Addition of anti-GD2 antibody to chemotherapy improves outcomes in high-risk neuroblastoma
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The addition of the novel monoclonal antibody hu14.18K322A to induction chemotherapy significantly improved outcomes among children with newly diagnosed high-risk neuroblastoma, according to phase 2 study results.
The findings, published in Journal of Clinical Oncology, showed the combination improved early objective response rates and end-of-induction response rates, reduced tumor volume in most children and resulted in encouraging 3-year EFS rates.
Rationale
“We have watched too many children with high-risk neuroblastoma succumb to this disease,” Wayne L. Furman, MD, researcher in the department of oncology at St. Jude Children’s Research Hospital, told Healio. “Dinutuximab [Unituxin, United Therapeutics] in the post-consolidation setting came out as we were finishing the dose-finding study of hu14.18K322A, a unique antibody with the same target as dinutuximab. Both agents target disialoganglioside [GD2], which is almost universally expressed on the cell surface of neuroblasts and is also on the surface of peripheral nerves.”
The major challenge with this class of agents is severe pain thought to be due to the binding of the antibody to peripheral nerves with subsequent activation of complement, Furman added.
“Hu14.18K322A is humanized [about 98% human] compared with dinutuximab, which is a chimeric antibody. Presumably, this should reduce allergic reactions to hu14.18K322A. Also, the complement activation site has been mutated to decrease complement activation [K322A], reducing pain,” he said. “Our dose-finding study of hu14.18K322A showed children were able to tolerate more hu14.18K322A than dinutuximab and we thought that if dinutuximab worked in post-consolidation, what would happen if we used an anti-GD2 antibody throughout therapy? The right dose of anti-GD2 antibody is unknown, but most agreed that more should be better, so we used hu14.18K322A at about 2.5 times the tolerable dose of dinutuximab.”
Methodology
The prospective, single-arm, three-stage, phase 2 trial examined whether hu14.18K322A administered throughout six cycles of induction chemotherapy could improve early response rates and outcomes among 64 children (median age, 3.1 years) with newly diagnosed high-risk neuroblastoma. Most patients were male (n = 37) and white (n = 43).
Furman and colleagues assessed early response rates after the first two cycles of induction therapy and additionally assessed end-of-induction response, EFS and OS.
Key findings
Researchers found the combination of hu14.18K322A plus chemotherapy in a response rate after the first two treatment cycles of 66.7% (95% CI, 55-78.3), compared with 39.1% (95% CI, 35.3-43) in a previous study that used the same induction regimen.
“This study would mean nothing if it did not translate into an improved EFS, so when we saw this early indication of benefit, we amended the study to get a better estimate of EFS,” Furman said.
Patients additionally demonstrated a 3-year EFS rate of 73.7% (95% CI, 60-83.4) and a 3-year OS rate of 86% (95% CI, 73.8-92.8).
“Our 3-year EFS of nearly 74% is the best outcome in this difficult-to-treat group of patients with high-risk neuroblastoma and includes all patients enrolled, not just those who made it to randomization,” Furman said. “Another intriguing finding of our study is that no patients experienced progressive disease during induction, which occurred in between 7% and 14% of patients in prior studies.”
Implications
If validated in a larger study, these results could be practice changing, according to Furman.
“This is a rather small single-institution study, and although very promising, these results need to be verified — ideally in a randomized, multi-institutional study comparing ‘chemoimmunotherapy’ with an anti-GD2 monoclonal antibody given with induction chemotherapy vs. standard induction chemotherapy,” Furman said.
It is unknown whether hu14.18K322A is a better antibody, but patients can tolerate a much higher dose given over a shorter time, he added.
“Thus, a key implication is that these data could be due to a dose-effect of antibody and dinutuximab cannot be given at the doses of hu14.18K322A used in this study. If a randomized study, as mentioned above, is conducted with dinutuximab, it may not have the same positive results, simply because the ‘best’ dose of antibody can’t be given,” Furman said. “We are looking for a commercial partner to help get hu14.18K322A approved by the FDA. However, for a rare disease like neuroblastoma, this is economically challenging. It is estimated that about 700 children in the U.S. are diagnosed with neuroblastoma every year. Fortunately, only about half of these children will have high-risk disease and potentially benefit from this chemoimmunotherapy.”
For more information:
Wayne L. Furman, MD, can be reached at St. Jude Children’s Research Hospital, 262 Danny Thomas Place, MS 260, Memphis, TN 38105; email: wayne.furman@stjude.org.
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