FDA Issues CRL for Therapy for Brain Metastasis from Neuroblastoma

The FDA has issued a complete response letter (CRL) for the Y-mAbs Therapeutics’ biologics license application (BLA) for the investigational medicine omburtamab to treat patients with CNS/leptomeningeal metastasis from neuroblastoma. This follows the outcome of October 2022 advisory committee voted against omburtamab. The FDA’s Oncologic Drug Advisory Committee (ODAC) voted 16 to 0 that the company had not provided sufficient evidence to conclude that omburtamab improves overall survival.

Neuroblastoma is the most common solid tumor in childhood with about 650 cases diagnosed in the United States per year. Central nervous system/leptomeningeal metastases are a rare and difficult-to-treat late-stage complication in which cancer cells from other affected areas spread to the meninges in the brain.

Omburtamab is a monoclonal antibody radiolabeled with Iodine-131 that targets B7-H3, an immune checkpoint molecule that is widely expressed in tumor cells of several cancer types. The omburtamab BLA is for the treatment of pediatric patients with CNS/leptomeningeal metastasis from neuroblastoma.

The submission was based on the safety and efficacy results of the pivotal phase 2 studies 101 and 03-133. According to the company, interim results for 32 patients enrolled showed a 12-month overall survival (OS) of 73.5%, with a median follow-up of 25 months, and an objective response rate (ORR) of 31.3% in the patients with measurable disease after central review based on Response Assessment in Neuro-Oncology (RANO) criteria and European Association of Neuro-Oncology (EANO)/European Society for Medical Oncology (ESMO) criteria, and that a total of 75.0% of the patient with measurable disease achieved disease control. Serious adverse events found in 40.6% of the patients and were mostly related to myelosuppression.

Regulators’ concern centered around whether the studies demonstrated a treatment effect. Specifically, they said, the Study 03-133 was a single-arm trial. “OS should generally be evaluated in randomized trials because data from externally controlled trials may not be reliable or interpretable,” regulators wrote in a briefing document. “Apparent differences in outcome between external controls and current treatment groups can arise from factors other than the drug under investigation, such as differences in patient or disease characteristics, supportive care, concomitant treatments, or other factors.”

Christopher H. Lieu, M.D.

The FDA performed additional analyses to examine bias and these results indicated that differences in survival cannot be reliably attributed to omburtamab. Regulators indicated that the application did not include reliable response rate data to provide supportive evidence of the treatment effect of omburtamab.

“This is a tough situation. I think we are all motivated to provide more therapeutics to these patients who desperately need them. The issue here is whether there is clear overall survival and this bar has not been met,” committee member Christopher H. Lieu, M.D., said after the vote. He is associate director for Clinical Research and co-director of Gastrointestinal Medical Oncology University of Colorado Cancer Center.