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.
OncLive: Could you provide some background information on this phase III equivalence trial of CT-P6?
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.
Can you touch on the development and testing of a biosimilar?
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.