EMA DRUG APPROVALS-NO TO ADJUVANT SUNITINIB-NO TO NERATINIB

In Europe, the Committee for Medicinal Products for Human Use (CHMP) has recommended for approval a new drug for acute myeloid leukemia (AML), and the indication includes use in patients from age 15 years upward.

The product, gemtuzumab ozogamicin (Mylotarg, Pfizer), will be indicated for use in combination therapy with daunorubicin and cytarabine for patients with previously untreated, de novo CD33-positive AML (the exception is acute promyelocytic leukemia).  

Gemtuzumab ozogamicin is a humanized IgG subtype 4 directed at CD33, which is conjugated to calicheamicin, a toxin that induces breaks in double-stranded DNA, subsequently inducing cell cycle arrest and apoptotic cell death.

The CHMP noted that "the benefit with Mylotarg is improvement in event-free survival."

The most common (>30%) side effects of Mylotarg when used together with daunorubicin and cytarabine are hemorrhage and infection, the Committee noted.

The product is already approved in the United States for a similar indication.

It returned to the US market after a 7-year absence, as previously reported by Medscape Medical News. The drug was voluntarily withdrawn from the market in 2010 at the request of the US Food and Drug Administration  because confirmatory trials after its original approval failed to verify clinical benefit and demonstrated problems with safety, including a high number of early deaths. Since then, however, several clinical trials initiated by clinical researchers showed benefit with the drug, and hematologists argued that a reconsideration may be warranted, especially because the drug had shown a survival benefit. The new approval, in September 2017, was for the same indication but at a lower dose.

Extended Indications for Several Cancer Drugs 

The CHMP also recommended extensions of indications for several cancer drugs, as follows:

• Bosutinib (Bosulif, Pfizer) is now also indicated for first-line use in newly diagnosed chronic-phase Philadelphia chromosome–positive chronic myelogenous leukemia (CML); the drug had previously been indicated for use in CML only among patients who had been treated with one or more tyrosine kinase inhibitors and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options.
• Olaparib (Lynparza, AstraZeneca) is now also indicated for use as monotherapy for the maintenance treatment of adults with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy. Previously the drug was indicated for use only in cases with BRCA mutations.
• Denosumab (Xgeva, Amgen) is now indicated for the prevention of skeletal-related events (pathologic fracture, radiation to bone, spinal cord compression, or surgery to bone) in adults with advanced malignancies involving bone (previously it was indicated in adults with bone metastases from solid tumors).

  o to Adjuvant Sunitinib After Kidney Cancer Surgery 

  However, at the same meeting the CHMP adopted a negative opinion for an extension of the therapeutic indication for sunitinib (Sutent, Pfizer) and recommended refusal for the new indication of adjuvant use after surgery for kidney cancer.
  The CHMP said that the application for this extra indication was based on a main study comparing sunitinib with placebo in 615 patients at high risk for relapse of kidney cancer after surgery. Patients were treated for around a year, and the study looked at how long it took for the cancer to come back (disease-free survival).
  This is the S-TRAC study, published in 2016 in The New England Journal of Medicine. It found that the median duration of disease-free survival was 6.8 years in the sunitinib group and 5.6 years in the placebo group (hazard ratio, 0.76; P = .03). At the time, the lead author, Alain Ravaud, MD, PhD, head of medical oncology at the University Hospital of Bordeaux, France, said, "If you ask me, does this become the standard, the answer is 'no.'" Instead, he feels that sunitinib is "an option to be discussed with patients," with the potential gains to be balanced against the risk for adverse events and their impact on quality of life, as reported at the time by Medscape Medical News.
  The CHMP said that it felt the evidence for sunitinib's delaying cancer relapse was "not convincing." Even when only the patients who were at highest risk for relapse were looked at separately, the benefits "were still not convincing."
  "Given the known side effects of the medicine," the Committee concluded that the benefits did not outweigh the risks and recommended that this change to the marketing authorization be refused.
  Sunitinib is already approved in Europe for use in metastatic kidney cancer, as well as gastrointestinal stromal tumors and pancreatic neuroendocrine tumors.

  Additional Indication for Idelalisib Withdrawn 

  In addition, an application to extend the use of idelalisib (Zydelig, Gilead) has been withdrawn. This drug is already approved for use in chronic lymphocytic leukemia (CLL) and follicular lymphoma.
  For CLL, idelalisib is currently indicated for use in combination with rituximab or ofatumumab in patients who have received at least one previous treatment.
  The new extension to that indication, which has now been withdrawn, would have been for use of idelalisib combined with rituximab and bendamustine. The application for this extended indication had already been reviewed by the CHMP. The Committee had said that additional longer-term data were needed, so the company withdrew the application.
  
  

  n Europe, the breast cancer drug neratinib (Nerlynx, Puma Technology) has been given a negative opinion, which means that approval is not recommended.

  The European Committee for Medicinal Products for Human Use (CHMP) was not impressed by the clinical data submitted from the pivotal trial of the drug, which showed only a small difference in efficacy between the drug and placebo, yet many patients experienced side effects with the drug. The CHMP therefore concluded that the benefits were not enough to outweigh the risk for side effects, and recommended that neratinib be refused market approval.

  This must have come as a nasty surprise to the company involved, for it had submitted the same clinical data in the United States, and there, the US Food and Drug Administration approved neratinib in July 2017.

  Neratinib is a tyrosine kinase inhibitor that targets HER2. It is intended for use in women with HER2+ breast cancer who have already been treated with the HER2 antibody trastuzumab (Herceptin, Roche/Genentech).

  The clinical data that were submitted for the drug's approval come from the pivotal ExteNET phase 3 trial, which was conducted in 2840 women with early breast cancer with high levels of HER2. These women had already received treatment that included trastuzumab. They were randomly assigned to a year of daily treatment with either neratinib or placebo.

  The CHMP notes that the main measure of effectiveness was the proportion of women who had lived without having their cancer return by the end of the 2-year study (the endpoint was invasive disease free–survival [iDFS]). This target was met in 94% of patients who received neratinib and in 92% of patients who received placebo.

  "It is uncertain that this difference in benefit would be seen in clinical practice," the CHMP stated.

  In addition, the CHMP pointed out that "neratinib causes side effects in the digestive system, particularly diarrhoea, which affected most patients and might be difficult to manage."

  In the trial, almost 40% of patients experienced grade 3 diarrhea within the first 30 days of treatment, according to data presented at the 2015 San Antonio Breast Cancer Symposium.

  In its approval of the drug, the FDA said that patients should be given the antidiarrheal drug loperamide (Imodium, Johnson & Johnson) for the first 56 days of treatment with neratinib and as needed thereafter.

  Uncertainty Over Neratinib Benefit

  When the results from the ExteNET study were published in November 2017 in the Lancet Oncology, an accompanying editorial and an outside expert both questioned how neratinib should be incorporated into breast cancer therapy, as previously reported by Medscape Medical News.

  Patients in the ExteNET trial took trastuzumab for 1 year and then neratinib for another year, so they had a total of 2 years on HER2-targeted therapy, pointed out Lisa A. Carey, MD, professor of breast cancer research at the North Carolina Cancer Hospital, Chapel Hill. "It's not trivial. Patients are going through a lot for a little [benefit]."

  A separate consideration is that neratinib is an oral drug, so with copays, considerable financial toxicity may be passed on to the patient, she added. (The wholesale cost of neratinib is estimated to be $126,000 for 1 year of therapy.)

  "Even though it is a positive study, neratinib's role may be fairly limited," she told Medscape Medical News at the time. "We need a better clarity on who needs this drug and who will benefit from it," she emphasized.

  Alexandra Zimmer, MD, from the Women's Malignancies Branch, Center for Cancer Research, the National Cancer Institute (NCI), raised similar concerns. In an NCI blog, she explained that despite the approval, because of several factors — the modest reduction in the recurrence rate, the fact that data on overall survival are not yet available, and the high rate of side effects — it is unlikely that neratinib will be widely used.

  The FDA's approval of neratinib was met with criticism from the breast cancer advocacy group Breast Cancer Action. The executive director of the group, Karuna Jaggar, noted the high cost of treatment, minimal clinical benefit from a surrogate endpoint (iDFS), and the absence of survival data. "A so-called 'surrogate endpoint' like invasive disease–free survival that is not clinically significant may be useful in guiding the development of experimental treatments, but it cannot replace the outcome that patients and doctors ultimately care about: women actually living longer, or at least living better with fewer side effects," she noted.

  "With the approval of neratinib, the FDA has once again approved an experimental drug that has not been shown to lengthen or improve breast cancer patients' lives — either by helping them live longer or live better, with fewer side effects," she wrote. "It means that thousands of cancer patients each year are exposed to expensive, toxic treatments that don't actually help them live longer," she said.

  
  

  U.S. regulators have approved expanded use of Eli Lilly and Co's Verzenio breast cancer drug as an initial treatment for certain women with advanced or metastatic disease, a decision that should boost sales of the medicine, the company said on Monday.

  The Food and Drug Administration approved the drug in combination with an aromatase inhibitor in previously untreated postmenopausal women with HR positive, HER2-negative advanced breast cancer.

  Verzenio was originally approved last September in combination with AstraZeneca's Faslodex (fulvestrant) once the disease had progressed following endocrine therapy.

  The Lilly oral drug competes with Pfizer's Ibrance and Kisqali from Novartis.

  The expanded approval was based on a late-stage study in which Verzenio, known chemically as abemaciclib, taken twice a day with either anastrozole or letrozole significantly delayed disease progression compared with a placebo and one of the aromatase inhibitors.

  "Today's news represents continued progress towards helping more people living with this devastating disease," Marc Hurlbert, chairman of the Metastatic Breast Cancer Alliance, said in a statement.

  Eli Lilly shares rose 31 cents to $80.49 in extended trading after closing up 1.8 percent on the New York Stock Exchange on Monday.