FDA Grants Priority Review to Naxitamab in R/R High-Risk Neuroblastoma

The FDA has granted Priority Review to the recently accepted Biologics License Application (BLA) for naxitamab (Danyelza) as treatment of patients with relapsed/refractory high-risk neuroblastoma. Without an advisory board meeting, the Prescription Drug User Fee Act action date for naxitamab is set for November 30, 2020.¹

“We believe that the FDA’s acceptance of our BLA for priority review of our first leading antibody compound, Danyelza (naxitamab), is a significant achievement for Y-mAbs and a crucial step forward as we anticipate that Danyelza if approved, can address a significant unmet medical need for children with relapsed/refractory high-risk neuroblastoma,” stated Thomas Gad, founder, chairman, president and head of Business Development and Strategy.

Data from a phase 2 study, 12-230 ,served as basis for the BLA. An update was announced in October of 2019 showing an overall response rate (ORR) of 78% in the subgroup of 28 patients with primary refractory high-risk neuroblastoma. This subgroup also had a 50% 2-year progression-free survival (PFS) rate. In seperate subgroup of 30 patients with relapsed neuroblastoma resistant to salvage therapy, the ORR was 37% and the PFS rate was 36%. Finally, in the subgroup of 44 patients with high-risk neuroblastoma who are in second or later complete remission, the PFS rate was 52%, but patients were not evaluable for ORR.²

Findings from naxitamab as treatment of relapsed/refractory high-risk neuroblastoma were also presented in a different study by Jaume Mora, MD, PhD, in a poster at the 2020 American Society of Clinical Oncology Virtual Scientific Program and showed potential for naxitamab for treatment in the outpatient setting.³

At a data cutoff of June 2019, data from 24 patients were available from the study. In the study population, the median age was 5.0 years (range, 1-10 years). Thirty-six percent of the children were female and 64% were male. In terms of race, 48% of patients were classified as white, 48% were Asian, and 4% were identified as other.

Baseline screening showed MYCN amplification in 16% (4 out of 25) and gain in 4% of patients (1 out of 25). However, 56% had no gain or amplification (14 out of 25), and 24% of patients had unknown MYCN amplification status (6 out of 25). The majority of patients (84%) were stage 4 (21 out of 25). There were no stage 2A, 2B, or 4S patients, and for 12% of patients, the INSS stage at diagnosis was not reported. A prognostic evaluation revealed that most patients (64%) had unfavorable histology (16 out of 25), and only 4% had favorable histology (1 out of 25). For 32% of participants, no prognostic group was reported ( 8 out of 25). For prior treatment, 23% of patients had prior surgery (23 out of 25), 96% had prior chemotherapy (24 out of 25), and 36% had prior radiation (9 out of 25).

Regarding neuroblastoma location and status at baseline, the disease was mainly located in both the bone and bone marrow (48%, 12 out of 25). The disease was located in the bone only in 44% of patients (11 out of 25), and in the bone marrow only in 8% of patients (2 out of 25). Sixty-four percent of patients were primary refractory (16 out of 25), and 36% had incomplete responses to salvage therapy (9 out 25).

At a median follow-up of 30 weeks (range, 6-48), the efficacy analysis showed an overall response rate (ORR) of 88% (95% CI, 62%-98%) in the primary refractory group, including a complete response (CR) rate of 81% (95% CI, 54%-96%). The group of 8 patients with incomplete response to salvage therapy had an ORR of 63% (85% CI, 24%-91%), with a CR rate of 50% (95% CI, 16%-84%). Overall, objective responses were seen in 19 patients in the study, showing an ORR of 79% (95% CI, 58%-93%) and a CR rate of 71% (95% CI, 49%-87%).

The median progression-free survival was 24 weeks with naxitamab (95% CI, 26-not estimable).

Grade 3 or 4 treatment-emergent adverse events (TEAEs) were reported in 10% of patients overall per the Common Terminology Criteria for Adverse Events, and overall 88% of patients experienced at least 1 grade 3/4 TEAE. Most events fell under the category of general disorder and administration site conditions (72%). The most common grade 3/4 TEAEs were pain (72%), vascular disorders (60%), and hypertension (60%). There were 6 serious TEAEs reported in 5 patients, which included 4 events of an anaphylactic reaction, 1 pyrexia events, and 1 respiratory depression event. Additionally, 8% of patients (2 out of 25) experienced anti-drug antibody formation.

The study of naxitamab, a humanized monoclonal antibody that targets GD2 expressed in neuroblastoma, was an international, multicenter clinical trial. Naxitamab was administered to patients in this study at 9mg.kg, which was divided into 3 doses given over 4 weeks, intravenously. Infusions lasted 30 minutes to 60 minutes in an outpatient setting.

Based on this study, Mora et al considered naxitamab a unique option for the treatment of relapsed/refractory high-risk neuroblastoma in the outpatient setting. The finding presented at ASCO 2020 warrant further development of the drug.

Y-mabs Therapeutics, Inc, developer of naxitamab, plans to work closely with the FDA to ensure a smooth commercial launch for the drug if it is approved.¹

_References:

_{Y-mAbs announces U.S. FDA acceptance of Biologics License Application for Danyelza™ (naxitamab) for the treatment of neuroblastoma for Priority Review. New release. Y-mAbs Therapeutics, Inc. June 2, 2020. Accessed June 2, 2020. https://bit.ly/300qA2H}

_{Y-mAbs Announces Naxitamab Update. New release. Y-mAbs Therapeutics, Inc. October 25, 2019. Accessed June 2, 2020. https://bit.ly/3dvqSm9}

_{Mora J, Chan GC, Morgenstern DA, et al. Naxitamab, a new generation anti-GD2 monoclonal antibody (mAb) for treatment of relapsed/refractory high-risk neuroblastoma (HR-NB). J Clin Oncol. 38: 2020 (suppl; abstr 10543). doi: 10.1200/JCO.2020.38.15_suppl.10543}