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Long-Term Infusion of Immunotherapy May Reduce Pain in Children With High-Risk Neuroblastoma

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Key Points

  • Changing the infusion delivery method of ch14.18/CHO in combination with interleukin-2 and oral 13-cis-retinoic acid from short-term infusion to long-term in the treatment of children with high-risk neuroblastoma reduced neuropathic pain.
  • Patients receiving the therapy with the long-term delivery method maintained effective drug levels over the treatment period and had fewer grade 3 or higher adverse events.
  • Long-term infusion of ch14.18/CHO may result in an improved pain toxicity profile and is active and effective in high-risk relapsed/refractory neuroblastoma.

Changing the infusion delivery method of the monoclonal antibody ch14.18/CHO (dinutuximab-beta, the European counterpart of dinutuximab [Unituxin]) in combination with interleukin-2 and oral 13-cis-retinoic acid from short-term infusion to long-term infusion in the treatment of children with high-risk neuroblastoma reduced neuropathic pain, a major side effect of short-term infusion of the drug, according to a study by Lode et al. The phase I/II study also found that the patients receiving the therapy with the long-term delivery method maintained effective drug levels over the treatment period and had fewer grade 3 or higher adverse events.

The study, abstract A032, is being presented at the CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference, September 16–19 in New York. The conference is being cosponsored by the American Association for Cancer Research, the Cancer Research Institute, the Association for Cancer Immunotherapy, and the European Academy of Tumor Immunology.

Study Methodology

The investigators enrolled 97 patients with high-risk relapsed/refractory neuroblastoma in two clinical trials: an ongoing SIOPEN phase II study (APN311-202; 44 patients) and a closed single-center program (APN311-303; 53 patients). All patients received a total dose of 100 mg/m2 of ch14.18/CHO per cycle as long-term infusion continuously over 10 consecutive days. Five cycles were given in 5-week intervals, and all patients also received 6 x 106 IU/m2 subcutaneous interleukin-2 and 160 mg/m2 oral 13-cis retinoic acid.

The researchers evaluated treatment-related pain by three-time daily assessment of validated age-adapted pain-scoring systems by parents and/or the medical team, and daily use of intravenous morphine was recorded for each patient in each cycle. They then compared their observations of pain and adverse events from the long-term infusion studies with the previously published data on neuroblastoma patients treated with short-term infusion of dinutuximab.

Overall survival and progression-free survival data from this study were compared with the previously reported historical gold standard, which is a compilation of clinical trial data from comparable patients treated with current front-line and relapse therapy.

Study Findings

The researchers’ analysis of pain assessment scores and use of intravenous morphine indicated that long-term infusion of ch14.18/CHO was associated with reduced pain, compared with data previously reported for children treated with short-term infusion. The patients also had lower frequencies of grade 3 or higher adverse events in the long-term infusion group vs the short-term infusion group, except for equal frequencies in vomiting.

After following the patients for a median of 2.9 years, 1-year and 4-year overall survival rates for patients treated with long-term infusion in the SIOPEN cohort were about 94% and 61%, respectively, compared with about 56% and 14%, respectively, for those from the previous report.

After following the patients for a median of 2.8 years, 1-year and 4-year progression-free survival rates for patients treated with long-term infusion in the SIOPEN cohort were about 54% and 32%, respectively, compared with about 19% and 8%, respectively, for those from the previous report.

Reducing Pain While Maintaining Drug Efficacy

“In our study, by changing the method of antibody delivery from short-term infusion to long-term infusion, we observed an impressive reduction of on-target [pain] and off-target [inflammation] side effects, while maintaining effective drug levels over the entire treatment period, as assessed in a variety of bioassays, demonstrating the immune-modulatory effect of ch14.18/CHO and its potency to mediate destruction of neuroblastoma cells constantly over a period of 6 months,” said Holger N. Lode, MD, PhD, Professor and Chair of Pediatrics at the University Medicine Greifswald in Germany and lead author of the study, in a statement.

Long-term infusion of ch14.18/CHO results in an improved pain toxicity profile and is active and effective in high-risk relapsed/refractory neuroblastoma, concluded the researchers.

The study was funded by SIOPEN-R-NET, Hector-Stiftung, University Medicine Greifswald, Deutsche Kinderkrebsstiftung, Polymun Scientific, Apeiron Biologics, and by charities in Europe. Dr. Lode is a consultant for Apeiron Biologics.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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