Minimal Disease, Maximum Potential
Every year, leukemias and lymphomas take the lives of tens of thousands of people. However, in clinical studies of blood cancers, it can take years to measure the impact a medicine has on survival. Many people need new treatment options today, and the desire to bridge that gap is how alternate measurements, or endpoints, come about.
The means justify the ends
An endpoint is an event or outcome that can be measured objectively to determine whether a medicine is actually helping people. Alternate endpoints (for example “surrogate” endpoints) are measurements that “stand in” for other clinical trial endpoints that may take longer to measure. The goal is to provide a way to more quickly measure whether or not a treatment is working.
For blood cancers, alternate endpoints are especially important because many types of the disease are indolent (slow-growing). We’ll likely see a lot of discussion about new endpoints at ASH this year, and I’m really excited about their potential to expedite drug development and get medicines to patients more quickly. Of all these emerging endpoints, one of the most promising is minimal residual disease (MRD).
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.”
Importantly, MRD can be measured at any time, and strong evidence suggests that MRD-negative status (a “deep” response) may predict a longer remission, or more time before the disease comes back. That means MRD may provide a powerful indication of treatment efficacy early on, long before an outcome like survival could be measured.
The concept of MRD has been around for decades, but only in recent years have laboratory technologies become sensitive enough to detect it. That’s why now could be a turning point in making MRD a reliable and meaningful endpoint in clinical trials.
While the use of MRD has become quite common in recent clinical studies of blood cancer, it typically takes a back seat to traditional endpoints like survival. In fact, with the exception of use in chronic myeloid leukemia (CML), MRD has never been used as a principal measure of how a drug works in a clinical study.
The result is a lot of untapped potential. MRD could have a big impact on expediting clinical trials and getting medicines to patients faster – especially for slow-growing blood cancers like chronic lymphocytic leukemia (CLL). So the question is, how do we get MRD to reach its full potential?
A blueprint for success
It’s easy to forget, but every endpoint had a beginning – a point when people in the scientific community had to get together and decide whether the measure was clinically valid and reliable, and if so, how it should be defined and applied to evaluate a medicine’s benefit to patients.
The key is dialogue. Recently, the U.S. Food and Drug Administration (FDA) held workshops about MRD in blood cancers such as CLL and acute myeloid leukemia (AML). Conversations like these, which include everyone from cancer experts and patient advocates to companies and the FDA, are an essential foundation for the road ahead.
A major focus of the dialogue is standardization. When it comes to MRD, technical sophistication also means significant challenges. For example, which technology platform is the best – flow cytometry (FC) or polymerase chain reaction (PCR)? When are the best times to collect samples from patients, and what type of samples should be collected – blood or bone marrow? To move forward, we need to make sure we’re consistently assessing MRD in the best way possible.
We also need data. We need to design studies in a robust way that statistically supports MRD as well as a more established endpoint like progression-free survival (PFS), which measures how long patients live without the disease worsening. Designing a study with MRD as a primary endpoint is a bold move, but it’s an important step that we’re considering carefully.
Starting an endpoint
It’s still early, but I’m hopeful about the future of MRD, and it isn’t the first potential endpoint that we’ve championed. My colleague Dietmar Berger recently wrote a great article about pathological complete response (pCR), a proposed endpoint that can help get new breast cancer medicines to patients more quickly. Just this past September, the FDA granted its first provisional approval of a medicine based on pCR in early stage breast cancer before surgery (neoadjuvant setting). We hope to translate that type of progress to other cancers like blood cancer.
We’re working closely with others in the industry as well as clinicians, advocates, and the FDA to help make new alternate endpoints a reality across many types of cancer, and we hope to see significant progress in the near future. With MRD specifically, we have a ways to go and there will undoubtedly be challenges along the way.
If we succeed, we may be able to witness the adoption of a new and powerful endpoint – one that has great potential to improve clinical studies of many types of blood cancers and get important new medicines to the people who need them even faster. Discussion around MRD is yet another reason why it’s a great year to be at ASH and an exciting time in the field of hematology.