The Positive Side of Negativity
In the fight against cancer, information is one of our most important assets. On an individual basis, understanding a person’s prognosis and their response to previous therapies empowers them, together with their doctor, to optimize treatment and forge a smart path forward. On a larger scale, information in the form of clinical trial data also helps determine whether and how quickly a medicine may be approved by regulatory agencies.
This is especially crucial in blood cancers where new therapies are needed and many forms of the disease can take a long and unpredictable course. Information about the efficacy of specific treatments comes from endpoints, the events or outcomes measured in clinical trials. Common endpoints in blood cancer trials include the time people live (overall survival), the time people live without their disease worsening (progression-free survival), and reductions in the number of cancer cells (response rates). Recently, interest has grown for a measure known as minimal residual disease (MRD) status that is emerging as a potential surrogate endpoint.
Many of today’s treatments aim to initially remove most of the blood cancer from the body, but residual cancerous cells can linger in tiny numbers that evade detection by traditional tests. These remaining cells, known as MRD, slowly regrow and are responsible for the relapses seen in many types of blood cancer.
The motivation to detect MRD has been around for a long time. However, it’s only recently that technological advances have made such tests a reality. Identifying the presence or absence of residual blood cancer (i.e. MRD-positivity or -negativity) may provide a gauge of the extent of a person’s response to treatment sooner than “traditional” clinical trial endpoints such as overall survival or progression-free survival. This information may help guide better treatment decisions and expedite the development of new medicines.
The efficacy of treatments for blood cancer is often measured by how completely the cancer is removed from the body. Recent advances in technology have made it possible to detect traces of cancer – called minimal residual disease (MRD) – that persist even when traditional tests come up clean.
Below is a summary of how MRD assessments have evolved over the years.
The difference between traditional assessments of blood cancer and MRD is like the difference between a classic detective and a modern crime scene investigator.
The earliest studies of MRD used a technique called immunofluorescence microscopy. This was a major advance over traditional counting of cancer cells (up to 1,000x more sensitive), but the science was still very early.
Newer methods for MRD detection were developed, using a genetic technique known as PCR...
… and flow cytometry, a technique for detecting specific proteins on the surface of cells.
MRD technology was further refined, with improvements to existing approaches and with the addition of new technologies like next-generation sequencing. Now the sensitivity can reach up to 1 in 1,000,000 cells.
Today, doctors and scientists are continuing to refine the way MRD is assessed, and regulatory authorities are considering MRD status in diseases including chronic lymphocytic leukemia (CLL) as a potential surrogate for endpoints like progression-free survival or overall survival that take longer to measure. By potentially providing an earlier indication of efficacy, MRD may ultimately help get new medicines to patients faster and, although the science is still evolving, could become a useful tool for guiding treatment decisions.
When negative is positive
Tests for MRD are designed to be highly sensitive. For example, in chronic lymphocytic leukemia (CLL), MRD is generally defined as detection of cancerous cells with a sensitivity of at least 10-4, which means you can identify 1 cancer cell in 10,000 normal cells. In contrast, traditional assessments of responses to treatment are based on cell-counting under a microscope and can detect only about 1 in 100 cells. An outcome of MRD-negativity is therefore encouraging for a person with blood cancer because it means that even with sophisticated specific tests, no cancer can be detected.
But MRD-negativity may have implications beyond simply the absence of residual blood cancer at the time of testing. There is a growing body of evidence that MRD-negativity after certain treatments may suggest a longer remission and potentially longer survival in a variety of different blood cancers. Though there is more work that needs to be done in this area, this data suggests that MRD may be useful as a “drug development tool” and surrogate endpoint that could enable faster approval of promising new medicines.
At Roche and Genentech, we’re actively collaborating with regulatory authorities and others in the industry to advance MRD as an endpoint. For example, we recently contributed to the EMA’s consultations initiative for finalizing the draft guidance for MRD, and we shared commentary with the industry to keep the conversation going. We’ve also included MRD as a prospective endpoint in several of our clinical trials, and we continue to have discussions with the FDA regarding the use of MRD as a primary endpoint along with progression-free survival in future studies of CLL. We are also working closely with others in the industry as well as clinicians and advocates to apply our learnings from our efforts to investigate the potential of MRD in different types of blood cancers.
Additionally, MRD status may some day help doctors determine which people could reduce or stop treatment versus who should maintain, intensify, or even change treatment. Regular monitoring of MRD status may also help provide the first warning if the disease reemerges.
Putting MRD to the test
As the use of MRD evolves, it’s time to standardize testing. While conversations are still going, many doctors and regulatory authorities have noted that MRD tests should be developed to be highly sensitive, broadly applicable, accurate, reliable, fast, and affordable before they can become widely adopted.
There are several important factors that must be considered:
Two techniques have been most commonly used to detect MRD: polymerase chain reaction (PCR) and flow cytometry (FC). Each has its advantages and disadvantages in terms of sensitivity, time, labor, expertise required, and ease of standardization. More recently, next-generation sequencing has become available as an approach to detect MRD with even greater sensitivity.
There are many options for when to test for MRD, such as during the first round of treatment, during maintenance therapy, and at regular intervals after treatment is over. Sampling too frequently can be a burden to the patient, while infrequent testing may delay the detection of recurrent disease.
MRD testing can be done with blood or bone marrow samples. Bone marrow is preferred because it offers greater sensitivity and is a more thorough assessment of residual disease after certain types of treatment. However, blood is less invasive to obtain than bone marrow – an especially important consideration for regular, repeated monitoring.
MRD testing must be optimized and validated (both analytically and clinically) for each specific blood cancer. All of the considerations above are likely to differ depending on a variety of factors, including the blood cancer type, where in the body the cancer is located (blood, bone marrow or lymph node), disease stage, and whether it’s in adults or children.
Good news for new medicines?
MRD may ultimately help get new medicines to patients faster by potentially demonstrating treatment efficacy much sooner – possibly even years earlier – than an endpoint like overall survival.
There’s been progress in regulatory science and the advancement of surrogate endpoints across oncology. MRD status has the potential to be an approvable surrogate endpoint for several types of blood cancer in the relatively near future.
There’s clearly still much work to be done, but I’m encouraged by the potential of MRD and confident that together we can move it forward.`QED Mark`