FDA panel backs residual disease as ‘reasonable surrogate’ endpoint in myeloma trials
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Key takeaways:
- FDA panel advised MRD is an acceptable endpoint for accelerated approval of new treatments for multiple myeloma.
- MRD data can be calculated quickly.
An FDA advisory committee unanimously voted minimal residual disease should be an accepted endpoint for accelerated approval of clinical trials investigating treatments for patients with multiple myeloma.
PFS and OS are the current endpoints in multiple myeloma trials, but the committee believed the data presented, which encompassed numerous trials, proved minimal residual disease (MRD) had a strong association with PFS and could be acted upon much earlier.
“I’ve actually never before seen this level of data presented on simply moving the bar on response,” Jorge J. Nieva, MD, associate professor of clinical medicine and section head for solid tumors at USC Norris Comprehensive Cancer Center, said during the meeting. “We have three independent statistical analyses from thousands of patients showing that it does in fact correlate very nicely with long-term outcomes, and I think if ever there was an endpoint that showed a good statistical association, this is the one that does.”
Treatment of multiple myeloma has advanced significantly over the last 20 years, as 19 new agents have been approved over that time, according to information presented at the meeting.
These therapies have provided notable clinical benefits, with an overall response rate approaching 100% in certain populations, median PFS greater than 6 years and median OS of more than 10 years.
However, it can take more than a decade for data to be collected to reach PFS and OS endpoints. Using MRD could cut that number down to about a year.
The clinical trials examined showed a significant correlation between MRD negativity and improved survival.
“This was a herculean effort,” Neil Vasan, MD, PhD, assistant professor in the division of hematology and oncology at Herbert Irving Comprehensive Cancer Center at Columbia University, said.
“I think it really changes the playbook for how we think about biomarkers across all cancer types,” Vasan added. “To me, the important word was ‘reasonable.’ Is this a reasonable surrogate endpoint? Is this a reasonable intermediate endpoint? I think it is more than reasonable.”
Some committee members expressed concern about how the approval of MRD as an endpoint could negatively impact clinical trials and drug development, although they ultimately voted yes.
“We need to be cautious that once FDA guidance ... gets out that MRD is acceptable for accelerated approval, it will change the incentive structure for preclinical modeling, clinical development, early clinical trials. That requires the FDA to be vigilant,” Ravi A. Madan, MD, Oncologic Drugs Advisory Committee (ODAC) chairperson and head of the prostate cancer clinical research section of the Genitourinary Malignancies Branch at NCI’s Center for Cancer Research.
“That may lead to throwing the baby out with the bath water, as financial incentives may pressure industry to hit the MRD mark or not decide to continue,” Madan added. “On the flip side, it could raise other concerns that hitting MRD may not translate into long-term clinical efficacy. Therefore, the FDA needs to play close attention, as it always does, to safety, progression-free survival and other relevant endpoints like survival.”
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April 12, 2024: Meeting of the Oncologic Drugs Advisory Committee.
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