inhibitor—could you improve the immune response?

Dr Rugo: This was generally a pretty healthy group of patients. They had to have received treatment and have at least stable disease. They could have had hormone therapy or chemotherapy and they couldn't have had more than two progressions in the metastatic setting, so they were generally pretty healthy. They didn't have organ dysfunction. You had to have felt comfortable stopping their chemotherapy. They could have continued on hormone treatment. We couldn't find any specific variables, which was disappointing for me. I wanted to know the type of person who mounts an immune response. My guess is that there is a genetic component as well as something else that we don't understand yet. We need to understand it and also understand whether, if you could augment the immune response using an immune agonist—maybe a checkpoint inhibitor—could you improve the immune response? And by improving the immune response to Globo-H, would everybody do better? That is a very interesting question that we need to address moving forward.

Dr Miller: Fascinating work. Even though this study, or the vaccine given in this way, isn't going to move forward, it's more evidence that the immune response is important. We've seen that with studies on the prognostic value of tumor-infiltrating lymphocytes, but we clearly have so much more to learn about how to harness that power or how to get an immune response in our patients where it's not inherently there.

Dr Rugo: It is true. I think back to the vitamin D study[5] that we all know. People who had low vitamin D levels had worse outcome from breast cancer. So, of course, everybody thought that they should just give their patients a lot of vitamin D and they'll do better and they'll be fine, but we still don't know whether it makes any difference. It might help your bone health, but we don't know whether it helps your cancer or whether it's just a marker. For example, it has been shown in melanoma[6] and many cancers[7] that your immune infiltration, particularly CD8 T cells—a humoral immune response to the vaccine—correlates with better outcome. But what we don't know is, if you enhance that immune response in somebody [without an immune response], do they do better? That's the next step. That's what we need to know. We could infer that patients who get checkpoint inhibitors do better, but the real question is, were they already the patients with better prognosis in whom you're enhancing the response?

Dr Miller: There is so much to learn in this area.

Dr Rugo: Indeed, but it's exciting.

Mouthwash Prevents Stomatitis

Dr Miller: I know you have another passion for decreasing the toxicity of our therapies, particularly toxicities that we know are going to occur. You've looked at trying to prevent the stomatitis that can come with everolimus. For many of our patients, that is one of the most devastating and most limiting toxicities of that agent. We know that it's going to happen. Can we prevent it?

Dr Rugo: It turns out that we can. We used a very simple off-the-shelf, alcohol-free dexamethasone solution. We used it as a mouthwash. Patients who were prescribed everolimus and exemestane used the mouthwash four times a day for 8 weeks. From a previous study[8] that I did, we knew that 80% of patients who are going to get stomatitis get it by 8 weeks, so we looked at the 8-week endpoint. We saw no grade 3 stomatitis and very little grade 2.[9] It was a marked decrease compared with what we saw in the BOLERO-2 trial[10] and certainly all other trials in a pooled analysis.[11]

It's a new standard of care. Why wait and see whether somebody is going to get stomatitis? You might as well give them the steroid mouthwash.

We saw no thrush and not much toxicity. Some people didn't like the taste. But overall, it's a new standard of care. Why wait and see whether somebody is going to get stomatitis? You might as well give them the steroid mouthwash. It's cheap and you can compound a steroid mouthwash if you don't have one available. Then, if somebody is well, you can always taper it off and see how they do. It has also given us some input about how to treat grade 1 stomatitis aphthous ulcers that people sometimes get from palbociclib, for example. You just give them this triamcinolone acetonide (Kenalog) steroid paste, they put it on the ulcer when they start to feel it coming, and it doesn't get worse.

Dr Miller: Are there any systemic effects with the steroid mouthwash? Whenever I mention steroids to any of my patients, they really don't like that word.

Dr Rugo: You're not supposed to swallow it, and we didn't see thrush. People who have some glucose intolerance who might forget and swallow it would have a little increased glucose, but if people swish and spit it out, they do really well.

Dr Miller: So, not enough was absorbed that you saw systemic effects?

Dr Rugo: No, not at all. And hyperglycemia is a toxicity from everolimus, so it's something that you should monitor in any case, but we just didn't see it.

Dr Miller: Fascinating. Thank you for joining us to share these interesting results with us. We will look forward to seeing how they play out.

Dr Rugo: Thanks so much, Kathy.

Dr Miller: Thank you for joining us for this edition of Medscape Oncology Insights. This is Kathy Miller, reporting from ASCO 2016.

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