Roxanne Nelson, BSN, RN

June 04, 2016

CHICAGO — An experimental monoclonal antibody has demonstrated promising results in neuroblastoma, according to new findings.

In an interim analysis, 80% of newly diagnosed, young, high-risk patients experienced shrinkage of their tumors after treatment with the combination of cyclophosphamide, topotecan, and the investigational agent Hu14.18K322A (EMD Serono).

In  16 of the 20 patients (80%) who responded, tumors shrank 47% to 96%; in the other patients, disease remained stable.

In a previous study, neuroblastoma patients treated with the same chemotherapy regimen but without the monoclonal antibody achieved only a 40% response rate  (J Clin Oncol. 2011;29:4351-4357).

With the addition of the monoclonal antibody, "all patients had clinical benefit, and none of them progressed," said first author Wayne Furman, MD, from St. Jude's Children's Research Hospital, Memphis, Tennessee. He presented interim findings here at the American Society of Clinical Oncology 2016 Annual Meeting.

"Anti-GD2 monoclonal antibodies, given with induction chemotherapy, warrant further investigation," he said.

"There are numerous anti-GD2 monoclonal antibodies in clinical use today," he explained. "All of the antibodies bind to peripheral nerves, and it is felt that the binding to the nerves and the subsequent activation of the complement cascade leads to pain, which is one of the dose-limiting aspects of these agents."

The agent used in this trial was engineered and humanized to reduce immune reactions and treatment-limiting pain. Hu14.18K322A includes a point mutation in the hu14.18 protein that is designed to eliminate complement-dependent lysis, believed to be responsible for triggering pain.

The patients in the 2011 study who achieved the 40% response rate with chemotherapy alone served as the historic control group. Dr Furman explained that the study was designed to test whether adding the anti-GD2 antibody would improve that rate to at least 60%.

The study is ongoing, and has currently enrolled 34 patients, the majority of whom are older than 18 months and have metastatic disease.

All patients received two initial courses of chemotherapy with cyclophosphamide and topotecan, using the same protocol as in the 2011 study.

At the interim analysis, two courses of chemotherapy demonstrated significant benefits in all 20 evaluable patients (10 male; median age, 34 months).

The response rate was 80%; 15 patients achieved a partial response, one patient achieved very good partial response, and disease remained stable in four patients.

"The antibody was very well tolerated in general, and all patients were started on continuous narcotic infusion to control the pain," Dr Furman reported.

All patients received all planned doses of Hu14.18K322A, but 11 patients had their infusions extended because they developed adverse events, including cough, hypoxia, and/or hypotension.

Related Studies

Two other studies presented during the same session investigated the role of anti-GD2 antibodies in neuroblastoma.

Results from a phase 3 trial on the addition of subcutaneous interleukin-2 (scIL2) to dinutuximab (Unituxin, United Therapeutics), a GD2-binding monoclonal antibody, in the front-line setting in high-risk patients with neuroblastoma were presented by Ruth Ladenstein, MD, from St. Anna Children's Hospital and Research Institute in Vienna, for the SIOP Europe Neuroblastoma Group investigators.

There was an overall response rate of 51% to immunotherapy  in the 406 high-risk study participants.

The outcome data with dinutuximab in the first-line setting were "in line with previous reports at 2 years, and are highly encouraging," said Dr Ladenstein.

The event-free survival rate was 66% in patients treated with dinutuximab plus scIL2 and oral 13-cis retinoic acid, and was 68% in those treated with the same regimen but without scIL2.

However, there were "major toxicities in the IL arm, which prevented full delivery of immunotherapy," she said.

That group had a higher rate of treatment interruptions and had to stop dinutuximab cycles more often. Therefore, Dr Ladenstein and her colleagues concluded after survival and toxicity analysis, cotreatment with scIL2 in this setting provides no benefit.

Results from a phase 2 study on the use of irinotecan/temozolomide with temsirolimus or dinutuximab plus granulocyte colony-stimulating factor in children with refractory or relapsed neuroblastoma were presented by Rajen Mody, MD, from the University of Michigan in Ann Arbor, for the Children's Oncology Group.

The trial involved 35 children.

In the temsirolimus group, one partial response was observed. In the dinutuximab group, there was considerably more activity — nine (53%) objective responses (four partial, five complete). This included responses in five of the 10 patients with relapsed/progressive disease and four of the seven with refractory disease.

Temsirolimus combined with irinotecan/temozolomide has insufficient activity to merit further study, but the dinutuximab regimen met the criteria for activity and is declared the "winner," Dr Mody said.

There was no unexpected toxicity in either group.

Questions Remain

"All three talks put some aspects of immunotherapy into perspective and answer some questions, but much remains unanswered," said Barbara Hero, MD, from the University of Cologne in Germany.

"We do not know the role of cytokines in the setting, and a very important point is that we don't know if the antineuroblastoma activity is maintained," she explained.

The optimal setting is also not known. For example, in the Hu14.18K322A study presented by Dr Furman, it is not known how the response rate translates into outcomes, or whether it is feasible to apply this high-intensity regimen in a multicenter setting, Dr Hero noted.

Further studies are needed, as well as further development of antibodies that create less toxicity, she added.

Dr Furman has disclosed no relevant financial relationships. Dr Ladenstein reports receiving honoraria from Apeiron Biologics and Boehringer Ingelheim; serving on consulting or advisory roles for Apeiron Biologics (Inst) and Boehringer Ingelheim (Inst); and receiving research funding, expenses, or royalties from, and giving expert testimony for, Apeiron Biologics. Dr Mody reports serving in a consulting or advisory role for United Therapeutics

American Society of Clinical Oncology (ASCO) 2016 Annual Meeting: Abstracts 10500, 10501, 10502. Presented June 4, 2016.

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