TRK Inhibitors in Lung and GI Cancers - Episode 3
John L. Marshall, MD: What I want to focus on a little is just the evolution of molecular testing and next-generation sequencing [NGS]. Mark, let me let you go first. Do you think all patients should be tested? What’s your policy on testing your patient population using some type of broad molecular test that might pick up something like an NTRK fusion?
Mark A. Socinski, MD: John, I think the greatest thing a medical oncologist can do for a lung cancer patient—obviously my practice has been restricted to lung cancer for almost 30 years now; I finished my fellowship 31 years ago—is to diagnose an oncogenic driver. We have what I like to call a closetful of highly effective targeted therapies. Those closet doors are closed until you make a molecular diagnosis.
For those of us in lung cancer who have a growing list of these actionable oncogenic drivers, 1 week a patient is sick. But then they take a pill for a week, and they are so much better. You start to look at where we’re having some longer-term survival outcomes. The average or median survival of a patient who is ALK-positive nowadays is measured in 6, 7, 8 years.
When I started in this business, we were proud to have a median survival of 8 months with platinum doublets. So comprehensive molecular testing is important. I espouse the concept of “leave no man behind.” I do comprehensive testing. We have an internal panel, and I’m happy to use external vendors to make sure that the list I have in lung cancer, which includes NTRK fusions, is interrogated.
I happen to actually believe in testing both tissue and plasma. I send both tissue and plasma on all my newly diagnosed patients at the time of diagnosis. We know that there are things you find in tissue that you don’t find in blood. Tissue is sometimes a very scarce commodity in non–small-cell lung cancer, so it’s tough to test everybody based on tissue.
We know that for finding things in plasma, if you find them, you can believe them, and you can act on them. The outcomes and response rates seem to be the same for plasma-identified patients versus tissue.
John L. Marshall, MD: Let me jump in, Mark. Jyoti, Dr Patel, in your practice as another lung cancer perspective, when are you doing this testing? I’ve been so impressed by the lung cancer culture to where you have the discipline to do molecular testing before initiating just some carbo-taxol [carboplatin-paclitaxel] or whatever it is this year. Give me a sense of when in lung cancer you are doing this testing, because I think we’re going to see some differences with the way our GI [gastrointestinal] specialists would approach this.
Jyoti D. Patel, MD: In lung cancer, for all patients at diagnosis with metastatic disease, we recommend up-front testing. I should say all nonsquamous patients. That’s sort of category 1; we have great data. The questions become, do we do this sequentially? Do we do tiered testing where we may do some RT-PCR [reverse transcription polymerase chain reaction] and then move on to more comprehensive testing to get an answer?
For most of our patients where tissue, as Mark correctly points out, is so precious, it makes sense now to get comprehensive NGS at the get-go. Although, even with NTRK fusions, you can have good sensitivity and pretty good specificity with IHC [immunohistochemistry]; it’s wasting tissue. I think most of us feel that up-front NGS in RNA makes a great deal of sense.
John L. Marshall, MD: But let me follow-up on that in terms of the liquid piece of that too. Again, this is a cultural difference between the GI specialists and the lung cancer specialists. Mark brought up this great idea—should we doing parallel plasma or blood circulating markers? Are you doing the same?
Jyoti D. Patel, MD: Absolutely. I guess that is with the caveat that the blood tests are getting better and the technology is improving. Maybe a few years ago some of the infusions that were so bulky, particularly NTRK, which is difficult technically to pick up because it’s a very large fusion. As the testing has improved, there’s good concordance in patients with significant disease. There are very few false positives. False negatives can occur, again, based a little on bulk of disease.
John L. Marshall, MD: Let me ask, it’s something that I’m always curious about, when you’ve got only a small biopsy that’s not enough for a molecular profile, your liquid biopsy, don’t you need the tissue base to be at least as comparator for that initial test? What do you do if you don’t have it?
Jyoti D. Patel, MD: If it’s a positive, then absolutely.
John L. Marshall, MD: Positives are positives. Yes.
Jyoti D. Patel, MD: Negatives need a repeat biopsy, absolutely.
John L. Marshall, MD: Yes. Mark?
Mark A. Socinski, MD: Yes, John. The only time the plasma is useful is if you find something. If you don’t find anything, you can’t trust it, and most of us would go back and get more tissue at that point.
John L. Marshall, MD: Thank you. Luis, go ahead.
Luis E. Raez, MD: Also it’s important that we also do bulk plasma and tissue. Also it’s specifically for what we’re talking about, with NTRK. For example, if you took plasma, I’m not aware that there is any platform in plasma that can check for just NTRK3. That’s why when we do plasma only, there is the possibility to miss NTRK3 or NTRK2, which are very rare. But that’s why I think it’s important to complement and do both of them.
The second thing—I know it happens in your community, the GI community—but in lung cancer we were experts in testing until we developed these chemotherapy-immunotherapy combinations. We have a problem because as soon as you get the PD-L1 2 days later, a lot of people get excited and want to shoot and start the chemotherapy-immunotherapy, and the patient is impatient. They think that maybe it’s education. We need to wait 2 weeks for the plasma and 2 weeks for the tissue, because these are targeted therapies. As Mark said, it’s very important. We can always do the chemotherapy-immunotherapy 1 year later, 2 years later, or 5 years later if it’s an outpatient.
John L. Marshall, MD: Right. That’s stressing that discipline I was praising you for. You’ve got some pretty good carrots there to get on with systemic chemotherapy-immunotherapy going forward.
Transcript edited for clarity.