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Trastuzumab biosimilar safe, effective for advanced breast cancer
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CHICAGO — MYL-1401O, a biosimilar trastuzumab antibody, appeared to have comparable safety and efficacy to its FDA–approved reference product in women with HER-2–positive advanced breast cancer, according to results of a randomized phase 3 study presented at the ASCO Annual Meeting.
The addition of trastuzumab (Herceptin, Genentech) — a biologic agent approved by the FDA in 1998 and now indicated for women with early- or late-stage breast cancer — to chemotherapy has resulted in a 5- to 8-month survival improvement for women with late-stage disease. The addition of 1 year of trastuzumab to chemotherapy also reduces the risk for recurrence by 10% and improves survival by about 9% in women with early-stage disease.
Hope S. Rugo
“Biologic agents are usually targeted therapies and are costly, limiting access across the globe,” Hope S. Rugo, MD, professor of medicine at University of California, San Francisco, said during a press conference. “Many biologic agents are losing patent protection soon, or have already lost patent protection in other countries. Biosimilars have the potential to significantly improve access to expensive agents.”
Regulatory agencies have established requirements for biosimilar approval. They include a demonstration of structural and functional similarity to the reference product; a demonstration of similar pharmacokinetics and pharmacodynamics; and confirmation of similar safety, efficacy and immunogenicity.
Rugo and colleagues evaluated the safety, efficacy and immunogenicity of MYL-1401O (Mylan Inc.) compared with trastuzumab.
The analysis included data from 458 women treated at 95 sites worldwide. All women had HER-2–positive metastatic breast cancer, and they had not received prior chemotherapy or trastuzumab for metastatic disease. Forty-four percent of women had hormone receptor–positive disease.
Researchers randomly assigned patients to receive Myl-1401O (n = 230) or trastuzumab (n = 228) with docetaxel or paclitaxel every 3 weeks for at least eight cycles. Patients with stable disease beyond the eighth cycle could continue to receive the antibody therapy alone until disease progression or unacceptable toxicity.
Overall response rate at week 24 served as the study’s primary endpoint. The FDA also asked researchers to calculate ORR ratio as an endpoint, and the European Medicines Agency asked for the difference in ORR between the proposed biosimilar and trastuzumab. Secondary endpoints included PFS, OS and safety.
At week 24, the ORR rate was 69.6% for Myl-1401O and 64% for trastuzumab. Researchers calculated an ORR ratio of 1.09 (90% CI, 0.97-1.21; and 95% CI, 0.95-1.23), meeting the predefined equivalency margin. The difference in ORR was 5.5 (90% CI, –1.7 to 12.69; and 95% CI, –3.08 to 14.04), which also fell within the required equivalency range.
Based on 41 events in the biosimilar arm and 48 in the reference product arm, median PFS had not yet been reached.
The overall antidrug antibody rate was 2.4% with Myl-1401O and 2.8% with trastuzumab, consistent with published data, Rugo said. The dose-normalized maximum concentration and area under the curve also were similar between the two agents.
Safety appeared comparable between study groups, and no significant changes in cardiac function occurred in either cohort. Serious adverse events — which were primarily hematologic and related to taxane therapy — occurred in 38.1% of those assigned the biosimilar and 36.2% of those assigned the reference product. Common adverse events included neutropenia (biosimilar, 27.5%; reference product, 25.2%) febrile neutropenia (4.5% vs. 4.1%), leukopenia (1.6% vs. 4.9%) and pneumonia (1.6% vs. 2%).
Four fatal events occurred in each study arm.
“This proposed biosimilar has the potential to meet the need for an affordable treatment option for patients with HER-2–positive cancers,” Rugo said. “This is one of the first trials of biosimilars in oncology to demonstrate these similar results. Ongoing trials with other biosimilars should further improve access worldwide to these lifesaving therapies.” – by Alexandra Todak
Reference: Rugo HS, et al. Abstract LBA503. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.
Disclosure: The study was funded in part by Mylan. Rugo reports a speakers bureau role with and honoraria from Genomic Health; travel expenses from Mylan, Nektar, Novartis, OBI Pharma and Roche/Genentech; and institutional research funding from Celsion, Eisai, Genentech, MacroGenics, Merck, Nektar, Novartis, OBI Pharma, Pfizer and Plexxikon. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Alberto J. Montero, MD, MBA
Biosimilar monoclonal antibodies are very new. A well-designed study like that presented by Hope S. Rugo, MD, gives us a level of comfort that this antibody is essentially equivalent to trastuzumab (Herceptin, Genentech), and I hope that we will begin to see lower costs as these biosimilars begin to roll out.
There are countries outside of the United States that do not have access to branded trastuzumab, and these results will be very good for them. Here in the United States, as we approach the question of value and consider how we can reduce costs, having a biosimilar monoclonal antibody that provides the same benefit as its branded counterpart at a lower cost is a win.
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Debu Tripathy, MD
We expect that the area of biosimilars is going to have a bigger cost impact than maybe some of the oral drugs when they go generic. Many of these biologic drugs are now just coming off patent, so the whole field of biosimilars is new. We do not exactly know how it is going to play out but, of course, the cost is expected to go down significantly.
Trastuzumab (Herceptin, Genentech) is no longer one of the most expensive biologic drugs, although it used to be when it first was approved. It can cost anywhere from $3,000 to $4,000 a month, whereas some of the newer biologic drugs are four times that price. Still, we expect the price will come down — we hope by at least half.
For some patients, the price will not make a difference because insurance covers most infused medications. However, there are other patients who do have copays, and it will make a difference for them. In many parts of the world, where these drugs are simply not available because of the cost, the availability of a biosimilar would make a huge difference.
The FDA requires a certain degree of testing to prove the efficacy and safety of a biosimilar. First of all, the methods for manufacturing have to be very clearly laid out. Secondly, the product has to have the same chemical composition and physical/functional properties as the parent drug. Thirdly — and most importantly — the biological effects on patients and on the tumor must be similar, the pharmacokinetics have to be well worked out and, ultimately, the safety and efficacy has to be proven to be similar.
In the randomized double-blind phase 3 trial, the overall response rate for the biosimilar for trastuzumab, MYL-1401O (Mylan Inc.) given with a taxane in the first line, was about 70% compared with 64% with trastuzumab. This was statistically similar and met the threshold that is set for eventual approval of the drug. In addition, mean serum concentrations over time were similar as were fatal adverse events (1.6% in each group), but number of patients who had to discontinue early due to subclinical or clinical cardiomyopathy was not reported.
For aromatase inhibitors, the level of comfort in prescribing a generic is pretty high. Still, there are some differences between the generics and branded drugs. I have had some patients have reactions to, not the chemical, but the packaging, like the capsule and its coloring. However, this is pretty uncommon. For the most part, when it comes down to a single, simple chemical, people feel confident.
However, an antibody is different — they are complicated and you cannot make an antibody identical to another. Antibodies are not only encoded proteins from a gene, but they also are folded and glycosylated, and undergo many other post-translational changes that affect their function. So, even though you may show similar responses in a trial, it does not beyond a shadow of a doubt prove that it is identical. There will be no perfect trial to prove these agents are 100% identical, and there will always be a small amount of uncertainty.
How do physicians perceive that level of uncertainty, and how willing are they to convince their patient, who also may be reluctant? Sometimes reluctance comes more from the patient, who may consider the biosimilar a fake or knockoff. But, we shouldn’t think of it that way but rather as a biosimilar even though we cannot prove it is fully equivalent.
I believe that based on the design of the study, if the confidence intervals are set low enough (as specified by FDA and other regulatory agencies), I would generally feel confident. I say that not only as a scientist and as a clinician, but also as a member of society, where we all have to make sure that, together, we can be a healthy society by equitable distribution of health care. It is not just about one individual person; it is about making sure that societal health is covered. With runaway drug prices and health care costs — especially when they do not make a difference in relevant patient outcomes — we have to make sure we are doing what we can to make medical care available and affordable to everyone.
Biosimilars are an important step in that direction, but we do have to maintain our vigilance over time that we are doing everything we can to make sure they are truly biosimilar.
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Don S. Dizon, MD, FACP
These results using a proposed biosimilar to trastuzumab (Herceptin, Genentech) are incredibly exciting and have the potential to really broaden the access to what has been a lifesaving agent for women with HER-2–positive breast cancer. We excitedly await more results on this type of agent.
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