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Emerging Triplet Regimens in Advanced Melanoma

Panelists: Axel Hauschild, MD, University Hospital Schleswig-Holstein; Michael A. Davies, MD, PhD UT MD Anderson Cancer Center; Jason J. Luke, MD, FACP, University of Chicago; Caroline Robert, MD, PhD Gustave-Roussy; Merrick I. Ross, MD UT MD Anderson Cancer Center
Published: Friday, Dec 21, 2018



Transcript: 

Axel Hauschild, MD:
In 2019, we are expecting to see the results of 2 large, randomized clinical trials on triplet regimens, namely the BRAF and MEK inhibitors, plus a PD-1 [programmed cell death protein 1] antibody and a PD-L1 [programmed death-ligand 1] antibody, respectively. Specifically, we are looking forward to results of the TRILOGY trial and the COMBI-i trial. The TRILOGY trial looks at atezolizumab as a PD-L1 antibody plus vemurafenib and cobimetinib. The other one is spartalizumab, which was originally named PDR001, plus dabrafenib and trametinib. We don’t know the clinical trial results from the phase III trials, but we have smaller-sized phase I and II trials. At ESMO [European Society for Medical Oncology], there was a presentation that provided us a hint on thinking about the outcome of the triplet regimens compared with dual inhibition. Is anybody willing to talk about this, or should I summarize the data briefly? I’ll go ahead.

In the KEYNOTE-022 trial, the design was very simple. It was a randomized phase II trial with 60 patients in each group. One group received pembrolizumab plus dabrafenib and trametinib, and the other group received a matching placebo to pembrolizumab plus dabrafenib and trametinib. I need to mention that dabrafenib and trametinib were given at regular doses as approved for stage IV patients.

The progression-free survival is 16 months for the triplet combination. For the dual inhibition regimen, it’s 10.4 months. The results are not statistically significantly different because the hazard ratio is 0.66, and the trial statistical design was saying it’s statistically significant if it is at least 0.62 or better. But there is a clear trend to a longer progression-free survival. There are no striking differences in overall survival so far, and the response rate is 71% for the dual inhibition regimen. For the triplet regimen, it was 63%. So it is a bit lower. But the duration of response is better for the triplet regimen compared with the dual inhibition regimen. So if you have these results, Jason, what’s your first gut feeling?

Jason J. Luke, MD, FACP: This makes me think that we’ve got to find the right people for this kind of approach. I think that this is early data, and we certainly want the phase III data first. But there are multiple issues that come into play here, in terms of deciding whether we really want to use all of our treatments immediately in our patients. Or are there certain patients who would benefit more from up-front use of this really aggressive approach? From a clinical perspective, the idea that I would want to use all of my treatments at once would have to kind of have a transformational potential benefit. Did we double the overall survival, and so on and so forth? So far, while we have a trend in progression-free survival, that’s not as much as we would have hoped to see by giving all of these drugs at once. This is not the definitive take on this approach, and we’ll await more data. All of these other phase III trials are fully accrued, as far as I know. So we’ll get the data and we’ll see, but one has to wonder whether or not this is going to end up being the way that we go for the broad majority of patients.

Axel Hauschild, MD: We see 20% more grade 3 and 4 toxicity and 20% more treatment discontinuation with the triplet regimen.

Merrick I. Ross, MD: Actually, can I ask you an informative question? In these 3 trials, were all 3 therapies given at the same time?

Axel Hauschild, MD: Not really. There was a run-in phase in 1 of the clinical trials in which, as in the other trial, it was given immediately as the triplet regimen.

Merrick I. Ross, MD: That’s important, actually. I think there may be some competing issues that we don’t understand yet because the mechanisms of actions of the targeted therapies and immune therapies are different. For targeted therapy, if you look really early, there is an immune response. Within a couple of weeks, you could see infiltration of T cells that weren’t present in patients who received targeted therapy.

Axel Hauschild, MD: So it’s a question on concomitant versus sequential schemes when you combine the therapies, right?

Merrick I. Ross, MD: Right. That’s what I’m asking about.

Axel Hauschild, MD: But there is a small difference. The TRILOGY trial used 4 weeks of a run-in phase with a regular dose of vemurafenib and cobimetinib.

Jason J. Luke, MD, FACP: What is even more confusing here is that given this result now, another arm that was not included in any of these trials was the real-world crossover arm. So these phase III trials are comparing triplet versus doublet regimens. In reality, what we’d really want to know for our patients is triplet or doublet. But for the ones for which you also do the crossover, which is what you could use in clinical practice, that’s not really captured.

Caroline Robert, MD, PhD: Can I add something? This crossover you talk about is done, and the patient receives something else. Maybe we are not going to expose the patient to this high toxicity, and we do that unless there is something that would convince me otherwise. It’s still interesting—if the complete responders with dabrafenib and the triplet combination can stop treatment. Until now, that has told us that something is different. Of course, we all look forward to seeing more than this threshold of 20% of complete responders, and nothing else reached this threshold. But also, to be able to stop therapy—we cannot do it with targeted agents. If the addition of an anti–PD-1 or an anti–PD-L1 therapy allows us to stop, that would be an advantage, I think.

Jason J. Luke, MD, FACP: That’s what I understand. That question is not being studied in any of these trials, however. They are all taking the approach that once you start targeted therapy, you don’t stop. And that’s a very good point. This goes back to our discussion on using ipilimumab and nivolumab earlier and treating patients aggressively and then allowing them to be taken off therapy. I wonder if that’s going to be a part of this learning process, however, to try to figure out who those patients are.

Michael A. Davies, MD, PhD: My impression is that in patients with stage IV melanoma who have normal levels of LDH [lactate dehydrogenase], we have really good therapeutic options. If they are BRAF mutant, we have good targeted therapies and good immunotherapies. I think the question is how to manage those high-LDH patients and brain metastases patients with edema. There is still a significant group of patients out there for whom none of our current therapies are very effective. There is also this idea of looking at whether we need to come up with trials specifically for that patient population. Not that they couldn’t help the other group, but again, maybe there is a population willing to tolerate more toxicity. Again, we would all agree that dose intensification of medications may make particular sense in patients who we know don’t do very well with our current therapies at our current doses.

Axel Hauschild, MD: This is a very interesting discussion.


Transcript Edited for Clarity
 

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Transcript: 

Axel Hauschild, MD:
In 2019, we are expecting to see the results of 2 large, randomized clinical trials on triplet regimens, namely the BRAF and MEK inhibitors, plus a PD-1 [programmed cell death protein 1] antibody and a PD-L1 [programmed death-ligand 1] antibody, respectively. Specifically, we are looking forward to results of the TRILOGY trial and the COMBI-i trial. The TRILOGY trial looks at atezolizumab as a PD-L1 antibody plus vemurafenib and cobimetinib. The other one is spartalizumab, which was originally named PDR001, plus dabrafenib and trametinib. We don’t know the clinical trial results from the phase III trials, but we have smaller-sized phase I and II trials. At ESMO [European Society for Medical Oncology], there was a presentation that provided us a hint on thinking about the outcome of the triplet regimens compared with dual inhibition. Is anybody willing to talk about this, or should I summarize the data briefly? I’ll go ahead.

In the KEYNOTE-022 trial, the design was very simple. It was a randomized phase II trial with 60 patients in each group. One group received pembrolizumab plus dabrafenib and trametinib, and the other group received a matching placebo to pembrolizumab plus dabrafenib and trametinib. I need to mention that dabrafenib and trametinib were given at regular doses as approved for stage IV patients.

The progression-free survival is 16 months for the triplet combination. For the dual inhibition regimen, it’s 10.4 months. The results are not statistically significantly different because the hazard ratio is 0.66, and the trial statistical design was saying it’s statistically significant if it is at least 0.62 or better. But there is a clear trend to a longer progression-free survival. There are no striking differences in overall survival so far, and the response rate is 71% for the dual inhibition regimen. For the triplet regimen, it was 63%. So it is a bit lower. But the duration of response is better for the triplet regimen compared with the dual inhibition regimen. So if you have these results, Jason, what’s your first gut feeling?

Jason J. Luke, MD, FACP: This makes me think that we’ve got to find the right people for this kind of approach. I think that this is early data, and we certainly want the phase III data first. But there are multiple issues that come into play here, in terms of deciding whether we really want to use all of our treatments immediately in our patients. Or are there certain patients who would benefit more from up-front use of this really aggressive approach? From a clinical perspective, the idea that I would want to use all of my treatments at once would have to kind of have a transformational potential benefit. Did we double the overall survival, and so on and so forth? So far, while we have a trend in progression-free survival, that’s not as much as we would have hoped to see by giving all of these drugs at once. This is not the definitive take on this approach, and we’ll await more data. All of these other phase III trials are fully accrued, as far as I know. So we’ll get the data and we’ll see, but one has to wonder whether or not this is going to end up being the way that we go for the broad majority of patients.

Axel Hauschild, MD: We see 20% more grade 3 and 4 toxicity and 20% more treatment discontinuation with the triplet regimen.

Merrick I. Ross, MD: Actually, can I ask you an informative question? In these 3 trials, were all 3 therapies given at the same time?

Axel Hauschild, MD: Not really. There was a run-in phase in 1 of the clinical trials in which, as in the other trial, it was given immediately as the triplet regimen.

Merrick I. Ross, MD: That’s important, actually. I think there may be some competing issues that we don’t understand yet because the mechanisms of actions of the targeted therapies and immune therapies are different. For targeted therapy, if you look really early, there is an immune response. Within a couple of weeks, you could see infiltration of T cells that weren’t present in patients who received targeted therapy.

Axel Hauschild, MD: So it’s a question on concomitant versus sequential schemes when you combine the therapies, right?

Merrick I. Ross, MD: Right. That’s what I’m asking about.

Axel Hauschild, MD: But there is a small difference. The TRILOGY trial used 4 weeks of a run-in phase with a regular dose of vemurafenib and cobimetinib.

Jason J. Luke, MD, FACP: What is even more confusing here is that given this result now, another arm that was not included in any of these trials was the real-world crossover arm. So these phase III trials are comparing triplet versus doublet regimens. In reality, what we’d really want to know for our patients is triplet or doublet. But for the ones for which you also do the crossover, which is what you could use in clinical practice, that’s not really captured.

Caroline Robert, MD, PhD: Can I add something? This crossover you talk about is done, and the patient receives something else. Maybe we are not going to expose the patient to this high toxicity, and we do that unless there is something that would convince me otherwise. It’s still interesting—if the complete responders with dabrafenib and the triplet combination can stop treatment. Until now, that has told us that something is different. Of course, we all look forward to seeing more than this threshold of 20% of complete responders, and nothing else reached this threshold. But also, to be able to stop therapy—we cannot do it with targeted agents. If the addition of an anti–PD-1 or an anti–PD-L1 therapy allows us to stop, that would be an advantage, I think.

Jason J. Luke, MD, FACP: That’s what I understand. That question is not being studied in any of these trials, however. They are all taking the approach that once you start targeted therapy, you don’t stop. And that’s a very good point. This goes back to our discussion on using ipilimumab and nivolumab earlier and treating patients aggressively and then allowing them to be taken off therapy. I wonder if that’s going to be a part of this learning process, however, to try to figure out who those patients are.

Michael A. Davies, MD, PhD: My impression is that in patients with stage IV melanoma who have normal levels of LDH [lactate dehydrogenase], we have really good therapeutic options. If they are BRAF mutant, we have good targeted therapies and good immunotherapies. I think the question is how to manage those high-LDH patients and brain metastases patients with edema. There is still a significant group of patients out there for whom none of our current therapies are very effective. There is also this idea of looking at whether we need to come up with trials specifically for that patient population. Not that they couldn’t help the other group, but again, maybe there is a population willing to tolerate more toxicity. Again, we would all agree that dose intensification of medications may make particular sense in patients who we know don’t do very well with our current therapies at our current doses.

Axel Hauschild, MD: This is a very interesting discussion.


Transcript Edited for Clarity
 
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