In a unanimous vote, the FDA’s Oncologic Drugs Advisory Committee has voted that there is not enough evidence to conclude omburtamab improves overall survival in neuroblastoma with central nervous system/leptomeningeal metastases.
In a 16 to 0 vote, the FDA’s Oncologic Drug Advisory Committee (ODAC) decided that the benefit/risk profile of omburtamab does not have sufficient enough data to support that improves overall survival (OS) in patients with neuroblastoma with central nervous system (CNS)/leptomeningeal metastases.1
On October 28, 2022, the FDA’s ODAC discussed the biologics license application for I-omburtamab solution, which was submitted by Y-mAbs Therapeutics, Inc for the proposed use as treatment for patients with neuroblastoma with CNS/leptomeningeal metastases.
Neuroblastoma is the most common extracranial solid tumor in childhood with approximately 650 cases diagnosed in the United States per year. CNS involvement is exceedingly rare, typically presenting at the time of relapse in about 6% of patients. 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 would provide these patients with a new treatment option. During the ODAC meeting, the committee voted on whether or not the applicant provided sufficient evidence to conclude that omburtamab improves OSl in this patient population.
Omburtamab is a radiolabeled monoclonal antibody 8H9(131I-8H9) which targets B7-H3–expressing cells in solid tumors, including embryonal tumors, carcinomas, sarcomas, and brain tumors.2 The agent, which was developed by researchers at Memorial Sloan Kettering Cancer Center, has been shown to bind to an FG loop-dependent conformation on the B7-H3 molecule, which plays a key role in biologic function.
Previously in April 2022, a BLA was re-submitted to the FDA seeking approval for I-omburtamab for use in pediatric patients with CNS/leptomeningeal metastasis from neuroblastoma. The resubmission follows a refusal to file letter from the FDA.3
In the letter, the FDA stated that certain parts of the chemistry, manufacturing, control module, and the clinical module of the application were lacking important details. The company in turn shared that they would address the concerns raised by the agency by providing more CMC information and including supplementary data from Study 101 (NCT03275402) on tumor response in the first 24 evaluable patients.
The FDA assigned a prescription drug user fee act goal date of November 30, 2022, for the completion of its priority review of the BLA.
Now, this new BLA which was in question had support from the findings of with findings from the phase 2 pivotal studies, 101 and 03-133 (NCT00089245).
In the 03-133 study, investigators evaluated omburtamab monotherapy when used in patients with CNS/leptomeningeal metastatic from neuroblastoma.
Patients enrolled in the phase 1 study 03-133 were administered up to 2 doses of the omburtamab with the goal of the study to determine safety by the number of patients with treatment-related toxicities. Investigators also wanted to evaluate the maximum tolerated dose for part 2 of the study.
In part 2, the cohort-expansion portion of the trial,all patients were given 50 mCi and treatment doses reduced depending on age. The primary end point of this portion of the trial was OS at 3 years with secondary end points of progression-free survival (PFS) at 12 months.
Patients were mostly male (67%) and White (79%). The median age of those enrolled was 4.7 years (range, 0.85-13). Regarding the site of metastases at CNS relapse, 48% of patients had unifocal parenchymal lesion (PM), 15% had multifocal PM, 9% had leptomeningeal (LM), 8% had PM plus LM, and the other 19% were unknown or not reported.
Findings revealed that among the 107 evaluable patients, the median OS with omburtamab was 50.8 months and the final OS had not yet been reached. Of the first 93 patients enrolled to the trial, the median OS with omburtamab was 47.1 months.
In 68 patients with other CNS cancers–including medulloblastoma (n = 27), ependymoma (n = 9), and embryonal tumors with multilayered rosettes (n = 4), sarcoma (n = 9), melanoma (n = 5), and other tumors (n = 14), 201 injections of omburtamab were safely administered in the outpatient setting.
The 3-year OS rate was 57% (95% CI, 47-66). The median OS was 51 months (95% CI, 31-NE), and the median follow-up was 52 months.
Investigators identified no dose-limiting toxicities. Grade 1/2 fever, headache, and vomiting were rare adverse events (AEs) observed in these patients. Further, grade 3 chemical meningitis, and increasing communicating hydrocephalus were AEs requiring discontinuation of the agent.
Study 101 was a global, multicenter trial which assessed the combination of naxitamab (Danyelza) and omburtamab in patients with neuroblastoma.3,4
In the pivotal 101 study, patients were administered omburtamab at 1 dose at 50mCi at week 1. For patients treated in Japan, only 1 treatment cycle of omburtamab was given, consisting of 2 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.
Among the 50 patients enrolled in trial 101, the median age was 4 (range, 0-11), a majority of patients were male (58%), and White (76%). and followed for a median of 26 weeks. The OS rate observed with the combination was 87%, compared with 30% in a historic control.5,6
The PFS rate at 6 months in this trial was 75% (95%, CI, 61-85) and the median follow-up was 23 months. Regarding OS, the 12 month rate was 79% (95% CI, 64-89) with a median follow-up of 23 months. According to investigators, the results of study 101 are consistent with that seen in trial
Currently, there are no treatments available for patients with CNS/leptomeningeal neuroblastoma. However, the applicant believed that omburtamab is a promising option, due to the results of trial 03-133 and trial 101.
To support that the product 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.
The applicant believes that the external control arm is fit-for-purpose as trial 03-133 showed a clinically meaningful improvement at 42% in OS compared with the external controls. The results of trial 101 also are consistent and supportive of OS and PFS, and omburtamab demonstrated single-agent activity.
“Based on the totality of evidence from the 2 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 in the meeting.
Overall, the position of the applicant is that omburtamab is indicated for pediatric patients with neuroblastoma with CNS/leptomeningeal metastases following standard multimodality treatment for this patient population.
The proposed dose is 2 doses of 50 mCi administered 2 weeks apart as intraventricular infusions. Based on the primary end point of OS, they believe the agent should receive traditional approval.
According to the FDA, the applicant has not provided evidence to support that omburtamab works through elimination of micrometastatic disease in the CNS or provided compelling evidence to support the uptake of omburtamab in this patient population.
The FDA identified 3 key issues regarding the evidence to demonstrate the benefit of omburtamab for patients with neuroblastoma with CNS/leptomeningeal metastases. These include that the external control is not a relevant comparator due to clinically important differences in populations, comparisons of survival are not reliable,
“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 Amy Barone, MD, cross disciplinary team leader, Division of Oncology 2, FDA, during the meeting.
According to the FDA, there is no statistical method which can overcome the uncertainty created with an external control that is not fit-for-purpose. Because of this, they conducted multiple sensitivity analyses which concluded that the differences in survival cannot be attributed to omburtamab as hazard ratios were approaching and exceeding 1 in multiple cases.
“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 ot other CNS-directed therapies.
Due to these reasons, the FDA believes that there are major review issues with this application which stem from fundamental differences in the external control, and that there is a lack of robust evidence to demonstrate the benefit of omburtamab.
The ODAC committee concluded that the applicant did not provide enough sufficient evidence to conclude that omburtamab improves OS in patients with neuroblastoma with CNS/leptomeningeal metastases.
Though there is a serious unmet need for more options for this patient population, experts believe that there is not enough data to conclude that omburtamab improves OS.
“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 Christopher Lieu, MD, 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.”