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Sequencing with Olaratumab in STS

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: Thursday, Jan 12, 2017


Transcript:

Victor Villalobos, MD, PhD:
Based on the phase II data, the likelihood of using more cycles of doxorubicin is higher. What we saw is that patients on the combination arm received more cycles of doxorubicin and more cycles of olaratumab compared to those that received doxorubicin alone and even those that crossed over to olaratumab. So, I think it makes everyone nervous to treat patients beyond that 450-mg/m2 dosing window for doxorubicin because of the risk of cardiac implications.

I think as long as you consider giving them prophylactic medication, such as dexrazoxane up front and early on, you can mitigate that risk. There was a slightly increased risk of cardiac symptoms with the combination over doxorubicin alone, but it was not dramatic. So, I think just use your judgment about how the patient is doing and being, assuring close monitoring of the cardiac function to assess dosing.

Brian Van Tine, MD, PhD: I think there are a lot of nuances to the treatment of sarcoma, and so there are a number of drugs for a number of indications where you might use something before your anthracycline. And a lot of the times it’s say gemcitabine with docetaxel in leiomyosarcoma, depending on the preference of the sarcoma treating institution. If you look at the phase I/II trial data, line of therapy did not come up as important for response. And so, when to use this should be when you’re using your anthracycline.

Richard F. Riedel, MD: For patients who have already received 1 or more lines of therapy and who have not yet received an anthracycline, I think consideration for the combination still is appropriate, particularly given the survival benefits seen in the phase II study.

Victor Villalobos, MD, PhD: The sequencing of this regimen in patients that had prior lines of therapy, I think I would give it as early as possible. In the subgroup analysis of this trial, there was not a whole lot of difference between patients that are treated in the first line versus those treated in later lines. That being said, if someone had progressed on single-agent doxorubicin before and they still had room to go with regard to the total doxorubicin dosing, I would consider re-dosing them with doxorubicin and olaratumab to try and achieve some benefit. If they had not received doxorubicin before, I would certainly offer them this combination if they were able to tolerate it.

Richard F. Riedel, MD: My decision on continuing or discontinuing a therapy depends, in part, on a number of factors, namely the radiographic assessments that are performed routinely while on therapy. If a patient has clear evidence of progressive disease—significant growth in existing lesions or a new lesion showing up on imaging—for me, that’s the indicator to consider a change in therapy. For a patient who may have slight progression in disease—slight worsening of disease radiographically—but is having clinical improvement in symptoms, that may be a situation that I continue with a particular therapy, in part because the total number of therapies that we have for soft tissue sarcoma remain somewhat limited. And so, I think giving up on a therapy too soon has potential problems. With respect to the combination of doxorubicin and olaratumab, the study was designed for the combination of the 2 drugs to continue for appropriately 8 cycles. And then the study allowed for the continuation of olaratumab as a maintenance therapy until progression.

Transcript Edited for Clarity
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Transcript:

Victor Villalobos, MD, PhD:
Based on the phase II data, the likelihood of using more cycles of doxorubicin is higher. What we saw is that patients on the combination arm received more cycles of doxorubicin and more cycles of olaratumab compared to those that received doxorubicin alone and even those that crossed over to olaratumab. So, I think it makes everyone nervous to treat patients beyond that 450-mg/m2 dosing window for doxorubicin because of the risk of cardiac implications.

I think as long as you consider giving them prophylactic medication, such as dexrazoxane up front and early on, you can mitigate that risk. There was a slightly increased risk of cardiac symptoms with the combination over doxorubicin alone, but it was not dramatic. So, I think just use your judgment about how the patient is doing and being, assuring close monitoring of the cardiac function to assess dosing.

Brian Van Tine, MD, PhD: I think there are a lot of nuances to the treatment of sarcoma, and so there are a number of drugs for a number of indications where you might use something before your anthracycline. And a lot of the times it’s say gemcitabine with docetaxel in leiomyosarcoma, depending on the preference of the sarcoma treating institution. If you look at the phase I/II trial data, line of therapy did not come up as important for response. And so, when to use this should be when you’re using your anthracycline.

Richard F. Riedel, MD: For patients who have already received 1 or more lines of therapy and who have not yet received an anthracycline, I think consideration for the combination still is appropriate, particularly given the survival benefits seen in the phase II study.

Victor Villalobos, MD, PhD: The sequencing of this regimen in patients that had prior lines of therapy, I think I would give it as early as possible. In the subgroup analysis of this trial, there was not a whole lot of difference between patients that are treated in the first line versus those treated in later lines. That being said, if someone had progressed on single-agent doxorubicin before and they still had room to go with regard to the total doxorubicin dosing, I would consider re-dosing them with doxorubicin and olaratumab to try and achieve some benefit. If they had not received doxorubicin before, I would certainly offer them this combination if they were able to tolerate it.

Richard F. Riedel, MD: My decision on continuing or discontinuing a therapy depends, in part, on a number of factors, namely the radiographic assessments that are performed routinely while on therapy. If a patient has clear evidence of progressive disease—significant growth in existing lesions or a new lesion showing up on imaging—for me, that’s the indicator to consider a change in therapy. For a patient who may have slight progression in disease—slight worsening of disease radiographically—but is having clinical improvement in symptoms, that may be a situation that I continue with a particular therapy, in part because the total number of therapies that we have for soft tissue sarcoma remain somewhat limited. And so, I think giving up on a therapy too soon has potential problems. With respect to the combination of doxorubicin and olaratumab, the study was designed for the combination of the 2 drugs to continue for appropriately 8 cycles. And then the study allowed for the continuation of olaratumab as a maintenance therapy until progression.

Transcript Edited for Clarity
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