The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has issued a negative opinion of neratinib as an extended adjuvant treatment of early stage, HER-2 positive breast cancer.
The negative opinion means the committee recommends the EMA reject a marketing application for neratinib for this indication as submitted by its developer, Puma Biotechnology.
Adjuvant therapies are used as an addition to primary treatment to help further decrease the risk of cancer returning in these patients.
The committee’s decision contrasts that of the U.S. Food and Drug Administration, which approved the medicine for this indication in July 2017. The therapy is sold as Nerlynx tablets.
Puma Biotechnology had announced in January that the CHMP was unlikely to recommend neratinib for this indication, following a meeting between company officials and members of the CHMP.
Puma can request the decision be reevaluated if it does so within 15 days of the receipt of the CHMP decision. The company said it would submit a letter of intent by that deadline.
ExteNET, a double-blind, placebo-controlled study, randomized 2,840 patients to receive neratinib or a placebo. The trial tested the therapy in patients who already had completed post-surgery Herceptin (trastuzumab) within the previous two years. Its main goal was to determine if neratinib could extend the time a patient remained alive and the time without signs of disease recurrence.
After two years, 94.2% of patients receiving neratinib showed no signs of cancer recurrence or death, compared to 91.9% in the placebo arm.
One of the side effects of neratinib, however, is diarrhea, with 95.4% of patients in ExteNET experiencing it, and 39.9% having severe diarrhea.
The CONTROL trial was conducted to investigate whether preventive treatment with Imodium (loperamide) — with or without other agents — could reduce neratinib-associated diarrhea.
The trial included three patient groups. One received Imodium alone, the second received Imodium and budesonide, an anti-inflammatory corticosteroid believed to reduce diarrhea, and the third received Imodium plus colestipol, a bile acid sequestrant that is also expected to reduce diarrhea.
The study found that preventive treatment reduced the incidence of severe diarrhea to 30.7%, 23.4%, and 11.5%, respectively. Importantly, while patients in the ExteNET trial reported persistent diarrhea during the treatment period, patients in the CONTROL trial reported early but not recurring diarrhea.