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TRK Inhibition: Future Challenges and Evolutions

Insights From: David S. Hong, MD, MD Anderson Cancer Center; David Hyman, MD, Memorial Sloan Kettering Cancer Center; David Reardon, MD, Dana-Farber Cancer Institute
Published: Tuesday, Oct 29, 2019



Transcript: 

David S. Hong, MD: What are the ongoing challenges for TRK inhibitors? One, I think the main challenge is really to help how we identify these patients because these patients do have incredible benefit from larotrectinib and other TRK inhibitors. So that remains a challenge because I would argue at this point, even in the United States, the vast majority of patients with metastatic cancer do not get tested with NGS [next-generation sequencing] or other standard platforms. I heard a statistic out there that of patients with lung cancer, only about 40% of patients actually get even tested for standard mutations, such as EGFR or ALK/ROS. And so I think that remains a major challenge. How do we ensure that patients increasingly get this NGS testing? All patients at some point, or most patients at some point, will develop some type of resistance to any therapy, especially in the metastatic setting.

To date, this drug has had incredible durability. And, as I shared, median progression-free survival is 25.8 months. These patients remain on study for years sometimes. The hope is that many of these patients will remain on study for years, but as we know from past experiences is that most patients that go on a small molecule inhibitor will eventually develop resistance. And our colleagues around the world and at Memorial Sloan Kettering Cancer Center and myself are already developing the next generation of TRK inhibitors. There are other TRK inhibitors that have already emerged that target specific mutations that may arise from resistant phenotypes such as solvent front mutations, gatekeeper mutations.

And so that will be the next generation of TRK inhibitors. I’m sure there will be other mechanisms of resistance that we’ll discover as we learn more about this disease and about this pathway. But I think what’s hopeful and what’s exciting is that the chemistry has gotten better, the biology has become more understood, and we are moving very quickly, with our colleagues at the FDA, to get new drugs to our patients. So I think it’s really a hopeful time in oncology.

David Hyman, MD: I think what the experience of TRK inhibitors has taught us is that we really have to be ambitious in the targets that we go after. This was a target that I think just a couple of years ago—or even when we set out to do this—was considered by many to be impractical. This is too rare. We’re never going to find the patients. And I think what this shows us is that the biology is right, and the drugs are right. We have the ability to have dramatic effects, albeit sometimes in small patient populations, but it’s a worthwhile endeavor. And the regulators will get behind this effort and work with us to bring these highly effective therapies to patients.

So I’m very excited about what the development of these agents means, not just for the patients who have TRK fusions but for the broader oncology community, as well as the pediatric oncology community, which I think has really been shown that if you can identify even very rare populations of patients where safe drugs can be highly effective, that we ought to have the ambition to develop the drugs in those populations of patients.

Transcript Edited for Clarity
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Transcript: 

David S. Hong, MD: What are the ongoing challenges for TRK inhibitors? One, I think the main challenge is really to help how we identify these patients because these patients do have incredible benefit from larotrectinib and other TRK inhibitors. So that remains a challenge because I would argue at this point, even in the United States, the vast majority of patients with metastatic cancer do not get tested with NGS [next-generation sequencing] or other standard platforms. I heard a statistic out there that of patients with lung cancer, only about 40% of patients actually get even tested for standard mutations, such as EGFR or ALK/ROS. And so I think that remains a major challenge. How do we ensure that patients increasingly get this NGS testing? All patients at some point, or most patients at some point, will develop some type of resistance to any therapy, especially in the metastatic setting.

To date, this drug has had incredible durability. And, as I shared, median progression-free survival is 25.8 months. These patients remain on study for years sometimes. The hope is that many of these patients will remain on study for years, but as we know from past experiences is that most patients that go on a small molecule inhibitor will eventually develop resistance. And our colleagues around the world and at Memorial Sloan Kettering Cancer Center and myself are already developing the next generation of TRK inhibitors. There are other TRK inhibitors that have already emerged that target specific mutations that may arise from resistant phenotypes such as solvent front mutations, gatekeeper mutations.

And so that will be the next generation of TRK inhibitors. I’m sure there will be other mechanisms of resistance that we’ll discover as we learn more about this disease and about this pathway. But I think what’s hopeful and what’s exciting is that the chemistry has gotten better, the biology has become more understood, and we are moving very quickly, with our colleagues at the FDA, to get new drugs to our patients. So I think it’s really a hopeful time in oncology.

David Hyman, MD: I think what the experience of TRK inhibitors has taught us is that we really have to be ambitious in the targets that we go after. This was a target that I think just a couple of years ago—or even when we set out to do this—was considered by many to be impractical. This is too rare. We’re never going to find the patients. And I think what this shows us is that the biology is right, and the drugs are right. We have the ability to have dramatic effects, albeit sometimes in small patient populations, but it’s a worthwhile endeavor. And the regulators will get behind this effort and work with us to bring these highly effective therapies to patients.

So I’m very excited about what the development of these agents means, not just for the patients who have TRK fusions but for the broader oncology community, as well as the pediatric oncology community, which I think has really been shown that if you can identify even very rare populations of patients where safe drugs can be highly effective, that we ought to have the ambition to develop the drugs in those populations of patients.

Transcript Edited for Clarity
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