Y-mAbs Therapeutics has suffered a setback in its efforts to win US approval for I-omburtamab to treat a rare pediatric cancer.
On October 28, a Food and Drug Administration (FDA) advisory panel found a lack of evidence to support the drug’s approval for pediatric neuroblastoma in patients with central nervous system (CNS)/leptomeningeal (LM) metastases.
After reviewing data from two pivotal phase 2 trials, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted unanimously 16-0 that Y-mAbs Therapeutics had failed to provide sufficient evidence to show I-omburtamab improves overall survival.
The Y-mAbs application for regular approval of I-omburtamab rested largely on results from 107 patients in a single-arm study, 03-133. This study began in 2004 at Memorial Sloan Kettering Cancer Center (MSKCC), which developed I-omburtamab and then licensed it to New York-based Y-mAbs.
Neuroblastoma accounts for 7% to 10% of childhood cancers, with more than 650 cases diagnosed per year in the United States, the FDA said. About 90% of patients are younger than 5 years at the time of diagnosis. The FDA allows companies latitude when developing drugs for such rare and serious conditions.
In 2020, the FDA granted an accelerated approval for Y-mAbs’ first product, naxitamab (Danyelza), for certain patients with neuroblastoma based on response rate results in small open-label trials.
For I-omburtamab, the FDA allowed Y-mAbs to pursue an approach where an existing pool of data would serve as a comparator group, an acknowledgement that gathering data from patients with rare conditions is difficult. In July 2017, the FDA granted l-omburtamab a breakthrough therapy designation based on data from study 03-133.
In briefing documents, Y-mAbs argued in favor of approving the drug based on results from the 03-133 trial. In the trial, 107 evaluable patients with CNS/LM metastases from neuroblastoma received up to two doses of radiolabeled l-omburtamab.
The company reported a median overall survival of 51 months and a median 3-year overall survival of 57%. When including the external control group, which came from German registry data, Y-mAbs needed to narrow the patient pool analyzed. When comparing the two groups, the 3-year overall survival was 54% in the 03-133 trial versus 31% in the external control arm — indicating a 42% relative reduction in the risk of death, according to Y-mAbs.
But ODAC panelists and FDA staff raised concerns about the comparisons Y-mAbs drew, casting doubts on the company’s conclusions.
More specifically, the FDA panel noted that patients in 03-133 generally received more intensive treatment than those whose outcomes are recorded in the German registry, which “could contribute to longer survival” in the MSKCC group.
The FDA staff also wrote that patients who took I-omburtamab had to be well enough to travel to MSKCC, which is a major confounding factor.
In addition, the panel noted that the differences in the time periods between the two groups may have influenced patient outcomes. Patients in the German comparator group were diagnosed with CNS/LM relapse between 1991 and 2020, whereas those from study 03-133 included patients diagnosed with CNS/LM relapse between 2005 and 2018. “Differences in treatment era and changing cancer-directed or supportive care over time may result in improved survival,” the panel wrote.
Jorge Nieva, MD, an ODAC panel member, said he wanted to believe the survival differences cited by Y-mAbs were valid, but the conclusion drawn in favor of the drug appeared to be the result of selection bias.
“Unfortunately, we don’t have any data that isolates the treatment in the absence of a lot of other treatments,” said Nieva, of the University of Southern California. “And I’m very much bothered by the fact that the best picture that we had showing a response was a picture that was confounded by intervening chemotherapy.”
Nieva and other ODAC panelists said they would like to see further study of this drug.
The FDA has a November 30 deadline to decide on Y-mAbs’ biologic license application. The agency is not bound to follow the recommendations of its advisory committees, but often does so.
After the vote, Thomas Gad, president, and interim chief executive officer of Y-mAbs, said in a statement that the company remained committed to working closely with FDA on the application.
“We are disappointed by the outcome of today’s meeting, as patients with CNS/LM metastasis from neuroblastoma are in need of effective and safe treatment options,” said Gad whose daughter Daniella was treated at MSKCC for high-risk neuroblastoma.
But during the public hearing at the ODAC meeting, a representative of a watchdog organization questioned whether Y-mAbs had even provided enough evidence for an accelerated approval, let alone the regular approval the company is seeking. Diana Zuckerman, PhD, of the nonprofit National Center for Health Research, recommended expanded access as a better pathway for providing patients I-omburtamab, given the doubts about the current research findings.
“Expanded access is usually free. It’s carefully monitored and most important, the families and the patients understand this is an experiment and they know that they’re taking a risk and they’re freely choosing to do that,” Zuckerman said.
Kerry Dooley Young is a freelance journalist based in Miami Beach. Follow her on Twitter @kdooleyyoung.