Trastuzumab Biosimilar May Alleviate Financial Toxicity in HER2+ Breast Cancer

Chen Fu, MD

Preclinical and clinical data have demonstrated the equivalence of CT-P6 (Herzuma; trastuzumab-pkrb) to reference trastuzumab (Herceptin), said Chen Fu, MD, and the integration of the product into clinical practice could increase patient access by alleviating some of the financial toxicity associated with treatment.¹

“The entire purpose behind developing these biosimilars is to introduce competition to the market and make these targeted agents, which have since become these pivotal medications, more affordable for patients,” explained Fu. “The rationale behind the development of CT-P6 in particular was for it to be as equivalent to its reference product trastuzumab as it could be.”

The biosimilar received regulatory approval from the FDA in December 2018 for the treatment of patients with HER2-overexpressing breast cancer based on an extensive review of a comprehensive data package, which comprised foundational analytical similarity data, nonclinical data, and clinical pharmacology, immunogenicity, clinical efficacy, and safety data.²

Prior data from a double-blind, randomized phase III trial showed that the biosimilar boasted similar safety and efficacy to trastuzumab in the neoadjuvant setting.³ In updated data, investigators reported on pathological complete response (pCR), breast pCR, as well as safety and efficacy measures of a subgroup analysis in the adjuvant setting.⁴ Similar to the neoadjuvant data, results indicated that the pCR and breast pCR rates were found to be comparable between the products, regardless of patient characteristics such as age, region, or clinical stage.

Although equivalence between the two products has been demonstrated, the challenge of incorporating biosimilars into practice remains a challenge due to hesitancy within the community. The key to combat that, said Fu, is to provide more training and education on the use of the biosimilar as well as its fundamental equivalence to reference trastuzumab.

In an interview with OncLive, Fu, an assistant professor of medicine at NYU School of Medicine, discussed the data supporting the use of CT-P6, the benefits to bringing more biosimilars to the market, and the future that these products have in oncology.

OncLive: Could you speak to the approval process for biosimilars?

Fu: In 2010, the FDA introduced an abbreviated pathway for the development of biosimilars, because healthcare costs were such a priority for the government at the time. As a response to rising healthcare costs, the FDA introduced this abbreviated process, which cut a lot of the cost to developing these agents. Specifically, they cut out the need to base evidence on a giant body of clinical trials. This really blazed the way for multiple other agencies around the globe to follow suit by introducing the abbreviated pathway for biosimilars. CT-P6 followed that pathway.

In order for a biosimilar to be approved, you don't have to prove efficacy or safety; you have to prove equivalence, which is a very important distinction. Because the reference product trastuzumab has already been proven to be safe and effective, the approval process for biosimilars, such as CT-P6, are grounded on proving that the biosimilar product is equivalent and not clinically different from the reference product, which in this case was trastuzumab.

What data have been reported thus far with CT-P6?

There are 2 very large clinical studies that were done in order to prove the equivalence of CT-P6 as an agent. There was a phase I clinical trial of about 70 patients in a cohort that compared CT-P6 with trastuzumab, and found that there weren't any major differences in the adverse outcomes between the two groups.

Then, there was a larger phase III clinical trial that enrolled about 500 patients and looked at a multitude of endpoints—mainly efficacy, tolerability, and again, the safety of the agent when compared with trastuzumab. Results showed that there really wasn't any difference between the adverse events (AEs). Particularly, investigators wanted to look at cardiac AEs because trastuzumab is pretty well known to cause cardiac events in patients.

We used an efficacy measure that was recommended by the FDA, and it was a metric that allowed us to analyze our data much quicker. We found that there wasn't any real difference between CT-P6 and reference trastuzumab. In addition to that, tolerability was also the same. All in all, the data all coalesce to show that there was an equivalence between the two products.

Were any differences found between the two agents that are worth mentioning?

There weren't any clinically significant differences between the two. Every single difference that we saw wasn't statistically significant in our sample size. That was a big thing that the phase III trial was trying to prove, that there were no clinically significant differences. I can tell you that the major difference is going to be cost, which is the intended [goal].

Is there any work being done to examine CT-P6 in a real-world setting?

Not yet. That would be a phase IV clinical trial that would potentially be worth conducting. However, as of now, we're still waiting for more data to come in.

What are some of the benefits to implementing biosimilars, such as CT-P6, into practice?

The thing that I'm interested in is the effect of [the biosimilar] on costs. There’s this growing sentiment that we talk about the chemical toxicity of these drugs when we're in [the] developmental [phases]. Everyone is focused on chemical toxicity and AEs, but there's also this growing notion of financial toxicity for the patient.

Those who need these lifesaving treatments shouldn't have to go broke in order to receive them. As such, one of the big [factors] that I'm particularly interested in is the economic impact of these agents. In fact, we're already starting to see that there is a signal there—that there is an impact. Recently, earlier this year, the cost of trastuzumab in the United Kingdom went down dramatically. I personally believe that that biosimilars played a key role in that. In terms of longitudinal outcome benefits, nothing that we see so far suggests an outcome benefit [with] them. All in all, the outcomes that we've seen are more or less equivalent. However, again, we need to wait for more case reports and data to come in.

Are many physicians still hesitant to use biosimilars in practice? If so, what are some of the ways to get them more comfortable with their use?

Absolutely. As we know, medicine is storied tradition and it's very conservative by nature. It is absolutely a challenge to get oncologists to implement these agents into their practice. I believe the key to doing that is to provide more training and education, not just in the use of these agents, but also in their biosimilarity and fundamental equivalence to the reference agents that these oncologists are already used to utilizing in their daily practice.

What role could biosimilars play in the oncology space overall in the future?

More of [these products] are going to come out. CT-P6 was one of the first to came out, and, in fact, trastuzumab biosimilars as a whole were the first to come out simply because trastuzumab was the first large monoclonal antibody to emerge in cancer treatment back in 1998.

The patent in the United States for these drugs last for about 20 years and then that opens the market up to biosimilar agents. As such, I suspect that more and more biosimilars are going to come out for various agents pretty soon. This is going to revolutionize our practice. We're going to have more agents to choose from, and it's going to be the oncologist's role to act as a guide for patients and hospitals in choosing the appropriate agents for their patients.

The mission of biosimilars and the mission of the US government as a whole in creating this expedited pathway for biosimilars is to reduce the cost of healthcare and that requires the buy-in, input, and expertise of practicing clinical oncologists. My takeaway point to oncologists, as a whole, is that biosimilars are a safe and equivalent alternative to reference agents and could potentially alleviate some of the financial toxicity that is experienced by patients.

References

1. Fu C, Stebbing J, and Esteva FJ. Clinical development of CT-P6 in HER2 positive breast cancer [published online ahead of print September 11, 2019]. Expert Opin Biol Ther. doi: 10.1080/14712598.2019.1665019.
2. Celltrion and Teva Announce FDA Approval of Herzuma (trastuzumab-pkrb), a Biosimilar to Herceptin, for the Treatment of HER2-overexpressing Breast Cancer for Certain Indications. Celltrion. Published December 14, 2018. https://bit.ly/2KY6s8i. Accessed September 27, 2019.
3. Esteva FJ, Lee S, Yu S, et al. 24 months results from a double-blind, randomized phase III trial comparing the efficacy and safety of neoadjuvant then adjuvant trastuzumab and its biosimilar candidate CT-P6 in HER2-positive early breast cancer (EBC). Lancet Oncol. 2017;18(7):917-928. doi: 10.1016/S1470-2045(17)30434-5.
4. Esteva FJ, Baranau YV, Baryash V, et al. Efficacy and safety of CT-P6 versus reference trastuzumab in HER2-positive early breast cancer: updated results of a randomised phase 3 trial [published online ahead of print August 19, 2019]. Cancer Chemother Pharmacol. doi: 10.1007/s00280-019-03920-4.