“MRD is our closest next thing—our closest next tool that will actually be in prime time—as far as biomarkers go, particular in heme, but I’m also interested in solid tumor applications,” said Dana Connors, director of cancer research partnerships at the Foundation for the NIH. “MRD is the is essentially the disease itself; it has such kinship with what it is that we’re trying to ask of it… There are very few markers that have that kind of relationship with the information that they convey, that I think give us an advantage.”
The challenge now, Connors said, is not to lose momentum.
MRD tests vary in design, tissue input, and goal. Most of the pharma representatives on the panel are using it in early stage drug development and testing. Rajiv Raja, senior director of experimental medicines oncology at GSK, reported using MRD to monitor a patient’s response to a drug as diagnosis moves earlier and earlier. “More traditional endpoints like PFS [progression-free survival] and OS [overall survival] take a long time, and these provide a much quicker way of assessing how effective your drug is.”
Christopher Conn, global director and diagnostics strategy lead at Amgen, reported using MRD to stratify patients into various study arms when they anticipate regulatory engagement. “Over that time, what I’ve seen is just how powerful of a tool this can be for understanding mechanism of action in our drugs, identifying patients that still have residual disease, and doing escalation of treatment for label expansion,” he said.
Circulating tumor DNA after treatment is clearly prognostic, added Jean-Francois Martini, executive director and translational oncology lead at Pfizer. “Patients are more likely to move to a metastatic stage very quickly, and being able to have a point of intervention sooner rather than later is definitely critical for the patient’s care,” he said. “Being able to intervene sooner, especially in the case of those solid tumors where radiography is not sufficient after surgery, for example, it’s becoming critical to be able to implement those in the clinic.
MRD is facilitating staging based on biology rather than simply staging based on anatomy, said Connors, agreeing with panel moderator Peter Bach, CMO of Delfi Diagnostics. “We have historically tried to chop [our understanding of biology] up into little bits, and no analyte is viable in isolation, right?” Connors said. “I think a systems biology approach is going to be really important.” It’s a priority at NIH, he added.
While all of the speakers were pleased with MRD’s potential in early drug development, getting more clinical data will require more incorporation into clinical trials, ideally at multiple time points. “There’s always a struggle because there’s always pushback from a cost perspective,” noted Raja. But understanding circulating tumor DNA endpoints will really require longitudinal data from more than one study. “You want to catch it at the sweet spot,” he said.
But thus far, the panel reported, getting multi-site MRD studies has been challenging. Standardizing assays across sites has been a challenge, and processing samples at a central site is time consuming. From a regulatory standpoint, Connors added, even multi-site studies within one European country will probably not be deemed sufficient by FDA. In China, the challenge is even greater as a study would need 15% of the enrolled population to be in China and samples can’t leave the country.
Working with FNIH, Amgen has received approval for blinatumomab (Blincyto) for the treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (B-ALL) that is in first or second complete remission with minimal residual disease (MRD) of 0.1% or more, Conn reported. With that success to build on, he said, Amgen has still seen regulatory oversight of MRD increase, especially in the US. “Health authorities want to assess the analytical validity of the assays in quite specific detail,” he said.
Conn recommended setting up clinical studies with the analytical validation package in mind, watching for pre-analytic variables that could be overlooked. “What are the sample types that you’re collecting? What’s the matrix that you’re collecting them in, time points, stability windows? Does that align with the way the assay was analytically validated? Do the samples that were used in the analytical validation adequately represent your intended use population?” This is the level of detail companies need to successfully approach health authorities, he reports.
Many of these studies have been ongoing for a decade, Conn said. “We’ve used a variety of different partners, laboratory-developed tests, flow cytometry, and molecular methodologies, and we’ve seen some challenges when we go to seek marketing authorization,” he said.
Perhaps that recounted experience prompted the question from the audience about how pharma thinks about assessing the various diagnostic assay vendors and choosing which ones to incorporate into drug development programs. “How do you sort through the noise of all the different tests out there,” an attendee asked.
It’s a tough question, Conn acknowledged. “In my experience, we’re not seeking marketing authorization of the assay at the end of the day, so it kind of changes what we’re looking for. Obviously, we’re looking for an assay with robust validation—not only analytically but clinically.” Echoing a pain point mentioned earlier, Conn added: “Growingly, an area we’re really seeking for competency in is the ability to support global studies, especially when it comes to areas like China.”
GSK’s Raja pointed out that different assays will succeed in different clinical settings, and aligning an offering with a pharma’s area of interest is crucial. “For example, in non-resectable non-small cell lung cancer, a tissue-informed assay is just not going to work because we just don’t have enough tissue to do an H&E stain, a PD-L1 test, then have enough for a bridging assay, and then do a tumor-informed assay. Those kinds of clinical considerations also build into your choice of the assay.”
Pfizer’s Martini pointed out that a big challenge in Phase 3 is deploying tests across multiple testing sites with good reproducibility.
“Logistical considerations are really top of mind for us in terms of how we implement these assays in studies currently,” Conn summarized for the panel.
But pharma aren’t the only ones needing to “sort through the noise of all the different tests.” There is ground to cover in physician education as well, Connors highlighted. He echoed concerns that surfaced at other conversations during the week. With most cancer patients being treated in community cancer centers, how do we advance adoption of new tests, especially early ones?
“Regardless of our ability to move our regulatory perspective on MRD forward, assays and standardization forward, that education and training is going to be a key point,” Connors said. “The paradigm shift that has to happen in utilizing new tools when we have too many tools in general is going to hinge heavily on education and training. And frankly, we cannot leave that up to the companies.”
Bach pressed him on his last comment. Why can’t test development companies take responsibility for the education?
Connors clarified that companies most certainly should engage in education and training. “But it shouldn’t be left up to 10x Genomics to educate every rural physician out there about the slew of assays available to them, how they coordinate, how they don’t, and what their best options are. I just don’t think that’s in somebody’s bottom line.”
Instead, Connors identified, perhaps, a role for NIH. “We’re seeing more of [these tools]; they’re more intricate, they’re more useful, certainly, but also more complicated. I think this question is only going to grow and… we have to get ahead of it.”