LILAC Safety Analysis Confirms Similarity of Trastuzumab Biosimilar ABP 980

Hans-Christian Kolberg, MD

Prespecified analyses from the phase III LILAC trial confirmed the tolerability and clinical similarity in cardiac safety between ABP 980 (Kanjinti; trastuzumab-anns), a trastuzumab (Herceptin) biosimilar, and reference trastuzumab. These types of analyses are critical in enhancing provider confidence, said Hans-Christian Kolberg, MD.

“If we’re going to replace a standard that we’ve been working with for years now, it has to be safe,” said Kolberg, head of the Department of Obstetrics and Gynecology, Breast Cancer Center, and Gynecologic Cancer Center at Marienhospital Bottrop. “We have to be completely sure [of its similarity] and ensure that it is not harming the patient. Papers like the one we presented will provide people with that confidence.”

In the trial, 725 patients with early-stage HER2-positive breast cancer received 4 cycles of neoadjuvant chemotherapy and were randomized to receive either ABP 980 (n = 364) or trastuzumab (n = 361). After surgery, patients continued on treatment for an additional year; those on ABP 980 continued on the biosimilar and those on reference trastuzumab were then re-randomized to either continue on trastuzumab (n = 190) or to switch to ABP 980 (n = 171).

Prior results demonstrated equivalent pathologic complete response (pCR) rates between ABP 980 and reference trastuzumab per central review. Follow-up safety data that were presented at the 2019 ASCO Annual Meeting showed a similar incidence in left ventricular ejection fraction decline between arms (ABP 980, 2.8%; trastuzumab, 3.3%; trastuzumab/ABP 980, 3.5%). No new cardiac safety signals were observed in patients who received ABP 980 or those who crossed over to ABP 980 after surgery. Notably, no patients discontinued adjuvant ABP 980 as a result of cardiac failure.

In June 2019, ABP 980 became the fifth trastuzumab biosimilar to receive regulatory approval for use in patients with HER2-overexpressing breast cancer as well as those with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.

In an interview with OncLive, Kolberg discussed the design of the LILAC study, the cardiac safety profiles of ABP 980 and reference trastuzumab, and patient and provider comfort with ABP 980 in practice.

OncLive: Could you provide background to the LILAC study?

Kolberg: We presented the outcome data from the LILAC study at the 2018 ASCO Annual Meeting that were subsequently published in Lancet Oncology. LILAC was a registration study for a trastuzumab biosimilar. It was a neoadjuvant study, in which we used pCR as the endpoint because it's much cleaner than other endpoints in metastatic studies such as response rate, which is much more difficult to [measure]. Many biosimilars are tested in the neoadjuvant setting for breast cancer although you can choose [any setting to evaluate these agents]. The only caveat is that the study has to use an accepted endpoint. Many studies are choosing the pCR endpoint like we did.

We treated patients with a run-in of epirubicin and cyclophosphamide chemotherapy followed by paclitaxel or docetaxel. Paclitaxel was given every 3 weeks or weekly, according to local standard, in combination with trastuzumab or ABP 980. After therapy, patients underwent surgery. LILAC is the first and only study that did a pCR review in a multicenter setting; this was very difficult, because investigators had to send specimens from all over the world. We had patients in Russia, Europe, and the United States. Although it was really difficult, this effort paid off because biosimilarity could only be proven in central review. We showed that it's feasible to do a multicenter, international central review for pCR specimens.

The second unique aspect about LILAC is it is the only biosimilar registration study that included a re-randomization. Not all patients stayed on trastuzumab if they were assigned to it initially. After patients underwent surgery, we did a re-randomization of the trastuzumab arm, in which half of the patients stayed on trastuzumab, and the other half went on to receive ABP 980. That’s important. Many colleagues have a [trastuzumab biosimilar] quota and may have to

switch their patients over to a trastuzumab biosimilar during therapy. This is the only study that showed that this is safe and feasible.

At the 2019 ASCO Annual Meeting, we presented a poster regarding cardiac safety. Cardiac safety is very important regarding biosimilars. Biosimilars are not completely the same as their originator product, but they have the same efficacy, more or less, in terms of the predefined boundaries. Because of these quotas, people will [likely] have to use biosimilars.

It's very important to do a lot of safety work because people have to have confidence that the biosimilar is really safe. Efficacy is one thing, but safety is another. Saving money is, of course, important in terms of healthcare economics, but the agent must also be safe. We were able to show that the cardiac events of trastuzumab and ABP 980 were completely the same. Neither agent showed a higher cardiac event rate, in the arm that only received ABP 980 as well as the arm that switched from trastuzumab to ABP 980. When it comes to cardiac safety, we are sure that this is a safe approach.

What advice can you give to practicing oncologists who are weary about prescribing biosimilars?

Even among oncologists who have been in the field for years, it's still very difficult to differentiate between a generic medication and a biosimilar. A generic is simply like cooking the same recipe, whereas developing a biosimilar is completely different; it's like developing a new medication—you just do it the other way around. It is reversed engineering because you have to find out what the original company was doing.

Biosimilars can be sold for less than their biologic counter products. Developing a new antibody is an investment that can cost more than $1 billion, whereas developing a biosimilar for a known antibody costs around $200 million. This is, of course, important in countries such as the United States or Germany because we can use that cost savings for other things in healthcare. [Cost savings is] even more important in developing countries where giving a patient an antibody is not a question because there's no money for it. In that case, biosimilars may offer a huge opportunity to gain access to antibodies.

We're developing biosimilars because [these products are] making healthcare cheaper, but to come back to your question, people have to have confidence that what they're prescribing is safe. Every signal we can report showing that this is a safe therapy is crucial—particularly regarding cardiac safety, as this is a main issue with trastuzumab. That will provide people with confidence.

Regarding registration, biosimilars are always looked at with a “totality of evidence.” Authorities examine the clinical signals, safety signals, pharmacokinetics, and pharmacodynamics much closer than they do with the originators. This is, of course, understandable. A biosimilar is [essentially replicating] the originator product, so it warrants a closer examination.

Could you discuss the importance of gathering real-world evidence with biosimilars?

Real-world data are needed; [however], it's very difficult to get funding for it. We are planning a real-world study on the cardiac safety [of ABP 980], and we're trying to predict cardiac safety with early endpoints by drawing blood after 2 cycles of the biosimilar or antibody. Then, we’re going to try to measure biomarkers that may predict cardiac failure in patients; this is very important because the cardiac signals in trastuzumab trials have been decreasing over the years. That’s not because trastuzumab is less cardiotoxic, it is because we are more aware of the associated cardiac toxicities and the inclusion/exclusion criteria are stricter. It's very important to include patients who are real-world candidates for trastuzumab in a safety study, and not only for a clinical registration trial. Of course, the inclusion/exclusion criteria are designed to be safe and ethical.

Has patient access to anticancer therapy improved with the availability of biosimilars?

In the developed countries, it's very hard to say that access has really improved but globally, it has. In the United States and in Germany, access to trastuzumab was not really a problem. In the developing countries, it definitely has improved; I know that from a hospital in China I'm cooperating with.

Kolberg H-C, Colleoni M, Demetriou G, et al. Cardiac safety of the trastuzumab biosimilar ABP 980 in women with HER2-positive early breast cancer in the LILAC study. J Clin Oncol. 2019;37 (suppl 15; abstr 557). doi: 10.1200/JCO.2019.37.15_suppl.557.