TRK Inhibitors in Lung and GI Cancers - Episode 8
John L. Marshall, MD: Let me say in closing for this session, I hear a lot of people complain about their molecular reports that come back, they don't understand how to incorporate that and interpret it. A favorite study we ran at Medstar Georgetown University Hospital was an eye-tracking experiment, because academic oncologists kept saying, “Don't tell me what drugs are related.” They wanted to see the genes or the fusions, and they'll do the reporting. Whereas community oncologists traditionally have said, “I don't want to know the genes. Just tell me what drug to give.”
When we did eye-tracking experiments we showed academic and community oncologists the report. Guess where everyone's eyes went as soon as they showed it? It was right to the drugs, and only then people would go back and reconfirm with that. I think that put our partner companies that do molecular profiling on the hot seat for some of the recommendations they were making with therapies. It was interesting to watch that tighten up over time. Tony, give me a sense of what your favorite type of report is. Do you want the genes, do you want to know the drugs, or you want both?
Tanios S. Bekaii-Saab, MD, FACP: I primarily want to know the genes. I frankly find the drug listing a bit random sometimes for most of the drugs. We're looking for the drug genes that are relevant to the disease. If they're relevant, then we know we have to target them. I don't care what's on the listing.
On the other hand, a lot of the other background noise can actually end up detrimental in some ways. This is because I've seen patients with a random mutation, there was a case report that links it to everolimus, and then the physician wrote everolimus before even sending the patient to consider a clinical trial that may or may not be relevant for that tissue.
I find that very problematic. Linking it to clinical trials is very useful, and that does help. It helps especially when we have driver mutations or driver alterations that are targetable. By the way, I look at the variant of nonsignificance, as well, and what time they graduate to normal significance, and they do. Essentially, some of the ATM alterations of unknown significance have, in my clinic, initiated with some dramatic responses to FOLFIRI [leucovorin calcium, 5-fluorouracil, and irinotecan] or FOLFOX [leucovorin calcium, 5-fluorouracil and oxaliplatin].
John L. Marshall, MD: Yes, sometimes that little tiny pulmonary nodule is actually a met [metastasis]. Mark, any thoughts?
Mark A. Socinski, MD: I struggle a lot with some of the reports that we see. I agree with Tony, I'd rather see which genes are altered and how they're altered because I know what to do once you tell me what's going on with the DNA or the RNA. We had a recent case at our center where a patient was sent for a second opinion on a Guardant Health assay. He had a ROS1 mutation, and not a fusion. But he got started on entrectinib because the report said ROS1, entrectinib, not making the distinction between the point mutation and the fusion.
John L. Marshall, MD: The payer from Blue Cross Blue Shield missed it.
Mark A. Socinski, MD: Yes, or wherever he was from, but I agree with Tony. Sometimes the reports are very damaging, so I think we have to be aware of that and educate our community doctors about these types of things. I get several calls a month about, “How do you interpret this report, or that report, what should I do?” It's good that they should be calling us to get the information.
John L. Marshall, MD: You have to remember, though, that we are very focused, and it would be difficult if we had to know everything for every disease.
Mark A. Socinski, MD: Oh yes.
John L. Marshall, MD: Right.
Mark A. Socinski, MD: The nice thing about our center, too, is we do have a twice-a-month molecular tumor board. I'm sure others have it, too. We discuss a lot of these things in the tumor board, so that's very helpful as well.
John L. Marshall, MD: I think the main point I want to leave us with is it's OK not to know. We're all learning. If you're looking at something that you're not sure of, you should check on it. There are ways to do that. Any other comments?
Shubham Pant, MD: One last comment. Looking at the drugs, a lot of the time there are 2 things out there. Let's say we’re talking about a KRAS G13 mutation for pancreatic cancer. For the longest time, 1 of the NGS [next-generation sequencing] companies that we use all over has listed a MEK inhibitor for it. You've seen it, I've seen it, and we've seen it. We know what the response is. From our side it's an educational perspective, exactly as Mark said.
Then the second thing is the co-mutation when it comes up, not with NTRK so much. But let's say if you have a HER2 mutation and a KRAS, or something that is a co-mutation in which you could give a more of an antibody-targeted therapy, not a small molecule antibody target, it's not going to work in that. So I think they also list out, these are the 5 mutations, these are the 5 drugs you can give them. Sometimes that leads to the thought of what if I combine A, B, C, and D? We've seen that, too.
There's a lot of education needed on that. I really think the focus should be on the genes, and especially what Tony is saying because it doesn't mean that therapies don't exist, it just means that they really haven't looked at it. It's just not been that well described in the database.
There are a lot of little points in the report, and the reports are around 30 pages. Sometimes that can lead to things getting lost. That's the other thing with some of these NGS reports—they just go pages and pages. How many people look at more than the first 2 pages? Because some of the other things, nuances maybe hidden deep inside; that's the other issue.
Luis E. Raez, MD: I want to say that there is no perfect report, because for us, we only practice 1 tumor, so it's very easy to know. Actually, I'm very excited with the genes because we have been discovering new genes, things like that. But I will mention I passed my boards, and in CML [chronic myeloid leukemia], I just discovered it's 4 or 5 lines now of TKIs [tyrosine kinase inhibitors], with a lot of names and resistant mutations.
I guess it's very hard for our community oncologists or general oncologists to know all of this. There is 1 platform where they mention the drug, but when you click there, you go to a link that includes the original study. You can not only educate yourself, but there is also corroboration that this is not a fluke. So if it's something very important or more serious that you can evaluate and take a more important suggestion in that case.
Tanios S. Bekaii-Saab, MD, FACP: That's one of the complexities of the simple gene predicting for a response that ends up being the gist of the report. For example, as Shubham just mentioned, in colorectal cancer and I'm assuming in all cancers, if you have a RAS and a HER2 amplification, 2 things happen. One, you're not going to respond to the EGFR inhibitor. Two, you're not going to respond as well to the HER2-targeted strategy.
Yet you're going to see a HER2-targeted strategy that's essentially in the checkbox. That's unfortunate, because then at the end of the day it's contraindicated, meaning it's not going to work for the patient. You may have to go through a million hoops to get the patient on the study. I also mentioned the rare alterations that have a case report here and there. I'm not disagreeing with the fact that it's OK to have some recommendations that are there.
The problem is that many of those are very random, and they're probably generated by a computer listing that instructs, “If you have this, you go to this drug,” without looking at the global picture. That picture gets much more complicated now that we find a lot of these co-occurrences, some driver mutations, some mutations that actually drive resistance when you have a fusion or an amplification present.
I think the story is so complex now, it's much more complex, that I really want to have access to the gene. If I want to have access to understanding what all these co-alterations are doing together, I want a much more comprehensive type of report that tells me, “Wait a second, you shouldn't use this. Although the amplification is there, watch out for the mutation that's telling you that this will not work.”
John L. Marshall, MD: We're all very used to if we get a funny radiology report, CT scan report, we'll either call up or go down to talk to the radiologist and say, “What do you mean with this?” I think we should treat these types of reports the same way and go to the source. We should apply good clinical judgment to the decision-making on the therapeutics.
Shubham Pant, MD: John, I have one last point. Also these reports don’t make a distinction between tumor types. So as we know, if you target the KRAS G12C mutation in lung cancer, you will see that it is very different than for colorectal cancer.
We know these differences, so it's really more of a push toward comprehensive NGS reports to get better on their algorithms they use to report this out. This is because it's very tumor-specific as well. So it's more of a challenge toward them. Obviously, it's very hard in the community to make sense of all this.
I think if they get their act together it might also help out a little bit more with the community oncologists getting the right therapeutics to the right patient. That's what it's about.
John L. Marshall, MD: OK, we'll let that be the last word for that discussion.
Transcript edited for clairty.