The anti-GD2 monoclonal antibody naxitamab plus GM-CSF for relapsed or refractory high-risk neuroblastoma: a phase 2 clinical trial

Abstract

In this single-arm, non-randomized, phase 2 trial (NCT03363373), 74 patients with relapsed/refractory high-risk neuroblastoma and residual disease in bone/bone marrow (BM) received naxitamab on Days 1, 3, and 5 (3 mg/kg/day) with granulocyte-macrophage colony-stimulating factor (Days -4 to 5) every 4 weeks, until complete response (CR) or partial response (PR) followed by 5 additional cycles every 4 weeks. Primary endpoint in the prespecified interim analysis was overall response (2017 International Neuroblastoma Response Criteria). Among 26 responders (CR + PR) in the efficacy population (N = 52), 58% had refractory disease, and 42% had relapsed disease. Overall response rate (ORR) was 50% (95% CI: 36-64%), and CR and PR were observed in 38% and 12%, respectively. With the 95% CI lower limit for ORR exceeding 20%, the primary endpoint of overall response was met. Patients with evaluable bone disease had a 58% (29/50) bone compartment response (CR, 40%; PR, 18%). BM compartment response was 74% (17/23; CR, 74%). One-year overall survival and progression-free survival (secondary endpoints) were 93% (95% CI: 80-98%) and 35% (95% CI: 16-54%), respectively. Naxitamab-related Grade 3 adverse events included hypotension (58%) and pain (54%). Overall, naxitamab demonstrated clinically meaningful efficacy with manageable safety in patients with residual neuroblastoma in bone/BM.

Fig. 1. Consort flow diagram for Trial 201.

^aOther reasons include the following: did not meet required disease status or time from start of induction therapy to trial enrollment (n = 3); received immunosuppressive agents (n = 1); prior naxitamab treatment (n = 1); withdrawal of consent (n = 1); considered by investigator to be better suited for other treatment (n = 1). ^bExcluded due to the following: anaphylaxis (n = 2, SAEs, Grade 4); PRES (n = 1, SAE, Grade 3); respiratory depression (n = 1, SAE, Grade 4); hypotension (n = 1, non-serious, Grade 2, occurring in the same patient with respiratory depression leading to treatment discontinuation); urticaria (n = 1, SAE, Grade 2); myocarditis (n = 1, SAE, Grade 3, occurring in a patient with a history of hypertrophic cardiomyopathy). Some patients were excluded for more than one reason. ^cExcluded due to the following: reviewer agreement to CS = 0 and no BM involvement (n = 2); reviewer agreement to CS = 1 in retroperitoneal soft tissue (not spine) (n = 1); reviewer disagreement to CS = 0, with third reviewer confirming CS = 0 (n = 7); no BM samples available for independent review (n = 3). Some patients were excluded for more than one reason. BM bone marrow, CS Curie score, PRES posterior reversible encephalopathy syndrome, SAE serious adverse event, TEAE treatment-emergent adverse event.

Fig. 2. Efficacy assessment of naxitamab.

a Duration of response as per independent review for each of the responders in the efficacy population (n = 26). b Maximum change in CS from baseline in patients with baseline disease in the bone compartment (n = 48; 2 of the 50 patients with evaluable bone disease at baseline did not have postbaseline CS assessment). Source data are provided as a Source Data file. CS Curie score.

Fig. 3. Kaplan–Meier estimates for (a) PFS and (b) OS for patients treated with naxitamab plus GM-CSF in Trial 201 at data cutoff (December 31, 2021). Efficacy population, n = 52.

a PFS is defined as the time from the first infusion of naxitamab until PD or death, whichever comes first, and censoring occurs at the earliest of the date of last disease evaluation before initiation of new anti-neuroblastoma treatment or last assessment during long-term follow-up. b OS is defined as the time from the first infusion of naxitamab until death, and censoring occurs at the last date where the subjects are known to be alive during long-term follow-up. Source data are provided as a Source Data file. GM-CSF granulocyte-macrophage colony-stimulating factor, OS overall survival, PD progressive disease, PFS progression-free survival.