TRK Inhibitors: Evolution of a Tumor-Agnostic Treatment Approach - Episode 9

Other Approaches to TRK-Fusion Cancers


David Hyman, MD: Now that we’ve really established the efficacy of this initial generation of TRK inhibitors, and we have our first approved agent in larotrectinib, we’re of course looking toward the next generation of therapies for these patients. And what we’ve observed is that in a proportion of patients who develop resistance following response on these agents, they do so because their tumors acquire new or secondary mutations in the TRK fusion gene that lead to resistance to these existing generation of TRK inhibitors.

And we have at least 2 drugs in the clinical setting now that have the possibility to address this patient population. One is LOXO-195, which has been acquired by Bayer. We presented initial data in about the first 31 patients treated with LOXO-195 and were able to show that in the population who develop these secondary kinase domain mutations, the response rate was about 50%. And so that’s very encouraging initial data that we can actually salvage responses in patients who have eventually progressed on existing TRK inhibitors and in doing so, further extend the benefit of TRK inhibition collectively in these patients.

There’s another drug, repotrectinib, which has shown more limited clinical data in a publication, also showing the ability in theory to drug some of these kinase domain mutations that can emerge as resistance mechanisms. So we were really hoping to accelerate the development of this second wave of TRK inhibitors, and I think hopefully this will mirror the experience of other targeted therapies, where it’s not only that the patients derive benefit from that initial stage, which here can be quite durable, but that we can further extend the total duration of benefit through sequential and serial use of drugs that target the TRK protein.

David S. Hong, MD: There are thought to be other multikinase inhibitors of TRK, such as crizotinib or cabozantinib. However, the data on many of these agents that already exist for other indications are really unclear on whether they will actually be efficacious in this population. I think the recommendation—there’s already an improved drug, larotrectinib—is to use larotrectinib in this situation rather than crizotinib or any of those other somewhat multikinase inhibitors that may partially inhibit NTRK.

Transcript Edited for Clarity