ASCO 2016

Randomised double blind phase III safety and efficacy trial of the proposed trastuzumab biosimilar, MYL-1401O vs. Herceptin

Dr Hope Rugo - University of California, San Francisco, USA

Good afternoon. On behalf of our co-authors, the investigators worldwide who participated in this trial and my colleagues at Mylan and Biocon who sponsored and conducted the trial, it’s my pleasure to present to you the results of the HERITAGE trial which is a randomised double-blind phase III safety and efficacy trial of a proposed biosimilar called MYL-1401O versus the branded trastuzumab Herceptin.

Biologics are complex proteins with a high molecular weight. This is in contrast to the many generics we see on the market that are usually small molecules, simple chemicals and have a relatively low molecular weight. The biologic agents are usually targeted therapies and are costly, limiting access across the globe although in the case of trastuzumab, branded Herceptin, use of trastuzumab has improved survival in both early and late stage breast cancer. Many biologic agents are using patent protection soon or have already lost patent protection in other countries. Biosimilars have the potential to significantly improve access to expensive agents. The requirements for biosimilar approval across indications have been set by regulatory agencies and include demonstrating similar structural and functional similarity to the reference product, in this case branded Herceptin; to demonstrate similar pharmacokinetics and pharmacodynamics and to confirm similar safety, efficacy and immunogenicity which is the subject of this presentation. Of note, the PK and PD equivalence between the European and US branded Herceptin products and MYL is presented in an abstract at a poster session at this meeting.

The HERITAGE study randomised women with untreated metastatic HER2 positive breast cancer to receive the taxane of institution choice with either MYL-1401O or Herceptin. Patients received the standard dosing schedule of every three weeks along with the dosing schedule for the taxane, either docetaxel or paclitaxel. Patients who had stable or responding disease after eight cycles of chemotherapy could continue on the antibody alone until demonstration of progressive disease or toxicity. This is the standard way that these agents are used in clinical practice and were tested in the trials that demonstrated that Herceptin could improve survival in these patients.

500 patients were randomised in 95 sites across the globe. Our primary endpoint, following regulatory guidance, was overall response rate at week 24, that is the time that patients completed chemotherapy and went on antibody therapy alone. The FDA asked for a ratio of overall response rates and the EMEA, the European Agency, asked for a difference in response rates between the proposed biosimilar and Herceptin. Our secondary objectives were standard disease-related: time to treatment progression, progression free survival and overall survival at week 24 and also we will evaluate progression free survival at week 48, after patients have received therapy with antibody alone.

In addition, we looked at safety and immunogenicity as well as tolerability of the proposed biosimilar versus Herceptin and did a population pharmacokinetic study of the proposed biosimilar, as required by the regulatory agencies.

The overall response rate is listed on this slide and the number of patients on each arm. You can see that the overall response rates are almost identical between the proposed biosimilar with taxane compared to Herceptin with taxane. In addition we are showing you here the two endpoints required by the two different regulatory agencies, the ratio of overall response rate at both 90% and 95% confidence intervals, showing that this ratio fell well within the efficacy equivalence required. In addition, the difference in overall response rate required by the EMEA also falls well within the equivalency range required.

We looked at safety, population pharmacokinetics and immunogenicity. Overall the anti-drug antibody rate for the proposed biosimilar and Herceptin were equivalent at 2.4% and 2.8%, consistent with published data. In addition, we looked at the dose maximised concentration and area under the curve which are the pharmacokinetics and they were similar. As you can see, the toxicity is primarily hematologic with a few cases of pneumonia related to low blood counts and mainly attributed to the taxane chemotherapy but importantly identical between the two arms.

In summary, the HERITAGE study has demonstrated efficacy equivalence between the proposed trastuzumab biosimilar, MYL-1401O or Herceptin in combination with taxanes as first line therapy for HER2 positive metastatic breast cancer at 24 weeks. We also demonstrated similar safety, immunogenicity and pharmacokinetics. This proposed biosimilar has the potential to meet the need for an affordable treatment option for patients with HER2 positive cancers. This is one of the first trials with biosimilars in oncology to demonstrate these similar results. Ongoing trials with other biosimilars should further improve access worldwide to these life-saving therapies. Thank you.