Larotrectinib for Solid Tumors With NTRK Gene Fusions
Panelists: Benjamin Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center, Sibley Memorial Hospitale; Mark Agulnik, MD, Northwestern University Feinberg School of Medicine; Marcia Brose, MD, PhD, University of Pennsylvania; Edward Kim, MD, Levine Cancer Institute, Atrium Health ; John Marshall, MD, Georgetown University; Philip Agop Philip, MD, PhD, FRCP, Barbara Ann Karmanos Cancer Institute
Benjamin P. Levy, MD: Let’s move on to the TRK data with larotrectinib, clearly the first drug approved for this rare yet actionable mutation. Ed, do you want to walk us through the data on larotrectinib in NTRK fusion cancers?
Edward S. Kim, MD: Yeah. It was fascinating because for the first time, we saw data on not 1 singular tumor type you’d show up and look for. I’m looking for the lung sessions; you’re looking for thyroid, you’re looking sarcoma, and you’re looking for GI [gastrointestinal]. This is 1 of those all-encompassing tumor types, and especially for all of us—mostly for adults, as oncologists, but even the pediatric stuff…I don’t think any of us had even heard of some of those tumor types that were being described in the original study, which showed these fibrosarcomas and especially salivary glands, being head and neck. So it’s been really cool to actually see that happen. I love these types of designs, where you’re focusing on a biomarker. You don’t need 1000 patients. They had 50-some-odd patients for their study. The waterfall plots are just looking incredible. Everything is a different color, and it’s all going down.
Benjamin P. Levy, MD: It’s a lot of water.
Edward S. Kim, MD: It’s like the rainbow sort of aspect. I think they ran out of colors to actually describe every histologic subtype that was included. Again, you have adults, you have kids. I’ll harp back on eligibility. There should have been 2 eligibility criteria in that study. One was that you had to have a pulse, and the second is you had to have an NTRK fusion. That’s all that was needed. You see response rates in the multiple-treated cancers of 70%-plus. They did another analysis. They added some additional patients from a couple of other studies. There were 35 as presented at ESMO [European Society for Medical Oncology 2018 Congress] last year. The response rate is holding. They’re actually seeing conversion of PRs, partial responses, to CRs [complete responses] later. We all love those delayed CRs, right? It means that there’s [a] continued sort of efficacy that’s ongoing. You’re not just getting your first hit out. With chemotherapy, we’re used to that. If you’re treating a small cell, if you don’t see that response after the first 2 cycles, it’s not a good sign. Here, it’s quite the opposite. It’s just sort of ramping up and getting a little steam ahead of it.
It’s way too early, with a lot of this data, to show survival numbers because their endpoints and their different targets haven’t been met yet. So the events are continuing, but you’re looking at 58% or plus patients who are progression-free. The durations are long, and the survivals are long. This is exactly what we want to see in a targeted therapy. I think many of us were confused. Frankly, we pride ourselves at Levine [Cancer Institute] of being very nimble in how we incorporate things. We do internal testing, reflex testing. In lung, we were doing PD-L1 [programmed death-ligand 1] within 6 weeks after the ESMO presentation a few years back. Frankly, we had to step back and say, “OK, which tumor types are we going to test this in? Are we going to outsource it? Are we going to insource it?” We are actually implementing reflex testing in about 7 different tumor types that we’ve identified, and that’s what we’ll do up front. So every one of our lung patients, stage IV, will start getting this test, as well as glioblastomas, thyroids, sarcomas.
Marcia S. Brose, MD, PhD: Can I ask you a question, though? It’s interesting. I just have to ask this. How do you think this is impacting our paradigm of, “Oh, we don’t give these new drugs to people unless they have failed all the standard therapies?” When you have targeted therapy with very few adverse effects, are you going to still give them first-line carboplatin-taxane?
Edward S. Kim, MD: That’s why we’re doing reflex up front. We totally believe that you should be on the right therapy from the start. We believe in that targeted therapy paradigm.
Benjamin P. Levy, MD: As lung cancer oncologists, it’s relatively easy for us, I think, to do that.
Mark Agulnik, MD: How could you ever sell chemotherapy when someone could potentially get this? What patient would agree to take all of the adverse effects of chemotherapy?
Marcia S. Brose, MD, PhD: But it goes back to the eligibility criteria. So the trials actually required, technically, that they’ve failed standard therapy.
Benjamin P. Levy, MD: Previous treatment. That’s right.
Marcia S. Brose, MD, PhD: And now what we’re finding is patients are saying, “I’m refusing.” They’re eligible because they’re refusing standard therapy.
Edward S. Kim, MD: And that’s the sort of little sliver you go through, right? They’re not eligible, and not just because the patient refuses to take it. So they’re no longer eligible, in my opinion. And how we document that is how we document it.
Philip Agop Philip, MD, PhD, FRCP: So the question is, will the insurance have a problem?
Edward S. Kim, MD: We haven’t seen that. Honestly. They will save money if they actually give the drugs in the appropriate patients. They will lose more money in giving I-O [immuno-oncology] to everyone rather than targeted therapy. What’s also beautiful is the adverse effect profile, or the adverse effect data on this stuff. We went through a period of time in targeted therapy where the pills sometimes were a little more toxic than some of the chemotherapies out there, especially because we have pemetrexed in lung cancer. It’s such an easy drug to give. But this has got very few grade 3 adverse effects and dizziness and constipation. I mean, gosh, that’s Tuesday for us.
Benjamin P. Levy, MD: Or Friday.
Mark Agulnik, MD: It’s so impressive. A third of them had 3 or more lines of therapy, which really goes to show… Imagine if you’ve gone through the discouragement. I think when I trained there was always that misconception that if you didn’t do well with the first, you were going to have less likelihood of doing well with the second, and less likelihood with the third. In sarcoma, that doesn’t pan out. It’s great to see it with this. To have a response rate this high for someone who potentially could have had 4 lines of other therapy is really encouraging for patients.
Philip Agop Philip, MD, PhD, FRCP: Which means you can use it in the frontline.
Mark Agulnik, MD: Correct, but all the patients who have currently have other lines of therapy....
Philip Agop Philip, MD, PhD, FRCP: No, but that’s a trial. That’s a clinical trial.
Mark Agulnik, MD: And tomorrow you start it fresh, yeah.
Marcia S. Brose, MD, PhD: With expected life expectancies of 3 months. A lot of these patients had, like, 50% of their lungs filled with sarcoma. I had a patient with a tumor wrapped around his carotid at the base of the skull and was told, “You’ve got 3 months.” That was 5 years ago.
Benjamin P. Levy, MD: Incredible story—this trial. We saw 17 different tumor types and an age range from 4 months to 74 years of age. We saw response rates with this drug, irrespective of the gene fusion, irrespective of age, irrespective of histology. Interestingly, 2 patients in that trial went on to have it as curative intent therapy and have limb-saving surgeries, limb-sparing surgeries. They were unresectable. They got the drug, and young kids went on for curative intent therapy. So an incredible story.
Philip Agop Philip, MD, PhD, FRCP: I mean, the fortunate thing was this was histology agnostic, not the same as, for example, BRAF. So that was the lucky thing about this drug.
Benjamin P. Levy, MD: It’s interesting. I’ve learned a lot. As you mentioned, BRAF-targeted therapies don’t work for all BRAF-mutated solid tumors.
John L. Marshall, MD: Not the same way.
Benjamin P. Levy, MD: Not the same way, and this is a little different. This seemed to work irrespective of the tissue type.