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Adding a novel anti-GD2 antibody (hu14.18K322A) to induction chemotherapy for children with newly diagnosed high-risk neuroblastoma yielded impressive survival outcomes and improved early responses versus historical benchmarks, investigators reported.

In a single-arm phase II trial, the event-free survival (EFS) rate at 3 years reached 73.7% among evaluable patients (95% CI 60.0-83.4), while overall survival was 86.0% (95% CI 73.8-92.8), according to Wayne L. Furman, MD, of St. Jude Children's Research Hospital in Memphis, Tennessee.

These findings were accompanied by results showing response in two-thirds of patients after the first two chemoimmunotherapy cycles, a significant improvement when compared with a historical group of children treated with identical chemotherapy alone, they stated in the .

The survival results were "almost beyond belief," Furman told 名媛直播. "I've been doing this for almost 40 years, and I've never seen anything like this. The early clues were the early responses. These kids' -- which is the most sensitive scan for this tumor -- would clear up very early in many patients."

"But that doesn't mean anything if the tumor still comes back," he added. "And, so far, that EFS is holding."

While the researchers acknowledged that the EFS data came from a small sample of just 63 evaluable patients, they said it compared favorably with recent trials, which demonstrated 3-year EFS rates ranging from 32% to 55.6% in this population.

Treatment for high-risk neuroblastoma includes induction therapy; consolidation with high-dose chemotherapy followed by autologous hematopoietic stem-cell transplant; radiotherapy; and post-consolidation treatment with isotretinoin and the monoclonal antibody dinutuximab (Unituxin), which targets disialoganglioside GD2.

Based on preclinical and adult clinical studies showing that concurrent chemotherapy with monoclonal antibodies provides additive or synergistic benefits, Furman and colleagues hypothesized that throughout therapy for the treatment of high-risk neuroblastoma would improve clinical responses and outcomes.

However, one of the major issues with dinutuximab -- and with the whole class of anti-GD2 antibodies -- is that patients experience neuropathic pain during infusions. In the case of dinutuximab, the average infusion time is 10 hours, Furman said, during which patients are given continuous pain medication.

Hu14.18K322A was designed to reduce complement-associated pain, Furman said. "Now, we know that's not the whole story. It still causes pain, and we still need pain medications, but we can give it much faster. More than half of the kids in the study got [hu14.18K322A] over 4 hours, as opposed to the 10 with dinutuximab."

And hu14.18K322A can be given in higher doses, he added. "The dose that most kids can tolerate of dinutuximab is 17.5 mg/m², as opposed to the 40 mg/m² we gave in this study."

Of the 64 patients enrolled in this study, 63 had measurable or evaluable disease at enrollment. Median age was 3.1 years, 58% were male, and two-thirds were white. Most (n=56) had International Neuroblastoma Staging System (INSS) stage IV or International Neuroblastoma Risk Group stage M disease.

The authors noted that in the COG , investigators reported a 40% partial response rate after two cycles of induction therapy (cyclophosphamide and topotecan) in high-risk patients. This response was similar to that observed in the in which patients received the same induction regimen.

This study used the same induction regimen as these other two studies. The primary objective of this study was to compare the response rates after the first two cycles of chemoimmunotherapy -- cyclophosphamide, topotecan, and hu14.18K322A, followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 -- with the early response rates observed in the other trials. EFS was added as a primary objective when the response rate exceeded the benchmark for activity in an interim analysis.

Of the children in the study evaluable for early response, 42 (66.7%, 95% CI 55.0-78.3) experienced partial responses or better, which the authors pointed out was a significant improvement over the 39.1% (95% CI 35.3-43.0) demonstrated in ANBL0532.

At the end of induction, 60 of 62 evaluable patients (96.8%) had partial responses or better (95% CI 88.8-99.6). No patients experienced progressive disease during induction.

As of Nov. 4, 2020, 54 of the 64 patients were alive, with a median follow-up time of 4.3 years (range 1.1-6.7 years) for the 48 patients who did not experience an event.

"These results, if validated in a larger study, may change the standard of care for children with [high-risk] neuroblastoma," Furman's group concluded.

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