Experts Decode the Future of Biosimilars in Breast Cancer

Lee S. Schwartzberg, MD

The introduction of biosimilars is having a growing impact on breast oncology, as these agents move from supportive care to active treatment settings. As more patents for costly biologics have expired, biosimilars are expanding patients’ access to novel treatments at significantly reduced cost. For patients with HER2-positive breast cancer, the FDA has approved 5 trastuzumab biosimilars: Ogivri (trastuzumab-dkst), approved 2017; Herzuma (trastuzumab-pkrb), approved 2018; and Kanjinti (trastuzumab-anns), Ontruzant (trastuzumab-dttb), and Trazimera (trastuzumab-qyyp), approved in 2019 (Table).

Table. Breast Cancer Indications for Biosimilar Versions of Trastuzumab (Herceptin)

Although biosimilars have been shown to be safe and effective—with more than a decade’s worth of data to support their use—numerous hurdles to their adoption in clinical practice remain.¹

During a recent OncLive Peer Exchange^®, a panel of hematology-oncology experts discussed some of the challenges surrounding the integration of biosimilars in clinical practice using the breast cancer landscape as a prime example. These hurdles include the need for better education about these agents, including improved understanding of guideline recommendations and improved clarity on how to select between available options. They also shared insights on the feasibility of extrapolating data for these agents, whether these agents can be used interchangeably, and future developments that have the potential to reshape the biopharmaceutical sector.

Filling Education Gaps

The panelists emphasized the need for health care providers in the United States to be better informed about biosimilars, as these agents are still relatively new in the US oncology marketplace, especially outside of the supportive care setting. Subsequently, they said many misconceptions exist that may be limiting the use of these agents. “The first thing is that [a biosimilar is] not a generic. It’s not a small molecule that can be manufactured simply and repetitively like photocopying something. I’m being a little hyperbolic, but [making generics is] simpler than making a biologic in a living organism,” said Lee S. Schwartzberg, MD, who encouraged health care providers to familiarize themselves with the regulatory process for biosimilars, which is different than that for their originators.

“We were already used to incorporating biosimilars into the treatment management of breast cancer patients,” Schwartzberg said, noting the difference being that most of biosimilars were used in the supportive care setting. “Some physicians have taken a different approach to a supportive care medication as opposed to a therapeutic medication, where the outcome is truly potentially lifesaving. The stakes are high for the use of a drug like trastuzumab where it has such critical value in HER2-positive breast cancer.”

Schwartzberg said that while he feels comfortable using biosimilars because he trusts the FDA’s approval process, there is an information gap concerning their effect on long-term clinical outcomes. “A clinical trial population is different from the real-world patients who get the drug. So monitoring these patients, particularly now that we have an electronic health record system that enables us to aggregate data and obtain good outcomes information, will be particularly important,” he said.

Examining Guidelines

In clinical practice, guidelines are often used to facilitate evidence-based treatment decision-making. The panelists explained that the National Comprehensive Cancer Network (NCCN) guidelines have started to incorporate biosimilars into their recommendations, an action that recognizes the value of having less expensive drugs that achieve comparable outcomes to their more expensive counterparts. For example, the NCCN breast cancer guidelines enable substituting an FDA-approved biosimilar for trastuzumab whenever trastuzumab is indicated, but they do not advocate for the use of any specific biosimilar over another.² “It’s going to be agnostic because it’s really going to depend on the payer mix in the part of the country [where the biosimilar is being prescribed],” said Adam M. Brufsky, MD, PhD.

Adam M. Brufsky, MD, PhD

Schwartzberg said in his practice they have also written their own guidelines to facilitate use of biosimilars. “Because some patients are still using the originator product, it’s been a little more complex because we’ve had to keep both agents in use simultaneously,” he said. He also noted the same challenge as Brufsky: Different insurers mandate use of different drugs. “This has added a tremendous amount of complexity in community oncology and cost to the system, which one could argue is not value based in the general term because stocks of various drugs need to be maintained based on the insurer that the patient has,” he said.

Subsequently, Schwartzberg said it is important for health care providers to know which drugs they will get reimbursed for before prescribing any agent. “Even though we’re very confident that any of them would work, we would like the ability to pick which drug we use. But that’s not the system we live in today,” he said.

Examining Interchangeability

The panelists also examined the issue of interchangeability—whether one agent can be substituted for another, including changing a patient from the originator biologic to a biosimilar. Kashyap Patel, MD, said in his practice he tries to put all his patients on a biosimilar. “I’m very comfortable saying that if a biosimilar is approved, if it’s covered by the payer, if they’ve got the supply chain guaranteed, and if they have the appropriate patient assistance program, I’ll move them [to the biosimilar] right away,” he said.

Kashyap Patel, MD

Schwartzberg expressed a similar sentiment, adding that switching from an originator to a biosimilar also requires a discussion with the patient. “We ask the provider to talk to the patient and say, ‘We have another version of the drug you’re getting. It works just as good as the other one. It is highly similar in terms of its efficacy and its safety, but it will cost you less, it will cost us less, and we’d like to change you to that. Are you comfortable with that?’ And almost invariably we get, ‘Yes,’ ” he said.

The panelists noted that the mechanics of interchangeability vary between states, with some states having passed biosimilar substitution laws that govern substitution requirements, pharmacy notification requirements (ie, to prescriber, patient, others), and recordkeeping requirements. Thus, health care providers need to be familiar with the biosimilar substitution laws in their states before making substitutions.

Although most states allow for substitutions if the FDA has determined a biosimilar to be interchangeable and a prescriber has not expressed a preference against the substitution, some states have additional stipulations. For example, Georgia also requires that patients approve the substitution and that the substituted biosimilar have the lowest retail price of all interchangeable biologics in stock when a prescriber prescribes a biologic by its nonproprietary name.³

“Given the fact that [biosimilars have] undergone appropriate vetting from the FDA, I’m very comfortable that we could change to the biosimilar at the time it becomes available,” Patel said. “But there are some states where you may have to go through more bureaucratic nightmares. And, again, it’s one of those realities of life that we have to live with.”

Deciding Between Biosimilars

Because multiple biosimilars are often available for one originator, selecting between them can be a challenge. However, Schwartzberg said the marketplace will help guide that decision. First, he said cost will come into play, particularly the reimbursement scheme for each biosimilar considered. Second, the reputation of the company should be considered. Third, it is important to select the agent that is less likely to run into delivery issues. “It’s thinking about the company that’s providing the drug—their reliability, their history, their experience with manufacturing biologics, and so forth,” he said.

Schwartzberg noted that even though not all state laws factor patients into the equation for biosimilar substitution or selection, it is important to consider patient preferences. Most patients are concerned with costs, so they should be offered the opportunity to switch to a biosimilar whenever possible. “It’s a tragedy that the most common reason for bankruptcy in the United States today is medical bills. And oncology, unfortunately, is one of the most expensive treatments out there. Every new drug that comes out now is over $100,000 a year, which is not sustainable,” he said, adding that when he tells patients there is a drug that is going to work just as well for them as what they are currently on but that it will cost them 30% less, most patients select the less costly option.

Although payers, providers, and patients are generally in favor of using biosimilars, Schwartzberg warned that payers sometimes have contracts that enable them to obtain the originator drug at a reduced cost. “It speaks to the complexity of the way drugs are reimbursed in the United States today. It’s something we’re living with and something that we’re trying to simplify and change,” he said.

Extrapolating Data Across Tumor Types

Because biosimilars are not exact replications of their biologic counterparts, the panelists examined whether data for biologics could be extrapolated to biosimilars. Schwartzberg explained that extrapolation regarding biosimilars has a regulatory definition. “The regulatory definition from the FDA is that you do one clinical trial in a sensitive population so that you can pick up any differences between the originator and the biosimilar, and if you get a result that shows equivalence, you can extrapolate that data into other settings in the same disease,” he said, explaining that this also extends into any other approved indications for the originator drug.

Based on this concept, Schwartzberg said a biosimilar for a drug like trastuzumab, which has approval for HER2-positive breast cancer as well as HER2-positive gastric and gastroesophageal junction cancers, could be used in all these settings despite the biosimilars not being extensively tested outside of HER2-positive breast cancer. He said it also enables trastuzumab biosimilars to be used across breast cancer indications. “If you’re using a biosimilar that was tested in the neoadjuvant and adjuvant setting, it can also be used in the metastatic setting. I believe that any biosimilar can be extrapolated to any other indication that is in the FDA label,” he said.

Patel concurred: “I’m very comfortable with extrapolation because that’s one of the terms that the FDA has been fairly clear about.” However, he noted there are sometimes challenges to using biosimilars for all indications its originator has been approved for, citing use of bevacizumab-awwb (Mvasi) in the ovarian cancer space as an example. “The companies that have the competing product in the market have some sort of legal wrangling going on to ensure that that indication right now is not covered,” he said. Subsequently, the label for bevacizumab-awwb does not include ovarian cancer as an indication.⁴

Schwartzberg said the only setting he would not be comfortable using a biosimilar is when there are no data to extrapolate. “I would be hesitant to use a biosimilar, just like I would be with the originator, in a nonindication situation, or at least where there have not been studies to date,” he said.

Future Trends

The panelists then discussed some emerging trends they suspect are going to impact the field of biosimilars in the future. For example, they noted the potential for biosimilar development to expand into other biopharmaceutical classes as more patents expire. “It’s possible we will have biosimilars in the realm of antibody-drug conjugates in the next few years,” Schwartzberg said.

Patel suggested the same about immuno-oncology (I-O) products. “When the I-O medications come off their patents in maybe 4 or 5 years from now, I think that we will probably look at all the different I-O compounds. I’m sure in 5 years, that probably will be another wave,” he said.

Another major development the panelists noted was the emergence of “biobetters,” which refer to drugs in the same class as an existing biopharmaceutical that are improved over their originators. “If you understand the biology and the manufacturing, potentially you could make a drug that works better [than the originator],” Schwartzberg said, explaining that biobetters would be a step up, not only in terms of less cost for the same efficacy, but maybe less cost for more efficacy—and that would be an exciting development.

References:

1. Konstantinidou S, Papaspiliou A, Kokkotou E. Current and future roles of biosimilars in oncology practice. Oncol Lett. 2020;19(1):45-51. doi:10.3892/ol.2019.11105
2. NCCN. Clinical Practice Guidelines in Oncology. Breast Cancer, version 5.2020. Accessed July 19, 2020. https://www.nccn.org/professionals/physician_gls/pdf/breast_blocks.pdf
3. Kuyers SBS. 45 states now have biosimilar substitution laws. Mintz. February 11, 2019. Accessed July 19, 2020. bit.ly/39dwNux
4. Mvasi. Prescribing information. Amgen Inc; 2019. Accessed August 3, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761028s004lbl.pdf