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Subtyping in Soft Tissue Sarcoma: The PALLETTE Study

Panelists:Robin L. Jones, MD, MRCP, Royal Marsden Hospital; Shreyaskumar R. Patel, MD, University of Texas MD Anderson Cancer Center; R. Lor Randall, MD, FACS, Huntsman Cancer Institute; Jonathan C. Trent, MD, Sylvester Comprehensive Cancer Center; Brian A. Van Tine, MD, PhD, Siteman Cancer Center; Andrew J. Wagner, MD, PhD, Dana-Farber Cancer Institute
Published: Monday, Dec 28, 2015



Transcript:

Brian A. Van Tine, MD, PhD:
I’m actually hoping that ifosfamide just goes away, and I’d actually like to get to that subject soon. But before then, one of the things that I was told when I was a fellow is that if I was going to go into sarcoma, it was good to have a PhD because you were going to be dealing with phase II clinical data for the rest of your career. And I said, “Well, I have a PhD. That sounds great.” Then, all of a sudden, we started doing phase III trials left and right, and this field is actually maturing really nicely because you can do a phase III clinical trial in sarcoma now in under 2 years, and we’re no different than anyone else. And we have these large trial-based centers that really make a difference.

I think we started with a very interesting maintenance mTOR study that was negative, but right after that, came out the PALETTE study and all of a sudden we had something that we weren’t used to talking about, which was an FDA-approved drug. That really began to change what we’re doing and our thinking of what we wanted to push. So, we actually had evidence-based medicine going into our treatments. Andy, why don’t we, instead of having you talk about ifosfamide, take you over to pazopanib, which is now a Novartis drug that I use quite readily in the advanced line. Maybe we can start by just having you discuss briefly how it’s given, how you use it, and what are really the approved indications?

Andrew J. Wagner, MD, PhD: Well, pazopanib is a pill. It’s an oral tyrosine kinase inhibitor. It hits a fair number of different kinases. Probably, most notably are the vascular endothelial growth factor receptors, in particular VEGF receptor 2. It also hits KIT, which is important in gastrointestinal stromal tumors and other kinases, as well. It’s taken orally once a day. It’s not entirely clear in sarcomas whether it’s a direct anti-tumor effect or whether it’s an anti-tumor vasculature effect. And it’s somewhat irrelevant, I think, for that distinction, as long as it has some combined antitumor effect.

The study that you referred to, the PALETTE study, followed on an earlier phase II study that was conducted and published by Stefan Sleijfer and at the EORTC, which looked at patients who were categorized into different subgroups. These are leiomyosarcoma, synovial sarcoma, adipocytic sarcomas, or other tumor types. In a single arm study, three of the four groups showed what appeared to be an improvement in progression-free survival compared to historical controls. The one group that didn’t seem to have that benefit were the adipocytic neoplasms. And that’s what led to PALETTE, which was a randomized study in patients who’d been previously treated either with pazopanib—this study was randomized to pazopanib—or to placebo.

Brian A. Van Tine, MD, PhD: And what’s interesting is—and we can get into a discussion another time about the problems with assignment design—choosing of subtypes. Nicely, there will be a trial reported soon about pazopanib in adipocytic, which may actually solve that problem. But as we get into this, there were a couple subtypes in the PALETTE study that really stood out as having a little bit more activity than general. Jonathan, do you know or remember exactly what those were?

Jonathan C. Trent, MD: Yeah, it seemed to show promising activity in synovial sarcoma, leiomyosarcoma. And those are certainly metastatic diseases for which patients will clearly reach third-line therapy. This is a perfectly reasonable therapy for additionally solitary fibrous tumors, another histology for which I personally, in our group, will use pazopanib in second-line therapy for that entity. So, it clearly has activity in those histologies, but also has clear activity in a broad range of other soft tissue sarcomas and probably in some that were excluded from the PALETTE study.

Brian A. Van Tine, MD, PhD: I know, and I absolutely agree. Shreyas, where are you incorporating this in terms of your treatment strategies now that we are getting a more complicated landscape?

Shreyaskumar R. Patel, MD: With a lack of true molecular markers helping us subset the therapies out, we’ve used the poor man’s way of doing it, which would be histology-based subsetting out. So, I think there would be tumors.

Like, take the example of synovial sarcoma, as Jon just mentioned. If they got doxorubicin/Ifosfamide-based regimens up-front, we know that gemcitabine/docetaxel has very marginal to low activity in that setting. But pazopanib has reasonable or decent activity, so that would move up to second line. I don’t think that the second-line/third-line usage is necessarily that generalizable these days.

I think it’s fair to say that the anthracycline-based is frontline, generally gem/docetaxel is the second-line, and pazopanib becomes third-line. But that will change as we talk about some of the other drugs that come along.

I think we’re starting to pick out the patient populations where VEGF inhibition is very relevant. Take alveolar soft part sarcomas, for example. So, there are subsets where it may make sense and would be used in the earlier lines of therapy and there are others where it typically gets into the third-line or beyond, depending on the patient’s disease situation.

R. Lor Randall, MD, FACS: And just informationally for the audience: in the Children’s Oncology Group, there was the non-rhabdomyosarcoma study. I think everyone’s aware of it, 0332, for high-risk soft tissue sarcomas getting AI, and for a variety of tumors. And from that study, we really did see a number of tumors that we all know intuitively—alveolar soft part epithelioid, MPNST—that were chemorefractory. And now there is a combined study, COG and energy with a pazopanib backbone for those types of tumors that are at high risk. So, there’s really some momentum building with this drug.

Brian A. Van Tine, MD, PhD: But that’s a tough regimen.

Andrew J. Wagner, MD, PhD: So just—and I didn’t go into details of the results of the PALETTE study—but it did show improvement in progression-free survival of 4.6 months compared to 1.6 months for the placebo arm, but no significant improvement in overall survival. These were patients that were supposed to have completed all prior lines of therapy, but there were patients who continued to get therapy after that.

Brian A. Van Tine, MD, PhD: But it does come, and I think it’s one thing we should point out if we’re moving on, with a black box warning. I think it’s always important to know how to manage a black box warning. Do you want to discuss briefly the liver toxicity?

Andrew J. Wagner, MD, PhD: It has a variety of different toxicities, including the potential for liver toxicity. The drugs of this class, I think, share very similar toxicities and certainly LST abnormalities, elevations in ALT, AST, and bilirubin can occur. And it has to be monitored very carefully and either drug suspended permanently or held until improvement and then dose reduced.

The other toxicities we see are hypertension, which also needs to be managed. Patients who are treated with VEGF receptor antagonists can get palmar/plantar erythrodysesthesias or hand-foot syndrome, oral dysesthesias, so mouth pain, which can be really quite symptomatic and limit oral intake. And working with our oral medicine colleagues, we have found that a clonazepam mouthwash really can dramatically improve those symptoms. And diarrhea is another common toxicity.

But all those things need to be watched and managed. And it’s not just here, take a pill, and come back and see me later. It’s really close follow-up with patient support.

Brian A. Van Tine, MD, PhD: The liver LFT management is the one thing that ends up on the social media message boards because people can die if it’s managed wrong.

Andrew J. Wagner, MD, PhD: You spend a lot of time on those social media message boards, don’t you?

Brian A. Van Tine, MD, PhD: Well, I think it’s important, as part of patient advocacy, that you’re also available to patients.
                                                                                                                                                                                                                                                                                                                

Transcript Edited for Clarity

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Transcript:

Brian A. Van Tine, MD, PhD:
I’m actually hoping that ifosfamide just goes away, and I’d actually like to get to that subject soon. But before then, one of the things that I was told when I was a fellow is that if I was going to go into sarcoma, it was good to have a PhD because you were going to be dealing with phase II clinical data for the rest of your career. And I said, “Well, I have a PhD. That sounds great.” Then, all of a sudden, we started doing phase III trials left and right, and this field is actually maturing really nicely because you can do a phase III clinical trial in sarcoma now in under 2 years, and we’re no different than anyone else. And we have these large trial-based centers that really make a difference.

I think we started with a very interesting maintenance mTOR study that was negative, but right after that, came out the PALETTE study and all of a sudden we had something that we weren’t used to talking about, which was an FDA-approved drug. That really began to change what we’re doing and our thinking of what we wanted to push. So, we actually had evidence-based medicine going into our treatments. Andy, why don’t we, instead of having you talk about ifosfamide, take you over to pazopanib, which is now a Novartis drug that I use quite readily in the advanced line. Maybe we can start by just having you discuss briefly how it’s given, how you use it, and what are really the approved indications?

Andrew J. Wagner, MD, PhD: Well, pazopanib is a pill. It’s an oral tyrosine kinase inhibitor. It hits a fair number of different kinases. Probably, most notably are the vascular endothelial growth factor receptors, in particular VEGF receptor 2. It also hits KIT, which is important in gastrointestinal stromal tumors and other kinases, as well. It’s taken orally once a day. It’s not entirely clear in sarcomas whether it’s a direct anti-tumor effect or whether it’s an anti-tumor vasculature effect. And it’s somewhat irrelevant, I think, for that distinction, as long as it has some combined antitumor effect.

The study that you referred to, the PALETTE study, followed on an earlier phase II study that was conducted and published by Stefan Sleijfer and at the EORTC, which looked at patients who were categorized into different subgroups. These are leiomyosarcoma, synovial sarcoma, adipocytic sarcomas, or other tumor types. In a single arm study, three of the four groups showed what appeared to be an improvement in progression-free survival compared to historical controls. The one group that didn’t seem to have that benefit were the adipocytic neoplasms. And that’s what led to PALETTE, which was a randomized study in patients who’d been previously treated either with pazopanib—this study was randomized to pazopanib—or to placebo.

Brian A. Van Tine, MD, PhD: And what’s interesting is—and we can get into a discussion another time about the problems with assignment design—choosing of subtypes. Nicely, there will be a trial reported soon about pazopanib in adipocytic, which may actually solve that problem. But as we get into this, there were a couple subtypes in the PALETTE study that really stood out as having a little bit more activity than general. Jonathan, do you know or remember exactly what those were?

Jonathan C. Trent, MD: Yeah, it seemed to show promising activity in synovial sarcoma, leiomyosarcoma. And those are certainly metastatic diseases for which patients will clearly reach third-line therapy. This is a perfectly reasonable therapy for additionally solitary fibrous tumors, another histology for which I personally, in our group, will use pazopanib in second-line therapy for that entity. So, it clearly has activity in those histologies, but also has clear activity in a broad range of other soft tissue sarcomas and probably in some that were excluded from the PALETTE study.

Brian A. Van Tine, MD, PhD: I know, and I absolutely agree. Shreyas, where are you incorporating this in terms of your treatment strategies now that we are getting a more complicated landscape?

Shreyaskumar R. Patel, MD: With a lack of true molecular markers helping us subset the therapies out, we’ve used the poor man’s way of doing it, which would be histology-based subsetting out. So, I think there would be tumors.

Like, take the example of synovial sarcoma, as Jon just mentioned. If they got doxorubicin/Ifosfamide-based regimens up-front, we know that gemcitabine/docetaxel has very marginal to low activity in that setting. But pazopanib has reasonable or decent activity, so that would move up to second line. I don’t think that the second-line/third-line usage is necessarily that generalizable these days.

I think it’s fair to say that the anthracycline-based is frontline, generally gem/docetaxel is the second-line, and pazopanib becomes third-line. But that will change as we talk about some of the other drugs that come along.

I think we’re starting to pick out the patient populations where VEGF inhibition is very relevant. Take alveolar soft part sarcomas, for example. So, there are subsets where it may make sense and would be used in the earlier lines of therapy and there are others where it typically gets into the third-line or beyond, depending on the patient’s disease situation.

R. Lor Randall, MD, FACS: And just informationally for the audience: in the Children’s Oncology Group, there was the non-rhabdomyosarcoma study. I think everyone’s aware of it, 0332, for high-risk soft tissue sarcomas getting AI, and for a variety of tumors. And from that study, we really did see a number of tumors that we all know intuitively—alveolar soft part epithelioid, MPNST—that were chemorefractory. And now there is a combined study, COG and energy with a pazopanib backbone for those types of tumors that are at high risk. So, there’s really some momentum building with this drug.

Brian A. Van Tine, MD, PhD: But that’s a tough regimen.

Andrew J. Wagner, MD, PhD: So just—and I didn’t go into details of the results of the PALETTE study—but it did show improvement in progression-free survival of 4.6 months compared to 1.6 months for the placebo arm, but no significant improvement in overall survival. These were patients that were supposed to have completed all prior lines of therapy, but there were patients who continued to get therapy after that.

Brian A. Van Tine, MD, PhD: But it does come, and I think it’s one thing we should point out if we’re moving on, with a black box warning. I think it’s always important to know how to manage a black box warning. Do you want to discuss briefly the liver toxicity?

Andrew J. Wagner, MD, PhD: It has a variety of different toxicities, including the potential for liver toxicity. The drugs of this class, I think, share very similar toxicities and certainly LST abnormalities, elevations in ALT, AST, and bilirubin can occur. And it has to be monitored very carefully and either drug suspended permanently or held until improvement and then dose reduced.

The other toxicities we see are hypertension, which also needs to be managed. Patients who are treated with VEGF receptor antagonists can get palmar/plantar erythrodysesthesias or hand-foot syndrome, oral dysesthesias, so mouth pain, which can be really quite symptomatic and limit oral intake. And working with our oral medicine colleagues, we have found that a clonazepam mouthwash really can dramatically improve those symptoms. And diarrhea is another common toxicity.

But all those things need to be watched and managed. And it’s not just here, take a pill, and come back and see me later. It’s really close follow-up with patient support.

Brian A. Van Tine, MD, PhD: The liver LFT management is the one thing that ends up on the social media message boards because people can die if it’s managed wrong.

Andrew J. Wagner, MD, PhD: You spend a lot of time on those social media message boards, don’t you?

Brian A. Van Tine, MD, PhD: Well, I think it’s important, as part of patient advocacy, that you’re also available to patients.
                                                                                                                                                                                                                                                                                                                

Transcript Edited for Clarity
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