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Olaratumab + Doxorubicin for Metastatic Soft-Tissue Sarcoma

Panelists: William D. Tap, MD, Memorial Sloan Kettering Cancer Center; Kristen Ganjoo, MD, Stanford University Medical Center; Richard Riedel, MD, Duke Cancer Institute; Jonathan Trent, MD, PhD, Sylvester Comprehensive Cancer Center; Victor Villalobos, MD, PhD, University of Colorado
Published: Tuesday, Aug 07, 2018



Transcript: 

William D. Tap, MD: We’re talking about doxorubicin and olaratumab. And the data, although really good, are not clear cut, right? This was a phase II study. This wasn’t a study that we designed in a pivotal fashion. We were somewhat surprised that there was a 50% improvement in PFS from 4 months to 6 months, but we saw an 11-month improvement in median overall survival, which is something we’ve never seen before. But it’s a phase II study. It was granted accelerated approval. There were approximately 65 or 66 patients in each arm. The phase III study, which will really answer the question of what the approval is conditioned on, will be out hopefully sometime relatively soon.

What would you need to look for in that study to say this is the de facto regimen versus still having a discussion with patients? When we go past this, I also want to mention there are other regimens, such as gemcitabine/docetaxel. There was the GeDDiS study, which in my opinion—we’ll touch base on that a little bit—showed equivalence to doxorubicin. It definitely didn’t show tremendous inferiority to doxorubicin. What do you want to see in the phase III study, if anything? What would that mean to you, and how do you sequence all these regimens for patients? Because I think the community oncologist is going to ask, “Wow, how do I start? What do I use as second-line therapy?” Let’s think about this for a little bit. Who wants to start with that?

Richard F. Riedel, MD: I’m happy to start. For me, an anthracycline-based regimen for the vast majority of patients is cemented in the frontline setting, and we can debate whether it’s doxorubicin in combination with olaratumab or doxorubicin in combination with ifosfamide. My strategy is similar to Kristen’s for someone with an impending visceral crisis. I’m more likely to give doxorubicin in combination with ifosfamide. But to answer your question with respect to the phase III doxorubicin/olaratumab study, the ANNOUNCE study, the question is what do we consider clinically meaningful from an overall survival benefit? In the phase II trial, it was 11.8 months. I think all of us at the table would agree that’s clinically meaningful. If the phase III data come back and it’s 9 months or 6 months or 4 months, that to me is still valuable. For me, if it’s 3 months or higher, I’ll take it. We haven’t seen a survival benefit in any of our therapies.

Victor M. Villalobos, MD, PhD: The key is also going to be that tolerability. Comparing doxorubicin/olaratumab to doxorubicin/ifosfamide is dramatically easier. If you’re getting similar outcomes as you do with doxorubicin/ifosfamide and it has been proven to be clinically significant and statistically significant…

Richard F. Riedel, MD: We would need another study to answer that.

Kristen N. Ganjoo, MD: The best approach for John’s concerns would be to do a randomized study with ifosfamide/Adriamycin (doxorubicin) versus Adriamycin alone. That would definitely answer our questions for metastatic disease.

Richard F. Riedel, MD: It probably won’t happen.

Kristen N. Ganjoo, MD: It can’t happen because of the side effects, but that would be the ultimate study that would put ifosfamide aside for good.

William D. Tap, MD: Let’s also start to talk about gemcitabine-based regimens. In the United States, gemcitabine/docetaxel is very popular. In Europe, it’s more gemcitabine/dacarbazine. I do want to give a shout out to doxorubicin and dacarbazine in certain subtypes, particularly the uterine leiomyosarcomas. There are strong data in that as well. The Europeans did the GeDDiS study, which actually looked, in the frontline setting, at gemcitabine and docetaxel versus doxorubicin. The gemcitabine was grossly under-dosed at times, and there may have been some bias there. Relatively, the outcomes were the same. Is there any time that you would use gemcitabine/docetaxel in the frontline setting or gemcitabine/dacarbazine in the frontline setting?

Victor M. Villalobos, MD, PhD: Yes, if they have heart disease or if they have issues with toxicities. I think, to a certain degree, the sequencing of treatments is a bit semantic in general because almost all my patients are going to get all these therapies. It’s not like they’re going to fail one, stop everything, and then be done. I think the vast majority of my patients will receive 4 to 6 lines of therapy, on average. It’s very common.

William D. Tap, MD: Do you start your first-line therapy already thinking about your second-line therapy? Does that come into play?

Richard F. Riedel, MD: Yes.

Kristen N. Ganjoo, MD: It’s also important in terms of how to give the gemcitabine and docetaxel. We’ve been giving both drugs every 2 weeks at higher doses, with over 30 minutes of gemcitabine; whereas, when you give the day 1/day 8 schedule, on day 8 you’re giving a lot of docetaxel and you’re giving 90 minutes of gemcitabine. We’ve had really good results with every-2-week gemcitabine and docetaxel. The dose of gemcitabine is 1500 mg/m2 and docetaxel is 50 mg/m2. We have really good responses. I usually tend to use that for patients older than 70, when with Adriamycin, they may have atrial fibrillation or some cardiac issues.

Victor M. Villalobos, MD, PhD: The initial paper from Dr. Maki and Dr. Hensley, the gemcitabine/docetaxel study, utilized a very high dose of docetaxel, and oftentimes I don’t ever start with that dose. The 100-mg/m2 dose is very, very toxic, and I’m not sure that it adds that much more benefit frankly. I try to dose reduce that to begin with, but even then, I think that with gemcitabine/docetaxel general practitioners may be more familiar with it and more comfortable with it, and so they give it more frequently early on. Although it’s a tougher regimen, to a certain degree. People have a hard time. Docetaxel is quite toxic. At those doses, you’re getting a lot of edema. You’re getting a lot of neuropathy as well. It can be harsh, but it can be very, very effective.

Kristen N. Ganjoo, MD: My dosage is the best. I also put them on maintenance therapy. These people have metastatic disease. Do you just do 6 cycles? Do you do 4 cycles?

William D. Tap, MD: It’s a benefit of it. Actually, there are some centers that do a split dose of gemcitabine/docetaxel, where they do probably about 935 mg/m2 on day 1, day 8, and day 15, and that’s tolerated.

Transcript Edited for Clarity 

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Transcript: 

William D. Tap, MD: We’re talking about doxorubicin and olaratumab. And the data, although really good, are not clear cut, right? This was a phase II study. This wasn’t a study that we designed in a pivotal fashion. We were somewhat surprised that there was a 50% improvement in PFS from 4 months to 6 months, but we saw an 11-month improvement in median overall survival, which is something we’ve never seen before. But it’s a phase II study. It was granted accelerated approval. There were approximately 65 or 66 patients in each arm. The phase III study, which will really answer the question of what the approval is conditioned on, will be out hopefully sometime relatively soon.

What would you need to look for in that study to say this is the de facto regimen versus still having a discussion with patients? When we go past this, I also want to mention there are other regimens, such as gemcitabine/docetaxel. There was the GeDDiS study, which in my opinion—we’ll touch base on that a little bit—showed equivalence to doxorubicin. It definitely didn’t show tremendous inferiority to doxorubicin. What do you want to see in the phase III study, if anything? What would that mean to you, and how do you sequence all these regimens for patients? Because I think the community oncologist is going to ask, “Wow, how do I start? What do I use as second-line therapy?” Let’s think about this for a little bit. Who wants to start with that?

Richard F. Riedel, MD: I’m happy to start. For me, an anthracycline-based regimen for the vast majority of patients is cemented in the frontline setting, and we can debate whether it’s doxorubicin in combination with olaratumab or doxorubicin in combination with ifosfamide. My strategy is similar to Kristen’s for someone with an impending visceral crisis. I’m more likely to give doxorubicin in combination with ifosfamide. But to answer your question with respect to the phase III doxorubicin/olaratumab study, the ANNOUNCE study, the question is what do we consider clinically meaningful from an overall survival benefit? In the phase II trial, it was 11.8 months. I think all of us at the table would agree that’s clinically meaningful. If the phase III data come back and it’s 9 months or 6 months or 4 months, that to me is still valuable. For me, if it’s 3 months or higher, I’ll take it. We haven’t seen a survival benefit in any of our therapies.

Victor M. Villalobos, MD, PhD: The key is also going to be that tolerability. Comparing doxorubicin/olaratumab to doxorubicin/ifosfamide is dramatically easier. If you’re getting similar outcomes as you do with doxorubicin/ifosfamide and it has been proven to be clinically significant and statistically significant…

Richard F. Riedel, MD: We would need another study to answer that.

Kristen N. Ganjoo, MD: The best approach for John’s concerns would be to do a randomized study with ifosfamide/Adriamycin (doxorubicin) versus Adriamycin alone. That would definitely answer our questions for metastatic disease.

Richard F. Riedel, MD: It probably won’t happen.

Kristen N. Ganjoo, MD: It can’t happen because of the side effects, but that would be the ultimate study that would put ifosfamide aside for good.

William D. Tap, MD: Let’s also start to talk about gemcitabine-based regimens. In the United States, gemcitabine/docetaxel is very popular. In Europe, it’s more gemcitabine/dacarbazine. I do want to give a shout out to doxorubicin and dacarbazine in certain subtypes, particularly the uterine leiomyosarcomas. There are strong data in that as well. The Europeans did the GeDDiS study, which actually looked, in the frontline setting, at gemcitabine and docetaxel versus doxorubicin. The gemcitabine was grossly under-dosed at times, and there may have been some bias there. Relatively, the outcomes were the same. Is there any time that you would use gemcitabine/docetaxel in the frontline setting or gemcitabine/dacarbazine in the frontline setting?

Victor M. Villalobos, MD, PhD: Yes, if they have heart disease or if they have issues with toxicities. I think, to a certain degree, the sequencing of treatments is a bit semantic in general because almost all my patients are going to get all these therapies. It’s not like they’re going to fail one, stop everything, and then be done. I think the vast majority of my patients will receive 4 to 6 lines of therapy, on average. It’s very common.

William D. Tap, MD: Do you start your first-line therapy already thinking about your second-line therapy? Does that come into play?

Richard F. Riedel, MD: Yes.

Kristen N. Ganjoo, MD: It’s also important in terms of how to give the gemcitabine and docetaxel. We’ve been giving both drugs every 2 weeks at higher doses, with over 30 minutes of gemcitabine; whereas, when you give the day 1/day 8 schedule, on day 8 you’re giving a lot of docetaxel and you’re giving 90 minutes of gemcitabine. We’ve had really good results with every-2-week gemcitabine and docetaxel. The dose of gemcitabine is 1500 mg/m2 and docetaxel is 50 mg/m2. We have really good responses. I usually tend to use that for patients older than 70, when with Adriamycin, they may have atrial fibrillation or some cardiac issues.

Victor M. Villalobos, MD, PhD: The initial paper from Dr. Maki and Dr. Hensley, the gemcitabine/docetaxel study, utilized a very high dose of docetaxel, and oftentimes I don’t ever start with that dose. The 100-mg/m2 dose is very, very toxic, and I’m not sure that it adds that much more benefit frankly. I try to dose reduce that to begin with, but even then, I think that with gemcitabine/docetaxel general practitioners may be more familiar with it and more comfortable with it, and so they give it more frequently early on. Although it’s a tougher regimen, to a certain degree. People have a hard time. Docetaxel is quite toxic. At those doses, you’re getting a lot of edema. You’re getting a lot of neuropathy as well. It can be harsh, but it can be very, very effective.

Kristen N. Ganjoo, MD: My dosage is the best. I also put them on maintenance therapy. These people have metastatic disease. Do you just do 6 cycles? Do you do 4 cycles?

William D. Tap, MD: It’s a benefit of it. Actually, there are some centers that do a split dose of gemcitabine/docetaxel, where they do probably about 935 mg/m2 on day 1, day 8, and day 15, and that’s tolerated.

Transcript Edited for Clarity 
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