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Recent Approvals in Soft Tissue Sarcoma

Panelists:William D. Tap, MD, Memorial Sloan Kettering Cancer Center; Mark Agulnik, MD, Feinberg School of Medicine;George D. Demetri, MD, Dana-Farber Cancer Center;Martee L. Hensley, MD, Memorial Sloan Kettering Cancer Center; Shreyaskumar Patel, MD, The University of Texas MD Anderson Cancer Center;Damon Reed, MD, Moffitt Cancer Center
Published Online: Monday, Sep 12, 2016



Transcript:

William D. Tap, MD:
One of the exciting things I want to shift into is what our options are. There has just been a tremendous amount of research over the last 5 years. I think over 5000 patients with sarcoma were put on well-designed prospective clinical trials. We’re not only seeing new efficacy signals, but we’re also really defining our efficacy signals of these standards of care that we’ve been talking about. So, this is an exciting time, this emerging landscape. Martee, we’re beginning to see a lot of this in leiomyosarcoma. I want to get your take on that, and then we’ll just begin to shift into some of these new drugs.

Martee L. Hensley, MD: Well, there’s the approval of pazopanib. It’s for most soft tissue sarcoma histologies, except it’s not for liposarcoma. A large proportion of the patients on that study had leiomyosarcoma. It’s a common soft tissue sarcoma histology. So, it was exciting to have that drug added to the armamentarium.

More recently, trabectedin, where we had been seeing some phase II data or carve-out subsets from larger trials showing activity in liposarcoma and leiomyosarcoma, led to an enthusiasm about looking at the drug prospectively. But it was exciting to see a histology-specific drug with trabectedin. We’re looking in gynecologic cancers, and at least as we start to sequence more of these tumors, we’re hoping to identify certain driver mutations.

I can talk about some things that didn’t work. We tried adding anti–angiogenesis-type therapy. It’s ironic that pazopanib, though being a multi-kinase inhibitor that is anti-angiogenesis, has activity. And yet, bevacizumab, when added to the backbone of gemcitabine and docetaxel, did not improve any endpoints, for example. Also, you know from your colleagues’ data with sunitinib and sorafenib that really those are also not particularly good drugs for leiomyosarcoma. Negative data are also useful data because it means you don’t use a drug that won’t work, so you take the opportunity to hopefully choose a drug that has a chance to work.

William D. Tap, MD: Nuances. But even apart from clinical trials, these are several new agents that we now have for patients with leiomyosarcoma. And you brought up pazopanib, so that’s a good transition. Mark, why don’t you tell us a little bit about pazopanib. How does it work? How do you use it? What is it FDA-approved in? What was the study that led to that?

Mark Agulnik, MD: So, I think pazopanib really opened the gate. Being the first drug that’s approved in a long time for this disease, it really allowed us to change the way we focus on the disease. Everything else prior to this was chemotherapeutic. Finally, we have a tyrosine kinase inhibitor on the market. It’s a VEGF inhibitor, as well as a PDGF-R (platelet-derived growth factor receptor) and KIT inhibitor. And it was wonderful to see it worked right across-the-board in multiple histologies. When you broke it down, you saw that progression-free survival held true for the synovial sarcoma that was about 10% of the population. It held through for the leiomyosarcoma—it was the largest group in this—and then it held through also for the other histologies, with an approval for all histologies except liposarcoma.

And we take GIST out of this, as well, because that’s not usually part of these when we talk about this. It had a progression-free survival advantage of 3 months over placebo, which is meaningful and statistically significant. And certainly, there’s a role for it. It’s approved as a second-line agent. It’s generally well tolerated in the patient population. I counsel my patients that they do need to have the labs checked periodically and quite strictly at the beginning, looking for hepatotoxicities. But I think if you follow the regimen, what’s in the package insert, you’re going to catch a lot of things and potentially allow them to stay on the dose intensity of 800 mg a day.

I think you also counsel them about their blood pressure—and this isn’t new. We’ve seen these antiangiogenic tyrosine kinase inhibitors. We know about the blood pressure. We know that they could have other toxicities with their fatigue. They could have some diarrhea. There’s a change in hair color that’s quite unique to this. I think that for most patients, you do need to tell them their hair will turn white or potentially turn white. Because when they show up telling you they’re getting a senior discount at the movie theater, they need to be prepared for that. But, generally, I think it added something tremendous to the field. I think patients like taking an oral agent, and most of them would have seen an anthracycline or they would have seen gemcitabine/Taxotere. It’s a really different philosophy, different viewpoint. If we think about this as a chronic disease, it’s the journey, and we talk about that they’re going to be a lot of things. It does allow them to have fewer appointments. They’re not coming in for IV infusions. They’re quicker appointments. It’s just a lot more lab draws.

And there are other nuances. You certainly need to pay more attention with these with the other drugs they are taking. So, you’re looking at that QT prolongation, making sure that you’re not going to be giving offenders. And a lot of the anti-GERD (anti–gastroesophageal reflux disease) medications, anti-nausea medications, and pain medications do play a role in this. But I think that working with your pharmacist is key to this. But everything is very doable, and I think patients really appreciate a change, whether or not you use a second-line, third-line, fourth-line, fifth-line treatment. There’s a huge role for it.

William D. Tap, MD: It’s interesting, and I’d like to get some other opinions. But this is a drug that’s easy to use by community oncologists. It’s an important drug to use correctly. How many people here start off at 800 mg, or do you work the dose up? I tend to work the dose up and see where I can go.

George D. Demetri, MD: Right, that’s the hidden secret of this drug, just like it was with imatinib back in 2000. If you start with 800 mg of imatinib, nobody can tolerate that, if that’s the dose you’re choosing. You have to work up. And it’s the same thing with pazopanib. So, now there’s going to be a formal clinical trial about to start that will say, “Here’s a way of ramping up, in the course of a week, in a way that’s going to be more tolerable.” Because I think our collective experience, I don’t want to speak for you all, at our centers is, it’s much easier for a patient to start at one or two pills and 2 days later go up to more. It makes a huge difference to patient tolerability and the ability for that patient to be compliant longer term.

William D. Tap, MD: Yes. And I think we’ve learned this from the GIST community where you really have to work with toxicities and how to manage this. You outlined, beautifully, a lot of the things to look for. Because if you can preempt, manage, or adjust for toxicities, you can really keep patients on a drug. Ultimately, that’s the most important thing. What about any thoughts on subtypes? How is it used in some of the pediatric sarcomas? What else about pazopanib that made us excited about this drug when it was approved?

Damon Reed, MD: There are some phase II trials going on in pediatrics right now, but not commonly used at this time. But with synovial sarcoma being one of the more common sarcomas in young adults and adolescents, it does certainly seem to have rather good activity in that subtype compared to others.

William D. Tap, MD: What are our expectations when we start it?

Shreyaskumar Patel, MD: So, back from a toxicity standpoint, I think there are two points that I want to make for everybody: first, the labile-hypertensive, the sensitive-patients. This is where I think the dose matters a lot. If you’re slowly starting and ramping up, you have much better control of finding out how their blood pressure is going to react, and manage it proactively, rather than running into problems. Another area where dose matters is people with GI disorders and diarrhea; that becomes another known side effect. But active and proactive management of that just enables them to take the maximum dose that they can take for a much longer period of time.

William D. Tap, MD: I agree. And I think one of the things is not only the GI toxicity, but also the hepatotoxicity because we all know that we could see bumps and transaminases. But looking for those rare cases of true hepatic damage, where it’s going to manifest through highs/lows, I think those are important things that you can really monitor with more frequent blood work in the beginning. Then, you can really spread that out over time. Are there subtypes that you tend to go to more often than not with Votrient or pazopanib? Are there some that you tend to use it and some you tend not to use it?

Shreyaskumar Patel, MD: We talked about synovial earlier. I think, if you look at the hazard ratios for the leiomyosarcoma subset, all other subsets, and the synovial, the synovial seem to benefit more. Now, that may be mathematically, or statistically—not the right way of looking at it—but if you come back to synovial sarcoma management in general, once you’re through with doxorubicin and ifosfamide, we’re really struggling. There aren’t that many good drugs. And in that context, at least in my practice or in our group’s practice, pazopanib has become the default second-line treatment. That doesn’t mean that they don’t get gemcitabine/docetaxel, but all of you suggested that it’s not very active and, therefore, it has gotten bumped down to a later line of therapy and pazopanib has moved up in the line of treatment for synovial sarcomas.

George D. Demetri, MD: I think this is where we also become rare stamp collectors, because my favorite subtype are the follicular dendritic cell sarcomas—all five of them that we’ve seen in the last 2 years. But it does seem to have an extraordinary activity in that very unusual subset.

Shreyaskumar Patel, MD: It’s some malignant granular cell tumor, while you’re listing things right now.

Mark Agulnik, MD: But I also think for this—and I think you asked, and I don’t know that it was necessarily answered—set expectations. The response rate to this is quite low. So, if the response rate is quoted about 11%, that’s the expectation. I think patients need to be aware of this. When you tell people what to expect, we love stabilization. Stabilization is good, it’s not a bad word, but they need to know that, and I think this is one of these drugs that they… But this is similar to other tyrosine kinase inhibitors. We’ve been doing this already.

William D. Tap, MD: But that’s a good question, too. Are there clinical features—bulk of tumor, rapidity of growth, where you would say I may not use a TKI, I may go to chemotherapy—or is it just a matter of, “If it’s going to work, it’s going to work’?

Martee L. Hensley, MD: I guess patients who have had problems already with the fistula, for example, I would have some anxiety about pazopanib. In my older cancer patients, I see more patients with chronic small bowel obstructions. Those are not great candidates for any kind of oral therapy, whether it’s pazopanib or something else. So, that would enter into my decision making. And I’d actually be curious to hear your experience about people with centrally located lung metastases adjacent to large vessels or to the bronchus, whether anyone has concern about bleeding or fistulae in that setting. I haven’t seen it, but I carry a little concern about it.

William D. Tap, MD: But, important considerations, right? Taking the disease in context with it?

Shreyaskumar Patel, MD: So, in terms of selecting out patients, if there were criteria that would tell us that here is where we would use it, the investigators of the Pollock trial did actually go back and combine their phase II and III trials experience. I think E. Casper presented and published this in the Annals of Oncology about 2 years ago now. The disease has manifested a slower trajectory, or a slower pace of growth. Those who have a longer time to progression or longer time to recurrence are the ones that may benefit the most in terms of progression-free survival and overall survival.

Transcript Edited for Clarity

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Transcript:

William D. Tap, MD:
One of the exciting things I want to shift into is what our options are. There has just been a tremendous amount of research over the last 5 years. I think over 5000 patients with sarcoma were put on well-designed prospective clinical trials. We’re not only seeing new efficacy signals, but we’re also really defining our efficacy signals of these standards of care that we’ve been talking about. So, this is an exciting time, this emerging landscape. Martee, we’re beginning to see a lot of this in leiomyosarcoma. I want to get your take on that, and then we’ll just begin to shift into some of these new drugs.

Martee L. Hensley, MD: Well, there’s the approval of pazopanib. It’s for most soft tissue sarcoma histologies, except it’s not for liposarcoma. A large proportion of the patients on that study had leiomyosarcoma. It’s a common soft tissue sarcoma histology. So, it was exciting to have that drug added to the armamentarium.

More recently, trabectedin, where we had been seeing some phase II data or carve-out subsets from larger trials showing activity in liposarcoma and leiomyosarcoma, led to an enthusiasm about looking at the drug prospectively. But it was exciting to see a histology-specific drug with trabectedin. We’re looking in gynecologic cancers, and at least as we start to sequence more of these tumors, we’re hoping to identify certain driver mutations.

I can talk about some things that didn’t work. We tried adding anti–angiogenesis-type therapy. It’s ironic that pazopanib, though being a multi-kinase inhibitor that is anti-angiogenesis, has activity. And yet, bevacizumab, when added to the backbone of gemcitabine and docetaxel, did not improve any endpoints, for example. Also, you know from your colleagues’ data with sunitinib and sorafenib that really those are also not particularly good drugs for leiomyosarcoma. Negative data are also useful data because it means you don’t use a drug that won’t work, so you take the opportunity to hopefully choose a drug that has a chance to work.

William D. Tap, MD: Nuances. But even apart from clinical trials, these are several new agents that we now have for patients with leiomyosarcoma. And you brought up pazopanib, so that’s a good transition. Mark, why don’t you tell us a little bit about pazopanib. How does it work? How do you use it? What is it FDA-approved in? What was the study that led to that?

Mark Agulnik, MD: So, I think pazopanib really opened the gate. Being the first drug that’s approved in a long time for this disease, it really allowed us to change the way we focus on the disease. Everything else prior to this was chemotherapeutic. Finally, we have a tyrosine kinase inhibitor on the market. It’s a VEGF inhibitor, as well as a PDGF-R (platelet-derived growth factor receptor) and KIT inhibitor. And it was wonderful to see it worked right across-the-board in multiple histologies. When you broke it down, you saw that progression-free survival held true for the synovial sarcoma that was about 10% of the population. It held through for the leiomyosarcoma—it was the largest group in this—and then it held through also for the other histologies, with an approval for all histologies except liposarcoma.

And we take GIST out of this, as well, because that’s not usually part of these when we talk about this. It had a progression-free survival advantage of 3 months over placebo, which is meaningful and statistically significant. And certainly, there’s a role for it. It’s approved as a second-line agent. It’s generally well tolerated in the patient population. I counsel my patients that they do need to have the labs checked periodically and quite strictly at the beginning, looking for hepatotoxicities. But I think if you follow the regimen, what’s in the package insert, you’re going to catch a lot of things and potentially allow them to stay on the dose intensity of 800 mg a day.

I think you also counsel them about their blood pressure—and this isn’t new. We’ve seen these antiangiogenic tyrosine kinase inhibitors. We know about the blood pressure. We know that they could have other toxicities with their fatigue. They could have some diarrhea. There’s a change in hair color that’s quite unique to this. I think that for most patients, you do need to tell them their hair will turn white or potentially turn white. Because when they show up telling you they’re getting a senior discount at the movie theater, they need to be prepared for that. But, generally, I think it added something tremendous to the field. I think patients like taking an oral agent, and most of them would have seen an anthracycline or they would have seen gemcitabine/Taxotere. It’s a really different philosophy, different viewpoint. If we think about this as a chronic disease, it’s the journey, and we talk about that they’re going to be a lot of things. It does allow them to have fewer appointments. They’re not coming in for IV infusions. They’re quicker appointments. It’s just a lot more lab draws.

And there are other nuances. You certainly need to pay more attention with these with the other drugs they are taking. So, you’re looking at that QT prolongation, making sure that you’re not going to be giving offenders. And a lot of the anti-GERD (anti–gastroesophageal reflux disease) medications, anti-nausea medications, and pain medications do play a role in this. But I think that working with your pharmacist is key to this. But everything is very doable, and I think patients really appreciate a change, whether or not you use a second-line, third-line, fourth-line, fifth-line treatment. There’s a huge role for it.

William D. Tap, MD: It’s interesting, and I’d like to get some other opinions. But this is a drug that’s easy to use by community oncologists. It’s an important drug to use correctly. How many people here start off at 800 mg, or do you work the dose up? I tend to work the dose up and see where I can go.

George D. Demetri, MD: Right, that’s the hidden secret of this drug, just like it was with imatinib back in 2000. If you start with 800 mg of imatinib, nobody can tolerate that, if that’s the dose you’re choosing. You have to work up. And it’s the same thing with pazopanib. So, now there’s going to be a formal clinical trial about to start that will say, “Here’s a way of ramping up, in the course of a week, in a way that’s going to be more tolerable.” Because I think our collective experience, I don’t want to speak for you all, at our centers is, it’s much easier for a patient to start at one or two pills and 2 days later go up to more. It makes a huge difference to patient tolerability and the ability for that patient to be compliant longer term.

William D. Tap, MD: Yes. And I think we’ve learned this from the GIST community where you really have to work with toxicities and how to manage this. You outlined, beautifully, a lot of the things to look for. Because if you can preempt, manage, or adjust for toxicities, you can really keep patients on a drug. Ultimately, that’s the most important thing. What about any thoughts on subtypes? How is it used in some of the pediatric sarcomas? What else about pazopanib that made us excited about this drug when it was approved?

Damon Reed, MD: There are some phase II trials going on in pediatrics right now, but not commonly used at this time. But with synovial sarcoma being one of the more common sarcomas in young adults and adolescents, it does certainly seem to have rather good activity in that subtype compared to others.

William D. Tap, MD: What are our expectations when we start it?

Shreyaskumar Patel, MD: So, back from a toxicity standpoint, I think there are two points that I want to make for everybody: first, the labile-hypertensive, the sensitive-patients. This is where I think the dose matters a lot. If you’re slowly starting and ramping up, you have much better control of finding out how their blood pressure is going to react, and manage it proactively, rather than running into problems. Another area where dose matters is people with GI disorders and diarrhea; that becomes another known side effect. But active and proactive management of that just enables them to take the maximum dose that they can take for a much longer period of time.

William D. Tap, MD: I agree. And I think one of the things is not only the GI toxicity, but also the hepatotoxicity because we all know that we could see bumps and transaminases. But looking for those rare cases of true hepatic damage, where it’s going to manifest through highs/lows, I think those are important things that you can really monitor with more frequent blood work in the beginning. Then, you can really spread that out over time. Are there subtypes that you tend to go to more often than not with Votrient or pazopanib? Are there some that you tend to use it and some you tend not to use it?

Shreyaskumar Patel, MD: We talked about synovial earlier. I think, if you look at the hazard ratios for the leiomyosarcoma subset, all other subsets, and the synovial, the synovial seem to benefit more. Now, that may be mathematically, or statistically—not the right way of looking at it—but if you come back to synovial sarcoma management in general, once you’re through with doxorubicin and ifosfamide, we’re really struggling. There aren’t that many good drugs. And in that context, at least in my practice or in our group’s practice, pazopanib has become the default second-line treatment. That doesn’t mean that they don’t get gemcitabine/docetaxel, but all of you suggested that it’s not very active and, therefore, it has gotten bumped down to a later line of therapy and pazopanib has moved up in the line of treatment for synovial sarcomas.

George D. Demetri, MD: I think this is where we also become rare stamp collectors, because my favorite subtype are the follicular dendritic cell sarcomas—all five of them that we’ve seen in the last 2 years. But it does seem to have an extraordinary activity in that very unusual subset.

Shreyaskumar Patel, MD: It’s some malignant granular cell tumor, while you’re listing things right now.

Mark Agulnik, MD: But I also think for this—and I think you asked, and I don’t know that it was necessarily answered—set expectations. The response rate to this is quite low. So, if the response rate is quoted about 11%, that’s the expectation. I think patients need to be aware of this. When you tell people what to expect, we love stabilization. Stabilization is good, it’s not a bad word, but they need to know that, and I think this is one of these drugs that they… But this is similar to other tyrosine kinase inhibitors. We’ve been doing this already.

William D. Tap, MD: But that’s a good question, too. Are there clinical features—bulk of tumor, rapidity of growth, where you would say I may not use a TKI, I may go to chemotherapy—or is it just a matter of, “If it’s going to work, it’s going to work’?

Martee L. Hensley, MD: I guess patients who have had problems already with the fistula, for example, I would have some anxiety about pazopanib. In my older cancer patients, I see more patients with chronic small bowel obstructions. Those are not great candidates for any kind of oral therapy, whether it’s pazopanib or something else. So, that would enter into my decision making. And I’d actually be curious to hear your experience about people with centrally located lung metastases adjacent to large vessels or to the bronchus, whether anyone has concern about bleeding or fistulae in that setting. I haven’t seen it, but I carry a little concern about it.

William D. Tap, MD: But, important considerations, right? Taking the disease in context with it?

Shreyaskumar Patel, MD: So, in terms of selecting out patients, if there were criteria that would tell us that here is where we would use it, the investigators of the Pollock trial did actually go back and combine their phase II and III trials experience. I think E. Casper presented and published this in the Annals of Oncology about 2 years ago now. The disease has manifested a slower trajectory, or a slower pace of growth. Those who have a longer time to progression or longer time to recurrence are the ones that may benefit the most in terms of progression-free survival and overall survival.

Transcript Edited for Clarity
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