Activating the Immune System Could be Key to Treating Pediatric Neuroblastoma

Wayne Furman, MD

Chemoimmunotherapy is still a relatively new strategy for patients with pediatric neuroblastoma. Wayne Furman, MD, hopes that the humanized anti-disialoganglioside (anti-GD2) monoclonal antibody hu14.18K322A provides a breakthrough for children with high-risk disease.

“Our 3-year event-free survival was 74%, I believe, which is, to my knowledge, the absolute best results in this disease with high risk patients,” said Furman, a hematologist/oncologist and professor of pediatrics at St. Jude Children’s Research Hospital, and leader of the phase 2 trial assessing hu14.18K322A [NCT01857934] in these patients. “I’ve been doing this for 38 years and I've never seen anything like it.”

Pediatric neuroblastoma annually affects about 800 children aged 14 years or younger in the United States. However, 90% of diagnoses occur in children younger than 5 and the average age of diagnosis is 1 year to 2 years old. Neuroblastoma is the most common cancer diagnosed in children younger than 1 year, but it is rare in those older than 10.¹

For children with low-risk neuroblastoma, the 5-year survival rate is greater than 95% compared with about 50% for those with high-risk disease. Roughly two-thirds of patients with neuroblastoma are diagnosed with metastatic disease.Survival is 20% to 35% for children with stage 4 neuroblastoma with current treatments.²

Furman said that roughly 90% of pediatric patients with low- or intermediate-risk disease are cured. Patients with high-risk disease are treated in 3 phases: induction, consolidation, and maintenance. The current standard of care in the United States is intensive induction chemotherapy, surgery, tandem stem cell transplantation, and radiation. This is followed by “post-consolidation therapy” with the oral differentiating agent isotretinoin, and now dinutuximab (Unituxin), the first FDA-approved anti-GD2 monoclonal antibody, with granulocyte-macrophage colony-stimulating factor (GM-CSF).

“[In] the high-risk kids, we throw the kitchen sink at them,” he added. “They get very intensive chemotherapy, where the risk of…getting an infection—when your white [blood cell] count is low, kids can get very sick, very quickly—that risk after chemo approaches 50%.

“Also, the stem cells of the patients are harvested sometime during induction, so that they can be used later to rescue them from myeloablative therapy or consolidation.”

In the prospective, single-arm clinical trial, Furman and his colleagues recruited 64 patients treated at St. Jude for newly diagnosed high-risk neuroblastoma from May 2013 to July 2019. Patients received 6 cycles of induction chemotherapy administered along with infused hu14.18K322A, GM-CSF, and low-dose interleukin-2 (IL-2).

Consolidation included busulfan and melphalan (Evomela). Thirty-one patients received an additional cycle of parent-derived natural killer cells with hu14.18K322A during consolidation. Post-consolidation treatment included hu14.18K322A, GM-CSF, IL-2, and isotretinoin.

All patients received a continuous infusion of opioids beginning approximately 30 minutes before antibody infusions. Radiation therapy was administered at the end of consolidation.

In results published in December 2021, the overall response rate (ORR) following 2 cycles of treatment was 66.7% in evaluable patients (n = 42/63; 95% CI, 55.0-78.3).³ In comparison, ORR was 39.1% after 2 cycles in data from the phase 3 COG ANBL0532 trial (NCT00567567) evaluating tandem myeloablative consolidation therapy with cyclophosphamide and topotecan published in 2019.⁴

“The speed and the quality of response was like nothing I’d ever seen,” Furman said. “With standard therapy, 80% [of patients] will respond but the response takes a long time. Often it takes all 6 courses to get there; we were seeing disease almost vanish after 2. The patients bounced back to being themselves, except that they had to come back and see us every 3 weeks to get another course of therapy.”

Furman added that he and his colleagues elected to evaluate hu14.18K322A for efficacy after just 2 cycles because investigators in a previous pilot study using the same chemotherapy regimen did the same. “We just thought, ‘Well, if this is going to work, it’s going show up as a better response after the first 2 cycles,’” he said. “To our surprise and delight, early response was almost doubled in our study.”

Primary tumor volume was reduced by a median of 75%. Median peak hu14.18K322A serum levels in cycle 1 were correlated with early response (P = .0154).³

Nearly 97% of patients had partial response or better at the end of induction therapy and no patients experienced disease progression during induction. At 3 years, event-free survival (EFS) was 73.7% (95% CI, 60.0%-83.4%) and overall survival was 86.0% (95% CI, 73.8%-92.8%).³

The Dose Makes the Medicine

In 2015, the FDA approved the first anti-GD2 monoclonal antibody, dinutuximab, for children with high-risk neuroblastoma in combination with GM-CSF, IL-2, and 13-cis-retinoic acid given in post-consolidation. In findings from the multicenter, open-label, randomized phase 3 COG ANBL0032 trial (NCT00026312), dinutuximab induced an EFS of 66±5% at 2 years compared with 46±5% for standard isotretinoin therapy (P = .01).⁵

Furman added that the outcome data for dinutuximab does not compare directly with findings with hu14.18K322A. The COG ANBL0032 data only include patients who had at least partial response to induction chemotherapy while the hu14.18K322A results include all patients enrolled.

Dinutuximab is approved for a daily dose of 17.5 mg/m² as a diluted intravenous infusion over 10 to 20 hours for 4 consecutive days for up to 5 cycles. Furman et al administered 40 mg/m² hu14.18K322A, a dose approximately 2.5 times greater, and infusion takes just 4 hours. Furman added that hu14.18K322A may not be more effective than dinutuximab, but patients cannot tolerate dinutuximab at such a high dose level.

“Most of the kids tolerate 10 hours of infusion with dinutuximab, but with many, you have to give it over 20 hours,” said Furman. “Obviously, there’s only 24 hours in the day, so they just cannot tolerate double the dose of dinutuximab. Is this a better antibody? It's better in the sense of more tolerable—there’s no question.

“Hu14.18K, when you’re giving twice the dose, it’s much easier on the patient. Less pain meds, less infusion time, less chances of having allergic reactions, which, again, the antibody was designed to do. It may just be the dose, but like I said, it’s the only antibody that you can give at that dose.”

For all the potential of hu14.18K, Furman fears it will only be available to patients in clinical trials. St. Jude is looking for a pharma industry partner to support further research and eventually bring the agent to market. The economics are working against it.

“We said 700 kids are diagnosed annually and roughly half of those are high risk,” he said. “Three hundred-fifty patients a year does not pay too many bills for pharma. That’s the unfortunate reality.”

References

1. Cancer.net. Neuroblastoma - childhood: statistics. June 2021. Accessed January 5, 2022. https://bit.ly/3zHy3DP
2. Children’s Oncology Group Study #ANBL0532. Accessed January 6, 2021. www.childrensoncologygroup.org/anbl0532
3. Furman WL, McCarville B, Shulkin BL, et al. Improved outcome in children with newly diagnosed high-risk neuroblastoma treated with chemoimmunotherapy: updated results of a phase II study using hu14.18K322A. J Clin Oncol. Published online December 6, 2021. doi:10.1200/JCO.21.01375
4. Park JR, Kreissman SG, London WB, et al. Effect of tandem autologous stem cell transplant vs single transplant on event-free survival in patients with high-risk neuroblastoma: a randomized clinical trial. JAMA. 2019;322(8):746-755. doi:10.1001/jama.2019.11642
5. Yu AL, Gilman AL, Ozkaynak MF, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363(14):1324-1334. doi:10.1056/NEJMoa0911123