EMA Recommends Granting a Marketing Authorisation for Neratinib After Re-examining Its Negative Opinion for This Medicine

It is indicated in extended adjuvant treatment of adult patients with early stage, hormone receptor positive, HER2-overexpressed/amplified breast cancer

On 28 June 2018, the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP), following a re-examination procedure, adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product neratinib (Nerlynx), intended for the adjuvant treatment of adult patients with breast cancer. 

The applicant for this medicinal product is Puma Biotechnology Limited. 

On 22 February 2018, the CHMP had originally adopted a negative opinion for Nerlynx for broader use in HER2-positive early breast cancer. At the request of the applicant, the CHMP started a re-examination of its opinion. Following the re-examination, the CHMP adopted a final positive opinion on 28 June 2018, but in a restricted patient population. 

Nerlynx will be available as 40-mg film-coated tablets. The active substance of Nerlynx is neratinib, an irreversible pan-ERBB tyrosine kinase inhibitor (ATC code: L01XE45). It blocks mitogenic growth factor signal transduction through covalent, high-affinity binding to the ATP binding site of 3 epidermal growth factor receptors resulting in sustained inhibition of these growth promoting pathways in breast cancers with HER2-amplified or over-expressed, or which are HER2-mutant. 

The benefits with Nerlynx are its ability to reduce the risk of invasive disease recurrence after two years compared with placebo. 

The most common side effects are diarrhoea, nausea, fatigue, vomiting, abdominal pain, rash, decreased appetite, upper abdominal pain, stomatitis and muscle spasms. 

The full indication is: "Nerlynx is indicated for the extended adjuvant treatment of adult patients with early-stage hormone receptor positive, HER2-overexpressed/amplified breast cancer and who are less than one year from the completion of prior adjuvant trastuzumab based therapy". 

It is proposed that Nerlynx be prescribed by physicians experienced in the treatment of cancer. 

Detailed recommendations for the use of this product will be described in the summary of product characteristics, which will be published in the European public assessment report and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission. 

Summaries of positive opinion are published without prejudice to the Commission decision, which will normally be issued 67 days from adoption of the opinion. 

What did the company present to support its application? 

The company provided the results from one main study involving 2,840 women with early breast cancer with high levels of HER2 who had already received treatment that included trastuzumab. In these women, daily treatment with Nerlynx for a year was compared with placebo. The main measure of effectiveness was the proportion of women who had lived

without the cancer coming back at the end of the 2-year study. 

What were the CHMP’s main concerns that led to the initial negative opinion? 

The CHMP noted that a greater proportion of women given Nerlynx in the study lived for 2 years without their disease coming back than women given placebo (around 94% versus 92% respectively). However, it was uncertain that this difference in benefit would be seen in clinical practice. Furthermore, Nerlynx causes side effects in the digestive system, particularly diarrhoea, which affected most patients and might be severe and difficult to manage. The Committee therefore concluded that the benefits were not enough to outweigh the risk of side effects and recommended that Nerlynx be refused marketing authorisation.

What happened during the re-examination? 

During the re-examination the CHMP looked again at all the data and considered whether there would be a group of patients where the benefits outweighed the risks. 

What were the conclusions of the CHMP following the re-examination? 

Following its review of the data and discussion within the Committee, the CHMP noted that benefits seemed to be largely confined to patients whose cancer was hormone receptor positive. The Committee therefore concluded that the benefits of the medicine would outweigh its risks if the medicine’s use were restricted to treatment of early breast cancer that not only had high levels of HER2 but was also hormone receptor positive. Measures would need to be put in place to manage Nerlynx’ side effects.