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Larotrectinib: The First FDA-Approved TRK Inhibitor

Insights From: David S. Hong, MD, MD Anderson Cancer Center; David Hyman, MD, Memorial Sloan Kettering Cancer Center
Published: Tuesday, Jul 30, 2019



Transcript: 

David Hyman, MD: The development of larotrectinib was a little bit unusual in 2 ways. It was in a very focused development that really homed in on targeting TRK fusions in the earliest parts of its clinical development. The other interesting feature of larotrectinib’s development was the ability to integrate the patient experience across 3 clinical trial programs. And those were the first-in-human phase I adult study, which is a study where we initially defined the proper dose of this agent in adults. Then there was a first-in-child phase I study that actually uniquely entered the clinic shortly after the adult study, and we rarely see that in cancer where children are getting very early access to a novel targeted therapy. And then the third was a phase II study in adult and adolescents who were characterized by the presence of TRK fusions. The 2 phase I studies initially didn’t require TRK fusion positivity, and the phase II study did. So, ultimately, the data set that was used to register this drug was the combination of all the TRK fusion-positive patients enrolled across these three clinical trials that represent the development program of larotrectinib.

The other feature that was really unusual about the larotrectinib development plan was the inclusion of patients with any kind of cancer, provided that they had a TRK fusion. And that tumor-agnostic development was a first for targeted therapy development in cancer.

David S. Hong, MD: Overall, in general, this is one of the first histology agnostic indications in the initial data set of 55 patients. We really didn’t see a huge difference in response rates across all different histologies, different ages, different types of NTRK fusions, 1, 2, or 3 translocations. And so that’s what eventually led to the FDA approval. In the most updated data set here in the adult patients, of 83 patients that we saw, we didn’t really see any significant differences.

There were some subsets of tumor types that had lower numbers. For example, colorectal I think had a slightly lower number of patients enrolled, and therefore had a 50% or 60% response rate, which is lower than the 75% that we’ve seen in some. But I suspect that some of that was just small numbers.

Transcript Edited for Clarity
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Transcript: 

David Hyman, MD: The development of larotrectinib was a little bit unusual in 2 ways. It was in a very focused development that really homed in on targeting TRK fusions in the earliest parts of its clinical development. The other interesting feature of larotrectinib’s development was the ability to integrate the patient experience across 3 clinical trial programs. And those were the first-in-human phase I adult study, which is a study where we initially defined the proper dose of this agent in adults. Then there was a first-in-child phase I study that actually uniquely entered the clinic shortly after the adult study, and we rarely see that in cancer where children are getting very early access to a novel targeted therapy. And then the third was a phase II study in adult and adolescents who were characterized by the presence of TRK fusions. The 2 phase I studies initially didn’t require TRK fusion positivity, and the phase II study did. So, ultimately, the data set that was used to register this drug was the combination of all the TRK fusion-positive patients enrolled across these three clinical trials that represent the development program of larotrectinib.

The other feature that was really unusual about the larotrectinib development plan was the inclusion of patients with any kind of cancer, provided that they had a TRK fusion. And that tumor-agnostic development was a first for targeted therapy development in cancer.

David S. Hong, MD: Overall, in general, this is one of the first histology agnostic indications in the initial data set of 55 patients. We really didn’t see a huge difference in response rates across all different histologies, different ages, different types of NTRK fusions, 1, 2, or 3 translocations. And so that’s what eventually led to the FDA approval. In the most updated data set here in the adult patients, of 83 patients that we saw, we didn’t really see any significant differences.

There were some subsets of tumor types that had lower numbers. For example, colorectal I think had a slightly lower number of patients enrolled, and therefore had a 50% or 60% response rate, which is lower than the 75% that we’ve seen in some. But I suspect that some of that was just small numbers.

Transcript Edited for Clarity
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