Navigating Barriers to Molecular Testing and Role of Liquid Biopsy in NSCLC

Transcript:

Martin Dietrich, MD, PhD: We try to integrate liquid biopsy for early testing. I think that’s still controversial, and the guidelines are still favoring the tissue. I don’t think this is one vs the other, they do have synergies and produce the best possible outcomes, accounting for the high rate of insufficient tissue quantities. We talked about this to a certain extent already. Obviously, the turnaround time is also important. Many of the mutations we’re seeing—EGFR, KRAS, and BRAF—are simple molecular alterations that on liquid biopsy have a very high level of sensitivity.

For the fusions and other markers, we certainly rely on the RNA-based panels on tissue. There is higher sensitivity there, with a blind spot of up to 50% for the fusions, and some of them are not even covered on next-generation sequencing [NGS]-based liquid approaches. That’s certainly the part that we’re trying to establish for all patients. It’s not always feasible. Patients come through multiple channels; we do second opinions, we have patients who are transferring care. That makes it much more challenging if proper testing wasn’t done up front, trying to realign the molecular state of a patient with the treatment options chosen. This makes the data application much more challenging.

For us, it is always NGS. We feel from both a scientific as well as an economic standpoint that NGS has broken through all the benchmarks needed to make this the standard of care for patients. For us, still the contender, and we still run into some issues every now and then with the reimbursement with the concurrent approach of tissue and liquid biopsy. Again, I do think that soon we’ll be seeing that those 2 approaches are going to be aligned and going to be the standard of care. I don’t know what your barriers are in terms of utilizing your testing. I would also love to hear your thoughts about integrating liquid biopsy into your practice.

Meghan J. Mooradian, MD: I think those are the important questions, and in the clinic we see this happen all the time. We do have barriers to our tissue testing, namely insufficient tissue at the time of diagnosis, or tissue exhaustion after histological assessment. As you pointed out, potentially a driver panel was done and we’re seeing folks [to provide a] second opinion. In these instances, I think we really need to consider rebiopsy of a tissue site to perform additional NGS, ideally, a target that’s amenable to core biopsy to ensure that we have adequate tissue, trying to avoid bone. We know this is notoriously challenging when it comes to processing for molecular testing. I think as you point out, it can be challenging because from tissue acquisition to the time that we get the results, this can take 2 to 3 weeks.

In certain cases, I think it’s OK to wait for this testing, though acknowledging that patients and their families can be under considerable stress while we’re in this holding period before starting therapy. However, if a patient requires initiation of therapy right off the bat, they’re having symptoms, visceral crisis, I’ll often start chemotherapy alone and hold the ICI [immune checkpoint inhibitor therapy], particularly if I have a high pretest probability that they could have a driver mutation, like a young never-smoker. We know the rationale for holding immunotherapy in this context, the data demonstrate increased toxicity when TKIs [tyrosine kinase inhibitors], particularly EGFR and ALK, are started on the heels of immunotherapy within that 30-day to 3-month window.

In these instances, I almost always send a liquid biopsy when my hands are going to be tied in terms of getting that NGS testing from the tissue quickly. Assessing that circulating tumor DNA to help gain insight is important. If the mutation is there, fantastic. I feel confident that I can act on it, as we now have multiple studies showing high rates of concordance between tissue and liquid. However, if a liquid biopsy is negative, I still rely on tissue and will push for a rebiopsy. As you point out, liquid biopsy can lack sensitivity based on how much tumor is there, where the tumor is present, and still has some struggles picking up some of these complex phenotypes, like fusions. When I’m typically seeing a patient in the clinic, if I have the luxury of doing both right off the bat, I will. If I have tissue and I have a mutation, I’ll rely on it. If I’m waiting for tissue, I’ll absolutely send liquid, and it will be a race to the finish to see what information I get first.

Transcript edited for clarity.