HERITAGE shows MYL-1401O has similar overall response to Herceptin (trastuzumab)

At 48 weeks, no significant differences in PFS and OS were seen, and safety was comparable to Herceptin.

„If approval is granted then this should lead to greater use around the world… Once we see what the cost differential is, it will stimulate competition and this will lower the price further. This is critical and is really the end-game.” Hope Rugo, MD, Professor of Medicine at the University of California San Francisco (UCSF) Comprehensive Cancer Center, US.

“I’m encouraged by these data with no new safety signals at all, and additional efficacy endpoints that demonstrate biosimilarity,” remarked Professor Hope Rugo, Professor of Medicine, University of California San Francisco (UCSF) Comprehensive Cancer Center, US. “The proposed trastuzumab biosimilar MYL-1401O could be a new treatment option for HER2+ metastatic breast cancer,” she added.

Biologics are complex and costly proteins, which have limited access across the globe. Now many biologics are losing patent protection, biosimilars have the potential to significantly improve access to expensive agents. “There are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency,” said Professor Rugo, explaining how biosimilars compared to branded products, adding that, “Regulatory considerations are still being incorporated into trials and being understood for complex cancer drugs. Trastuzumab will be the first biosimilar cancer drug.”

The HERITAGE trial met the final criteria of the regulatory guidelines for biosimilar approval. Pharmacokinetic and pharmacodynamic studies have already been carried out in healthy humans, as well as comparisons of MYL-1401O to the European-generated and US-generated branded trastuzumab. In this study, Professor Rugo and her colleagues aimed to test this drug to show similarity in clinical outcomes. Herceptin had its greatest initial impact in metastatic HER2 positive breast cancer, and studies have shown impact on PFS and OS. This was the patient population chosen for this study.

The double-blind, randomised clinical trial was designed to evaluate comparative efficacy and safety of MYL-1401O versus Herceptin. Patients with measurable HER2 positive metastatic breast cancer were randomised to receive either MYL-1401O or Herceptin with docetaxel or paclitaxel for a minimum of eight cycles, and then trastuzumab until progression.

The primary endpoint was ORR at week 24 by blinded central evaluation using RECIST 1.1. Secondary endpoints include PFS and OS at week 24, safety, tolerability, immunogenicity, and in addition, PFS, OS, at week 48, and OS at 36 months.

“With biosimilars you want to choose a short term endpoint, that you can reach quickly that represents the initial effect of the biosimilar agent,” advised Dr Rugo. “The regulatory agencies have suggested that a difference or a ratio in overall response rate is the best way to look at this.”

An intention-to-treat sample of 456 patients was calculated to demonstrate equivalence in ORR at week 24 for the investigative biosimilar compared to the branded drug. Of these, 44% had hormone receptor positive MBC, 84% received docetaxel. A total of 230 patients were randomised to MYL-14010 plus a taxane, and 228 to Herceptin plus taxane. In the MYL-14010 group, 55 patients discontinued treatment, while 65 discontinued in the Herceptin group.

Reporting the results, Dr Rugo said that at week 24, the ORR was 69.6% for patients on MYL-1401O compared to 64% for those on Herceptin. The ratio of ORR was 1.09 with both the 90% confidence interval (CI) of 0.974-1.211, and 95% CI of 0.954-1.237, within the pre-defined equivalence margin.

“Here at ESMO 2016, we are excited to have the 48 week PFS. We actually don’t have 50% of progression events yet so we assessed this by looking at events in those patients who had had 48 weeks or more of follow-up and assessing them for PFS and OS. We showed equivalency for PFS and OS, with the caveat that there were very few survival events.”

There was no statistical difference between MYL-1401O versus Herceptin in PFS at a minimum of 48 weeks (HR 0.96 (95% CI: 0.730, 1.261) with a median PFS of 11.1 months in both arms.

At the time of presentation, the median OS had not been reached but OS at 48 weeks was 89.1% and 85.1% for MYL-1401O and Herceptin respectively.
Regarding serious adverse events at week 48, 39.3% occurred in the MYL-1401O arm, compared to 37% in patients on Herceptin. Of these, neutropenia occurred in 27.5% on MYL-1401O, and in 25.2% on Herceptin. Fatal events were found in six and four patients in the MYL-1401O and Herceptin arms respectively. One death due to respiratory failure in each arm was considered as possibly related to trastuzumab. Five patients in the MYL-1401O arm died due to pancytopenia and hepatic failure, cardiac failure and respiratory failure, carditis, dyspnoea and multi-organ failure; while in the Herceptin arm, fatal events for three patients were reported as: probable sepsis, pneumonia and sepsis, hepatic failure and tumour lysis.

Reflecting on the importance of a trastuzumab biosimilar, Professor Rugo said: “It’s really exciting because much of the world does not have access to trastuzumab and it clearly saves lives and increases survival in the metastatic setting.”

Herceptin is off-patent in Europe, and the MYL-1401O data have now been submitted to the European Medicines Agency. “If approval is granted then this should lead to greater use around the world,” she added.

“Once we see what the cost differential is, it will stimulate competition and this will lower the price further. This is critical and is really the end-game, making the drug available at reduced cost,” asserted Professor Rugo.

Based on Rugo H, Barve A et al. Heritage, a phase III safety and efficacy trial of the proposed trastuzumab biosimilar, Myl-1401O vs trastuzumab (LBA16). Presented on Sunday 9 October 2016.

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