Novel anti-GD2 antibody demonstrates activity in pediatric neuroblastoma

CHICAGO — The addition of a novel anti-GD2 monoclonal antibody to an intensive chemotherapy regimen significantly improved the response rate in pediatric patients with high-risk neuroblastoma, according to results of interim analysis of a phase 2 study presented at the ASCO Annual Meeting.

The regimen also appeared well tolerated.

“Data are emerging suggesting that the combination of monoclonal antibodies with chemotherapy can be at least additive, if not synergistic. For one, chemotherapy can induce cytopenias of various immune inhibitory cells as well as upregulate stress ligands,” Wayne L. Furman, MD, pediatric oncologist at St. Jude Children’s Research Hospital, said during a presentation. “There are numerous anti-GD2 monoclonal antibodies in clinical use — all of which bind to peripheral nerves. It is believed that the binding to peripheral nerves and the subsequent activation of the complement cascade leads to pain — a major side effect of all of these agents.

“This current antibody, Hu14.18k322A, was designed to remove the complement activating domain,” Furman added. “It was also humanized, in hopes of reducing mutant reactions to it.”

Furman and colleagues designed the study based on the 2011 Children’s Oncology Group Study by Park and colleagues, in which researchers tested the feasibility of adding two cycles of cyclophosphamide and topotecan to four standard induction chemotherapy courses in children with high-risk neuroblastoma.

Using this as the historical control arm, Furman and colleagues sought to optimize the novel antibody by combining it with the intensive chemotherapy regimen in 20 children (median age, 34 months; range, 6-180; 10 boys) with newly diagnosed high-risk neuroblastoma.

Patients received six cycles of induction chemotherapy plus 40 mg/m² of the novel antibody on days 2 through 5 followed by 250 mcg/m² daily granulocyte-macrophage colony–stimulating factor and low-dose interleukin-2 every other day for six doses.

An additional course of antibodies was administered during the immediate posttransplant recovery period, followed by parental natural killer cells, when available.

Furman and colleagues reported data on the first 20 patients accrued. Median follow-up from the time of first randomization was 23.9 months.

Compared with a 40% objective response rate achieved in the historical control arm, 80% (95% CI, 58.9-92.9) of children in the current analysis achieved a response rate after the first two courses of treatment (P = .0052). This included 15 partial responses, one very good partial response and four patients with stable disease. Patients who achieved stable disease experienced decreases in primary tumor volume by 47%, 75%, 81% and 96%.

Pain from the anti-GD2 monoclonal antibody was well controlled by continuous infusion narcotics, according to the researchers.

Fifteen patients had antibody infusions as a result of developing cough, hypoxia and/or hypotension. Other grade 3 adverse events included hypokalemia, hyponatremia, fever and typhlitis. All patients received all planned doses of the novel antibody.

“This antibody was very well tolerated, as seen with previous antibodies,” Furman said. “Presently, patient accrual is ongoing and we recommend further evaluation of anti-GD2 monoclonal antibodies given concomitantly with cyclophosphamide.” – by Jennifer Southall

References:

Furman WL, et al. Abstract 10501. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Park JR, et al. J Clin Oncol. 2011;doi:10.1200/JCO.2010.34.3293.

Disclosure: Furman reports no relevant financial disclosures. Please see the abstract for a list of all other researchers’ relevant financial disclosures.