EU Says Yes to Mylotarg for AML, No to Adjuvant Sunitinib

Zosia Chustecka


February 23, 2018

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 The drug was voluntarily withdrawn from the market in 2010 at the request of the US Food and Drug Administration  because confirmatory trials after its original approval failed to verify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).

No 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.

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