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Disease Burden and First-Line Melanoma Treatment

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: Friday, Aug 19, 2016



Transcript:

Keith T. Flaherty, MD:
This is a discussion that actually bleeds into more advanced metastatic disease. I’m trying to think of how it is in your practice that you judge disease burden and how that sets you up in thinking about targeted therapy approaches and immunotherapy approaches. Who are the patients who “need a response” is a phrase that breast cancer physicians have used for years when thinking about combination chemotherapy versus single-agent chemotherapy. So, I suppose we have a little bit of that emerging in melanoma, as well.

Georgina Long, BSc, MBBS: I was going to say, it’s fascinating that you said our treatment of choice would be the targeted therapy. It really rams home the concept that in the neoadjuvant setting, you’re basically looking for good response.

Jonathan S. Zager, MD: Good and fast response.

Georgina Long, BSc, MBBS: Fast, good, and deep, and that is the advantage with targeted therapies. However, it’s the longevity that becomes the issue. But it really shows the issues we’re going to be talking about in a minute with immunotherapies, where primary resistance is an issue, versus targeted therapy, where acquired resistance is an issue. In the neoadjuvant setting where you’ve got a patient and you need a quick reduction, you don’t worry so much about the acquired resistance. You just want to get the parameters and get the whole thing out easily.

Keith T. Flaherty, MD: But even if you include three liver metastases and a couple lung nodules where surgery is not the play—but you still have, as you say, psychologically impacting, if not symptomatic superficial or palpable lesions—where does that point you in terms of thinking about optimal targeted therapy strategy, mostly for the BRAF-mutant population versus optimal immunotherapy strategy?

Jason J. Luke, MD: This is definitely an area that’s evolving. I think our prior paradigm previously had been you want to go after high-volume disease with targeted therapy to reduce it, because it might be symptomatic. Immunotherapy was really for low-volume disease. I think our recent data are starting to say that at least there’s equipoise and perhaps it’s the reverse. So, recent data from colleagues here suggest that with targeted therapy, those patients that really do the best appear to be those with lower-volume disease, meaning less than three sites of disease, normal LDH (lactic acid dehydrogenase), and good performance status. Those previously had been the patients we want to put on immunotherapy for clinical trials for melanoma, right?

And it may be that those people drive the proportion of the benefit, a long-term benefit, to targeted therapy. The question for an individual patient is, absent of a trial, what do we do to help them the most? I think that this is an area we’re not totally clear on. But with higher bulky disease, if the patient doesn’t need an immediate response, there are growing data that suggest that combination immunotherapy in the high LDH population has the best potential for dramatic reduction with a long-term benefit.

So, making this treatment choice right now is difficult, and it is open to interpretation with different doctors. It takes into account patient-level factors in terms of patient preference for side-effect profile, etc, as well as how can you construct a treatment paradigm that’s going to be the best for an individual patient over a long period of time because it may include an initial use of a targeted therapy in a transition or an up-front use of immunotherapy. I have a patient with very-high-risk, bone-based brain metastases who got the ipilimumab/nivolumab combination and did very well, had a systemic CR, but not a CR in brain metastases. Because of the toxicity profile, she had to come off of ipilimumab/nivolumab, but then she transitioned quickly to BRAF targeted therapy with dabrafenib/trametinib, and the patient’s doing fantastic. And now this patient is basically CR throughout the body. She’s back to work, looks great, and I think these kinds of approaches are going to be how we have to structure our treatment paradigm looking in the future.

Keith T. Flaherty, MD: And this is the type of thing that’s well beyond what trial evidence we have.

Jason J. Luke, MD: Right.

Keith T. Flaherty, MD: So, this is an important point. Jeff, one of the things I’ve found unsatisfying about the published literature on this point, about kinetics of response, is the PD-1/CTLA4 combination data because the trials generally scan patients at 12 weeks, as was done with PD-1 monotherapy and as was done with CTLA4 monotherapy. In clinical practice, you have patients who have palpable disease. You get a feel for how things are playing out almost week-by-week. Maybe for this audience, what’s your feeling about the relative kinetics of response for ipilimumab/nivolumab versus PD-1 monotherapy?

Jeffrey S. Weber, MD: Well, certainly with PD-1 drugs alone, you can see rapid responses. But I think most of us would agree, as you accrue more and more patients on the combination therapy, the responses happen both quicker and they’re a little deeper. And then the toxicities are also coming on a little more quickly, a little deeper, and there are multiple toxicities which would happen more often with the combinations than with single agent therapy.

So, it’s a tradeoff, but the good news is for the high LDH, the high tumor burden patient: they may do very well with combination ipilimumab and nivolumab. But vis-à-vis what Jason said about mixing and matching, I like the idea in the BRAF-mutated population of a brief burst of dabrafenib/trametinib or vemurafenib/cobimetinib—whatever you choose—stopping before you see adaptive resistance, before you begin to see resistance through the MAP kinase pathway, which Toni Ribas has nicely shown. It may also be one of the mechanisms by which you get immune resistance and then come in with ipilimumab plus nivolumab. I think that’s a very clever approach. I’ve yet to see anyone planning a trial of, say, a brief course of targeted therapy followed by a longer course of immunotherapy versus a continuous targeted therapy plus the one immunotherapy agent or just continuous targeted therapy alone.

Keith T. Flaherty, MD: This bridging concept of targeted to immune therapy for the BRAF-mutant population has been on the table since vemurafenib and ipilimumab were first approved 5 years ago. But yes, the real evidence around these more powerful regimens is really yet to be demonstrated.

Jeffrey S. Weber, MD: It’s dying for a randomized trial to either put it to rest or establish it as a potential new treatment modality.

Transcript Edited for Clarity

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Transcript:

Keith T. Flaherty, MD:
This is a discussion that actually bleeds into more advanced metastatic disease. I’m trying to think of how it is in your practice that you judge disease burden and how that sets you up in thinking about targeted therapy approaches and immunotherapy approaches. Who are the patients who “need a response” is a phrase that breast cancer physicians have used for years when thinking about combination chemotherapy versus single-agent chemotherapy. So, I suppose we have a little bit of that emerging in melanoma, as well.

Georgina Long, BSc, MBBS: I was going to say, it’s fascinating that you said our treatment of choice would be the targeted therapy. It really rams home the concept that in the neoadjuvant setting, you’re basically looking for good response.

Jonathan S. Zager, MD: Good and fast response.

Georgina Long, BSc, MBBS: Fast, good, and deep, and that is the advantage with targeted therapies. However, it’s the longevity that becomes the issue. But it really shows the issues we’re going to be talking about in a minute with immunotherapies, where primary resistance is an issue, versus targeted therapy, where acquired resistance is an issue. In the neoadjuvant setting where you’ve got a patient and you need a quick reduction, you don’t worry so much about the acquired resistance. You just want to get the parameters and get the whole thing out easily.

Keith T. Flaherty, MD: But even if you include three liver metastases and a couple lung nodules where surgery is not the play—but you still have, as you say, psychologically impacting, if not symptomatic superficial or palpable lesions—where does that point you in terms of thinking about optimal targeted therapy strategy, mostly for the BRAF-mutant population versus optimal immunotherapy strategy?

Jason J. Luke, MD: This is definitely an area that’s evolving. I think our prior paradigm previously had been you want to go after high-volume disease with targeted therapy to reduce it, because it might be symptomatic. Immunotherapy was really for low-volume disease. I think our recent data are starting to say that at least there’s equipoise and perhaps it’s the reverse. So, recent data from colleagues here suggest that with targeted therapy, those patients that really do the best appear to be those with lower-volume disease, meaning less than three sites of disease, normal LDH (lactic acid dehydrogenase), and good performance status. Those previously had been the patients we want to put on immunotherapy for clinical trials for melanoma, right?

And it may be that those people drive the proportion of the benefit, a long-term benefit, to targeted therapy. The question for an individual patient is, absent of a trial, what do we do to help them the most? I think that this is an area we’re not totally clear on. But with higher bulky disease, if the patient doesn’t need an immediate response, there are growing data that suggest that combination immunotherapy in the high LDH population has the best potential for dramatic reduction with a long-term benefit.

So, making this treatment choice right now is difficult, and it is open to interpretation with different doctors. It takes into account patient-level factors in terms of patient preference for side-effect profile, etc, as well as how can you construct a treatment paradigm that’s going to be the best for an individual patient over a long period of time because it may include an initial use of a targeted therapy in a transition or an up-front use of immunotherapy. I have a patient with very-high-risk, bone-based brain metastases who got the ipilimumab/nivolumab combination and did very well, had a systemic CR, but not a CR in brain metastases. Because of the toxicity profile, she had to come off of ipilimumab/nivolumab, but then she transitioned quickly to BRAF targeted therapy with dabrafenib/trametinib, and the patient’s doing fantastic. And now this patient is basically CR throughout the body. She’s back to work, looks great, and I think these kinds of approaches are going to be how we have to structure our treatment paradigm looking in the future.

Keith T. Flaherty, MD: And this is the type of thing that’s well beyond what trial evidence we have.

Jason J. Luke, MD: Right.

Keith T. Flaherty, MD: So, this is an important point. Jeff, one of the things I’ve found unsatisfying about the published literature on this point, about kinetics of response, is the PD-1/CTLA4 combination data because the trials generally scan patients at 12 weeks, as was done with PD-1 monotherapy and as was done with CTLA4 monotherapy. In clinical practice, you have patients who have palpable disease. You get a feel for how things are playing out almost week-by-week. Maybe for this audience, what’s your feeling about the relative kinetics of response for ipilimumab/nivolumab versus PD-1 monotherapy?

Jeffrey S. Weber, MD: Well, certainly with PD-1 drugs alone, you can see rapid responses. But I think most of us would agree, as you accrue more and more patients on the combination therapy, the responses happen both quicker and they’re a little deeper. And then the toxicities are also coming on a little more quickly, a little deeper, and there are multiple toxicities which would happen more often with the combinations than with single agent therapy.

So, it’s a tradeoff, but the good news is for the high LDH, the high tumor burden patient: they may do very well with combination ipilimumab and nivolumab. But vis-à-vis what Jason said about mixing and matching, I like the idea in the BRAF-mutated population of a brief burst of dabrafenib/trametinib or vemurafenib/cobimetinib—whatever you choose—stopping before you see adaptive resistance, before you begin to see resistance through the MAP kinase pathway, which Toni Ribas has nicely shown. It may also be one of the mechanisms by which you get immune resistance and then come in with ipilimumab plus nivolumab. I think that’s a very clever approach. I’ve yet to see anyone planning a trial of, say, a brief course of targeted therapy followed by a longer course of immunotherapy versus a continuous targeted therapy plus the one immunotherapy agent or just continuous targeted therapy alone.

Keith T. Flaherty, MD: This bridging concept of targeted to immune therapy for the BRAF-mutant population has been on the table since vemurafenib and ipilimumab were first approved 5 years ago. But yes, the real evidence around these more powerful regimens is really yet to be demonstrated.

Jeffrey S. Weber, MD: It’s dying for a randomized trial to either put it to rest or establish it as a potential new treatment modality.

Transcript Edited for Clarity
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