Irinotecan, Temozolomide, and Dinutuximab With GM-CSF in Children With Refractory or Relapsed Neuroblastoma: A Report From the Children’s Oncology Group

Abstract

PURPOSE The combination of irinotecan, temozolomide, dintuximab, and granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) demonstrated activity in patients with relapsed/refractory neuroblastoma in the randomized Children’s Oncology Group ANBL1221 trial. To more accurately assess response rate and toxicity, an expanded cohort was nonrandomly assigned to I/T/DIN/GM-CSF. PATIENTS AND METHODS Patients were eligible at first relapse or first designation of refractory disease. Oral T and intravenous (IV) irinotecan were administered on days 1 to 5 of 21-day cycles. DIN was administered IV (days 2-5), and GM-CSF was administered subcutaneously (days 6-12). The primary end point was objective response, analyzed on an intent-to-treat basis per the International Neuroblastoma Response Criteria. RESULTS Seventeen eligible patients were randomly assigned to I/T/DIN/GM-CSF (February 2013 to March 2015); 36 additional patients were nonrandomly assigned to I/T/DIN/GM-CSF (August 2016 to May 2017). Objective (complete or partial) responses were observed in nine (52.9%) of 17 randomly assigned patients (95% CI, 29.2% to 76.7%) and 13 (36.1%) of 36 expansion patients (95% CI, 20.4% to 51.8%). Objective responses were seen in 22 (41.5%) of 53 patients overall (95% CI, 28.2% to 54.8%); stable disease was also observed in 22 of 53. One-year progression-free and overall survival for all patients receiving I/T/DIN/GM-CSF were 67.9% ± 6.4% (95% CI, 55.4% to 80.5%) and 84.9% ± 4.9% (95% CI, 75.3% to 94.6%), respectively. Two patients did not receive protocol therapy and were evaluable for response but not toxicity. Common grade ≥ 3 toxicities were fever/infection (18 [35.3%] of 51), neutropenia (17 [33.3%] of 51), pain (15 [29.4%] of 51), and diarrhea (10 [19.6%] of 51). One patient met protocol-defined criteria for unacceptable toxicity (grade 4 hypoxia). Higher DIN trough levels were associated with response. CONCLUSION I/T/DIN/GM-CSF has significant antitumor activity in patients with relapsed/refractory neuroblastoma. Study of chemoimmunotherapy in the frontline setting is indicated, as is further evaluation of predictive biomarkers.

Anti-GD2-IRDye800CW as a targeted probe for fluorescence-guided surgery in neuroblastoma

“…Finally, anti-GD2 is increasingly used for immunotherapy in high-risk NB 36 . Currently, after surgery, but ongoing trials will assess the advantage of neoadjuvant treatment 37 , 38 . Therefore, we also confirmed that anti-GD2-IRDye800CW can still detect NB tissue after upfront anti-GD2 treatment, further validating the wide range of patients that could potentially benefit from anti-GD2-IRDye800CW guided surgery.…”

The Role of Autologous Stem-Cell Transplantation in High-Risk Neuroblastoma Consolidated by anti-GD2 Immunotherapy. Results of Two Consecutive Studies

“…Even more importantly, improvement in OS also reflects a novel paradigm in the anti-GD2 immunotherapy era: relapse is no longer an invariably lethal event. In the current era of anti-GD2 immunotherapy relapses occur more limited, isolated, less aggressive, and more amenable to control ( Kushner et al, 2015 ; Mody et al, 2017 ; Mody, 2020 ). Further evidence of the overall survival benefit resulting from anti-GD2 immunotherapy is the outcome of the refractory cohort in this study and others ( Kushner et al, 2015 ; Mody et al, 2017 ; Mody, 2020 ).…”

Epigenetic state determines inflammatory sensing in neuroblastoma

“…Comparatively, there is a relatively poor response when used alone in the setting of bulk tumor 66 , which is likely to contain a significant portion of immunologically quiescent adrenergic cells. However, responses are much better when anti-GD2 therapy is combined with chemotherapy31,32 , which may allow for targeting of both states simultaneously.Immunocompetent animal models will be needed to understand the impact of the differences in inflammatory sensing between MES and ADRN states in vivo and a lack of such experiments is a limitation of the current study. This provides a challenge, however.…”