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OS vs PFS with Olaratumab

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 03, 2017



Transcript:

Mark Agulnik, MD:
As a physician who treats predominantly soft tissue sarcomas, when I look at the clinical trials, there are a number of data points that will be available to you. And these will include response rate, they’ll include progression-survival, and they’ll include overall survival. Generally, when I look at response rates, I’m not overwhelmingly that interested in them. It’s always great to have tumors shrink, but when we look at other drugs that have been approved on the market that have had an impact on patients, that have had an improvement in survival for patients or progression-free survival, we see that they’ve come to market without a very large response rate for the patients. And, therefore, I really like stabilizing disease as an endpoint. That, I think, is very meaningful. When I look at progression-free survival and overall survival, I’m interested in both of these. But, as a patient though, I would really want overall survival as my endpoint. I do feel that when we have incurable diseases, we have to look at, are we keeping people alive longer? If we’re able to delay progression, but not improve survival, are we really achieving anything? While if we’re able to improve survival without delaying progression, we do improve something. And so, while it was very unique to see the data for olaratumab with a profound overall survival with a modest increase in progression-free survival, you have to look at the data and say, “Overall survival was the winner, and that’s really the endpoint that I’m looking for.”

There will always be some debate and there will always be a discussion about why does a drug achieve an overall survival advantage without achieving a progression-free survival advantage. In the situation of olaratumab and doxorubicin versus doxorubicin alone, one has to question, does the addition of olaratumab do something to change the tumor and therefore make it less aggressive? Because, it didn’t really need that much more of the drug combination to achieve that profound a benefit because progression-free survival was quite similar between the 2 groups. As a physician looking at the data, as a physician who needs to treats these soft tissue sarcoma patients on a daily basis, I really do feel overall survival is the most important endpoint here. Would I use a drug that has a progression-free survival advantage without an overall survival advantage? Yes. Would I use a drug that has an overall survival advantage without a progression-free survival advantage? Yes. Would I use a drug that had neither? Absolutely not. And so, here we have a situation of, did it pan out exactly as we thought it would? No. But, could we make an explanation for it? Yes. And, therefore, it becomes important to use these drugs in order to give the best benefits to our patients.

Victor Villalobos, MD, PhD: An interesting portion of this trial was the divergence of overall survival compared to progression-free survival. The progression-free survival only had about a 2-1/2-month benefit, whereas the overall survival had almost 1 year of benefit. It’s really unclear about why that’s happening. It certainly may be a fact that inhibition of PDGRα, platelet-derived growth factor alpha, actually affects the stroma, not just in the tumors but also elsewhere. And so, it may inhibit the ability for cells to actually metastasize. This is all speculation and really we don’t know why this happens, but it’s really dramatic. I think the long-term implications are maybe about the timing and the use of olaratumab. And it may be, in fact, that earlier dosing and treating early on in the diagnosis of the cancer is going to be important.

An important question that we also need to answer at some point with the clinical trial is going to be whether continuation of olaratumab is going to be beneficial versus just stopping after progression of disease. It may very well be that it is more effective on smaller tumors that may not be visible, and so we’ll have to learn that as it goes along. But, first things first, I think we need to get a final approval of the drug that’s not conditional based on this phase II. So, it’s going to be open for a lot more clinical trials and questions to answer that.

Transcript Edited for Clarity
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Transcript:

Mark Agulnik, MD:
As a physician who treats predominantly soft tissue sarcomas, when I look at the clinical trials, there are a number of data points that will be available to you. And these will include response rate, they’ll include progression-survival, and they’ll include overall survival. Generally, when I look at response rates, I’m not overwhelmingly that interested in them. It’s always great to have tumors shrink, but when we look at other drugs that have been approved on the market that have had an impact on patients, that have had an improvement in survival for patients or progression-free survival, we see that they’ve come to market without a very large response rate for the patients. And, therefore, I really like stabilizing disease as an endpoint. That, I think, is very meaningful. When I look at progression-free survival and overall survival, I’m interested in both of these. But, as a patient though, I would really want overall survival as my endpoint. I do feel that when we have incurable diseases, we have to look at, are we keeping people alive longer? If we’re able to delay progression, but not improve survival, are we really achieving anything? While if we’re able to improve survival without delaying progression, we do improve something. And so, while it was very unique to see the data for olaratumab with a profound overall survival with a modest increase in progression-free survival, you have to look at the data and say, “Overall survival was the winner, and that’s really the endpoint that I’m looking for.”

There will always be some debate and there will always be a discussion about why does a drug achieve an overall survival advantage without achieving a progression-free survival advantage. In the situation of olaratumab and doxorubicin versus doxorubicin alone, one has to question, does the addition of olaratumab do something to change the tumor and therefore make it less aggressive? Because, it didn’t really need that much more of the drug combination to achieve that profound a benefit because progression-free survival was quite similar between the 2 groups. As a physician looking at the data, as a physician who needs to treats these soft tissue sarcoma patients on a daily basis, I really do feel overall survival is the most important endpoint here. Would I use a drug that has a progression-free survival advantage without an overall survival advantage? Yes. Would I use a drug that has an overall survival advantage without a progression-free survival advantage? Yes. Would I use a drug that had neither? Absolutely not. And so, here we have a situation of, did it pan out exactly as we thought it would? No. But, could we make an explanation for it? Yes. And, therefore, it becomes important to use these drugs in order to give the best benefits to our patients.

Victor Villalobos, MD, PhD: An interesting portion of this trial was the divergence of overall survival compared to progression-free survival. The progression-free survival only had about a 2-1/2-month benefit, whereas the overall survival had almost 1 year of benefit. It’s really unclear about why that’s happening. It certainly may be a fact that inhibition of PDGRα, platelet-derived growth factor alpha, actually affects the stroma, not just in the tumors but also elsewhere. And so, it may inhibit the ability for cells to actually metastasize. This is all speculation and really we don’t know why this happens, but it’s really dramatic. I think the long-term implications are maybe about the timing and the use of olaratumab. And it may be, in fact, that earlier dosing and treating early on in the diagnosis of the cancer is going to be important.

An important question that we also need to answer at some point with the clinical trial is going to be whether continuation of olaratumab is going to be beneficial versus just stopping after progression of disease. It may very well be that it is more effective on smaller tumors that may not be visible, and so we’ll have to learn that as it goes along. But, first things first, I think we need to get a final approval of the drug that’s not conditional based on this phase II. So, it’s going to be open for a lot more clinical trials and questions to answer that.

Transcript Edited for Clarity
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