MDNews - Central Pennsylvania

Planning to Scale Up WAY NE FURM A N, MD, recently retired member of the Department of Oncology at St. Jude Children's Research Hospital and first author of a study of a novel anti-GD2 monoclonal antibody for treating high-risk neuroblastoma, says plans are underway for a randomized, multi-institutional, Children's Oncology Group (COG) study that will seek to verify the results of his study. The COG study will compare chemoimmunotherapy featuring an anti-GD2 antibody as part of induction therapy with standard induction chemotherapy. "We are looking for a commercial partner to help get hu14.18K322A [the St. Jude novel anti-GD2 antibody] approved by the FDA," Dr. Furman says. "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. However, a drug that is only used in 350 patients per year is unlikely to be profitable for [the pharmaceutical industry]." his colleagues administered induction c h e m o t h e r a p y a n d hu 14 . 1 8 K 3 2 2 A , GM- C S F a nd I L -2 c onc u r r ent ly t o 6 4 pat ient s; 6 3 were ev a lu a ble. For consolidation therapy, patients received the chemotherapy medications busulfan and melpha lan — and, when available, patient-derived natural killer T cells with hu14.18K322A — followed by radiation therapy. Post-consolidation treatment consisted of hu14.18K322A , GM-CSF, IL-2 and isotretinoin. T h e S t . J u d e a n t i b o d y i s 9 8 % h u m a n i z e d — d i n u t u x i m a b , b y compa r ison, is ch i mer ic, cont a i n i n g b o t h h u m a n i z e d a n d m o u s e prot ei n s — a nd en g i neered t o cau se less complement-related neuropathic pa in tha n other a nti-GD2 a ntibodies, including dinutu ximab. Ba sed on the h i g her t oler a nc e for hu 14 . 1 8K 322 A obser ved in their dose-f inding study, the researchers administered a dose of the novel antibody nearly 2.5 times higher t ha n t he ma x i mu m tolerable dose of dinutuximab (40 milligrams per square me t er for hu 14 . 1 8K 32 2 A c ompa r e d w it h 17. 5 m g /m 2 for d i nut u x i m a b). Mo s t pa t ient s wer e a ble t o r e c eive hu14.18K322A infusions in four hours compared with 10 for dinutuximab. After the first two chemoimmunotherapy cycles, 66% of patients exhibited partial responses or better, a nearly 30-percentage- point improvement compared with the results of a 2019 Children's Oncolog y Group (COG) study that used the same induction chemotherapy regimen. Patients in the St. Jude study had a 3-year event-free survival (EFS) rate of 73.7% and an overall survival rate of 86%. The findings appeared in the Journal of Clinical Oncology. "Our 3-year EFS of nearly 74% are the best outcome results in this difficult-to- treat group of patients with high-risk neuroblastoma, and includes all patients enrolled, not just those that made it to ra ndom i zat ion [i n t he COG st udy]," Dr. Furma n says. "A nother intrig uing finding of our study is that no patients experienced progressive disease during induction, which occurred in patients s om e w h e r e b e t w e e n 7 % t o 14% i n prior studies." A SUPERIOR ANTIBODY OR A MORE POTENT DOSAGE? A key question is whether the promising results from the St. Jude study are due to the potential superiority of hu14.18K322A compared with dinutuximab, or whether it was the former's higher dose that made the difference. "It is unknown whether hu14.18K322A is a 'better' antibody, except [that] it is better tolerated — patients can tolerate more of it, given over a shorter time period, than dinutuximab," Dr. Furman says. "Thus, a key implication is that these impressive responses could just be due to a dose effect of [our] antibody. Unfortunately, dinutuximab cannot be given at the doses of hu14.18K322A used in this study." Dr. Furman points out that a larger, ra ndomized study needs to verif y the results of his investigation, and plans are in the works for that sort of effort (see "Planning to Scale Up"). If a sizable study corroborates the St. Jude group's f i nd i n g s , D r. F u r m a n s ay s it c ou ld change the standard of care for high-risk neuroblastoma patients. ■ 1 4

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