Early Development of TRK Inhibitors

John L. Marshall, MD: We’re going to shift gears to a very specific set of data around the clinical experience with the TRK inhibitors. Tony, we’ve tagged you to start with a fairly obscure abstract that just came out around biliary cancer. I know it’s a disease you like discussing. Talk about the recent ASCO GI [American Society for Clinical Oncology Gastrointestinal Cancers Symposium] meeting, and what that showed in biliary tract cancers.

Tanios S. Bekaii-Saab, MD, FACP: To focus on the gist of it, this was primarily focused on IHC [immunohistochemistry], but it also had NGS [next-generation sequencing] confirmation of the IFC [integrated fluidic circuit]. It just shows that there is a relative concordance between the 2, the IHC and the NGS. Although, as we’ve heard, we all favor an expanded genomic sequencing because we’re looking for a lot more than just the 1, at least in specific tumors such as biliary cancer, where FGFR is relevant. We just had an FGFR agent approved for FGFR fusions. We have IDH alterations, we have HER2 [human epidermal growth factor receptor 2] amplifications.

We want to have the full gamut, not just NTRK fusions. What this study mostly shows is that these NTRK fusions in biliary cancer are present in about 0.7% of all patients, and that aligns with the rarity of these fusions, which is pretty consistent for most cancers. We know some cancers have these fusions at a much higher rate, but in GI [gastrointestinal] malignancies, and others as well, the 0.7% seems to be consistent, and that’s pretty much the gist of this. This confirms the rarity of these fusions in a rare tumor like this.

John L. Marshall, MD: Biliary tract for us is a target-rich place, but it’s about the same as we’re seeing in other cancers as well.

Tanios S. Bekaii-Saab, MD, FACP: Yes. If you find it, you’re going to go after it, because these tend to be driver mutations, and the responses from the study look pretty interesting.

John L. Marshall, MD: Mark, we’ve tagged you with setting the stage for larotrectinib, along with its pathway and eventual approval. Set the stage for us about the trials, the inclusion criteria, and how that went.

Mark A. Socinski, MD: Yeah. The original trial that led to the FDA approval was a trial that selected prospectively patients that were TRK-fusion positive. It was actually a combination of 3 different studies, a phase 1 study in the pediatric population, a phase 1/2 in the adult population, and then a phase 2 study that involved both adolescents and adults with NTRK-fusion-positive cancers.

There were 17 different cancers that were included in this. There were only 4 patients with lung cancer. Talking about the bile tract, I think there were a couple of patients with biliary cancer in this. It was fascinating that patients ranged in age from 4 months to 76 years. The interesting thing is that the response rate objective by independent radiological review was 75%, so the vast majority of patients responded. They had a couple of patients who were early progressors, and it’s not clear they were true positives. There were some issues about the testing that was done.

They also had a patient that progressed early that had received a prior NTRK drug and had a resistance mutation, so that patient would not have been expected to respond in this particular setting. It was remarkable in the sense that no patient had the drug discontinued because of toxicity, so it was very well tolerated. There were very few grade 3 or 4 adverse events. Mostly they were grade 1 or 2, so it was the best of both situations. In the most recent update of this—correct me if I’m wrong, but I’m not quite sure the median duration of response has been reached at this point.

It’s the second drug after the pembrolizumab MSI [microsatellite instability]–high indication that was tumor agnostic but linked to a molecular alteration regardless of pathology. It’s an important step in how we think about cancer and get drugs approved.

John L. Marshall, MD: As another member of the panel who graduated from fellowship in a year beginning in 19, I remember being scolded for suggesting that we wouldn’t need phase 3 randomized trials if the benefit was obvious and that it would transform drug development. Even though I got beat up pretty bad for saying, “No, you’re wrong,” back then, I’m so pleased this is the way it’s going. Comment a little about how this has changed our whole perspectives of cancer and drug design.

Mark A. Socinski, MD: It’s been fascinating. John, you may be the only 1 on the call who remembers a gentleman named Joel Tepper, a radiation oncologist at the University of North Carolina. He would say, “I’d like to do a phase 3 trial that required only 50 patients.”

It was so big that he didn’t need 1000 patients to get the benefit. But again, the larotrectinib indication is a growing list of drugs that should be approved for these molecular subsets of patients that can be clearly defined. In lung cancer, we have the EGFR and ALK experience, where we actually went through a number of randomized trials to show that when you have a target that’s targetable with a targeted therapy, either an EGFR or an ALK drug, it’s better than chemotherapy.

Do we have to do that for NTRK fusions? Do we have to do that for a ROS1 mutation? Do we have to do it for every single molecular category that we have to prove that it’s better than platinum? Why are we in love with platinum-based therapy in this setting if you have a target where it’s driving the cancer? With the targeted therapy, all the response rates are north of 50%, and the durability is 3 to 4 times longer than we see with chemotherapy.

John L. Marshall, MD: This wouldn’t be feasible with something so rare to randomize it against something.

Mark A. Socinski, MD: Right.

John L. Marshall, MD: To me, the wisdom and the flexibility of the FDA has been terrific in this space.

Transcript edited for clarity.

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