First Therapy for High-Risk Neuroblastoma Approved by FDA

Zosia Chustecka

Disclosures

March 10, 2015

A new product approved by the US Food and Drug Administration (FDA) for use in the treatment of high-risk neuroblastoma has been shown, when used with other therapies, to prolong survival in children with this tumor. Dinutuximab (Unituxin, United Therapeutics) provides a treatment option that "fulfills a critical need," says the agency.

This is "a first approval for a therapy aimed specifically for the treatment of patients with high-risk neuroblastoma," noted Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research.

Dinutuximab is a chimeric monoclonal antibody that targets GD2, a glycolipid on the surface of neuroblastoma tumor cells, and has been shown to induce antibody-dependent cell-mediated cytotoxicity.

The approval covers its use as part of a multimodality regimen, including surgery, chemotherapy, and radiation therapy, for patients who have achieved at least a partial response to prior first-line multiagent, multimodality therapy.

"This approval has been a collaborative effort between the National Cancer Institute (NCI), the Children's Oncology Group (COG) and United Therapeutics for the first approved therapy for pediatric high-risk neuroblastoma," said Roger Jeffs, PhD, president and cochief executive officer at the company.

"Children with neuroblastoma will benefit from this collaboration, and the drug development pathway blazed by dinutuximab will likely be followed in the future to develop other novel agents directed against pediatric cancer therapeutic targets," said Malcolm Smith, MD, PhD, associate branch chief, pediatrics, in the Cancer Therapy Evaluation Program at NCI.

"This is not only the first successful immunotherapeutic to target a non-protein antigen, but also [the first] to be developed from an Investigational New Drug application through phase 3 trials largely through investigator-initiated effort and NCI support," commented Alice Yu, MD, PhD, from the University of California, San Diego, and principal investigator of the registration study.

While classified as a rare disease, neuroblastoma is the most common cancer in infancy. It typically occurs in children aged younger than 5 years, and occurs in immature nerve cells; it usually begins in the adrenal glands, but may also develop in the abdomen, chest, or in nerve tissue near the spine.

About half of neuroblastoma cases are diagnosed as high-risk disease, and these patients have only a 40% to 50% chance of long-term survival despite aggressive therapy.

According to the National Cancer Institute, neuroblastoma occurs in approximately one out of 100,000 children, and is slightly more common in boys. There are an estimated 650 to 700 new cases of neuroblastoma diagnosed in the United States each year.

The FDA granted the product priority review and orphan product designation. The agency also gave the manufacturer a rare pediatric disease priority review voucher, which confers priority review to a subsequent drug application that would not otherwise qualify for priority review. (This is only the second such voucher issued, it noted.)

Survival Benefit Demonstrated

The approval is based on results from a multicenter, open-label, randomized trial (known as ANBL0032 and conducted by COG) that involved 226 pediatric participants with high-risk neuroblastoma. Patients were aged 11 months to 15 years (median age 3.8 years).

These patients had already undergone intensive treatment and had shown at least a partial response to the treatment, which involved multiple-drug chemotherapy and surgery, followed by additional intensive chemotherapy and subsequent bone marrow transplantation support and radiation therapy.

After that intensive treatment, patients were then randomly assigned to receive either an oral retinoid drug, isotretinoin, or a combination of isotretinoin with the new product dinutuximab and also interleukin-2 and granulocyte-macrophage colony-stimulating factor, both of which are thought to enhance the activity of the product by stimulating the immune system.

After 3 years of follow-up, 63% of patients receiving the dinutuximab combination were alive and free of tumor growth or recurrence, compared with 46% of patients treated with isotretinoin alone. An updated analysis of survival found that the figures were even better, with 73% on the dinutuximab combination still alive, compared with 58% on isotretinoin alone, the FDA noted in its announcement. The manufacturer noted that at the time of this survival analysis, median overall survival was not reached (NR) in either arm, and noted that the difference in survival between the two arms had a hazard ratio [HR] of 0.58 (95% confidence interval [CI]: 0.37, 0.91).

The major efficacy outcome measure of the trial was investigator-assessed event-free survival (EFS), defined as the time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy, or death. At the seventh interim analysis, an improvement in EFS (HR: 0.57 [95% CI: 0.37, 0.89]; P = .01, log-rank test) was demonstrated and four remaining patients undergoing treatment with isotretinoin alone crossed over to the other treatment arm and received the dinutuximab combination. The median EFS was not reached (range from 3.4 years to NR) in the dinutuximab combination arm and was 1.9 years (1.3 - NR) in the isotretinoin arm.

The product carries a boxed warning that dinutuximab irritates nerve cells, causing severe pain that requires treatment with intravenous narcotics, and also a warning that it can cause nerve damage and life-threatening infusion reactions, including upper airway swelling, difficulty breathing, and low blood pressure, during or shortly following completion of the infusion. Other serious adverse effects include infections, eye problems, electrolyte abnormalities, and bone marrow suppression.

The most common adverse effects of dinutuximab were severe pain; fever; low platelet counts; infusion reactions; low blood pressure; low levels of sodium, potassium, and calcium in the blood; elevated liver enzymes; anemia; vomiting; diarrhea; neutropenia and lymphopenia; hives; and also capillary leak syndrome (which is characterized by a massive leakage of plasma and other blood components from blood vessels into neighboring body cavities and muscles), the agency noted.

The manufacturer notes that the recommended dose and schedule for dinutuximab is 17.5 mg/m2/day as a diluted intravenous infusion over 10 to 20 hours for 4 consecutive days for a maximum of five cycles. Patients require intravenous treatment with opioids prior to, during, and for 2 hours following the dinutuximab infusion to mitigate neuropathic pain; intravenous hydration and premedication with antihistamines, analgesics, and antipyretics are also required.

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