Will Blincyto's Expanded FDA Approval Open the Door for Wider Use of MRD as a Biomarker or Endpoint?

Regulatory NewsRegulatory News | 03 April 2018 |  By 

Last week, the US Food and Drug Administration (FDA) expanded the approval of Amgen’s Blincyto (blinatumomab) to treat adults and children with B-cell precursor acute lymphoblastic leukemia (ALL) who are in remission but still have minimal residual disease (MRD). 

The decision represents the first time FDA has used MRD as a biomarker for a regulatory decision, as the pivotal trial for the approval used a molecular assay for MRD to select patients for the study and to assess the response to therapy with blinatumomab.

But will the approval open up other opportunities to use MRD more widely among those developing treatments for blood cancers like ALL, multiple myeloma (MM), acute myeloid leukemia (AML), chronic myeloid leukemia (CML) or chronic lymphocytic leukemia (CLL)?

An FDA spokesman told Focus the agency “would be open to working with other sponsors on development pathways that involve using MRD,” noting there are MM, indolent non-Hodgkin lymphoma and other trials currently using MRD as an endpoint or biomarker.

One example, features Amgen collaborator Adaptive Biotechnologies in another agreement to use its next-generation sequencing-based (NGS) assay in a Phase 3 study with Amgen and Janssen, comparing Kyprolis (carfilzomib), Darzalex (daratumumab), and dexamethasone with Kyrpolis and dexamethasone, to measure MRD status in patients with relapsed or refractory MM.

Charles Sang, senior vice president of diagnostics at Adaptive, explained to Focus: “The regulatory landscape is challenged because the governing bodies trying to make the rules are learning about the use of MRD in real time.”

European regulators have been ahead of FDA in terms of adapting to the use of MRD, Sang said. But because of the decentralized nature of Europe, there have been difficulties in embracing a standardized approach, whereas the US has been slower but more standardized.

“We’re at the leading edge of a wave and trying to understand how to apply these tools,” he said, noting that more regulatory professionals need to be conversant on the topic.

Dario Campana, a professor at the National University of Singapore (NUS) who developed the technology that forms the basis for Unum Therapeutics, told Focus: “MRD is the most powerful prognostic parameter in both ALL and acute myeloid leukemia (AML). Data suggest that it may also be important in other hematologic malignancies, such as multiple myeloma.

“With the increasing availability of new agents, other uses of MRD are emerging, e.g., MRD as eligibility and response criteria. In the case of immune-oncology agents, such as Blincyto or CAR-T cells, treating patients with low leukemic burden might be advantageous, as it could maximize the likelihood of disease eradication while minimizing potential toxicities due to excessive T cell activation.  The approval of Blincyto for this specific indication seems to validate this concept,” Campana added.

In terms of regulatory obstacles, Campana said one “obstacle to regulatory approval of MRD, and to MRD interpretation in general, is the lack of standard, universally used, MRD assays. Several labs around the world have demonstrated proficiency at monitoring MRD, but many other labs perform such tests without the necessary expertise.

“It would be hard to get every lab to agree on a specific approach or technique. One possibility is to perform MRD only in expert reference labs. Alternatively, one could implement a quality control system to ensure that laboratories performing MRD for approved studies can consistently detect MRD at a certain level (say 0.01% in ALL), regardless of the method used,” he added.

Sang also noted there are a number of products working their way through company pipelines in the myeloma space where MRD will be leveraged in the labeling.

An article published in January 2017’s JAMA Oncology by Nikhil Munshi of the Dana-Farber Cancer Institute also found that the results of a large analysis showed: “Minimal residual disease status is a marker of long-term outcomes in patients with MM. It should therefore be considered a new endpoint in clinical trials and clearly has a role as a surrogate marker of OS [overall survival].”

Last week’s expanded approval from FDA also coincided with the publishing of a New England Journal of Medicine article on how NGS can enable the detection of molecular MRD “in virtually every patient” with AML, “but its clinical value for the prediction of relapse has yet to be established.”

David Steensma and Benjamin Ebert of the Dana-Farber Cancer Institute and Harvard Medical School noted in an editorial accompanying the NEJM article: “Although the concept of persistent minimal residual disease strikes fear in the hearts of oncologists because of its implications in acute lymphoblastic leukemia and other diseases, assessment for minimal residual disease in AML is more nuanced.”

But from a high-level perspective, how Blincyto’s expanded approval and the studies evaluating MRD will be part of a wider shift from FDA remains to be understood.

An FDA analysis from last June noted the considerable interest in using MRD in clinical trials of hematologic malignancies, especially as a potential surrogate endpoint to expedite drug approval, though surrogacy has not yet been established in most hematologic malignancies, except for CML.

Almost 40% of new drug and biologics license applications submitted to FDA’s Office of Hematology and Oncology Products between 2014 and 2016 included MRD data, the authors found.

But they noted: “While the data submitted was deemed adequate for inclusion in the PI [prescribing information] in 46% of cases, 31% of applications contained MRD data that the Agency deemed un-interpretable. Data collection and assay performance characteristics should be of significant rigor and completeness to allow for comprehensive review.”


Cancer drug developers have long sought to use MRD as an endpoint.

As Nancy Valente, VP of Genentech, explained in 2013: “MRD is a measurement of the ‘depth’ of response to a treatment for blood cancer – that is, to what degree the cancer itself is eliminated. It’s based on incredibly sensitive tests that can detect the presence of blood cancer even when standard laboratory tests come back clean. Whether or not traces of the disease persist determines whether a person’s status is considered ‘MRD-positive’ or ‘MRD-negative.’”

An MRD-negative status may predict a longer cancer remission, and such a prediction may occur prior to when an outcome like overall survival can be measured. And last week’s expanded approval for Blincyto was the first FDA-approved treatment for patients with MRD-positive ALL.

As Amgen explains, improvements in detection techniques can enable clinicians to identify MRD more frequently, which may help to assess the potential risk of relapse early on and inform treatment decisions.

For drugs intended to treat certain blood cancers, there have been multiple discussions between FDA and industry and other stakeholders on how MRD could be used as a surrogate endpoint.

FDA convened a series of workshops to address issues in MRD detection and its use in four cancers: MM, ALL, CLL and AML. The Duke Margolis Center for Health Policy in 2016 also held an event on the use of MRD as a surrogate endpoint in such trials.

But nearly a year later, several officials from FDA’s Office of Hematology and Oncology Products published an editorial discussing the lingering questions associated with the use of MRD as a potential surrogate endpoint.
Across the Atlantic, meanwhile, the European Medicines Agency (EMA) last June published a concept paper discussing the need to revise a guideline on the use of MRD as a clinical endpoint in MM clinical studies.

Back in 2015, EMA also discussed how undetectable MRD in patients with CLL “in clinical complete remission (= MRD response rate) after induction therapy may be used as an intermediate endpoint for licensure in randomised well controlled studies designed to show superiority in terms of PFS [progression-free survival].”

Editor's Note: Article updated on 4/3/18 with comment from Dr. Campana


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