FDA panel nod on MRD endpoint could expedite myeloma drug approvals

2024-04-14

免疫疗法加速审批临床结果临床研究

An FDA advisory committee on Friday voted 12-0 that evidence backs up the use of minimal residual disease (MRD) as a feasible surrogate endpoint in clinical trials of multiple myeloma, potentially facilitating the accelerated approval process for new treatments. If the FDA agrees, the decision could introduce a drug development pathway that allows new myeloma drugs to reach patients more quickly.

The agency's Oncologic Drugs Advisory Committee (ODAC) endorsement follows the evaluation of two separate meta-analyses presented by experts from the University of Miami's Sylvester Comprehensive Cancer Center and I2TEAMM, a group brought together by the International Myeloma Foundation (IMF).

These analyses demonstrated a strong association between MRD negativity (MRD-neg) and improved progression-free survival (PFS) and overall survival (OS) in multiple myeloma patients at the individual level. MRD is a measure of the number of multiple myeloma cells in a patient's bone marrow, and is often used in those who have achieved complete response (CR) to further quantify depth of response to treatment beyond CR.

"To date, many myeloma drug approvals take 9-12 years and must demonstrate a PFS of 5-8 years," the IMF said in a statement following the ODAC vote. With MRD testing as an early endpoint, the group argued that PFS study readouts could be available within 9-12 months, as opposed to 5-plus years.

Correlations to survival

The I2TEAMM said MRD-neg is linked to longer PFS and OS in all treatment modalities, including novel immunotherapies such as CAR-T cells and T-cell engagers. Further, the group said "consistent high individual-patient-level correlations" suggest that an MRDneg-CR rate at 10-5 threshold at nine months can "reasonably likely" predict clinical PFS benefit in relapsed/refractory myeloma, as well as newly diagnosed transplant-eligible and transplant-ineligible patients.

Meanwhile, C. Ola Landgren of the Sylvester Comprehensive Cancer Center Cancer Center presented findings from the EVIDENCE meta-analysis on MRD, a collaborative effort with a number of pharmaceutical companies including Sanofi, Johnson & Johnson, Amgen, Takeda and AbbVie.

Landgren said "the most effective treatments are in the first line," given that up to 35% of patients are lost at each successive line of therapy. However, studies with the currently accepted endpoints of PFS and OS in patients with newly-diagnosed disease "are taking a long time to mature. New effective therapies are unavailable to patients for over 10 years while waiting for studies to mature," he added.

The trouble with ORR

Overall response rate (ORR) is recognised as an intermediate endpoint reasonably likely to predict clinical benefit, but there's a snag – ORRs can be so high with conventional therapies such as RV-d (lenalidomide, bortezomib, and dexamethasone) and D-RVd (daratumumab plus RV-d) that some might argue there's no need for novel treatments in newly diagnosed myeloma patients.

However, ORR only requires 50% reduction in disease, which means patients with residual disease inevitably suffer from relapse or refractoriness. "It is no longer possible to develop new therapies in patients with newly diagnosed multiple myeloma with ORR in the accelerated approval pathway," Landgren said.

More to follow.

更多内容，请访问原始网站

文中所述内容并不反映新药情报库及其所属公司任何意见及观点，如有版权侵扰或错误之处，请及时联系我们，我们会在24小时内配合处理。

机构