PC3010: First Report of Naxitamab Response for Brain Metastasis in Refractory High Risk Neuroblastoma

Introduction: Naxitamab (NAX) is a humanized monoclonal antibody (mAb) directed against anti-disialoganglioside (GD2) approved for treatment of bone/bone marrow refractory high-risk neuroblastoma (HR-NB). The approval studies for NAX did not include patients with brain metastasis. It was thought that the antibody would not penetrate the blood brain barrier. We believe this is the first report of HR-NB responding to NAX in the brain.

Case Description: The patient is a now 20 year old female who originally presented 4 years prior with stage 4 (bone, bone marrow, lymph node), shwannian stroma-poor, poorly differentiated, mycn-non amplified, ALK (+), HR-NB. She achieved first remission after treated with intensive chemotherapy, radiation, surgery, and autologous stem cell transplant x 2. Three years from diagnosis, she experienced her first relapse from diffuse paraspinal, brain and bony disease, causing paraplegia. She progressed 4 more times despite brain and bone radiation, dinutuximab-irinotecan-temozolomide, nivolumab and crizotinib, with new bone lesions and a new 4cm parietal brain metastasis. Compassionate use NAX with 5 day pre-treatment with sargramostim (GMCSF) was then tried following the MD Anderson protocol [Pediatr Blood Cancer. 2021 Oct;68(10)], 6 days after resolution of sepsis. Eight days after the first dose of NAX, she had resection of the brain metastases. The largest tumor had decreased by 42% by MRI volume estimate (from 3.8 x 3.3 x 3.3cm to 4.3 x 2.8 x 2.0cm ) with new necrosis. Neuropathology reported 70 - 80% necrosis. Six months later there is no brain recurrence and her MIBG curie score has decreased.

Discussion: NAX is a promising new mAbs for HR-NB patients who have exhausted standard therapies. However penetration of mAbs into the central nervous system is hindered by the blood–brain barrier (BBB) and the high molecular weight. The BBB is thought to create a micro-environment that promotes metastasis, because the of increased permeability of tumor-associated endothelial cells and tumor driven cytokines associated brain edema. In advanced cancer and in other non-cancer-related brain disease, BBB dysfunction is seen [Cavaco M,Pharmaceutics. 2020;12(1):62.] In addition, GMCSF induces cerebral inflammation as seen in encephalitis and auto-immune diseases of the brain by stimulation of cytokines [Immunity 46(2), 2017, 65-167]. It is possible that the pre-treatment with GMCSF in the setting of recent sepsis, allowed the NAX mAbs to penetrate the BBB and access the brain metastasis.

Conclusion: Our case report suggests that NAX may penetrate the blood brain barrier under certain circumstances and benefit patients with HR-NB who have CNS disease. More information is needed to see if this can be a feasible option for HR-NB with brain metastasis and few options other options.