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Managing Lesions in Melanoma

Panelists:Keith T. Flaherty, MD Massachusetts General Hospital;Georgina Long, BSc, MBBS, FRACP, Melanoma Institute of Australia;Jason J. Luke, MD, FACP, University of Chicago;Jeffrey S. Weber, MD, NYU Langone Medical Center;Jonathan S. Zager, MD, Moffitt Cancer Center
Published: Monday, Sep 26, 2016


Transcript:

Keith T. Flaherty, MD:
Let’s shift away just for a moment. One of the new kids on the block is T-VEC, and right now approved in the United States as monotherapy. Jonathan, you mentioned before that patients with in-transit disease, for example, might be candidates. Where do you think of the, let’s say, multiple potentially scenarios—where before systemic therapy becomes the focus—that the T-VEC would play a role?

Jonathan S. Zager, MD: Well, I particularly use it in the IIIb, IIIc population, especially patients with lower burden of disease that’s not rapidly progressing. I think the phase III trial was positive with durable response rates, 16.3% versus 2.1% in favor of the T-VEC group. Again, like I mentioned before, it’s extremely well tolerated. It’s fast. I can give it to patients usually in 5 minutes. The patients tolerate it very well. The side effects are not unlike some of the side effects that you guys have already described, but they could have a mild to moderate flu-like illness the night of injection, maybe the following day, that usually responds to Tylenol, and then they’re better. And then, as you go along in treatment with each subsequent treatment, I think those side effects get less and less to the point where some of my patients aren’t having any side effects at all. For moderate to less disease burden that’s not rapidly progressing, stage IIIb, IIIc, especially in patients who have contraindications or don’t want systemic therapies, I think it’s a great option for them.

Keith T. Flaherty, MD: Jeff, in patients who are on immune therapy, well, it could have been PD-1/CTLA4 combination followed by nivolumab maintenance or just PD-1 monotherapy. If they have injectable disease that, let’s say, persists or appears, like oligoprogressive disease, but not a lot of it, does T-VEC have a role there?

Jeffrey S. Weber, MD: If someone has isolated progression during and after immunotherapy, I’ll always try to have it surgically resected. If it is not easily resectable—and, as Jon appropriately points out, resectability is always in the eye of the beholder—yes, direct injection therapy, I think, would be reasonable. That’s a very small niche population. I think T-VEC alone, again, is somewhat of a niche drug, and, by the way, a couple others are coming along in earlier trials. I see the value of those drugs as a way to prime an immune response in a patient who then would subsequently receive either PD-1 blockade or combination blockade. There’s an ongoing phase III trial, as I remember, with pembrolizumab/T-VEC versus pembrolizumab alone. So, I see that as the value. And if that’s a positive study, I think you’re going to see a lot more traction, a lot more use of T-VEC. I would venture a guess it has a modest utilization now in the United States. Since we have very good drugs, it’s just, like I said, a niche agent.

Keith T. Flaherty, MD: Jeff was mentioning surgery for oligoprogressive disease. What do you think about the role of surgery for patients who had a partial response, still had some disease that remains—and here, I’m mostly thinking of visceral metastasis? What time point? As a surgeon, you’re being asked to consider this patient 6 months in, 12 months in. How do you react to that?

Jonathan S. Zager, MD: Again, if the bulk of the disease has gone away, it doesn’t matter with combination targeted therapy, single agent, immunotherapy, and there are isolated lesions. Jeff and I have collaborated on this many times, I’ll go ahead and resect it and make the patient NED (no evidence of disease). And I think that’s the best thing for the patient. Sometimes you have these resistant lesions or some mutations that happen and they’re no longer responding to the systemic therapy. That’s a perfect candidate to have clean-up surgery and make them no evidence of disease.

Georgina Long, BSc, MBBS: So, the key there you just mentioned was resistant lesions. Just a question, because our surgeons discuss this, if we’ve got a great response, but there’s one lesion that’s growing or showing resistance, our surgeons are very keen to help us out and cut them out.

Jonathan S. Zager, MD: Same here, yes.

Georgina Long, BSc, MBBS: If they’ve had a great response and it’s just a residual lesion that’s not changing, they won’t necessarily go in and cut that out. However, if the patients came to understand what the disease is and we’re collecting biopsies for research to understand what the nidus of tumor is, then we’ll go ahead. What’s your approach on that?

Jonathan S. Zager, MD: If you have 10 lesions and there’s one lesion left over, changing or not, I think we should resect it as long as it can be done with low morbidity. Of course, I wouldn’t do a right hepatectomy, exactly, for one stable lesion, because that’s an operation that can have some morbidity. But, if it can be done with relatively low morbidity and the patient understands the risks and benefits, then I think it’s absolutely appropriate to resect a stable lesion that’s just hanging on.

Georgina Long, BSc, MBBS: Just one more question on that. Spleen? How far do you go?

Jonathan S. Zager, MD: I take out a spleen.

Georgina Long, BSc, MBBS: Okay. Adrenal gland?

Jonathan S. Zager, MD: Yes, adrenal and spleen.

Jeffrey S. Weber, MD: I agree with Jon. I don’t understand the rationale. Unless it was absolutely cold on a PET scan or you were somehow convinced it was in a necrotic dead mass of tissue with no tumor—let’s see if I can make a biblical paraphrase—if it offends thee, pluck it out. I would take it out.

Georgina Long, BSc, MBBS: That’s another key. We do that. If it’s PET hot, we’ll take it out. But, if you’ve had a patient who’s had a great response, you can see these little lesions in the liver and elsewhere, and they’re all PET cold, we just watch.

Jonathan S. Zager, MD: Little lesions we’ll watch, too. So, little lesions in more than one, two organs, at least we’re not going to go in and do the spleen and adrenal. But, a 2-cm metastasis that the liver is now clear of disease, and there’s an adrenal gland that still has this stable disease, that’s a low morbidity operation laparoscopically. And I think we would we go after it.

Jeffrey S. Weber, MD: But, again, there’s mineable data here. One of the interesting things about having a large number of patients that have been on randomized, well done phase III trials with nivolumab alone, pembrolizumab alone, the combination of both, dabrafenib/trametinib, or cobimetinib/vemurafenib is to mine these trials to get this information. What happens to the 80 patients who had a single site of disease left that was resected? If they all relapse very quickly, then maybe we shouldn’t be doing surgery. But, I would venture a bet they would do extremely well.

Jonathan S. Zager, MD: Yes, I think so.

Jeffrey S. Weber, MD: But, we need to know.

Transcript Edited for Clarity
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Transcript:

Keith T. Flaherty, MD:
Let’s shift away just for a moment. One of the new kids on the block is T-VEC, and right now approved in the United States as monotherapy. Jonathan, you mentioned before that patients with in-transit disease, for example, might be candidates. Where do you think of the, let’s say, multiple potentially scenarios—where before systemic therapy becomes the focus—that the T-VEC would play a role?

Jonathan S. Zager, MD: Well, I particularly use it in the IIIb, IIIc population, especially patients with lower burden of disease that’s not rapidly progressing. I think the phase III trial was positive with durable response rates, 16.3% versus 2.1% in favor of the T-VEC group. Again, like I mentioned before, it’s extremely well tolerated. It’s fast. I can give it to patients usually in 5 minutes. The patients tolerate it very well. The side effects are not unlike some of the side effects that you guys have already described, but they could have a mild to moderate flu-like illness the night of injection, maybe the following day, that usually responds to Tylenol, and then they’re better. And then, as you go along in treatment with each subsequent treatment, I think those side effects get less and less to the point where some of my patients aren’t having any side effects at all. For moderate to less disease burden that’s not rapidly progressing, stage IIIb, IIIc, especially in patients who have contraindications or don’t want systemic therapies, I think it’s a great option for them.

Keith T. Flaherty, MD: Jeff, in patients who are on immune therapy, well, it could have been PD-1/CTLA4 combination followed by nivolumab maintenance or just PD-1 monotherapy. If they have injectable disease that, let’s say, persists or appears, like oligoprogressive disease, but not a lot of it, does T-VEC have a role there?

Jeffrey S. Weber, MD: If someone has isolated progression during and after immunotherapy, I’ll always try to have it surgically resected. If it is not easily resectable—and, as Jon appropriately points out, resectability is always in the eye of the beholder—yes, direct injection therapy, I think, would be reasonable. That’s a very small niche population. I think T-VEC alone, again, is somewhat of a niche drug, and, by the way, a couple others are coming along in earlier trials. I see the value of those drugs as a way to prime an immune response in a patient who then would subsequently receive either PD-1 blockade or combination blockade. There’s an ongoing phase III trial, as I remember, with pembrolizumab/T-VEC versus pembrolizumab alone. So, I see that as the value. And if that’s a positive study, I think you’re going to see a lot more traction, a lot more use of T-VEC. I would venture a guess it has a modest utilization now in the United States. Since we have very good drugs, it’s just, like I said, a niche agent.

Keith T. Flaherty, MD: Jeff was mentioning surgery for oligoprogressive disease. What do you think about the role of surgery for patients who had a partial response, still had some disease that remains—and here, I’m mostly thinking of visceral metastasis? What time point? As a surgeon, you’re being asked to consider this patient 6 months in, 12 months in. How do you react to that?

Jonathan S. Zager, MD: Again, if the bulk of the disease has gone away, it doesn’t matter with combination targeted therapy, single agent, immunotherapy, and there are isolated lesions. Jeff and I have collaborated on this many times, I’ll go ahead and resect it and make the patient NED (no evidence of disease). And I think that’s the best thing for the patient. Sometimes you have these resistant lesions or some mutations that happen and they’re no longer responding to the systemic therapy. That’s a perfect candidate to have clean-up surgery and make them no evidence of disease.

Georgina Long, BSc, MBBS: So, the key there you just mentioned was resistant lesions. Just a question, because our surgeons discuss this, if we’ve got a great response, but there’s one lesion that’s growing or showing resistance, our surgeons are very keen to help us out and cut them out.

Jonathan S. Zager, MD: Same here, yes.

Georgina Long, BSc, MBBS: If they’ve had a great response and it’s just a residual lesion that’s not changing, they won’t necessarily go in and cut that out. However, if the patients came to understand what the disease is and we’re collecting biopsies for research to understand what the nidus of tumor is, then we’ll go ahead. What’s your approach on that?

Jonathan S. Zager, MD: If you have 10 lesions and there’s one lesion left over, changing or not, I think we should resect it as long as it can be done with low morbidity. Of course, I wouldn’t do a right hepatectomy, exactly, for one stable lesion, because that’s an operation that can have some morbidity. But, if it can be done with relatively low morbidity and the patient understands the risks and benefits, then I think it’s absolutely appropriate to resect a stable lesion that’s just hanging on.

Georgina Long, BSc, MBBS: Just one more question on that. Spleen? How far do you go?

Jonathan S. Zager, MD: I take out a spleen.

Georgina Long, BSc, MBBS: Okay. Adrenal gland?

Jonathan S. Zager, MD: Yes, adrenal and spleen.

Jeffrey S. Weber, MD: I agree with Jon. I don’t understand the rationale. Unless it was absolutely cold on a PET scan or you were somehow convinced it was in a necrotic dead mass of tissue with no tumor—let’s see if I can make a biblical paraphrase—if it offends thee, pluck it out. I would take it out.

Georgina Long, BSc, MBBS: That’s another key. We do that. If it’s PET hot, we’ll take it out. But, if you’ve had a patient who’s had a great response, you can see these little lesions in the liver and elsewhere, and they’re all PET cold, we just watch.

Jonathan S. Zager, MD: Little lesions we’ll watch, too. So, little lesions in more than one, two organs, at least we’re not going to go in and do the spleen and adrenal. But, a 2-cm metastasis that the liver is now clear of disease, and there’s an adrenal gland that still has this stable disease, that’s a low morbidity operation laparoscopically. And I think we would we go after it.

Jeffrey S. Weber, MD: But, again, there’s mineable data here. One of the interesting things about having a large number of patients that have been on randomized, well done phase III trials with nivolumab alone, pembrolizumab alone, the combination of both, dabrafenib/trametinib, or cobimetinib/vemurafenib is to mine these trials to get this information. What happens to the 80 patients who had a single site of disease left that was resected? If they all relapse very quickly, then maybe we shouldn’t be doing surgery. But, I would venture a bet they would do extremely well.

Jonathan S. Zager, MD: Yes, I think so.

Jeffrey S. Weber, MD: But, we need to know.

Transcript Edited for Clarity
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