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Entrectinib as Treatment for NTRK-Positive Solid Tumors

Panelists: Benjamin Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center, Sibley Memorial Hospitale; Mark Agulnik, MD, Northwestern University Feinberg School of Medicine; Marcia Brose, MD, PhD, University of Pennsylvania; Edward Kim, MD, Levine Cancer Institute, Atrium Health ; John Marshall, MD, Georgetown University; Philip Agop Philip, MD, PhD, FRCP, Barbara Ann Karmanos Cancer Institute
Published: Wednesday, May 15, 2019



Transcript: 

Benjamin P. Levy, MD: So we have another drug. Larotrectinib has come on as the first approved, but there’s another drug that is moving quickly, entrectinib. Philip, do you want to talk a little bit about entrectinib?

Philip Agop Philip, MD, PhD, FRCP: Yes. There was a study presented by George Demetri, MD, at ESMO [the European Society for Medical Oncology annual meeting] in 2018. This was in 54 patients, again with 10 malignancies and 19 histological types. It was a study done globally. In that trial, they found a response rate of over 50%. It was lower than what Ed was talking about, in terms of the other drug. The adverse effects were tolerable. The difference with this drug and larotrectinib is that it may cross the blood-brain barrier, and that might be an advantage in patients who have CNS [central nervous system] metastases. But I don’t know if that was also tested in the previous trial.

Benjamin P. Levy, MD: There will be an update analysis….

Philip Agop Philip, MD, PhD, FRCP: So that will be something we’ll be looking for. Only a handful of patients had to stop the treatment because of toxicity. Again, well tolerated. The difference is that it’s only specific to the NTRK fusion changes. So again, even with that, it’s not really showing any major increase in the adverse effects. That goes with the fact that it may not be that much different but also is helpful. The response rate is less, but I don’t know if we can make any real comparisons between the 2 because they are separate studies. There was a good duration of response—over 10 months—and regarding the survival at the time of the presentation, the median was 20 months. So overall, we’re still waiting for an update on the trial, but this is certainly another drug that may show good promise in this disease, in this class of agents.

Benjamin P. Levy, MD: I want you all to get out your crystal balls. Let’s say entrectinib gets approved.

John L. Marshall, MD: Let’s go back to that. I was sitting here thinking, what if we were the panel for the FDA? Is it basically meeting the same bar as the previous? And what’s the FDA’s role of governing how many products should be in a similar space, and all of that? I think the FDA would say, “Well, we’re objective and we’re going to approve this drug.” So I get where you’re going, but it’s a challenge.

Benjamin P. Levy, MD: It’s a challenge, I agree. It’s a rare genotype. The response rates are a little bit lower than we see with the larotrectinib data. I’m not the FDA, so I don’t know how these decisions are really made.

Mark Agulnik, MD: Does the ROS1 activity excite lung people?

Edward S. Kim, MD: Well, we actually found the STARTRK data to be a little more attractive because it had both ROS1 as well as ALK coverage. Now again, that might compromise some of the activity that we’re seeing with TRK. It’s still early. Fifty-five patients. Gosh, if you put 10 more on it could change to 80%. But that was somewhat attractive to us.

Benjamin P. Levy, MD: The drug doesn’t work in the crizotinib-refractory setting for ROS1 though. So it’s more for the crizotinib-naïve. It had response rates north of 65%, 70%. We see a response rate in the NTRK fusions that is around 50%.

Back to your question, John, it’s interesting. It puts the FDA in a difficult decision here for how crowded this space is going to be when you get 1 drug that’s come along with a response rate of 75% and has been the darling trial of the tissue agnostic space. Does this drug then come in and get approved? Let’s say it does get approved. Do we feel like this is something we would try? Is it a sequencing question then? We don’t have a lot of data on sequencing for these drugs.

Edward S. Kim, MD: I’m kind of a capitalist type of person, so I like for the market to play out with competition. I think it’s always good when you’re 1 of the first few drugs. You kind of get that exception and you come in. Now in renal cell and others, we’re seeing the seventh drug and the fifth I/O [immunotherapy]. And so, we talk about cost and the way prices of drugs go up despite no new indications and other things. I think this hopefully leads to check and balance, and the market will play out. We’re the doctors. We know what we feel comfortable with. There are some adverse effect differences between the 2 drugs. There could be activity. It’s happened in the ALK space, where certain drugs get 0% market share and others get a lot.

Benjamin P. Levy, MD: We know some of those drugs in the ALK space.

Edward S. Kim, MD: That’s right.

Philip Agop Philip, MD, PhD, FRCP: When you say the market, sometimes yes, the market and the doctors and that experience. Some would say, “Well, I treat so many patients with panitumumab, so many patients with cetuximab, that I can see a difference,” or something. But in this situation, it will be difficult because people will not have that sort of experience of saying, “I like this blood pressure medication. I don’t like that blood pressure medication.” It’s a rare situation.

Edward S. Kim, MD: It might come down to formularies, and then it would be cost. So at least that would be a benefit. If you said I can get larotrectinib at $10,000, or entrectinib at $5000, you know, maybe that’s what it comes down to.

Philip Agop Philip, MD, PhD, FRCP: So that may be a major player.

Mark Agulnik, MD: The question also would be: Are they in the same space? If we don’t have data for what happens for refractory patients or patients who acquire resistance, then there could be a harm done if you’re going to sequence them if they really shouldn’t be sequenced. And that would be my worry. Until we have more data about sequencing, I do worry that people will end up using both, which may not be the right answer, and I think it’s too early to tell.

Benjamin P. Levy, MD: I would agree.

Marcia S. Brose, MD, PhD: There are some data coming out about the resistant mutations, and of course, that was the reason why they have LOXO-195. LOXO-195 is particularly for the people who are developing resistance. The interesting thing is, there haven’t been that many of them yet. That’s a good thing. It’s not necessarily good for LOXO-195.

Edward S. Kim, MD: I remember hearing about that study and I was talking to one of the company folks. I was like, “Is that going to be 2 patients in 5 years?”

Marcia S. Brose, MD, PhD: I think that’s actually how many. It’s 2 or 3. There are not that many. I was like, “I guess we don’t need to open that study for 5 years.” Even just doing the study is actually...

Benjamin P. Levy, MD: It’s something we need to know.

Marcia S. Brose, MD, PhD: Well, then the question is: Should you be giving that in the first-line setting if it really is everything that larotrectinib does plus 1 more? Maybe we should start with that?

Philip Agop Philip, MD, PhD, FRCP: That could then lead to another mutation.

Benjamin P. Levy, MD: It’s interesting. The mechanisms of resistance are starting to be sorted out with NTRK.

Marcia S. Brose, MD, PhD: Before you even have the drug come out.

Benjamin P. Levy, MD: Yes. We see these solvent-front mutations that we see in ALK.

Edward S. Kim, MD: I love that.

Marcia S. Brose, MD, PhD: I love it. It makes me crazy, but I love it.

Transcript Edited for Clarity

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Transcript: 

Benjamin P. Levy, MD: So we have another drug. Larotrectinib has come on as the first approved, but there’s another drug that is moving quickly, entrectinib. Philip, do you want to talk a little bit about entrectinib?

Philip Agop Philip, MD, PhD, FRCP: Yes. There was a study presented by George Demetri, MD, at ESMO [the European Society for Medical Oncology annual meeting] in 2018. This was in 54 patients, again with 10 malignancies and 19 histological types. It was a study done globally. In that trial, they found a response rate of over 50%. It was lower than what Ed was talking about, in terms of the other drug. The adverse effects were tolerable. The difference with this drug and larotrectinib is that it may cross the blood-brain barrier, and that might be an advantage in patients who have CNS [central nervous system] metastases. But I don’t know if that was also tested in the previous trial.

Benjamin P. Levy, MD: There will be an update analysis….

Philip Agop Philip, MD, PhD, FRCP: So that will be something we’ll be looking for. Only a handful of patients had to stop the treatment because of toxicity. Again, well tolerated. The difference is that it’s only specific to the NTRK fusion changes. So again, even with that, it’s not really showing any major increase in the adverse effects. That goes with the fact that it may not be that much different but also is helpful. The response rate is less, but I don’t know if we can make any real comparisons between the 2 because they are separate studies. There was a good duration of response—over 10 months—and regarding the survival at the time of the presentation, the median was 20 months. So overall, we’re still waiting for an update on the trial, but this is certainly another drug that may show good promise in this disease, in this class of agents.

Benjamin P. Levy, MD: I want you all to get out your crystal balls. Let’s say entrectinib gets approved.

John L. Marshall, MD: Let’s go back to that. I was sitting here thinking, what if we were the panel for the FDA? Is it basically meeting the same bar as the previous? And what’s the FDA’s role of governing how many products should be in a similar space, and all of that? I think the FDA would say, “Well, we’re objective and we’re going to approve this drug.” So I get where you’re going, but it’s a challenge.

Benjamin P. Levy, MD: It’s a challenge, I agree. It’s a rare genotype. The response rates are a little bit lower than we see with the larotrectinib data. I’m not the FDA, so I don’t know how these decisions are really made.

Mark Agulnik, MD: Does the ROS1 activity excite lung people?

Edward S. Kim, MD: Well, we actually found the STARTRK data to be a little more attractive because it had both ROS1 as well as ALK coverage. Now again, that might compromise some of the activity that we’re seeing with TRK. It’s still early. Fifty-five patients. Gosh, if you put 10 more on it could change to 80%. But that was somewhat attractive to us.

Benjamin P. Levy, MD: The drug doesn’t work in the crizotinib-refractory setting for ROS1 though. So it’s more for the crizotinib-naïve. It had response rates north of 65%, 70%. We see a response rate in the NTRK fusions that is around 50%.

Back to your question, John, it’s interesting. It puts the FDA in a difficult decision here for how crowded this space is going to be when you get 1 drug that’s come along with a response rate of 75% and has been the darling trial of the tissue agnostic space. Does this drug then come in and get approved? Let’s say it does get approved. Do we feel like this is something we would try? Is it a sequencing question then? We don’t have a lot of data on sequencing for these drugs.

Edward S. Kim, MD: I’m kind of a capitalist type of person, so I like for the market to play out with competition. I think it’s always good when you’re 1 of the first few drugs. You kind of get that exception and you come in. Now in renal cell and others, we’re seeing the seventh drug and the fifth I/O [immunotherapy]. And so, we talk about cost and the way prices of drugs go up despite no new indications and other things. I think this hopefully leads to check and balance, and the market will play out. We’re the doctors. We know what we feel comfortable with. There are some adverse effect differences between the 2 drugs. There could be activity. It’s happened in the ALK space, where certain drugs get 0% market share and others get a lot.

Benjamin P. Levy, MD: We know some of those drugs in the ALK space.

Edward S. Kim, MD: That’s right.

Philip Agop Philip, MD, PhD, FRCP: When you say the market, sometimes yes, the market and the doctors and that experience. Some would say, “Well, I treat so many patients with panitumumab, so many patients with cetuximab, that I can see a difference,” or something. But in this situation, it will be difficult because people will not have that sort of experience of saying, “I like this blood pressure medication. I don’t like that blood pressure medication.” It’s a rare situation.

Edward S. Kim, MD: It might come down to formularies, and then it would be cost. So at least that would be a benefit. If you said I can get larotrectinib at $10,000, or entrectinib at $5000, you know, maybe that’s what it comes down to.

Philip Agop Philip, MD, PhD, FRCP: So that may be a major player.

Mark Agulnik, MD: The question also would be: Are they in the same space? If we don’t have data for what happens for refractory patients or patients who acquire resistance, then there could be a harm done if you’re going to sequence them if they really shouldn’t be sequenced. And that would be my worry. Until we have more data about sequencing, I do worry that people will end up using both, which may not be the right answer, and I think it’s too early to tell.

Benjamin P. Levy, MD: I would agree.

Marcia S. Brose, MD, PhD: There are some data coming out about the resistant mutations, and of course, that was the reason why they have LOXO-195. LOXO-195 is particularly for the people who are developing resistance. The interesting thing is, there haven’t been that many of them yet. That’s a good thing. It’s not necessarily good for LOXO-195.

Edward S. Kim, MD: I remember hearing about that study and I was talking to one of the company folks. I was like, “Is that going to be 2 patients in 5 years?”

Marcia S. Brose, MD, PhD: I think that’s actually how many. It’s 2 or 3. There are not that many. I was like, “I guess we don’t need to open that study for 5 years.” Even just doing the study is actually...

Benjamin P. Levy, MD: It’s something we need to know.

Marcia S. Brose, MD, PhD: Well, then the question is: Should you be giving that in the first-line setting if it really is everything that larotrectinib does plus 1 more? Maybe we should start with that?

Philip Agop Philip, MD, PhD, FRCP: That could then lead to another mutation.

Benjamin P. Levy, MD: It’s interesting. The mechanisms of resistance are starting to be sorted out with NTRK.

Marcia S. Brose, MD, PhD: Before you even have the drug come out.

Benjamin P. Levy, MD: Yes. We see these solvent-front mutations that we see in ALK.

Edward S. Kim, MD: I love that.

Marcia S. Brose, MD, PhD: I love it. It makes me crazy, but I love it.

Transcript Edited for Clarity
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