ASCO 2009: Immunotherapy Prolongs Survival in High-risk Pediatric Neuroblastoma

Zosia Chustecka

May 19, 2009

May 19, 2009 — An experimental immunotherapy product has been shown to improve overall survival and to reduce the risk for relapse in children with high-risk neuroblastoma. The results from a phase 3 clinical trial are due to be presented at the upcoming 2009 Annual Meeting of the American Society of Clinical Oncologists (ASCO).

A preview of the results was provided in an ASCO presscast on May 14 by lead author Alice Yu, MD, PhD, professor of pediatric hematology/oncology at the University of California in San Diego.

"This is a very difficult-to-treat patient population," Dr. Yu explained. Neuroblastoma is the most common cancer in the first year of life, and is responsible for about 15% of cancer-related deaths in childhood, she explained. Most cases are diagnosed in toddlers, but neuroblastoma can also present in infants and older teenagers.

About 650 cases are diagnosed annually in the United States, and about 40% present with high-risk neuroblastoma. They are treated with aggressive therapy, including intensive chemotherapy with stem-cell rescue, surgery, and radiotherapy.

It is very exciting to have a new treatment option for this disease.

"Even though we treat it with aggressive therapy, high-risk neuroblastoma often returns and most patients do not survive," she noted, so "it is very exciting to have a new treatment option for this disease."

Dr. Yu and colleagues now intend to offer the immunotherapy to all children with high-risk neuroblastoma, and to collect enough safety data from open-label studies for approval of the product.

Currently, the product — a chimeric antibody known as ch14.18 — is produced in a facility within the National Cancer Institute, and there is a sufficient supply of the drug for about 100 to 150 more patients, she said. Further production is underway, prompted by the positive results of this trial, which were first announced in March. This new batch of product should be available in about 18 months, by which time Dr. Yu estimates that her team will have treated about 100 patients. There is hope that eventually a commercial enterprise will take over the manufacturing of the product; several firms have expressed an interest since the positive results were announced, she said.

First Antibody Directed Against Glycolipid

The new product is a chimeric antibody directed against a glycolipid known as GD2, which sits on the surface of neuroblastoma cells and protects them from attack by the immune system. When the antibody binds to GD2, it provokes an attack by different types of immune cells against the cancer.

This is the first time that an antibody directed against a glycolipid has shown clinical efficacy and an improvement in survival, Dr. Yu noted. Most antibody therapies are directed against proteins, she pointed out.

The trial was conducted by the Children's Oncology Group in 226 newly diagnosed high-risk neuroblastoma patients who had achieved a complete or partial response to induction therapy and had received myeloablative consolidation with stem-cell rescue. All received standard treatment with 13-cis-retinoic acid for 6 cycles, and half the patients also received 5 concomitant cycles of the antibody. The antibody was administered along with 1 of 2 cytokines — granulocyte macrophage colony-stimulating factor and interleukin-2 — given in alternating cycles, as preclinical studies had shown an enhanced efficacy.

After 2 years, overall survival was 86% in the immunotherapy group and 75% in the standard-treatment group, and event-free survival was 66% and 46%, respectively. The study was terminated early because of the benefit seen in interim analyses.

"This is a 20% increase in the percentage of children who were alive without cancer after 2 years, and so this is now the standard of care," Dr. Yu commented.

There were adverse effects, including pain (in 21% of patients), vascular leak syndrome (accumulation of fluid in the body, in 7.3%), and allergic reactions (7.2%), but all of these "were manageable," she said.

This immunotherapy may also be useful in other tumor types, Dr. Yu explained. She suggested that melanoma, small-cell lung cancer, soft tissue sarcoma, and other brain tumors might respond.

"This is an important trial in a rare but vicious tumor," commented ASCO president Richard Schilsky, MD, professor of medicine at the University of Chicago in Illinois.

"This is the first clinical trial to show a substantive increase in the cure rate in well over a decade for this highly malignant childhood cancer," John Maris, MD, chair of the Children's Oncology Group, said in a statement.

The researchers have disclosed no relevant financial relationships. Dr. Schilsky has no relevant financial relationships to disclose since taking office in June 2007, but continues to serve (with compensation) on a Data Monitoring Committee for Novartis Oncology.

2009 Annual Meeting of the American Society of Clinical Oncologists (ASCO): Abstract 10067. To be presented on May 30, 2009.

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