CHICAGO – Adding the cytokine IL-2 to front-line therapy with the anti-GD2 antibody ch14.18/CHO provided no additional survival benefit and only added to toxicity in the treatment of pediatric patients with high-risk neuroblastoma (NB), Dr. Ruth Ladenstein reported at the annual meeting of the American Society of Clinical Oncology.

A form of the antibody (dinutuximab) is approved for use in combination with granulocyte-macrophage colony stimulating factor, IL-2, and 13-cis-retinoic acid (RA) to treat high risk NB. A previous study (N Engl J Med. 2010;363:1324-34) showed that a combination of ch14.18 and the cytokines improved event free survival to 66% at 2 years, but the role of cytokines in this context remained unclear. Dr. Ladenstein and associates therefore performed a phase III trial that randomized patients to the antibody with or without subcutaneous (sc) IL-2.

High-risk NB was defined as patients with International Neuroblastoma Staging System stage 4 disease 1 year old or older, stage 4 less than 1 year old with MYCN amplification, or stage 2,3 patients up to age 21 years with MYCN amplification. Patients underwent a rapid induction therapy, followed by peripheral stem cell harvest, local control with complete tumor resection, myeloablative therapy with peripheral stem cell transplant, local control with radiotherapy, and then ch14.18 anti-GD2 monoclonal immunotherapy with RA, with or without sc IL-2.

Inclusion criteria were a complete response or partial response with three or fewer skeletal metastatic spots and no positive bone marrow biopsies on two aspirates. Randomization occurred between day 60 and 90 post stem cell infusion. RA was given on days 1-14 post randomization. For the arm receiving IL-2, it was given as 5 daily injections of 6 x 106 IU/m² per day over 8 hours on days 15-19. IL-2 was repeated on days 22-26. Both groups also received the ch14.18 antibody on days 22-26. All patients received high-dose morphine for pain management.

For event free survival (EFS), the primary endpoint of the trial, “if we look at 3 years, we see with antibody alone it’s 57%. With IL-2, it’s 60%. It’s completely clear that there’s no superiority for the IL-2 arm,” said Dr. Ladenstein, professor of pediatrics at the Children’s Cancer Research Institute, Austria.

At 5 years, the EFS was no different for the two treatment arms, at 51% for antibody alone and 56% for antibody plus IL-2 (P = .561). There were 199/200 patients in the antibody-alone arm with follow-up after randomization and 203/206 in the antibody plus IL-2 arm. The same was true for the secondary endpoint of overall survival, with 66% survival with antibody-alone and 58% in the antibody plus IL-2 at 5 years.

The EFS for patients with a complete response prior to immunotherapy was 66% at 3 years and was 50% for patients with less than a complete response, a significant difference (P = .003) in favor of those with a complete response. IL-2 administration had no effect on the EFS of the patients with a complete response if it was given with the immunotherapy. Similarly, IL-2 made no difference for patients who had had a very good partial response or a partial response prior to immunotherapy. For complete, very good partial, or partial responses prior to immunotherapy, the overall response to immunotherapy was 51%.

“However, feasibility is a concern, particularly in the IL-2 arm. Only 61% of the cycles were completed whereas it was 85% in the antibody-only arm, and the interruptions are definitely related mainly to the IL-2 component,” Dr. Ladenstein said.

Toxicity was higher for those patients receiving IL-2 compared to those getting antibody alone: Lansky performance status of 30% or less was 41% vs. 17%, early termination of therapy was 39% vs. 15%, and Common Terminology Criteria grade 3/4 fever was 41% vs. 14%, respectively (all P less than .001). There were also significantly more grade 3/4 allergic reactions and incidences of capillary leak, as well as diarrhea, hypotension, central nervous toxicity, and pain with IL-2.

The outcomes were favorable with antibody immunotherapy alone, but the higher toxicity with IL-2 shows that “a less toxic treatment schedule therefore is needed for this late treatment phase,” Dr. Ladenstein said.

Commenting on the trial, Dr. Barbara Hero of University Children’s Hospital in Cologne, Germany, asked whether cytokines are a useful part of the regimen “because we know the cytokines add quite a lot of toxicity to the regimens.” Even if they are potentially useful, researchers still do not know which cytokines, route of administration, and at what doses and timing would be best. Also, it is not known if a different induction regimen or antibody treatment could make a difference in using cytokines.

Another question is whether cytokines may be of benefit in patients with a higher tumor burden, e.g., more than three skeletal spots, used as the eligibility cut-off in this trial, Dr. Hero said.

IL-2 adds only toxicity to neuroblastoma antibody tx