TRK Inhibitors: A Tumor Agnostic Targeted Therapy - Episode 2

Preliminary Safety/Efficacy Data for Larotrectinib


Alexander Drilon, MD: The larotrectinib development program was composed of 3 separate trials. There was an adult phase I trial, then a pediatric phase I trial, and an adult and adolescent phase II basket study called NAVIGATE. The inclusion criteria for the phase I studies were basically broader. However, looking at the registrational dataset that was published in the New England Journal of Medicine, these were essentially patients whose cancers had NTRK fusions that were consecutively identified. That comes up to a total of 55 cases.

Larotrectinib achieved a very impressive objective response rate by investigator assessment; it was 80%. And by central radiologic confirmation, it was 75%. I’d like to underscore the fact that these were responses across different solid tumor types, so it wasn’t limited to 1 histology as we classically see in other clinical trials. These responses were durable, and the median duration of response has not yet been reached as of the last data cutoff. Certainly, many of these patients remain on a therapy several years after they’ve initiated treatment with larotrectinib.

The interesting results from this dataset showed that there was tumor agnostic activity of larotrectinib, meaning it didn’t matter what your cancer looked like under the microscope. As long as your cancer harbors a TRK fusion, you have a proclivity for response to larotrectinib. If you look up the waterfall plot of best objective response to larotrectinib, you’ll see that there were many different tumor types that harbor these fusions but responded nicely to treatment. So, there was no difference based on tumor type.

David S. Hong, MD: Larotrectinib, relative to many of the other small molecule kinases, has shown to be incredibly safe and well tolerated. The most common side effect we’ve seen so far is some increase in the AST (aspartate aminotransferase) and ALT (alanine aminotransferase), fatigue, and some dizziness. Oftentimes, this dizziness actually improves over time while the patients are on study. As the durability data have shown, very few patients have actually come off because of toxicity. The efficacy to date has been fairly remarkable in the sense that not only are these patients responding, those who have NTRK fusions, but the durability of patients on the study has been remarkable, for even a small molecule inhibitor. The longest patient so far, as of the cutoff date of March of 2017, was almost 27 months on study.

David Hyman, MD: One of the distinguishing characteristics of the patients that were treated in the larotrectinib program was that this was a population of patients who were refractory, had become refractory to standard-of-care agents for their particular diseases. So, this is a question we get a lot, and we know that larotrectinib was able to generate this robust efficacy in patients who had relapsed on available therapy or for whom there were no standard therapies available based on their tumor type.

Transcript Edited for Clarity