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Case I: Newly Diagnosed BRAF Wild Type 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: Tuesday, Dec 20, 2016


Transcript:

Robert H.I. Andtbacka, MD, CM:
Mike Postow, this patient is a 75-year-old female. She has a BRAF–wild type tumor. She has a fairly small amount of disease with lung metastases and subcutaneous metastases. What are the treatment options for her if she was seen at your treatment center in New York?

Michael A. Postow, MD: For this patient, she’s 75 years old and she has very, very minimal amount of metastatic disease burden. So, in this patient, knowing that she does not have a BRAF mutation, I would take the BRAF and MEK inhibitors off the table and I would be thinking about initial immune therapy for this patient. And, then, the question would really be, in this patient, should I give a PD-1 drug by itself or should I think about PD-1 in combination with a drug like ipilimumab? For this patient with very low volume metastatic disease involving the subcutaneous tissues and lung, I’d feel very comfortable on starting this patient on a single-agent PD-1 inhibitor, such as nivolumab or pembrolizumab, as a first-line treatment approach. We’ve known that the groups of patients with small lung metastases can do very, very well with single-agent anti-PD-1 therapy. And, although we don’t have a perfect predictive set of clinical variables, or any kind of correlative variables that tell us who exactly can benefit from anti-PD-1 monotherapy versus who may need the combination, I think this would be a patient I’d feel very comfortable treating with single-agent PD-1 blockade.

Robert H.I. Andtbacka, MD, CM: For any of these patients, how long do you treat them for with the anti-PD-1 therapy?

Michael A. Postow, MD: That’s a very good question because we know that, thankfully, anti-PD-1 therapy, as a monotherapy, is a very well-tolerated approach, and so we have patients who are responding to anti-PD-1 treatment, some of whom have complete responses. And they’ve been on treatment for quite a long time, and it’s hard to really know how long to continue therapy in these patients. So, in our practice, I think, what we can now use are some data that Caroline Robert presented at ASCO this past year. Patients were treated with pembrolizumab in the KEYNOTE-01 study that attained a complete response of treatment, on average for about 2 years of therapy. For those patients who discontinued anti-PD-1 therapy, 97% of them remain in a complete response. That is some reassurance that patients with complete response may be okay to discontinue the anti-PD-1. However, follow-up is still short, and so I’m still not quite sure. It’s an ongoing conversation with each patient on a risk-benefit analysis, weighing the toxicity the patient may be having, and weighing the particular response characteristics. We don’t really quite know how long to be on anti-PD-1 therapy. I think that’s one of the most important issues in our field.

Robert H.I. Andtbacka, MD, CM: Georgina, I know in Australia, you have looked at the concept of response and have been trying to assess this radiographically and trying to determine when the patient has had a complete response pathologically. Although, radiographically, we may still see the patient has some tumors there. Can you comment a little bit on that, how we determine, then, when the patient, maybe, pathologically, has had a complete response, but still has some lesions?

Georgina Long, MD: Robert, that’s really an area for research. There’s nothing that we can do routinely in the clinic that will actually tell us with confidence, without surgically removing the remaining areas you can see on CT scan, that, pathologically, there are no melanomas. But, there’s really nothing you can do in the clinic to be 100% sure there’s no melanoma, although there are clues. For example, a PET scan and 100% complete metabolic activity may give you some confidence. But, ultimately, it’s about discussing, just as Mike did, the data we have on patients with RECIST complete responses. That’s where we have the most confidence at this point in time, but we’re lacking long-term follow-up data. The only other thing I would say on this issue is we still don’t have data on patients in whom we’ve stopped therapy, who have had a great response, whether it be a complete response or a really deep partial response—the patients you’re referring to. We still don’t have data if you stop and they do recur. If they do recur, can they be rechallenged with anti-PD-1 therapy and will they respond? We have anecdotal cases, but we actually don’t have prospective data answering that question. So, that’s another question in the field that we have yet to address.

Robert H.I. Andtbacka, MD, CM: Yes. And, then, Tony, in the approved therapies that we have at the moment, pembrolizumab and nivolumab, the scheduling for those are slightly different. One is given every 3 weeks. The other one is given every 2 weeks. Is there a difference in the responses that we see with those given every 3 weeks or every 2 weeks for these patients?

Antoni Ribas, MD, PhD: Actually, there is not, Robert. The phase I trial of pembrolizumab included dosing at every 3 weeks or every 2 weeks, and there were several randomized cohorts within the large phase I trial of 655 patients. The overall result was that there didn’t seem to be much difference within either of those cohorts, but some of them had 200 patients per arm. Also, the dose of both nivolumab and pembrolizumab does not seem to have much of an effect. In fact, people who have taken out lymphocytes from patients and looked for saturation of the receptor, it’s very high at the wide range of doses. So, it seems like in the majority of the dosing regimens that we’re using, we’re probably saturating the target all the time, and that means that more may not be better.

Robert H.I. Andtbacka, MD, CM: Mike, living in Texas, you have long distances to drive. Many of these patients drive for many, many hours to come to your center for treatment. Are there practical aspects when you try to decide which agent to put the patient on?

Michael A. Davies, MD, PhD: Absolutely. Again, I think the consensus is, it would absolutely be reasonable to treat this patient with anti-PD-1 monotherapy. I think it would be reasonable to treat this patient with combination immunotherapy, as well. We know that the ipilimumab/nivolumab combination had a higher response rate than single-agent anti-PD-1. And we have data, we don’t know if it’s a statistically significant difference, but it numerically improved relapse-free survival. Again, the data we’re really waiting on is overall survival. What we do know is that the combination of ipilimumab and nivolumab has a much higher toxicity rate. And so, as you said, one of the keys in a 75-year-old patient that you would want to know is if this patient were to get ill, how hard would it be for this patient to be brought for medical care? And, so, getting to how far they are from your office or a local oncologist’s office, their support system really does weigh in the decision of trying to balance the relative risk and benefits of the more aggressive combination immunotherapy versus the single-agent PD-1 therapy.

Robert H.I. Andtbacka, MD, CM: And, in this scenario, let’s say the patient, if she was 50-years-old, and instead of having just a fairly low amount of tumor burden, she actually had quite a bit of tumor burden, both in the lung and in the subcutaneous tissue, but she also has liver metastases. And this seems to be progressing quite rapidly. Would that then sway you to do one therapy, the monotherapy versus the combination therapy, in that setting?

Michael A. Davies, MD, PhD: I have to say, although, again, these are the cases that we all discuss with each other, at this point there’s nothing that says there’s a difference between a 50-year-old and a 70-year-old, in how well they’re going to tolerate combination immunotherapy versus single agent. I do think, for patients who have evidence that their disease has a more aggressive biology, it’s the natural instinct to again use the more aggressive therapy, as well. We do know that even those patients can respond to anti-PD-1 monotherapy and can do well in the long run. But, I do agree for patients who do have signs of more aggressive disease, such as a rapid sort of increase in size or an elevated serum LDH level, that those factors do tend to support the rationale for using the more aggressive immunotherapy regimen.

Transcript Edited for Clarity
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Transcript:

Robert H.I. Andtbacka, MD, CM:
Mike Postow, this patient is a 75-year-old female. She has a BRAF–wild type tumor. She has a fairly small amount of disease with lung metastases and subcutaneous metastases. What are the treatment options for her if she was seen at your treatment center in New York?

Michael A. Postow, MD: For this patient, she’s 75 years old and she has very, very minimal amount of metastatic disease burden. So, in this patient, knowing that she does not have a BRAF mutation, I would take the BRAF and MEK inhibitors off the table and I would be thinking about initial immune therapy for this patient. And, then, the question would really be, in this patient, should I give a PD-1 drug by itself or should I think about PD-1 in combination with a drug like ipilimumab? For this patient with very low volume metastatic disease involving the subcutaneous tissues and lung, I’d feel very comfortable on starting this patient on a single-agent PD-1 inhibitor, such as nivolumab or pembrolizumab, as a first-line treatment approach. We’ve known that the groups of patients with small lung metastases can do very, very well with single-agent anti-PD-1 therapy. And, although we don’t have a perfect predictive set of clinical variables, or any kind of correlative variables that tell us who exactly can benefit from anti-PD-1 monotherapy versus who may need the combination, I think this would be a patient I’d feel very comfortable treating with single-agent PD-1 blockade.

Robert H.I. Andtbacka, MD, CM: For any of these patients, how long do you treat them for with the anti-PD-1 therapy?

Michael A. Postow, MD: That’s a very good question because we know that, thankfully, anti-PD-1 therapy, as a monotherapy, is a very well-tolerated approach, and so we have patients who are responding to anti-PD-1 treatment, some of whom have complete responses. And they’ve been on treatment for quite a long time, and it’s hard to really know how long to continue therapy in these patients. So, in our practice, I think, what we can now use are some data that Caroline Robert presented at ASCO this past year. Patients were treated with pembrolizumab in the KEYNOTE-01 study that attained a complete response of treatment, on average for about 2 years of therapy. For those patients who discontinued anti-PD-1 therapy, 97% of them remain in a complete response. That is some reassurance that patients with complete response may be okay to discontinue the anti-PD-1. However, follow-up is still short, and so I’m still not quite sure. It’s an ongoing conversation with each patient on a risk-benefit analysis, weighing the toxicity the patient may be having, and weighing the particular response characteristics. We don’t really quite know how long to be on anti-PD-1 therapy. I think that’s one of the most important issues in our field.

Robert H.I. Andtbacka, MD, CM: Georgina, I know in Australia, you have looked at the concept of response and have been trying to assess this radiographically and trying to determine when the patient has had a complete response pathologically. Although, radiographically, we may still see the patient has some tumors there. Can you comment a little bit on that, how we determine, then, when the patient, maybe, pathologically, has had a complete response, but still has some lesions?

Georgina Long, MD: Robert, that’s really an area for research. There’s nothing that we can do routinely in the clinic that will actually tell us with confidence, without surgically removing the remaining areas you can see on CT scan, that, pathologically, there are no melanomas. But, there’s really nothing you can do in the clinic to be 100% sure there’s no melanoma, although there are clues. For example, a PET scan and 100% complete metabolic activity may give you some confidence. But, ultimately, it’s about discussing, just as Mike did, the data we have on patients with RECIST complete responses. That’s where we have the most confidence at this point in time, but we’re lacking long-term follow-up data. The only other thing I would say on this issue is we still don’t have data on patients in whom we’ve stopped therapy, who have had a great response, whether it be a complete response or a really deep partial response—the patients you’re referring to. We still don’t have data if you stop and they do recur. If they do recur, can they be rechallenged with anti-PD-1 therapy and will they respond? We have anecdotal cases, but we actually don’t have prospective data answering that question. So, that’s another question in the field that we have yet to address.

Robert H.I. Andtbacka, MD, CM: Yes. And, then, Tony, in the approved therapies that we have at the moment, pembrolizumab and nivolumab, the scheduling for those are slightly different. One is given every 3 weeks. The other one is given every 2 weeks. Is there a difference in the responses that we see with those given every 3 weeks or every 2 weeks for these patients?

Antoni Ribas, MD, PhD: Actually, there is not, Robert. The phase I trial of pembrolizumab included dosing at every 3 weeks or every 2 weeks, and there were several randomized cohorts within the large phase I trial of 655 patients. The overall result was that there didn’t seem to be much difference within either of those cohorts, but some of them had 200 patients per arm. Also, the dose of both nivolumab and pembrolizumab does not seem to have much of an effect. In fact, people who have taken out lymphocytes from patients and looked for saturation of the receptor, it’s very high at the wide range of doses. So, it seems like in the majority of the dosing regimens that we’re using, we’re probably saturating the target all the time, and that means that more may not be better.

Robert H.I. Andtbacka, MD, CM: Mike, living in Texas, you have long distances to drive. Many of these patients drive for many, many hours to come to your center for treatment. Are there practical aspects when you try to decide which agent to put the patient on?

Michael A. Davies, MD, PhD: Absolutely. Again, I think the consensus is, it would absolutely be reasonable to treat this patient with anti-PD-1 monotherapy. I think it would be reasonable to treat this patient with combination immunotherapy, as well. We know that the ipilimumab/nivolumab combination had a higher response rate than single-agent anti-PD-1. And we have data, we don’t know if it’s a statistically significant difference, but it numerically improved relapse-free survival. Again, the data we’re really waiting on is overall survival. What we do know is that the combination of ipilimumab and nivolumab has a much higher toxicity rate. And so, as you said, one of the keys in a 75-year-old patient that you would want to know is if this patient were to get ill, how hard would it be for this patient to be brought for medical care? And, so, getting to how far they are from your office or a local oncologist’s office, their support system really does weigh in the decision of trying to balance the relative risk and benefits of the more aggressive combination immunotherapy versus the single-agent PD-1 therapy.

Robert H.I. Andtbacka, MD, CM: And, in this scenario, let’s say the patient, if she was 50-years-old, and instead of having just a fairly low amount of tumor burden, she actually had quite a bit of tumor burden, both in the lung and in the subcutaneous tissue, but she also has liver metastases. And this seems to be progressing quite rapidly. Would that then sway you to do one therapy, the monotherapy versus the combination therapy, in that setting?

Michael A. Davies, MD, PhD: I have to say, although, again, these are the cases that we all discuss with each other, at this point there’s nothing that says there’s a difference between a 50-year-old and a 70-year-old, in how well they’re going to tolerate combination immunotherapy versus single agent. I do think, for patients who have evidence that their disease has a more aggressive biology, it’s the natural instinct to again use the more aggressive therapy, as well. We do know that even those patients can respond to anti-PD-1 monotherapy and can do well in the long run. But, I do agree for patients who do have signs of more aggressive disease, such as a rapid sort of increase in size or an elevated serum LDH level, that those factors do tend to support the rationale for using the more aggressive immunotherapy regimen.

Transcript Edited for Clarity
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