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Moving Forward With TRK Inhibition

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: Monday, Jul 30, 2018



Transcript: 

David Hyman, MD: The most immediately important question for patients that they’re going to ask as they begin to see these drugs is, What are my expectations for this drug? I think we’ve proved quite clearly that the overwhelming majority of patients who receive these drugs are going to respond. The question for the patient then becomes, for how long? We’re in a situation where we luckily can’t answer that question because the drugs have proved effective enough that we haven’t been following patients long enough to see.

The next immediate question for patients is, how long can I expect to benefit from these agents? Obviously, there’s going to be a range, but patients want some guidance. The next set of questions will be, What happens when my cancer stops responding? There we have programs like LOXO-195 that offer patients hope for continued benefit. And for those whom LOXO-195 can’t help because they have mechanisms of resistance that LOXO-195 can’t address—and I think we need to be honest about how that will happen—we need to understand why that’s happening and what approaches can be used to overcome and prolong benefit.

And then, of course, you can imagine the scenario where there’s a drug even after LOXO-195 as a third-generation compound to address the resistance that arises on LOXO-195. But now we’re getting a little bit ahead of ourselves. What I can say is that we defined this diagnostic entity and we’ve established an effective treatment paradigm, and I think we’re going to continue to try to improve and push out the benefit of this approach in this new diagnostic entity.

Alexander Drilon, MD: The question of whether or not combination therapy is useful for NTRK fusion-positive cancers is a good one. Certainly, what we know from many other driver-positive subsets—like BRAF V600E–mutant melanomas and EGFR, ALK, and ROS1 in lung cancers—is that for the latter 3, you can use a single agent and get very good responses and durability. That’s what we’re seeing with larotrectinib and entrectinib. Now, it’s a little different from BRAF V600E, where you use a second drug based on the biology of those tumors. If you had a MEK inhibitor, then a BRAF inhibitor, you’re getting better activity. That doesn’t seem to be a need in the NTRK fusion–positive space because the response rates are upward of 75%. But looking to the acquired resistance question, there may be cases where combination therapy might need to be utilized for a patient’s tumors that develop a resistance mechanism that’s amendable with a different pill.

David S. Hong, MD: I was just at the FDA talking about tumor-agnostic approvals and how this all fits into the regulatory framework of, for example, the Orphan Drug Act. I think what came out of that is that tumor-agnostic therapy from a regulatory standpoint is complex; but what also came out of that meeting was that the future is bright. I think everybody, from the FDA to regulators to sponsors, is moving toward and searching for ways to allow tumor-agnostic indications in the future. What’s also exciting is that there are going to be other opportunities outside NTRK fusion, outside MSI-high tumors, that we still have yet to explore. There are many new drugs that are now both in clinical trials and about to be developed that may have significant activity across histologies. It’s an exciting time in oncology, and we’ll see what the next 10 to 20 years hold.

Transcript Edited for Clarity
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Transcript: 

David Hyman, MD: The most immediately important question for patients that they’re going to ask as they begin to see these drugs is, What are my expectations for this drug? I think we’ve proved quite clearly that the overwhelming majority of patients who receive these drugs are going to respond. The question for the patient then becomes, for how long? We’re in a situation where we luckily can’t answer that question because the drugs have proved effective enough that we haven’t been following patients long enough to see.

The next immediate question for patients is, how long can I expect to benefit from these agents? Obviously, there’s going to be a range, but patients want some guidance. The next set of questions will be, What happens when my cancer stops responding? There we have programs like LOXO-195 that offer patients hope for continued benefit. And for those whom LOXO-195 can’t help because they have mechanisms of resistance that LOXO-195 can’t address—and I think we need to be honest about how that will happen—we need to understand why that’s happening and what approaches can be used to overcome and prolong benefit.

And then, of course, you can imagine the scenario where there’s a drug even after LOXO-195 as a third-generation compound to address the resistance that arises on LOXO-195. But now we’re getting a little bit ahead of ourselves. What I can say is that we defined this diagnostic entity and we’ve established an effective treatment paradigm, and I think we’re going to continue to try to improve and push out the benefit of this approach in this new diagnostic entity.

Alexander Drilon, MD: The question of whether or not combination therapy is useful for NTRK fusion-positive cancers is a good one. Certainly, what we know from many other driver-positive subsets—like BRAF V600E–mutant melanomas and EGFR, ALK, and ROS1 in lung cancers—is that for the latter 3, you can use a single agent and get very good responses and durability. That’s what we’re seeing with larotrectinib and entrectinib. Now, it’s a little different from BRAF V600E, where you use a second drug based on the biology of those tumors. If you had a MEK inhibitor, then a BRAF inhibitor, you’re getting better activity. That doesn’t seem to be a need in the NTRK fusion–positive space because the response rates are upward of 75%. But looking to the acquired resistance question, there may be cases where combination therapy might need to be utilized for a patient’s tumors that develop a resistance mechanism that’s amendable with a different pill.

David S. Hong, MD: I was just at the FDA talking about tumor-agnostic approvals and how this all fits into the regulatory framework of, for example, the Orphan Drug Act. I think what came out of that is that tumor-agnostic therapy from a regulatory standpoint is complex; but what also came out of that meeting was that the future is bright. I think everybody, from the FDA to regulators to sponsors, is moving toward and searching for ways to allow tumor-agnostic indications in the future. What’s also exciting is that there are going to be other opportunities outside NTRK fusion, outside MSI-high tumors, that we still have yet to explore. There are many new drugs that are now both in clinical trials and about to be developed that may have significant activity across histologies. It’s an exciting time in oncology, and we’ll see what the next 10 to 20 years hold.

Transcript Edited for Clarity
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