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Appropriate Patients for Olaratumab + Doxorubicin

Insights From: Mark Agulnik, MD, Northwestern University Feinberg School of Medicine; Brian Van Tine, MD, PhD, Washington University; Richard F. Riedel, MD, Duke University Health System; Victor Villalobos, MD, PhD, University of Colorado Denver
Published Online: Tuesday, Jan 10, 2017



Transcript:

Mark Agulnik, MD:
When we look at who would be the best patients moving forward, now that there’s an FDA-approved indication for olaratumab in combination with doxorubicin (Adriamycin), who should be receiving them? The first thing is, it becomes a no-brainer when we have a new patient who has never been treated, who presents with metastatic disease, who’s never been exposed to doxorubicin in the past, who has a functioning heart, good performance status, exactly like all our other patients that walk in the door. And, therefore, for that patient, I would use this as a first-line therapy. If a patient comes in as a known patient to you or referred in to you because they’ve had prior treatment and the treatment has failed them, what is a second-line therapy? I would use this combination of doxorubicin and olaratumab as a second-line therapy if they did not receive doxorubicin as a first-line therapy. I, specifically, would be cautious to use this regimen in someone who has had 6 or more cycles of doxorubicin because I think the exposure and the cardiotoxicity becomes difficult. I think, for a patient perhaps who had 2 cycles of doxorubicin, had slight progression on that, and was moved to a different regimen, I perhaps would circle back to this because I do think the addition of the olaratumab did provide an advantage that went beyond progression-free survival. It was an advantage in overall survival.

The harder thing for this is when we look at the phase II data and we break it out based on its histological subtype. You really don’t seem to pick one subset that is at a disadvantage with the combination. And, therefore, the question becomes: do all histological subtypes get a benefit from this or should we still keep Adriamycin/ifosfamide for some? At the present time, I probably would offer all of the histologies of the combination therapy as opposed to single-agent Adriamycin. Perhaps for a young patient with synovial sarcoma, I’d still stick with Adriamycin/ifosfamide, but that is something that I have to consider and present the data to the patient.

When I look at comorbidities, performance status issues, if the ejection fraction was moderate, if I was concerned about cardiotoxicities, I perhaps would use this agent [Adriamycin/ifosfamide] up to 6 times instead of 8 times with the doxorubicin. I would do slight modifications. I do think this is a regimen that would be fine for someone with a performance status of 0 or 1. Once you start reaching a performance status of 2 and 3, you start to have to question what will ultimately happen to this patient. And is the patient served by an aggressive regimen or a regimen that could have toxicities and worsen their quality of life? Because, at the end of the day, while we want to make people live longer, we want to preserve their function and their quality when they do that.

It’s been fascinating for the last decade and more to be able to treat patients with soft tissue sarcomas, and it’s been wonderful to be part of the community that has looked at the addition of targeted agents and other chemotherapies for these patients. Certainly, if we look at how we treat people today versus how we did 1 year ago or 5 years ago, we’ve had 4 new drugs get approved by the FDA. We have a lot more options for the patient. And I certainly think we could continue to push the envelope. I’m very hopeful with the addition of vaccine therapies and immunotherapies that perhaps we could add new drugs to what we already have. We could try to create drugs that have a better toxicity profile, try to create drugs that will actually continue to push upon our ability to prolong survival.

Brian Van Tine, MD, PhD: In my opinion, I think identifying the appropriate patient to use olaratumab is, 1, important, but 2, is probably secondary to who is appropriate for doxorubicin. So, if we look at the label and the label is going to read as follows, “For use with anthracycline,” I think the first question we have to ask is, who’s appropriate for an anthracycline? You have to look at performance status, you have to look at heart function. With an average sarcoma patient with a decent performance status and no cardiac contraindications, what we find is that they’re appropriate for doxorubicin. If you’re appropriate for doxorubicin, then I think, especially if you have widespread metastatic disease, that’s easy; you should use that in combination with olaratumab.

I think where this gets more complicated, and you’ll find that some of the sarcoma experts will begin to disagree, is low-burden disease, single-isolated metastases. And I think then, it’s going to come down to what you need to accomplish. If you look at the response rate to Adriamycin and ifosfamide, if you actually made a tumor smaller, you will probably actually reach for that. But this is probably not the average patient. It’s probably more of an exception than a standard patient, which is why that partnership between the community and the academic practices is actually so important. But if you then look past that, the average patient who’s a candidate for an anthracycline that should be used, you give 8 cycles. In the trial, we were allowed to drop the Adriamycin, depending on which version of the trials that were allowed earlier, and continue on just olaratumab if tolerance didn’t allow. There was a phase I that allowed that to happen.

As we kind of further develop this drug, there are some other clinical trials that I think, when they report, will be very, very important. I’ll shoot this both ways for you. There’s a clinical trial that’s ongoing or there is a clinical trial that has now accrued that is looking at the combination of olaratumab with gemcitabine and docetaxel. That will begin to add some more fundamental knowledge to where we should be using this and whether or not it should just be continued regardless of line of chemotherapy. In addition, we’re also doing a new trial in an up-front resectable setting looking at Adriamycin/olaratumab and seeing if we might see an overall survival. And so, I think there’s a lot of effort being put into these by developers.

I think there’s a lot of effort being put together, in combination with the investigators and developers, of this new compound to really figure out not only where it belongs, but to make sure there are appropriate clinical trial data to justify its use. If they’re not a candidate for doxorubicin, using this as a monotherapy wasn’t shown to be that effective. So, I think just reaching for this alone isn’t appropriate at this time until we have stronger data. Whereas I think that’s why, if you really begin to ask who the patient that should get this is, they’re mainly anthracycline questions. Should they get doxorubicin? Because the addition of this drug to doxorubicin has a minimal increase, in my opinion, in toxicity.

Richard F. Riedel, MD: I think the use of olaratumab in combination with doxorubicin is appropriate for any patient for whom you were considering an anthracycline chemotherapy backbone for. In my clinical practice, that is probably the vast majority of patients with soft tissue sarcoma. They are very rare histologic subtypes for whom chemotherapy, in general, is not felt to be appropriate. And I think for those rare subtypes, the use of the combination would not be appropriate because that would not be a subtype for whom I would consider an anthracycline. But for the vast majority of patients, regardless of histologic subtype, I think the use of the combination is appropriate. The use of the combination could be considered certainly in the frontline setting, but I think it also can be considered in subsequent lines, assuming that the patient hasn’t already received an anthracycline. With respect to the patients who are best considered for the combination and following the inclusion criteria for the phase II studies, patients, in general, had to have a good performance status, an ECOG performance status of 0 or 1. So, these are generally highly functional patients who were able to withstand the potential side effects of a combination-based chemotherapy.

My decision on a particular therapy for a patient depends on a number of factors. Most importantly, it depends on their performance status or the functional assessment of the patient. Generally speaking, for me to consider chemotherapy for a patient, the patient needs to be highly functional. They need to be able to perform their activities of daily living; they need to be able to tolerate the potential side effects of the chemotherapy. And so, depending on the functional status of the patient, I will often tailor my choice of chemotherapy based on that initial assessment.

The goals of therapy depend on the disease status. For a patient with metastatic disease, the goals of therapy are to try to palliate symptoms associated with the disease or to try to control the disease. What I will often tell my patients is that it’s highly unlikely that our therapy will cure them in that situation. Certainly, there are other situations where chemotherapy can be considered for patients with localized disease, and in those settings, the intent is to try to cure patients. So, the intent of the therapy depends, in part, on the status of the disease at the time of presentation.

Victor Villalobos, MD, PhD: In the frontline setting, I think all patients are eligible and should be considered for this therapy. The biggest caveat may be whether you need a really good response. And so, the combination of Adriamycin/ifosfamide does have a better response rate than this, but not that dramatically much better. The overall survival benefit of this combination versus Adriamycin/ifosfamide is quite dramatic. It’s almost 12 months as well, comparing it between trials. And so, I think all patients should be considered for this, particularly because of the decreased toxicity and increased efficacy. Patients that have not received doxorubicin in later lines of therapy should consider getting doxorubicin plus olaratumab. Even in the case of patients who have received or progressed on doxorubicin alone, I would still consider retreating with doxorubicin plus olaratumab because of the dramatic effects that we’ve seen in this trial.

Based on prior chemotherapies, even if a patient had received doxorubicin previously and progressed, if they still had room to go, as far as their total doxorubicin dosing, I would still consider retreating with doxorubicin plus olaratumab. The subgroup analysis of this study showed that there is really no difference in the histologic subtypes that benefited from the combination. And the trend was for the combination of doxorubicin alone for all subtypes, if they could manage. Now, the biggest limitation of that is the trial was small. There was only about 66 patients per arm in this study, and so we could not get good numbers from all the different subtypes. But as we get larger trials going and we get more data from the phase III, we should learn more about that.

For the tumor location or the size of the tumor—and primarily, I think, based on the symptoms of the tumor—if I needed to get a rapid response, I might consider doing Adriamycin/ifosfamide up front to try and get a better response. That being said, there are ongoing studies looking at the combination of Adriamycin/ifosfamide and olaratumab to see about toxicity and efficacy. So, that question may be answered in the next year or 2. But at this point, in somebody who’s having a very symptomatic tumor, I would consider starting off with Adriamycin/ifosfamide first and then consider changing over to single-agent if they do well with that.

Based on performance status or comorbidities, I think the primary drug that’s going to cause major issues with that is going to be doxorubicin. If a patient cannot tolerate doxorubicin by itself, I think the combination would be slightly more toxic. Unfortunately, the data looking at olaratumab alone does not flush out; they don’t have nearly as good responses as combined with chemotherapy. And you can actually see that with this trial, in fact, that there was a crossover component to this. So, patients that received doxorubicin alone that opted to go on to olaratumab continuation therapy did not receive nearly as much benefit as those that had been on the olaratumab from the beginning with the chemotherapy. And so, I wouldn’t necessarily advocate for giving olaratumab alone.

Transcript Edited for Clarity
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Transcript:

Mark Agulnik, MD:
When we look at who would be the best patients moving forward, now that there’s an FDA-approved indication for olaratumab in combination with doxorubicin (Adriamycin), who should be receiving them? The first thing is, it becomes a no-brainer when we have a new patient who has never been treated, who presents with metastatic disease, who’s never been exposed to doxorubicin in the past, who has a functioning heart, good performance status, exactly like all our other patients that walk in the door. And, therefore, for that patient, I would use this as a first-line therapy. If a patient comes in as a known patient to you or referred in to you because they’ve had prior treatment and the treatment has failed them, what is a second-line therapy? I would use this combination of doxorubicin and olaratumab as a second-line therapy if they did not receive doxorubicin as a first-line therapy. I, specifically, would be cautious to use this regimen in someone who has had 6 or more cycles of doxorubicin because I think the exposure and the cardiotoxicity becomes difficult. I think, for a patient perhaps who had 2 cycles of doxorubicin, had slight progression on that, and was moved to a different regimen, I perhaps would circle back to this because I do think the addition of the olaratumab did provide an advantage that went beyond progression-free survival. It was an advantage in overall survival.

The harder thing for this is when we look at the phase II data and we break it out based on its histological subtype. You really don’t seem to pick one subset that is at a disadvantage with the combination. And, therefore, the question becomes: do all histological subtypes get a benefit from this or should we still keep Adriamycin/ifosfamide for some? At the present time, I probably would offer all of the histologies of the combination therapy as opposed to single-agent Adriamycin. Perhaps for a young patient with synovial sarcoma, I’d still stick with Adriamycin/ifosfamide, but that is something that I have to consider and present the data to the patient.

When I look at comorbidities, performance status issues, if the ejection fraction was moderate, if I was concerned about cardiotoxicities, I perhaps would use this agent [Adriamycin/ifosfamide] up to 6 times instead of 8 times with the doxorubicin. I would do slight modifications. I do think this is a regimen that would be fine for someone with a performance status of 0 or 1. Once you start reaching a performance status of 2 and 3, you start to have to question what will ultimately happen to this patient. And is the patient served by an aggressive regimen or a regimen that could have toxicities and worsen their quality of life? Because, at the end of the day, while we want to make people live longer, we want to preserve their function and their quality when they do that.

It’s been fascinating for the last decade and more to be able to treat patients with soft tissue sarcomas, and it’s been wonderful to be part of the community that has looked at the addition of targeted agents and other chemotherapies for these patients. Certainly, if we look at how we treat people today versus how we did 1 year ago or 5 years ago, we’ve had 4 new drugs get approved by the FDA. We have a lot more options for the patient. And I certainly think we could continue to push the envelope. I’m very hopeful with the addition of vaccine therapies and immunotherapies that perhaps we could add new drugs to what we already have. We could try to create drugs that have a better toxicity profile, try to create drugs that will actually continue to push upon our ability to prolong survival.

Brian Van Tine, MD, PhD: In my opinion, I think identifying the appropriate patient to use olaratumab is, 1, important, but 2, is probably secondary to who is appropriate for doxorubicin. So, if we look at the label and the label is going to read as follows, “For use with anthracycline,” I think the first question we have to ask is, who’s appropriate for an anthracycline? You have to look at performance status, you have to look at heart function. With an average sarcoma patient with a decent performance status and no cardiac contraindications, what we find is that they’re appropriate for doxorubicin. If you’re appropriate for doxorubicin, then I think, especially if you have widespread metastatic disease, that’s easy; you should use that in combination with olaratumab.

I think where this gets more complicated, and you’ll find that some of the sarcoma experts will begin to disagree, is low-burden disease, single-isolated metastases. And I think then, it’s going to come down to what you need to accomplish. If you look at the response rate to Adriamycin and ifosfamide, if you actually made a tumor smaller, you will probably actually reach for that. But this is probably not the average patient. It’s probably more of an exception than a standard patient, which is why that partnership between the community and the academic practices is actually so important. But if you then look past that, the average patient who’s a candidate for an anthracycline that should be used, you give 8 cycles. In the trial, we were allowed to drop the Adriamycin, depending on which version of the trials that were allowed earlier, and continue on just olaratumab if tolerance didn’t allow. There was a phase I that allowed that to happen.

As we kind of further develop this drug, there are some other clinical trials that I think, when they report, will be very, very important. I’ll shoot this both ways for you. There’s a clinical trial that’s ongoing or there is a clinical trial that has now accrued that is looking at the combination of olaratumab with gemcitabine and docetaxel. That will begin to add some more fundamental knowledge to where we should be using this and whether or not it should just be continued regardless of line of chemotherapy. In addition, we’re also doing a new trial in an up-front resectable setting looking at Adriamycin/olaratumab and seeing if we might see an overall survival. And so, I think there’s a lot of effort being put into these by developers.

I think there’s a lot of effort being put together, in combination with the investigators and developers, of this new compound to really figure out not only where it belongs, but to make sure there are appropriate clinical trial data to justify its use. If they’re not a candidate for doxorubicin, using this as a monotherapy wasn’t shown to be that effective. So, I think just reaching for this alone isn’t appropriate at this time until we have stronger data. Whereas I think that’s why, if you really begin to ask who the patient that should get this is, they’re mainly anthracycline questions. Should they get doxorubicin? Because the addition of this drug to doxorubicin has a minimal increase, in my opinion, in toxicity.

Richard F. Riedel, MD: I think the use of olaratumab in combination with doxorubicin is appropriate for any patient for whom you were considering an anthracycline chemotherapy backbone for. In my clinical practice, that is probably the vast majority of patients with soft tissue sarcoma. They are very rare histologic subtypes for whom chemotherapy, in general, is not felt to be appropriate. And I think for those rare subtypes, the use of the combination would not be appropriate because that would not be a subtype for whom I would consider an anthracycline. But for the vast majority of patients, regardless of histologic subtype, I think the use of the combination is appropriate. The use of the combination could be considered certainly in the frontline setting, but I think it also can be considered in subsequent lines, assuming that the patient hasn’t already received an anthracycline. With respect to the patients who are best considered for the combination and following the inclusion criteria for the phase II studies, patients, in general, had to have a good performance status, an ECOG performance status of 0 or 1. So, these are generally highly functional patients who were able to withstand the potential side effects of a combination-based chemotherapy.

My decision on a particular therapy for a patient depends on a number of factors. Most importantly, it depends on their performance status or the functional assessment of the patient. Generally speaking, for me to consider chemotherapy for a patient, the patient needs to be highly functional. They need to be able to perform their activities of daily living; they need to be able to tolerate the potential side effects of the chemotherapy. And so, depending on the functional status of the patient, I will often tailor my choice of chemotherapy based on that initial assessment.

The goals of therapy depend on the disease status. For a patient with metastatic disease, the goals of therapy are to try to palliate symptoms associated with the disease or to try to control the disease. What I will often tell my patients is that it’s highly unlikely that our therapy will cure them in that situation. Certainly, there are other situations where chemotherapy can be considered for patients with localized disease, and in those settings, the intent is to try to cure patients. So, the intent of the therapy depends, in part, on the status of the disease at the time of presentation.

Victor Villalobos, MD, PhD: In the frontline setting, I think all patients are eligible and should be considered for this therapy. The biggest caveat may be whether you need a really good response. And so, the combination of Adriamycin/ifosfamide does have a better response rate than this, but not that dramatically much better. The overall survival benefit of this combination versus Adriamycin/ifosfamide is quite dramatic. It’s almost 12 months as well, comparing it between trials. And so, I think all patients should be considered for this, particularly because of the decreased toxicity and increased efficacy. Patients that have not received doxorubicin in later lines of therapy should consider getting doxorubicin plus olaratumab. Even in the case of patients who have received or progressed on doxorubicin alone, I would still consider retreating with doxorubicin plus olaratumab because of the dramatic effects that we’ve seen in this trial.

Based on prior chemotherapies, even if a patient had received doxorubicin previously and progressed, if they still had room to go, as far as their total doxorubicin dosing, I would still consider retreating with doxorubicin plus olaratumab. The subgroup analysis of this study showed that there is really no difference in the histologic subtypes that benefited from the combination. And the trend was for the combination of doxorubicin alone for all subtypes, if they could manage. Now, the biggest limitation of that is the trial was small. There was only about 66 patients per arm in this study, and so we could not get good numbers from all the different subtypes. But as we get larger trials going and we get more data from the phase III, we should learn more about that.

For the tumor location or the size of the tumor—and primarily, I think, based on the symptoms of the tumor—if I needed to get a rapid response, I might consider doing Adriamycin/ifosfamide up front to try and get a better response. That being said, there are ongoing studies looking at the combination of Adriamycin/ifosfamide and olaratumab to see about toxicity and efficacy. So, that question may be answered in the next year or 2. But at this point, in somebody who’s having a very symptomatic tumor, I would consider starting off with Adriamycin/ifosfamide first and then consider changing over to single-agent if they do well with that.

Based on performance status or comorbidities, I think the primary drug that’s going to cause major issues with that is going to be doxorubicin. If a patient cannot tolerate doxorubicin by itself, I think the combination would be slightly more toxic. Unfortunately, the data looking at olaratumab alone does not flush out; they don’t have nearly as good responses as combined with chemotherapy. And you can actually see that with this trial, in fact, that there was a crossover component to this. So, patients that received doxorubicin alone that opted to go on to olaratumab continuation therapy did not receive nearly as much benefit as those that had been on the olaratumab from the beginning with the chemotherapy. And so, I wouldn’t necessarily advocate for giving olaratumab alone.

Transcript Edited for Clarity
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