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TRK Inhibition's Potential Role in Clinical Practice

Insights From: David S. Hong, MD, MD Anderson Cancer Center; Alexander Drilon, MD, Memorial Sloan Kettering Cancer Center; David Hyman, MD, Memorial Sloan Kettering Cancer Center
Published: Tuesday, Jul 10, 2018



Transcript: 

David Hyman, MD: What we see with the data set that was generated with larotrectinib is that we’re essentially defining a new type of cancer. Historically, we define cancers based on where they come from, and that’s been very useful in developing effective treatment strategies for those various cancers. What we have here is essentially a new cancer diagnosis, which is TRK fusion–positive cancers because they define a group of tumors that are exquisitely sensitive to TRK inhibitors.

What I think we’ll see is really an evolution of defining this as a diagnosis, using larotrectinib as our initial agent in this population. Then I hope to see a series of drug developments in this population as we’ve seen with other genomically-defined populations like ALK fusion–positive lung cancers. By using not only highly effective agents up front but potentially multiple agents over time, you can really prolong the benefit tremendously in that population.

David S. Hong, MD: I think it’s too early right now to know exactly how TRK inhibitors are going to impact clinical practice in general. I think that most patients who are going to receive TRK inhibitors are patients who have been identified, either incidentally or specifically, because they have these rare tumors. That will lead to a fusion-positive patient who is then refractory to chemotherapy, like a patient with colorectal cancer who’s been refractory to standard chemotherapy, receiving this because they found it as an incidental finding in NGS (next-generation sequencing).

There could be other instances where we have a patient with infantile fibrosarcoma, which is a very specific disease, and an NGS panel or some assay identifies this patient truly to have an NTRK fusion. That patient could receive an NTRK inhibitor, and that could lead to either complete response, as in some cases we saw in the trials or, as in one instance in this study, significant reduction of that tumor that leads to a favorable surgical outcome. I think it’s not clear what the prevalence of NTRK fusion patients is in a universe of tumors in general. But as NGS testing becomes much more of a common thing, I think we will start seeing what the true prevalence is and that it may be higher than we initially thought.

Again, I think it depends on the clinical situation. If it’s a very common tumor, such as lung cancer or colorectal cancer, and available therapy does not seem to be working, I think at this point if they incidentally identify these patients with an NTRK fusion, it’s appropriate to treat these patients with NTRK inhibitors. However, in rare tumors that either have no therapy, or if surgery is the only option, this may be an option in these cases. For example, if infantile fibrosarcoma or MASC (mammary analogue secretory carcinoma) tumors, which oftentimes don’t respond to chemotherapy, harbor the NTRK fusion, it may be of benefit to give those patients this drug up front, especially in the metastatic setting.

David Hyman, MD: Obviously, with any targeted therapy, we’re always worried about the possibility of the emergence of acquired resistance: patients who were initially responding and then eventually develop resistance. One of the fortunate things about this program is that we haven’t seen a lot of this at this point in the larotrectinib program, and the drug really has demonstrated durable responses. But we have begun to see a few patients who do develop acquired resistance. I think the experience that we’re going to see in this space is going to mirror what we’ve seen in other oncogene addictive cancers, like ALK fusions or ROS fusions, where resistance is going to be needed by 1 of 2 mechanisms.

First, you can see acquired mutations within the TRK gene itself. In the initial paper that we published, we presented data from the first 9 patients who developed acquired resistance, and all 9 of them had a detectable new mutation in TRK fusion equivalent to a gatekeeper mutation we’ve seen with other diseases. What I think is really important about that mechanism of resistance is that it is potentially amenable to newer classes of agents like LOXO-195, which are rationally designed to not be interfered with by these acquired mutations and can continue to generate or salvage responses in patients who have lost sensitivity to earlier classes of agents.

We do think there will be a population of patients who develop resistance on the basis of so-called bypass TRKs, where other growth pathways potentially become activated in parallel to or downstream of the TRK signaling pathway that leads to regrowth of tumors in a way that may not be addressed by drugs like LOXO-195. Those patients may actually require drug combinations, and that’s an area of active investigation. But we’re going to learn a lot more about these as we get more experience with the use of the first generation of TRK inhibitors, specifically larotrectinib; as we get more experience with LOXO-195; and as more patients are treated with these agents. This is really a rapidly evolving space.

Alexander Drilon, MD: Once these TRK inhibitors are approved by regulatory agencies, I think we’re going to need to very seriously think about widely screening for these NTRK fusions across different solid tumors. We also know from the data in pembrolizumab, which was approved by the FDA for MSI-high cancers of any solid tumor type, that this is a molecular signature that can be found with comprehensive profiling. And so, I think that we need to come to a point where both regulatory agencies and payers buy into the concept of doctors’ screening for these molecular signatures in order to get these patients these highly active therapies.

Transcript Edited for Clarity 
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Transcript: 

David Hyman, MD: What we see with the data set that was generated with larotrectinib is that we’re essentially defining a new type of cancer. Historically, we define cancers based on where they come from, and that’s been very useful in developing effective treatment strategies for those various cancers. What we have here is essentially a new cancer diagnosis, which is TRK fusion–positive cancers because they define a group of tumors that are exquisitely sensitive to TRK inhibitors.

What I think we’ll see is really an evolution of defining this as a diagnosis, using larotrectinib as our initial agent in this population. Then I hope to see a series of drug developments in this population as we’ve seen with other genomically-defined populations like ALK fusion–positive lung cancers. By using not only highly effective agents up front but potentially multiple agents over time, you can really prolong the benefit tremendously in that population.

David S. Hong, MD: I think it’s too early right now to know exactly how TRK inhibitors are going to impact clinical practice in general. I think that most patients who are going to receive TRK inhibitors are patients who have been identified, either incidentally or specifically, because they have these rare tumors. That will lead to a fusion-positive patient who is then refractory to chemotherapy, like a patient with colorectal cancer who’s been refractory to standard chemotherapy, receiving this because they found it as an incidental finding in NGS (next-generation sequencing).

There could be other instances where we have a patient with infantile fibrosarcoma, which is a very specific disease, and an NGS panel or some assay identifies this patient truly to have an NTRK fusion. That patient could receive an NTRK inhibitor, and that could lead to either complete response, as in some cases we saw in the trials or, as in one instance in this study, significant reduction of that tumor that leads to a favorable surgical outcome. I think it’s not clear what the prevalence of NTRK fusion patients is in a universe of tumors in general. But as NGS testing becomes much more of a common thing, I think we will start seeing what the true prevalence is and that it may be higher than we initially thought.

Again, I think it depends on the clinical situation. If it’s a very common tumor, such as lung cancer or colorectal cancer, and available therapy does not seem to be working, I think at this point if they incidentally identify these patients with an NTRK fusion, it’s appropriate to treat these patients with NTRK inhibitors. However, in rare tumors that either have no therapy, or if surgery is the only option, this may be an option in these cases. For example, if infantile fibrosarcoma or MASC (mammary analogue secretory carcinoma) tumors, which oftentimes don’t respond to chemotherapy, harbor the NTRK fusion, it may be of benefit to give those patients this drug up front, especially in the metastatic setting.

David Hyman, MD: Obviously, with any targeted therapy, we’re always worried about the possibility of the emergence of acquired resistance: patients who were initially responding and then eventually develop resistance. One of the fortunate things about this program is that we haven’t seen a lot of this at this point in the larotrectinib program, and the drug really has demonstrated durable responses. But we have begun to see a few patients who do develop acquired resistance. I think the experience that we’re going to see in this space is going to mirror what we’ve seen in other oncogene addictive cancers, like ALK fusions or ROS fusions, where resistance is going to be needed by 1 of 2 mechanisms.

First, you can see acquired mutations within the TRK gene itself. In the initial paper that we published, we presented data from the first 9 patients who developed acquired resistance, and all 9 of them had a detectable new mutation in TRK fusion equivalent to a gatekeeper mutation we’ve seen with other diseases. What I think is really important about that mechanism of resistance is that it is potentially amenable to newer classes of agents like LOXO-195, which are rationally designed to not be interfered with by these acquired mutations and can continue to generate or salvage responses in patients who have lost sensitivity to earlier classes of agents.

We do think there will be a population of patients who develop resistance on the basis of so-called bypass TRKs, where other growth pathways potentially become activated in parallel to or downstream of the TRK signaling pathway that leads to regrowth of tumors in a way that may not be addressed by drugs like LOXO-195. Those patients may actually require drug combinations, and that’s an area of active investigation. But we’re going to learn a lot more about these as we get more experience with the use of the first generation of TRK inhibitors, specifically larotrectinib; as we get more experience with LOXO-195; and as more patients are treated with these agents. This is really a rapidly evolving space.

Alexander Drilon, MD: Once these TRK inhibitors are approved by regulatory agencies, I think we’re going to need to very seriously think about widely screening for these NTRK fusions across different solid tumors. We also know from the data in pembrolizumab, which was approved by the FDA for MSI-high cancers of any solid tumor type, that this is a molecular signature that can be found with comprehensive profiling. And so, I think that we need to come to a point where both regulatory agencies and payers buy into the concept of doctors’ screening for these molecular signatures in order to get these patients these highly active therapies.

Transcript Edited for Clarity 
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