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Achieving Durable Responses in Advanced Melanoma

Panelists: Robert H.I. Andtbacka, MD, CM, Huntsman Cancer Institute; Michael A. Davies, MD, PhD, MD Anderson Cancer Center; Antoni Ribas, MD, PhD, University of California Los Angeles; Georgina Long, MD, Melanoma Institute of Australia; Michael Postow, MD, Memorial Sloan Kettering Cancer Center
Published Online: Thursday, Jan 05, 2017



Transcript:

Robert H.I. Andtbacka, MD, CM:
What about if this mutation was V600K? Does that make a difference, then, in terms of the response?

Georgina Long, MD: It doesn’t make a difference in terms of the decision making we just discussed. And that is, for the individual patient in front of you, what’s their volume of disease, what is their baseline LDH? We know that BRAF and MEK inhibitors work with V600K. What we know, though, is that they tend to work for less time. But, you can’t predict that, and that’s not for every patient. It just seems to be a trend. As Tony was saying, when you look in large numbers of patients, the V600K-mutant patients seem to have a shorter progression-free survival on those drugs than V600E-mutant patients. But, in general, there is a curve of some people who do very well long term within each group, V600E or V600K. I just wanted to highlight the point Tony made, and that is: these durable responders with immunotherapy and the durable responders with targeted therapy, BRAF and MEK inhibitors, may be the same population. We don’t really know, and I think the randomized trial we just mentioned, of up-front immunotherapy versus targeted therapy, is critical for the field.

But if you look at normal LDH coupled with fewer sites of disease, these sort of patients have a 3-year overall survival on dabrafenib, well above 50% to 60% at 3 years. So, I think we need to be careful in this data-free zone. The one thing, though, that does drive my decision making is the emerging data of the landmark progression-free survival, particularly as it gets out to 2 or 3 years. I have to remind everybody that the only phase III randomized 3-year overall survival and progression-free survival we have comes from dabrafenib and trametinib. We don’t have the 3-year in any other combination or immunotherapy yet. That will come. But once we start getting out to 3, 4, or 5 years and see the pure activity of the drugs, looking at these landmark progression-free survivals, then we’ll be able to have better conversations about giving up front your very best treatment that’s going to give you the most durable response.

Antoni Ribas, MD, PhD: I’m picking on what Georgina is saying. These patients with normal LDH and only 3 sites of metastases or less, there’s a tail of the curve in the data that’s presented from both the COMBI and the coBRIM trials. You can see that patients at 2 to 3 years seemed to have plateaued on the relapse rate, which is what we would expect for immunotherapy, not for targeted therapy. So, maybe we’ll have to re-draw our expected survival curves. At least, I would have to.

Robert H.I. Andtbacka, MD, CM: But I think that this is something, at least out in the community, that seems to be a dogma that has become the rule, in a sense. If you go on a BRAF/MEK combination, you will not have any long-term survivors. But your data, Georgina, clearly show that there are long-term survivors for these patients. That is something that is not known out in the community. I think it is really important, as you said, to emphasize that there are some of these patients.

Transcript Edited for Clarity

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Transcript:

Robert H.I. Andtbacka, MD, CM:
What about if this mutation was V600K? Does that make a difference, then, in terms of the response?

Georgina Long, MD: It doesn’t make a difference in terms of the decision making we just discussed. And that is, for the individual patient in front of you, what’s their volume of disease, what is their baseline LDH? We know that BRAF and MEK inhibitors work with V600K. What we know, though, is that they tend to work for less time. But, you can’t predict that, and that’s not for every patient. It just seems to be a trend. As Tony was saying, when you look in large numbers of patients, the V600K-mutant patients seem to have a shorter progression-free survival on those drugs than V600E-mutant patients. But, in general, there is a curve of some people who do very well long term within each group, V600E or V600K. I just wanted to highlight the point Tony made, and that is: these durable responders with immunotherapy and the durable responders with targeted therapy, BRAF and MEK inhibitors, may be the same population. We don’t really know, and I think the randomized trial we just mentioned, of up-front immunotherapy versus targeted therapy, is critical for the field.

But if you look at normal LDH coupled with fewer sites of disease, these sort of patients have a 3-year overall survival on dabrafenib, well above 50% to 60% at 3 years. So, I think we need to be careful in this data-free zone. The one thing, though, that does drive my decision making is the emerging data of the landmark progression-free survival, particularly as it gets out to 2 or 3 years. I have to remind everybody that the only phase III randomized 3-year overall survival and progression-free survival we have comes from dabrafenib and trametinib. We don’t have the 3-year in any other combination or immunotherapy yet. That will come. But once we start getting out to 3, 4, or 5 years and see the pure activity of the drugs, looking at these landmark progression-free survivals, then we’ll be able to have better conversations about giving up front your very best treatment that’s going to give you the most durable response.

Antoni Ribas, MD, PhD: I’m picking on what Georgina is saying. These patients with normal LDH and only 3 sites of metastases or less, there’s a tail of the curve in the data that’s presented from both the COMBI and the coBRIM trials. You can see that patients at 2 to 3 years seemed to have plateaued on the relapse rate, which is what we would expect for immunotherapy, not for targeted therapy. So, maybe we’ll have to re-draw our expected survival curves. At least, I would have to.

Robert H.I. Andtbacka, MD, CM: But I think that this is something, at least out in the community, that seems to be a dogma that has become the rule, in a sense. If you go on a BRAF/MEK combination, you will not have any long-term survivors. But your data, Georgina, clearly show that there are long-term survivors for these patients. That is something that is not known out in the community. I think it is really important, as you said, to emphasize that there are some of these patients.

Transcript Edited for Clarity
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Online CME Activities
TitleExpiration DateCME Credits
Clinical Vignette Series: 34th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow®Feb 28, 20182.0
Community Practice Connections™: 13th Annual International Symposium on Melanoma and Other Cutaneous Malignancies®Apr 28, 20182.0
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