FDA Committee Votes Against Omburtamab for Metastatic Neuroblastoma

A group of experts in the Food and Drug Administration’s (FDA) Oncologic Drug Advisory Committee (ODAC) decided that there is not sufficient data on the benefit/risk profile of omburtamab for the treatment of patients with neuroblastoma with central nervous system or leptomeningeal metastases.

Neuroblastoma is the most common solid tumor that occurs outside of the skull in children, with approximately 650 cases diagnosed in the United States per year. Central nervous system involvement is exceedingly rare, typically presenting at the time of relapse in about 6% of patients.

READ MORE: Leptomeningeal Disease: A Rare Cancer Metastasis

Currently, there are no FDA-approved or curative therapies available for this patient population. However, patients in the United States deemed well enough to be treated are often provided with a combination of surgery, radiation and chemotherapy.

Experts hoped that omburtamab, which works by targeting a protein found on many types of cancer cells, would provide these patients with a new treatment option. During the ODAC meeting, the committee voted on whether the applicant provided sufficient evidence to conclude that omburtamab improves overall survival (time from treatment until death of any cause) in this patient population.

All 16 committee members voted that it did not, based on the findings from the phase 2 trials: study 101 and study 03-133.

About Studies 101 and 03-133

In study 03-133, investigators evaluated omburtamab monotherapy when used in patients with central nervous system/leptomeningeal metastatic from neuroblastoma.

Patients enrolled in the phase 1 study 03-133 were administered up to two doses of omburtamab. The goal of the study was to determine safety by the number of patients with treatment-related side effects. Investigators also wanted to evaluate the maximum tolerated dose and ideal dose for the drug, which would be used in part 2 of the study.

In part 2, the cohort-expansion portion of the trial, all patients were given 50 mCi of radioactive iodine, and treatment doses reduced depending on age. The main goal of this portion of the trial was overall survival at three years with secondary end points of progression-free survival (percentage of patients who were still alive without their disease getting worse) at 12 months.

Findings revealed that among the 107 evaluable patients, the average overall survival with omburtamab was 50.8 months and the final overall survival average had not yet been reached, because many of the patients on the trial were still alive, so average survival time could not be calculated.

Of the first 93 patients enrolled to the trial, the average overall survival with omburtamab was 47.1 months.

In 68 patients with other central nervous system cancers — including medulloblastoma (27 patients), ependymoma (nine patients), and embryonal tumors with multilayered rosettes (four patients), sarcoma (nine patients), melanoma (five patients) and other tumors (14 patients), 201 injections of omburtamab were safely administered in the outpatient setting.

The three-year overall survival rate was 57%. The average length of survival was 51 months, and the median follow-up was 52 months.

Investigators identified no dose-limiting side effects.

Mild to moderate fever, headache and vomiting were rare side effects observed in these patients. Further, severe chemical meningitis, and increasing communicating hydrocephalus (buildup of fluid on the brain) led to discontinuation of treatment with omburtamab.

Study 101 was a global, multicenter trial which assessed the combination of Danyelza (naxitamab) and omburtamab in patients with neuroblastoma.

In the pivotal 101 study, patients were administered omburtamab at one dose at 50 mCi at week 1. For patients treated in Japan, only one treatment cycle of omburtamab was given, consisting of two doses: 2mCi at week 1 and 50mCi at week 2.

The first cycle was initiated after there was confirmed eligibility at week 1. Then at week 5 and week 6 for Japan, patients were evaluated for safety. If eligible, they were also given a second cycle of omburtamab.

The overall survival rate observed with the combination was 87%, compared with 30% in previous studies of traditional treatment for the disease.

At an average follow-up of 23 months, the progression-free survival rate at six months was 75%. Regarding overall survival, the 12-month rate was 79%.

Applicant’s Stance

To support that the drug can receive breakthrough therapy, the multicenter 101 study was initiated in December 2018, following the single-center 03-133 trial initiated in 2004 at Memorial Sloan Kettering Cancer Institute in New York City.

The applicant believes that trial results showed a meaningful improvement in overall survival compared to data from other patients who were not treated with oomburtamab. The results of trial 101 also are consistent and supportive of overall survival and progression-free survival, and omburtamab demonstrated single-agent activity.

“Based on the totality of evidence from the two trials, we conclude that there is substantial evidence of effectiveness and omburtamab demonstrates a positive benefit-risk profile,” stated Rikke Valentin Oxholm Lileso of Y-mAbs Therapeutics, the manufacturer of omburtamab, in the meeting.

Overall, the position of the applicant is that omburtamab is indicated for pediatric patients with neuroblastoma with central nervous system/leptomeningeal metastases following standard multimodality treatment for this patient population.

The proposed dose is two doses of 50 mCi administered two weeks apart as intraventricular infusions. Based on the primary end point of overall survival, the drug manufacturer believes the agent should receive traditional approval.

ODAC’s Stance

According to ODAC, the applicant has not provided evidence to support that omburtamab works through elimination of micrometastatic disease in the central nervous system or provided compelling evidence to support the uptake of omburtamab in this patient population.

“Patients with neuroblastoma have an undeniable unmet medical need. However, the natural history is not well characterized due to its rarity, and we have analyses from published literature and additional data from this application, suggesting that survival has improved over time,” stated Dr. Amy Barone, cross disciplinary team leader, Division of Oncology 2, FDA, during the meeting.

According to the FDA, the statistical analysis conducted cannot adequately determine that improved survival was the direct result of treatment with omburtamab.

“These differences in results across analyses highlight the high degree of uncertainty associated with relying on this external control to establish a causal role from burden for omburtamab in any observed differences in survival between the populations,” added Barone.

Lastly, the FDA believes that there is a lack of supportive response rate data collected in Study 101 leading to more prominent issues of lack of confirmation of response, baseline assessment of disease, concerns for measurement error, and the timing of response relating to other central nervous system-directed therapies.

Final Vote

The ODAC committee concluded that the applicant did not provide sufficient evidence to conclude that omburtamab improves overall survival in patients with neuroblastoma with central nervous system/leptomeningeal metastases.

“This is a tough situation because we are all motivated to provide more to these patients, but the key question is whether there is clear benefit and the bar has not been met due to discrepancies,” stated Dr. Christopher Lieu, associate Director for Clinical Research, co-director, Gastrointestinal Medical Oncology at University of Colorado Medicineacting, chairperson of ODAC. “In terms of next steps, I believe there may be a pathway forward.”

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