Treatment Selection and Sequencing for Patients with NTRK Fusions in Clinical Practice

Ben Levy, MD: This is a rare fusion, but we’ve got 2 great drugs here with comparable efficacy. Martin, do you have a favorite? Do you have any data to support it? Have you treated a patient with an NTRK fusion?

Martin Dietrich, MD: Yes. I have 3 on therapy. Right now, I’m managing my first breakthrough case with an oligometastatic progression. But other than that, I’m seeing the trial experience with long-term durable responses. The genomic profiles of NTRK fusions are very clean. They basically thrive almost similar like a CML [chronic myeloid leukemia] on a single fusion. Oftentimes, there are very little secondary mutations in the background of never smokers. This is a true game-changing find for patients here.

For us, larotrectinib [Vitrakvi] was the first in class, the first approval. There are very convincing data that this is a cleaner drug. The history of larotrectinib as a potential pain medication required a positivity here for high affinity and little off-target effects. With entrectinib [Rozlytrek], we already see the multi-targeting in the label. For specificity in this small space, NTRK is better targeted with larotrectinib. We have seen some comparative analysis in the Journal of Managed Care that looked at the trial experience of these 2 drugs. Obviously, those are very small numbers and they’re both good drugs, but it seemed that larotrectinib seemed to be doing better in the lung space in both progression and overall survival. For familiarity, and because of those data pieces, that might be my preferred choice.

The question is what to do in sequence. That isn’t a trivial question in patients progressing on larotrectinib. Looking at rebiopsying and resequencing is critical. Many of these tumors remain dependent on the NTRK fusion, and they can develop. That’s the Memorial Sloan Kettering Cancer Center experience here as well. That has intracellular kinase domain mutations, for which we have second-line inhibitors. I believe LOXO-195 was the earliest one. Unfortunately, that has ceased being in development. It’s still available on compassionate use through the manufacturer. That’s an opportunity for patients who are progressing.

We’ve seen some very interesting data with repotrectinib in the TRIDENT trial that I’m still trying to comprehend. They had both pre-treated and naïve patients for the NTRK cohorts. In the first-line setting, in the treatment-naïve setting, the response rates were roughly 40%, which wasn’t as convincing. But it was much more striking with the versatility and ability to overcome resistance mutations in the second-line setting with a similar response rate. There’s certainly some interest in establishing this second-line standard of care beyond its development as a ROS1 inhibitor at the same time, so repotrectinib will be coming as well.

We don’t have very mature data of the other agents that are coming. Taletrectinib is another one. This is going to be in development. Hopefully we’ll get to see some data. But it’s going to be very hard to catch up and establish in the first-line space, with larotrectinib meeting all the hallmarks of brain efficacy, with the long-term durable responses that we’d ask of a TKI [tyrosine kinase inhibitor] in an oncogene-driven setting.

Ben Levy, MD: Great overview. It’s all about how we’re going to sequence these drugs, which drugs we’re going to use next, and what the mechanisms of resistance are. You mentioned some of this.

Transcript edited for clarity.