Precision Medicine in Advanced Non-Small Cell Lung Cancer - Episode 14

Treating Rare Actionable Mutations in NSCLC


Benjamin P. Levy, MD: Let’s now move on to rarer yet actionable mutations in non—small cell lung cancer. We’ve recently learned a tremendous amount about NTRK and RET fusions in non—small cell lung cancer. Alex, you’ve really led the way on this with a recent publication. You’re a first author in a publication in the New England Journal of Medicine, and you were a part of a nice oral presentation about two of these drugs at this ASCO Annual Meeting. Do you want to start out with the NTRK fusions? Talk about their potential relevance in all cancers and specifically in lung cancer, then talk about the activity of the drug.

Alexander Drilon, MD: Yes, absolutely. I think this really highlights a dilemma that we’re going to start to face as we kind of use up the more common drivers. We now have to deal with very actionable alterations that may be found in less than 1% of cases. And actually, recent data for non—small cell lung cancer show that these TRK fusions may be found in about 0.25% of patients. However, it’s fortunate that these NTRK fusions, put very simply, behave very similarly to ALK, ROS, and RET, which are found across many different cancers. In fact, there are some cancers where the frequency is greater than 90%. And so, the fusions are almost pathognomonic.

This data set was a data set of a variety of different cancers—17 unique types. All of them harbored an NTRK fusion. This included patients with non—small cell lung cancer. The overall response rate exceeded 70% for both the investigator and the confirmatory radiologic assessments across all tumor types. This is very different from what we’ve seen before, where we tested drugs within a particular histology. Here we’re seeing tumor-agonistic responses to therapy. As long as you have the appropriate target, it doesn’t seem to matter what the cancer looks like under the microscope. The drug is actually up for potential approval, maybe this year.

Benjamin P. Levy, MD: Larotrectinib is the drug, and it seems to have real practice-changing implications. Eliciting these types of responses across multiple tumor types reinforces this whole concept that we’re really looking at the genotype, tissue agnostic, looking at shared genotypes, and getting responses out of drugs that target these genotypes. Is there toxicity seen with larotrectinib?

Alexander Drilon, MD: Fortunately, it looks like it is a very well-tolerated drug, and that’s not just based on our experience with patients that we’ve treated. If you look at the adverse event profile, there were very few treatment-related adverse events. Rarely you might see things with chronic dosing like an increase in weight, some paresthesia, or even some positional dizziness that’s related to proprioception. The TRK family plays a role in the development of the nervous system, so we’re seeing some unique side effects. But by and large, larotrectinib and another TRK inhibitor, entrectinib, also in development, are fairly well tolerated.

Lyudmila A. Bazhenova, MD: How do you test for NTRK?

Benjamin P. Levy, MD: I was going to ask that. We can talk about this in the testing section, but briefly, how were NTRK fusions interrogated, identified in the study?

Alexander Drilon, MD: An interesting feature of the study was that this wasn’t central confirmation of the fusions. We allowed investigators to use a variety of different local molecular tests. I think the best way to look for this would be to use a good next-generation sequencing assay that not only detects NTRK with good enough fidelity but other alterations as well. IHC does play a role. There are many cases that highly express TRK. In regions where you may not have enough resources for NGS, it may be reasonable to start by screening with IHC, especially for those histologies with a high pretest probability. But at the end of the day, I would feel most comfortable confirming that with a NGS test prior to treating somebody.

Benjamin P. Levy, MD: They’re really incredible data. We need to remember that these are rare fusions, but they are ones that we need to test for, given the data we have with these drugs that are so well tolerated.

Alexander Drilon, MD: Yes.

Benjamin P. Levy, MD: Along that theme, we had a RET drug, LOXO-292. I hope I got that license plate therapy right. Your presentation blew up my Twitter at the ASCO Annual Meeting this year. What is your insight on the role of LOXO-292 in RET-rearranged solid tumors?

Alexander Drilon, MD: Just to summarize, RET rearrangements, in terms of frequency, are comparable to ROS1 rearrangements. We’ve had older drugs, like cabozantinib and vandetanib, that can achieve response rates in the order of about 30%. The problem is that they were very dirty drugs. They had a lot of side effects because of the inhibition of other non-RET targets. Fortunately, we now have RET-selective or more specific inhibitors that are cleaner and zoom in on targeting RET, and you don’t get a lot of those off-target side effects.

These data that I presented on LOXO-292, one of these selective RET inhibitors, show that the response rate in RET fusion—positive cancers, which included lung, papillary, and pancreatic adenocarcinomas, exceeded a 70% confirmed response rate.

Benjamin P. Levy, MD: These were pretreated patients, for the most part?

Alexander Drilon, MD: Yes, heavily pretreated—chemotherapy, immunotherapy—and many had 1 or more multikinase inhibitors in the past. Two-thirds of patients were pretreated with a prior RET inhibitor. I think they’re fantastic data, and we’ve been waiting for this for a very long time—since we discovered RET fusions in lung cancer in 2011. Hopefully we now have a drug that’s comparable to what we’re seeing with ALK and ROS1.

Jonathan W. Riess, MD, MS: Alex, when you pull out the lung cancer patients, how many were there, and what was the response rate for those with non—small cell lung cancer?

Alexander Drilon, MD: It was still more than 70%, and there were about 30 non—small lung cancer cases with RET fusions.

Jonathan W. Riess, MD, MS: How do I get this for our patients with non—small cell lung cancer?

Alexander Drilon, MD: Send them to me. Just for balance, there is another drug called BLU-667. It’s currently in the clinic and is also RET selective. Both of these drugs are currently in phase I testing with phase I expansion cohorts. These are available for patients at multiple centers.

Benjamin P. Levy, MD: Do we want to use these drugs first? Is this where the approval is going to come in?

Alexander Drilon, MD: In my mind, when you have response rates that exceed 60%, 70%, I think they should be used in the treatment-naïve setting. Again, you should use your best drug up front. That’s the theme of our conversation today.

Benjamin P. Levy, MD: Yes. I look forward to seeing more of these data and the updates, to get a better understanding. The drug is well tolerated, eliciting response rates…

Alexander Drilon, MD: Very well tolerated.

Benjamin P. Levy, MD: Yes. Seeing that many of these drugs elicit response rates north of 70%, improve survival, and are also extremely well tolerated, I think we really have done a good job of refinement of the off-target effects. We are really making this a patient-centric experience. These patients are able to take very well-tolerated drugs.

Transcript Edited for Clarity