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Practical Implications of Using Olaratumab in Patients with 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 Online: Thursday, Dec 29, 2016



Transcript:

Mark Agulnik, MD:
The addition of olaratumab to our availability with respect to treatment for patients is very interesting because over the last 5 to 10 years, we’ve done a number of large clinical trials trying to improve upon survival for patients with soft tissue sarcoma. Unfortunately, we have not been successful, until the addition of olaratumab to doxorubicin becomes available. From a patient standpoint, you certainly want to improve your survival, but you don’t want to do it at a cost. The cost that you don’t want it is at the cost of quality of life. And so, from a patient standpoint, we did see that there is an increased risk of neutropenia, there is an increased risk of mucositis, and there is an increased risk of nausea and vomiting. However, the increased risk is a subtle risk for most, or at least that’s my perception of it. And the increased risk is not really of grade 3 or 4 increased risk, which, to me, is what causes decreased quality of life for patients. And so, from a patient perspective, most have tolerated it quite well. Most have been able to maintain themselves on it, and really the addition has not really caused many dramatic negative impacts for these patients.

Victor Villalobos, MD, PhD: My experience with olaratumab in combination with doxorubicin, we’ve actually treated over 20 patients on different protocols with this combination. There is some increased rate of mucositis and of cytopenias with the combination, but overall, it’s relatively well tolerated. It’s similar, I would say, to single-agent doxorubicin in general. More importantly, patients that finish their doxorubicin dosing and continue on olaratumab have excellent quality of life. They really have almost no side effects from the single-agent olaratumab therapy in continuation.

We had a different trial called JGDI, which is a drug-drug interaction trial looking at doxorubicin/olaratumab and any cardiac affects. We had over 15 or 16 patients on that trial. A large proportion of them actually finished their doxorubicin therapy and have been on olaratumab single-agent for over 1 year without progression, and many of these patients had progressed previously on other chemotherapies. I think there’s definitely some activity here, even in the single agent after they have finished their doxorubicin dosing. So, I think it’s very exciting. And comparing to other combination arms such AIM, the Doxycin profile is dramatically better. That makes a big difference for patients that have incurable metastatic disease.

Mark Agulnik, MD: Whenever we look at clinical trials in oncology, one really has to look at what endpoints are the most important endpoints. I do feel strongly that when we look at soft tissue sarcomas, an overall survival endpoint is a very meaningful endpoint and probably the most meaningful endpoint, especially for metastatic disease or unresectable. One also has to look at how many patients have been treated, what was the quality of the data, where was the trial done, who was doing the trial. And I do feel very confident that based on the phase II and Ib data for olaratumab with doxorubicin, it is a superior treatment compared to single-agent doxorubicin. And, at least in my practice, it is to adopt this as the standard of care. Will this always become the standard of care? It’s hard to say. It really depends on what the phase III data show, but if the phase III data mimics the phase II data, then I would feel very unfortunate that I didn’t adopt it sooner. And, if the phase III data doesn’t mimic the phase II data and perhaps it’s not an overwhelming survival advantage, then I would feel I’ve done my best. I looked at the data that I had available and it didn’t cause much more toxicities, and so I don’t feel that patients were at a disadvantage.

Brian Van Tine, MD, PhD: Having worked with olaratumab since about 2010, when the original trial took off, I feel like I’ve had a lot of in-depth experience with this compound. And what I really like about olaratumab is its side-effect profile. What we found was there was a slight increase in neutropenia that may have been associated with the fact that people stayed on Adriamycin longer on the combination arm. There is the real side effect, in the Midwest, of anaphylactic reactions like we have to any other monoclonal antibody. But, outside of that, if you can get to maintenance with this drug—and we had some people that were on maintenance for years—this is well tolerated. And you come, you get it, and you go about your normal life. It’s the highest quality of life I think we really do have with just the maintenance with a monoclonal antibody. And so, having used this and having seen patients respond late on maintenance to therapy, having seen patients respond in combination, I’m really excited about this.

Victor Villalobos, MD, PhD: Regarding my confidence in the results of phase II, I’m very confident. The differences were so dramatic, it was not something that I think was an error in any way. So, I definitely feel, and my experience with, the combination has been really similarly dramatic as well. Yes, I definitely do feel confident in that. I’m extremely hopeful that the phase III will confirm that, and I’m waiting to hear those results enthusiastically, so we’ll see how it goes.

Transcript Edited for Clarity
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Transcript:

Mark Agulnik, MD:
The addition of olaratumab to our availability with respect to treatment for patients is very interesting because over the last 5 to 10 years, we’ve done a number of large clinical trials trying to improve upon survival for patients with soft tissue sarcoma. Unfortunately, we have not been successful, until the addition of olaratumab to doxorubicin becomes available. From a patient standpoint, you certainly want to improve your survival, but you don’t want to do it at a cost. The cost that you don’t want it is at the cost of quality of life. And so, from a patient standpoint, we did see that there is an increased risk of neutropenia, there is an increased risk of mucositis, and there is an increased risk of nausea and vomiting. However, the increased risk is a subtle risk for most, or at least that’s my perception of it. And the increased risk is not really of grade 3 or 4 increased risk, which, to me, is what causes decreased quality of life for patients. And so, from a patient perspective, most have tolerated it quite well. Most have been able to maintain themselves on it, and really the addition has not really caused many dramatic negative impacts for these patients.

Victor Villalobos, MD, PhD: My experience with olaratumab in combination with doxorubicin, we’ve actually treated over 20 patients on different protocols with this combination. There is some increased rate of mucositis and of cytopenias with the combination, but overall, it’s relatively well tolerated. It’s similar, I would say, to single-agent doxorubicin in general. More importantly, patients that finish their doxorubicin dosing and continue on olaratumab have excellent quality of life. They really have almost no side effects from the single-agent olaratumab therapy in continuation.

We had a different trial called JGDI, which is a drug-drug interaction trial looking at doxorubicin/olaratumab and any cardiac affects. We had over 15 or 16 patients on that trial. A large proportion of them actually finished their doxorubicin therapy and have been on olaratumab single-agent for over 1 year without progression, and many of these patients had progressed previously on other chemotherapies. I think there’s definitely some activity here, even in the single agent after they have finished their doxorubicin dosing. So, I think it’s very exciting. And comparing to other combination arms such AIM, the Doxycin profile is dramatically better. That makes a big difference for patients that have incurable metastatic disease.

Mark Agulnik, MD: Whenever we look at clinical trials in oncology, one really has to look at what endpoints are the most important endpoints. I do feel strongly that when we look at soft tissue sarcomas, an overall survival endpoint is a very meaningful endpoint and probably the most meaningful endpoint, especially for metastatic disease or unresectable. One also has to look at how many patients have been treated, what was the quality of the data, where was the trial done, who was doing the trial. And I do feel very confident that based on the phase II and Ib data for olaratumab with doxorubicin, it is a superior treatment compared to single-agent doxorubicin. And, at least in my practice, it is to adopt this as the standard of care. Will this always become the standard of care? It’s hard to say. It really depends on what the phase III data show, but if the phase III data mimics the phase II data, then I would feel very unfortunate that I didn’t adopt it sooner. And, if the phase III data doesn’t mimic the phase II data and perhaps it’s not an overwhelming survival advantage, then I would feel I’ve done my best. I looked at the data that I had available and it didn’t cause much more toxicities, and so I don’t feel that patients were at a disadvantage.

Brian Van Tine, MD, PhD: Having worked with olaratumab since about 2010, when the original trial took off, I feel like I’ve had a lot of in-depth experience with this compound. And what I really like about olaratumab is its side-effect profile. What we found was there was a slight increase in neutropenia that may have been associated with the fact that people stayed on Adriamycin longer on the combination arm. There is the real side effect, in the Midwest, of anaphylactic reactions like we have to any other monoclonal antibody. But, outside of that, if you can get to maintenance with this drug—and we had some people that were on maintenance for years—this is well tolerated. And you come, you get it, and you go about your normal life. It’s the highest quality of life I think we really do have with just the maintenance with a monoclonal antibody. And so, having used this and having seen patients respond late on maintenance to therapy, having seen patients respond in combination, I’m really excited about this.

Victor Villalobos, MD, PhD: Regarding my confidence in the results of phase II, I’m very confident. The differences were so dramatic, it was not something that I think was an error in any way. So, I definitely feel, and my experience with, the combination has been really similarly dramatic as well. Yes, I definitely do feel confident in that. I’m extremely hopeful that the phase III will confirm that, and I’m waiting to hear those results enthusiastically, so we’ll see how it goes.

Transcript Edited for Clarity
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