Francisco J. Esteva, MD, PhD, discusses the journey of CT-P6 and its promise as a potential biosimilar for trastuzumab in the United States.
Francisco J. Esteva, MD, PhD
Although MYL-1401O (Ogivri; trastuzumab-dkst) is the sole trastuzumab (Herceptin) biosimilar currently approved in the United States, there are multiple biosimilars for this biologic in the pipeline, said Francisco J. Esteva, MD, PhD.
CT-P6 is a trastuzumab biosimilar candidate that is currently being investigated for safety and efficacy to determine whether it is equivalent to reference trastuzumab in patients with early-stage breast cancer who are being treated with chemotherapy in the neoadjuvant setting (NCT02162667).
Data published in Lancet Oncology in 2017 showed that in patients with HER2-positive breast cancer, CT-P6 demonstrated equivalent efficacy to reference trastuzumab and the adverse events observed in both arms were similar.1 The randomized, double-blind, active-controlled, phase III trial led to the February 2018 European Union approval of CT-P6, marketed as Herzuma.2
The biosimilar is approved for the treatment of patients with early breast cancer, metastatic breast cancer, or metastatic gastric cancer whose tumors have either HER2 overexpression or HER2 gene amplification. This type of extrapolation beyond the indication studied in pivotal studies is expected from regulatory agencies in the future.
Celltrion, the manufacturer of CT-P6, resubmitted an abbreviated biologics license application for the biosimilar to the FDA in June 2018. In January, the company received a complete response letter from the FDA to their application regarding their manufacturing facility in Incheon, South Korea.
Of 546 patients enrolled on the pivotal phase III trial, 271 were randomized to CT-P6, while 278 received reference trastuzumab. The rates of pathologic complete response (pCR) were similar between the treatment arms. In the CT-P6 arm, the pCR was 46.8%, which is comparable with the pCR of 50.4% for reference trastuzumab.
“It is important to show that biosimilars for originator biologics can be as effective and safe as the reference product,” said Esteva, who is the global principal investigator for the pivotal registration trial. “I believe that with CT-P6, we have been able to show that.”
In an interview with OncLive, Esteva, director of breast medical oncology at NYU Langone’s Perlmutter Cancer Center, discussed the journey of CT-P6 and its promise as a potential biosimilar for trastuzumab in the United States.Esteva: We conducted a randomized, phase III, multicenter trial to compare the reference trastuzumab with the biosimilar candidate CT-P6. We decided to study it in patients with early-stage breast cancer in the neoadjuvant setting with standard chemotherapy with the primary endpoint of pCR as opposed to overall survival (OS) or disease-free survival (DFS), which takes much longer.
When we planned this trial with the sponsor, the FDA had provided some guidance regarding patient population and endpoints, but there were no biosimilars approved at that time. The guiding principle was that the agency would look at the totality of the evidence.
Several trastuzumab biosimilars were studied in the metastatic setting and some in early-stage breast cancer. However, it was not completely clear what the FDA would consider a valid endpoint for approval. We thought pCR was an appropriate endpoint in HER2-positive breast cancer, since pertuzumab (Perjeta) had been approved in the neoadjuvant setting by the FDA based on pCR. Therefore, we chose early stage—mostly stage II and III—breast cancer in the neoadjuvant setting with an endpoint of pCR. We showed that the pCR was within the statistical boundaries for the prespecified similarity between reference trastuzumab and the trastuzumab biosimilar CT-P6.
The primary endpoint of the study was pCR at the time of definitive surgery. We are now assessing the DFS and the OS rates, which are secondary endpoints on the study. We hope the totality of the data generated by this trial will be sufficient to get it approved by the FDA.When we started this project, no biosimilars were approved by the FDA [for the treatment of cancer]. Now, there are several monoclonal antibody biosimilars approved, and there will be more in the next few years. The standard drug development for originator antibodies such as [trastuzumab] involves phase I, II, and III trials. But, for biosimilars, that is not required by the FDA. Once similarity is demonstrated, the agency will likely allow extrapolation to other indications related to the reference drug.
For CT-P6, the sponsor completed a phase I trial3 and the pivotal randomized phase III trial described above. The phase I study showed the safety and pharmacokinetics of the CT-P6 biosimilar compared with reference trastuzumab. What is different about this phase I trial compared with traditional phase I trials is that this was a randomized trial. Phase I trials are not usually randomized, as they involve a small number of patients. In this trial, we had to randomize participants to be able to compare the pharmacokinetics of the biosimilar with the originator product. The other difference is that this was done in patients without cancer. These patients were given 1 dose, and then we looked at the pharmacokinetics of both monoclonal antibodies.
Prior to launching any clinical trials, manufacturers must produce extensive preclinical data to demonstrate that their molecule is the same as the reference drug through amino acid sequencing, purity, functional studies and other in vitro and in vivo experiments. This is very different to the drug development of generic drugs, for which the preclinical development is much less stringent. Biologics are protein-based therapies made in living cells, which is much more complex than chemical entities.
Manufacturing a monoclonal antibody similar to trastuzumab, bevacizumab (Avastin), or rituximab (Rituxan), is extremely difficult and requires sophisticated technology. First, they have to show that it is the same molecule in vitro and in vivo. Then in patients, sponsors must show that the pharmacokinetics and efficacy are the same in randomized trials.
Although all this guidance and experience is leading to the first wave of biosimilars, in the future we may not need to complete large randomized trials like the one we recently completed for CT-P6.My understanding is that biotechnology companies may not be able to market trastuzumab biosimilars until the original patents expire in the United States, even if the drug is FDA approved. Patents are different in each country.I was personally involved in the clinical development of CT-P6 and I believe the totality of the evidence supports its use for the appropriate indications. I hope this and other biosimilar monoclonal antibodies are incorporated into patient care, and help reduce the cost of healthcare in the long run. Although trastuzumab biosimilars are not an improvement over what is already available in terms of safety and efficacy, having more options should bring down the costs of older medications so that we can spend more resources developing new drugs.