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Date: 2018-02-22

Type of information: Refusal of a Market Autorisation in the EU

Product name: Nerlynx® (PB272)

Compound: neratinib

Therapeutic area: Cancer - Oncology

Action mechanism:

  • kinase inhibitor/tyrosine kinase inhibitor. PB272 (neratinib) is a potent irreversible tyrosine kinase inhibitor that blocks signal transduction through the epidermal growth factor receptors, or EGFRs, HER1, HER2 and HER4.

Company: Puma Biotechnology (USA - CA)

Disease:

  • extended adjuvant treatment of HER2-positive early stage breast cancer that has previously been treated with trastuzumab (Herceptin®)-based adjuvant therapy

Latest news:

  • • On February 22,2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of the marketing authorisation for Nerlynx®. The drug was expected to be used to treat adults with early breast cancer who had already had treatment that included trastuzumab, but who were at high risk of their cancer coming back. Nerlynx® was intended for extended use only with breast cancers that produce high levels of a protein called HER2, which helps cells to divide and grow.
  • Puma Biotechnology 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.
  • The CHMP considered 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 is 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 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.
  • • On July 17, 2017, the FDA approved Nerlynx® (neratinib) for the extended adjuvant treatment of early-stage, HER2-positive breast cancer. For patients with this type of cancer, Nerlynx is the first extended adjuvant therapy, a form of therapy that is taken after an initial treatment to further lower the risk of the cancer coming back. Nerlynx® is indicated for adult patients who have been previously treated with a regimen that includes the drug trastuzumab.
  • The safety and efficacy of Nerlynx® were studied in a randomized trial of 2,840 patients with early-stage, HER2-positive breast cancer who completed treatment with trastuzumab within the previous two years (ExteNET). The study measured the amount of time after the start of the trial that it took for the cancer to come back or for death to occur from any cause (invasive, disease-free survival). After two years, 94.2 percent of patients treated with Nerlynx® had not experienced cancer recurrence or death compared with 91.9 percent of patients receiving placebo.
  • Common side effects of Nerlynx® include diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, swollen and sore mouth (stomatitis), decreased appetite, muscle spasms, indigestion (dyspepsia), liver damage (AST or ALT enzyme increase), nail disorder, dry skin, abdominal swelling (distention), weight loss and urinary tract infection.
  • Patients should be given loperamide for the first 56 days of treatment with Nerlynx® and as needed thereafter to help manage diarrhea. Additional antidiarrheals, fluids and electrolytes should also be given as clinically indicated to help manage diarrhea. Patients who experience severe side effects, including diarrhea or liver damage (hepatoxicity), should stop taking Nerlynx. Women who are pregnant or breastfeeding should not take Nerlynx® because it may cause harm to a developing fetus or a newborn baby.
  • • On August 22, 2016, Puma Biotechnology announced that the Marketing Authorization Application (MAA) for neratinib has been validated by the European Medicines Agency (EMA). Validation of the MAA confirms that the submission is complete and starts the EMA's formal review process. The potential indication for neratinib is for the extended adjuvant treatment of HER2-positive early stage breast cancer that has previously been treated with trastuzumab (Herceptin®)-based adjuvant therapy. The MAA submission is based upon the ExteNET Phase III study, which reached its primary endpoint whereby neratinib demonstrated a statistically significant reduction of risk of invasive disease recurrence or death versus placebo.
  • In the ExteNET study, treatment with neratinib resulted in a 33% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.67, p = 0.009). The 2-year invasive disease free survival (DFS) rate for the neratinib arm was 93.9% and the 2-year DFS rate for the placebo arm was 91.6%. For the pre-defined subgroup of patients with hormone receptor positive disease, the results of the trial demonstrated that treatment with neratinib resulted in a 49% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.51, p = 0.001). For the patients with hormone receptor positive disease, the 2-year DFS rate for the neratinib arm was 95.4% and the 2-year DFS rate for the placebo arm was 91.2%. Results of the study were published online in The Lancet Oncology on February 10, 2016.
  • The most frequently observed adverse event for the neratinib-treated patients was diarrhea, with approximately 39.9% of the neratinib-treated patients experiencing grade 3 or higher diarrhea (1 patient (0.1%) had grade 4 diarrhea). Patients who received neratinib in the ExteNET trial did not receive any prophylaxis with antidiarrheal agents to prevent the neratinib-related diarrhea. Interim results of a Phase II study of neratinib monotherapy in patients with HER2-positive early stage breast cancer who have previously been treated with adjuvant trastuzumab, where patients received anti-diarrheal prophylaxis with loperamide, demonstrated that treatment with prophylactic loperamide reduced the rate of grade 3 or higher diarrhea to between 13.0% and 18.5%.
  • • On July 21, 2016 , Puma Biotechnology has submitted a New Drug Application (NDA) to the FDA for  PB272 (neratinib) for the extended adjuvant treatment of patients with early stage HER2-overexpressed/amplified breast cancer who have received prior adjuvant trastuzumab (Herceptin®)-based therapy. The submission is supported by the results of the ExteNET Phase III study, in which treatment with neratinib resulted in a 33% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.67, p = 0.009). The 2-year invasive disease free survival (DFS) rate for the neratinib arm was 93.9% and the 2-year invasive DFS rate for the placebo arm was 91.6%. For the pre-defined subgroup of patients with hormone receptor positive disease, the results of the trial demonstrated that treatment with neratinib resulted in a 49% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.51, p = 0.001). For the patients with hormone receptor positive disease, the 2-year invasive DFS rate for the neratinib arm was 95.4% and the 2-year invasive DFS rate for the placebo arm was 91.2%. Results of the study were published online in The Lancet Oncology on February 10, 2016.
  • • On June 27, 2016, Puma Biotechnology announced that it has submitted its Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for neratinib. The potential indication is for the extended adjuvant treatment of HER2-positive early stage breast cancer that has previously been treated with trastuzumab (Herceptin®)-based adjuvant therapy. The submission is based upon the ExteNET Phase III study.
     

Patents:

Submission of marketing authorization application USA : 2016-07-21

Submission of marketing authorization application UE: 2016-06-27

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2017-07-17

UE authorization:

Favourable opinion UE:

Favourable opinion USA:

Orphan status USA:

Orphan status UE:

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes