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Final Thoughts on 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, Jan 19, 2017



Transcript:

Brian Van Tine, MD, PhD:
I think that this is the first drug that has entered our space that actually complicates the use of doxorubicin. There are now going to be 3 branches you could go down. The first is to use doxorubicin alone, the next is to potentially use doxorubicin with ifosfamide, and the last would be to use doxorubicin with olaratumab. I think that more than likely, the use of single-agent doxorubicin will probably fall by the wayside and we’re going to be left with the choice of whether to use doxorubicin and ifosfamide or doxorubicin and olaratumab. And I think if you take most patients with some exceptions, I think the real answer, based on the data that we now have, will be to use doxorubicin with olaratumab.

Victor Villalobos, MD, PhD: With regard to the treatment paradigm and how the interaction of olaratumab affects how we treat soft tissue sarcoma, this is extremely exciting. I think this is really a first step into looking at targeted agents for soft tissue; sarcoma is a larger subset. We’ve already made some big strides in GI stromal tumors with the introduction of targeted dugs there. Really looking at and not just treating the tumor, but also treating the tumor microenvironment and treating other stroma and their effects on the tumor growth, are going to be expanding quite rapidly. So, I think this is the tip of the iceberg in how we approach sarcoma. And as we get more knowledgeable about how to treat these and approach with combinations, it’s going to be a very, very exciting time.

Brian Van Tine, MD, PhD: The future of sarcoma care is still going to involve molecularly taking apart the sarcomas, fitting more drugs into it. And it’s only going to make it more and more complicated. And I think as that happens, this partnership between community physicians and the academic sarcoma doctors will only need to strengthen. Because, unfortunately, there aren’t that many of us that spend our lives only treating sarcoma. This partnership needs to strengthen because the number of patients that will be now increasing in prevalence, because we’ll be keeping them alive longer, will need this partnership so that there are people that can adequately take care of them.

Richard F. Riedel, MD: There is tremendous excitement about the landscape for the treatment of soft tissue sarcoma. In the last 4 years, we’ve had 4 new FDA-approved drugs. In 2012, pazopanib, an oral tyrosine kinase inhibitor, was approved for an unselected patient population of soft tissue sarcoma, with the exception of liposarcomas and GISTs (gastrointestinal stromal tumors). In 2015 and 2016, both eribulin and trabectedin were approved. Eribulin showed an improvement in overall survival compared to dacarbazine, specifically in liposarcomas. Trabectedin showed improvement in progression-free survival for both liposarcomas and leiomyosarcomas. And then, most recently, we had the approval of olaratumab, again, in a broad unselected patient population in combination with an anthracycline backbone; in this case, doxorubicin. So, I think the landscape has changed dramatically in the last 4 years. Prior to the approval of pazopanib in 2012, we had not had an agent approved for the treatment of soft tissue sarcoma in approximately 30 or 40 years.

There continues to be a significant unmet need in the field as a whole. Despite recent approval of new drugs, which do bring therapeutic benefit to our patients, the reality is that sarcomas still represent a very rare and heterogeneous group of diseases. Depending on who you talk to, people will quote somewhere between 50 to more than 100 different types of sarcoma. And what’s clear is that our clinical trials traditionally have focused on being all inclusive, meaning a lumping strategy, including all histologic subtypes in the clinical trials. I think we’re now seeing the fact that we may, in fact, do better by splitting our histologies into individual subtypes and having subtype specific clinical trials. The examples include eribulin specifically in liposarcoma or trabectedin in liposarcomas and leiomyosarcomas. I think there’s a critical need to understand the underlying biology of these different histologic subtypes. And even within a specific histology, I think it’s clear that there can be different molecular signals that are driving pathogenesis of disease. So, I think there’s certainly encouragement in the sarcoma community with respect to recent approvals, but it’s clear that the magnitude of benefit still remains relatively small. We are recognizing that we have a lot to learn in terms of understanding that the underlying biology is key.

Victor Villalobos, MD, PhD: The advice I’d give a community physician that’s working with me in sarcoma is that we’re really here as a resource for them. These are incredibly rare tumors and highly variable. There are over 80 different subtypes. And if you think about it, a general community physician may see 2 to 4 per year, so they don’t have time to invest to actually understand what’s the newest and up-to-date treatments for these things and have a nuance on how to approach them appropriately. I’m here as a resource for them, and I want to make sure that they can reach out to me for that. I work very closely with our colleagues in Denver and we have a close relationship with patients, and oftentimes they will go back and be treated with their community physicians after seeing me. But if we have interesting clinical trials, we would love to have them available to the patients until they know we’re here.

My overall thoughts on the future of sarcoma care are that sarcoma is as diverse as carcinoma. So, trying to study them all together in 1 study is oftentimes difficult. You can imagine trying to assess a particular drug, looking at lung cancer versus prostate cancer versus breast cancer. It’s really difficult to do, and to compound that difficulty is the fact that these are quite rare. Now, the sarcoma community has been coming together and has developed a lot of these new trials looking at and focusing on smaller subgroups of patients and disease types that really are extremely important. And I can’t emphasize enough the importance of cooperative groups to study these tumor types.

SARC has been essential in developing a lot of these trials, and now the introduction of sarcoma into the different cooperative groups and the NCCN is also really important. There has also been a lot of cooperation with the European groups, as well, to develop new treatments. As we go further into this, we’re starting to define different subtypes of sarcoma that may respond differently to targeted therapies and really choosing which tumors to treat with appropriate biomarkers. And so, there’s much work to do, but I think we’re moving forward very quickly, and I don’t anticipate waiting another 40 years for another drug approval like we did for olaratumab in sarcoma.

Transcript Edited for Clarity
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Transcript:

Brian Van Tine, MD, PhD:
I think that this is the first drug that has entered our space that actually complicates the use of doxorubicin. There are now going to be 3 branches you could go down. The first is to use doxorubicin alone, the next is to potentially use doxorubicin with ifosfamide, and the last would be to use doxorubicin with olaratumab. I think that more than likely, the use of single-agent doxorubicin will probably fall by the wayside and we’re going to be left with the choice of whether to use doxorubicin and ifosfamide or doxorubicin and olaratumab. And I think if you take most patients with some exceptions, I think the real answer, based on the data that we now have, will be to use doxorubicin with olaratumab.

Victor Villalobos, MD, PhD: With regard to the treatment paradigm and how the interaction of olaratumab affects how we treat soft tissue sarcoma, this is extremely exciting. I think this is really a first step into looking at targeted agents for soft tissue; sarcoma is a larger subset. We’ve already made some big strides in GI stromal tumors with the introduction of targeted dugs there. Really looking at and not just treating the tumor, but also treating the tumor microenvironment and treating other stroma and their effects on the tumor growth, are going to be expanding quite rapidly. So, I think this is the tip of the iceberg in how we approach sarcoma. And as we get more knowledgeable about how to treat these and approach with combinations, it’s going to be a very, very exciting time.

Brian Van Tine, MD, PhD: The future of sarcoma care is still going to involve molecularly taking apart the sarcomas, fitting more drugs into it. And it’s only going to make it more and more complicated. And I think as that happens, this partnership between community physicians and the academic sarcoma doctors will only need to strengthen. Because, unfortunately, there aren’t that many of us that spend our lives only treating sarcoma. This partnership needs to strengthen because the number of patients that will be now increasing in prevalence, because we’ll be keeping them alive longer, will need this partnership so that there are people that can adequately take care of them.

Richard F. Riedel, MD: There is tremendous excitement about the landscape for the treatment of soft tissue sarcoma. In the last 4 years, we’ve had 4 new FDA-approved drugs. In 2012, pazopanib, an oral tyrosine kinase inhibitor, was approved for an unselected patient population of soft tissue sarcoma, with the exception of liposarcomas and GISTs (gastrointestinal stromal tumors). In 2015 and 2016, both eribulin and trabectedin were approved. Eribulin showed an improvement in overall survival compared to dacarbazine, specifically in liposarcomas. Trabectedin showed improvement in progression-free survival for both liposarcomas and leiomyosarcomas. And then, most recently, we had the approval of olaratumab, again, in a broad unselected patient population in combination with an anthracycline backbone; in this case, doxorubicin. So, I think the landscape has changed dramatically in the last 4 years. Prior to the approval of pazopanib in 2012, we had not had an agent approved for the treatment of soft tissue sarcoma in approximately 30 or 40 years.

There continues to be a significant unmet need in the field as a whole. Despite recent approval of new drugs, which do bring therapeutic benefit to our patients, the reality is that sarcomas still represent a very rare and heterogeneous group of diseases. Depending on who you talk to, people will quote somewhere between 50 to more than 100 different types of sarcoma. And what’s clear is that our clinical trials traditionally have focused on being all inclusive, meaning a lumping strategy, including all histologic subtypes in the clinical trials. I think we’re now seeing the fact that we may, in fact, do better by splitting our histologies into individual subtypes and having subtype specific clinical trials. The examples include eribulin specifically in liposarcoma or trabectedin in liposarcomas and leiomyosarcomas. I think there’s a critical need to understand the underlying biology of these different histologic subtypes. And even within a specific histology, I think it’s clear that there can be different molecular signals that are driving pathogenesis of disease. So, I think there’s certainly encouragement in the sarcoma community with respect to recent approvals, but it’s clear that the magnitude of benefit still remains relatively small. We are recognizing that we have a lot to learn in terms of understanding that the underlying biology is key.

Victor Villalobos, MD, PhD: The advice I’d give a community physician that’s working with me in sarcoma is that we’re really here as a resource for them. These are incredibly rare tumors and highly variable. There are over 80 different subtypes. And if you think about it, a general community physician may see 2 to 4 per year, so they don’t have time to invest to actually understand what’s the newest and up-to-date treatments for these things and have a nuance on how to approach them appropriately. I’m here as a resource for them, and I want to make sure that they can reach out to me for that. I work very closely with our colleagues in Denver and we have a close relationship with patients, and oftentimes they will go back and be treated with their community physicians after seeing me. But if we have interesting clinical trials, we would love to have them available to the patients until they know we’re here.

My overall thoughts on the future of sarcoma care are that sarcoma is as diverse as carcinoma. So, trying to study them all together in 1 study is oftentimes difficult. You can imagine trying to assess a particular drug, looking at lung cancer versus prostate cancer versus breast cancer. It’s really difficult to do, and to compound that difficulty is the fact that these are quite rare. Now, the sarcoma community has been coming together and has developed a lot of these new trials looking at and focusing on smaller subgroups of patients and disease types that really are extremely important. And I can’t emphasize enough the importance of cooperative groups to study these tumor types.

SARC has been essential in developing a lot of these trials, and now the introduction of sarcoma into the different cooperative groups and the NCCN is also really important. There has also been a lot of cooperation with the European groups, as well, to develop new treatments. As we go further into this, we’re starting to define different subtypes of sarcoma that may respond differently to targeted therapies and really choosing which tumors to treat with appropriate biomarkers. And so, there’s much work to do, but I think we’re moving forward very quickly, and I don’t anticipate waiting another 40 years for another drug approval like we did for olaratumab in sarcoma.

Transcript Edited for Clarity
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