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TRK Inhibition: Personal Experience With Larotrectinib

Insights From: David S. Hong, MD, MD Anderson Cancer Center; David Hyman, MD, Memorial Sloan Kettering Cancer Center
Published: Tuesday, Aug 13, 2019



Transcript: 

David Hyman, MD: One of the other defining features of larotrectinib has been its safety in patients, and that really comes from 2 factors. One is that we know that the role of TRK [tropomyosin receptor kinase] in our bodies normally is very limited. And so we’re targeting something that has a very limited normal physiologic role. And larotrectinib is an incredibly selective inhibitor, so it really only is inhibiting TRK in patients. And the consequence of that is that patients tolerate this drug incredibly well. And in fact, you can see this most clearly in the need for a dose reduction, which occurs between 10% and 15% of the time, which is an incredibly low rate for a cancer therapy. When you look at the percentage of patients who discontinue this drug due to adverse effects, it’s really only a very small handful of patients, in the 1% or 2% range of patients ultimately who need to discontinue this drug due to adverse effects. So this really is an entirely safe drug, and it’s a drug where, in comparison to the other anti-cancer therapies that these patients have experienced, the patients who I’ve treated have all remarked just how favorable the adverse effect profile of larotrectinib is in comparison to almost any other treatment that they had received as part of their cancer care.

David S. Hong, MD: What has been my experience with patients? In many ways, this drug has been truly transformative for many of my patients. I’ll give you a story and an example. I have a young gentleman who was diagnosed with very aggressive metastatic papillary thyroid cancer in his early 30s. He was a real estate agent in Houston. And he had failed standard radioactive iodine therapy. He had failed chemotherapy. He had actually failed several lines of other targeted agents and also a phase I trial. He came to me and was on oxygen, and in most cases in that situation, we would probably have said to him to consider hospice. But we sent off his tissue for analysis at Foundation Medicine, and what we got back was that he had NTRK fusion, ETV6-NTRK3 fusion. And as soon as I realized that, we put him on the study. Within a week he was off oxygen. He is still alive 3 years later. Three years ago, he had one child and a wife, and both of them did not think that he would live long enough to have any further children. He had actually saved some of his sperm. They now have twins.

This is just a small example of some of the transformative ways that this drug has worked. Is this going to work for everybody? Is this going to be this transformative for everybody? I say this to my other colleagues. If you ever identify a patient with NTRK fusion and you actually treat them with larotrectinib or an NTRK inhibitor, you will never forget the patient and you will never forget the drug.

David Hyman, MD: Treating patients with TRK inhibitors and larotrectinib has been really the highlight of our medical oncology career. It’s so rare that you can offer a patient a therapy that within days offers them dramatic clinical benefit. I’ve had the privilege of treating patients who were extremely ill from their cancers, almost bed-bound, but within a couple days of taking larotrectinib, they’re able to return to often near-normal function. I’ve been able to live with these patients, watching these dramatic clinical improvements, these dramatic changes on their scan. And most important is the durability of response with this drug, so these patients that I’ve been able to follow, in some cases for several years now, is an incredible experience. I’ve gotten to see patients who have seen their children graduate college, those who have seen their young children raised and have major milestones in their life. So it’s been a really amazing experience personally.

Transcript Edited for Clarity
 
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Transcript: 

David Hyman, MD: One of the other defining features of larotrectinib has been its safety in patients, and that really comes from 2 factors. One is that we know that the role of TRK [tropomyosin receptor kinase] in our bodies normally is very limited. And so we’re targeting something that has a very limited normal physiologic role. And larotrectinib is an incredibly selective inhibitor, so it really only is inhibiting TRK in patients. And the consequence of that is that patients tolerate this drug incredibly well. And in fact, you can see this most clearly in the need for a dose reduction, which occurs between 10% and 15% of the time, which is an incredibly low rate for a cancer therapy. When you look at the percentage of patients who discontinue this drug due to adverse effects, it’s really only a very small handful of patients, in the 1% or 2% range of patients ultimately who need to discontinue this drug due to adverse effects. So this really is an entirely safe drug, and it’s a drug where, in comparison to the other anti-cancer therapies that these patients have experienced, the patients who I’ve treated have all remarked just how favorable the adverse effect profile of larotrectinib is in comparison to almost any other treatment that they had received as part of their cancer care.

David S. Hong, MD: What has been my experience with patients? In many ways, this drug has been truly transformative for many of my patients. I’ll give you a story and an example. I have a young gentleman who was diagnosed with very aggressive metastatic papillary thyroid cancer in his early 30s. He was a real estate agent in Houston. And he had failed standard radioactive iodine therapy. He had failed chemotherapy. He had actually failed several lines of other targeted agents and also a phase I trial. He came to me and was on oxygen, and in most cases in that situation, we would probably have said to him to consider hospice. But we sent off his tissue for analysis at Foundation Medicine, and what we got back was that he had NTRK fusion, ETV6-NTRK3 fusion. And as soon as I realized that, we put him on the study. Within a week he was off oxygen. He is still alive 3 years later. Three years ago, he had one child and a wife, and both of them did not think that he would live long enough to have any further children. He had actually saved some of his sperm. They now have twins.

This is just a small example of some of the transformative ways that this drug has worked. Is this going to work for everybody? Is this going to be this transformative for everybody? I say this to my other colleagues. If you ever identify a patient with NTRK fusion and you actually treat them with larotrectinib or an NTRK inhibitor, you will never forget the patient and you will never forget the drug.

David Hyman, MD: Treating patients with TRK inhibitors and larotrectinib has been really the highlight of our medical oncology career. It’s so rare that you can offer a patient a therapy that within days offers them dramatic clinical benefit. I’ve had the privilege of treating patients who were extremely ill from their cancers, almost bed-bound, but within a couple days of taking larotrectinib, they’re able to return to often near-normal function. I’ve been able to live with these patients, watching these dramatic clinical improvements, these dramatic changes on their scan. And most important is the durability of response with this drug, so these patients that I’ve been able to follow, in some cases for several years now, is an incredible experience. I’ve gotten to see patients who have seen their children graduate college, those who have seen their young children raised and have major milestones in their life. So it’s been a really amazing experience personally.

Transcript Edited for Clarity
 
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