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Patient Selection in Soft Tissue Sarcoma

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: Sunday, Jan 10, 2016



Transcript:

Brian A. Van Tine, MD, PhD: Let’s transition to what are, I think, the most exciting things that are going on in our field right now, which are a series of new drugs that are going to be reported, one of which was reported at ASCO this year, one of which was reported at ASCO last year, one of which I’ve actually never managed to treat sarcoma patients without.

Since the beginning of my career, I’ve actually been involved in evofosfamide. And evofosfamide is just this wonderful drug which may make that Adriamycin/ifosfamide argument, I’m hoping, irrelevant. With that being said, since I think the third-most—the third in terms of people who’ve used this drug—person on the planet where I’m first, Bill Tapp is second, I believe you’re third.

Robin, why don’t you tell us about evofosfamide and how it works?

Robin L. Jones, MD, MRCP: Evofosfamide is a pro drug, an alkylating agent pro drug that’s obviously activated in hypoxic tissue. Solid tumors tend to be fairly hypoxic, particularly sarcomas, and this drug gets activated in the hypoxic region of the tumor and may also have a bystander effect by diffusion of the active moiety into normal oxic regions surrounding the hypoxic area of the tumor. It’s given intravenously on days 1 and 8 of a 3-weekly cycle.

Brian A. Van Tine, MD, PhD: Yeah. I think this is just. It’s one of my favorite new tools, but Jonathan, I know you’ve had some experience with this. What are your thoughts on the safety and efficacy?

Jonathan C. Trent, MD: I wasn’t involved in the trials, but reviewing the data, it seems to be clearly safer than the biologically equivalent dose of ifosfamide. Although there are certain toxicities that are unique to evofosfamide, involving the skin particularly and its efficacy also in clinical trial certainly looks promising.

Brian A. Van Tine, MD, PhD: I think one of the things we, as a community, are going to have to spend a lot of time with is our community colleagues, explaining rash management, especially the ones that occur in the groin. Because if they’re not managed correctly, they can be really, really severe. If managed correctly, this is a wonderful drug. It does have a tendency to activate melanocytes and make anybody who has higher levels of pigment much darker. Andy, do you want to comment a little bit about the design of our sarcoma trial?

Andrew J. Wagner, MD, PhD: Sure. Robin just alluded to it. The drug evofosfamide is given on days 1 and 8 of a 3-week cycle, where it’s in combination with doxorubicin on day 1 compared to doxorubicin alone. It’s very reminiscent to a study that we heard about a few years ago, which was of palifosfamide, a different ifosfamide-like drug, similar design.

I think the design is interesting in that it’s comparing doxorubicin with a drug to doxorubicin. Although, the additional drug you could look at as an ifosfamide substitute, and it could lead you to the question of well, what is the right comparator for the study? Should it be ifosfamide and doxorubicin compared to evofosfamide and doxorubicin, or not?

It’s very interesting because they’re different designs that I think are both acceptable. But the question is, is it the right comparison to make? I think we can use some of the EORTC data we talked about earlier, of the doxorubicin plus ifosfamide versus doxorubicin as a comparator, to kind of judge whether this is similar or better than Ifosfamide. But it’s still, it’s difficult to compare studies in that way because the patient population is different and the study design is different.

So, I think we’re all eagerly awaiting the results from this study. The palifosfamide study was not significant in outcome in addition to doxorubicin. So, we’ll see what this one shows. But it still raises the question of, is it the right comparison?

Brian A. Van Tine, MD, PhD: So, I’d like to challenge my MD Anderson colleagues because they’re married to ifosfamide so much, to ask: if this becomes approved, how will it be used in soft tissue sarcoma?

Shreyaskumar R. Patel, MD: So, the available data is quite clear that this is a kinder, gentler ifosfamide, right? I think the toxicity profile is significantly better; the convenience and ease of administration is clearly better. I think, as Andy alluded to, the efficacy comparisons between ifosfamide and evofosfamide are truly unknown.

It will be very hard to draw cross-trial comparisons. But this would absolutely be a welcome addition to the therapeutic armamentarium. I think there are clearly candidates or patients who are not candidates for ifosfamide. There are our community oncology friends who may not feel comfortable with ifosfamide and probably shouldn’t be using it. For them, this might be a good addition for the patient population that they are treating. So, it will clearly have a place.

I think where on the landscape it falls will depend on the actual data from the trial as it comes out. And then, in many ways, I think we learn a lot about a new drug after its approval anyways, right? It’s the postmarketing, postapproval trials that will then determine how this changes the overall landscape of management for soft tissue sarcomas. It could completely bump ifosfamide off or it could be reserved for some select situations where ifosfamide would be appropriate, but not deliverable, because of toxicity or convenience or other reasons.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity

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Transcript:

Brian A. Van Tine, MD, PhD: Let’s transition to what are, I think, the most exciting things that are going on in our field right now, which are a series of new drugs that are going to be reported, one of which was reported at ASCO this year, one of which was reported at ASCO last year, one of which I’ve actually never managed to treat sarcoma patients without.

Since the beginning of my career, I’ve actually been involved in evofosfamide. And evofosfamide is just this wonderful drug which may make that Adriamycin/ifosfamide argument, I’m hoping, irrelevant. With that being said, since I think the third-most—the third in terms of people who’ve used this drug—person on the planet where I’m first, Bill Tapp is second, I believe you’re third.

Robin, why don’t you tell us about evofosfamide and how it works?

Robin L. Jones, MD, MRCP: Evofosfamide is a pro drug, an alkylating agent pro drug that’s obviously activated in hypoxic tissue. Solid tumors tend to be fairly hypoxic, particularly sarcomas, and this drug gets activated in the hypoxic region of the tumor and may also have a bystander effect by diffusion of the active moiety into normal oxic regions surrounding the hypoxic area of the tumor. It’s given intravenously on days 1 and 8 of a 3-weekly cycle.

Brian A. Van Tine, MD, PhD: Yeah. I think this is just. It’s one of my favorite new tools, but Jonathan, I know you’ve had some experience with this. What are your thoughts on the safety and efficacy?

Jonathan C. Trent, MD: I wasn’t involved in the trials, but reviewing the data, it seems to be clearly safer than the biologically equivalent dose of ifosfamide. Although there are certain toxicities that are unique to evofosfamide, involving the skin particularly and its efficacy also in clinical trial certainly looks promising.

Brian A. Van Tine, MD, PhD: I think one of the things we, as a community, are going to have to spend a lot of time with is our community colleagues, explaining rash management, especially the ones that occur in the groin. Because if they’re not managed correctly, they can be really, really severe. If managed correctly, this is a wonderful drug. It does have a tendency to activate melanocytes and make anybody who has higher levels of pigment much darker. Andy, do you want to comment a little bit about the design of our sarcoma trial?

Andrew J. Wagner, MD, PhD: Sure. Robin just alluded to it. The drug evofosfamide is given on days 1 and 8 of a 3-week cycle, where it’s in combination with doxorubicin on day 1 compared to doxorubicin alone. It’s very reminiscent to a study that we heard about a few years ago, which was of palifosfamide, a different ifosfamide-like drug, similar design.

I think the design is interesting in that it’s comparing doxorubicin with a drug to doxorubicin. Although, the additional drug you could look at as an ifosfamide substitute, and it could lead you to the question of well, what is the right comparator for the study? Should it be ifosfamide and doxorubicin compared to evofosfamide and doxorubicin, or not?

It’s very interesting because they’re different designs that I think are both acceptable. But the question is, is it the right comparison to make? I think we can use some of the EORTC data we talked about earlier, of the doxorubicin plus ifosfamide versus doxorubicin as a comparator, to kind of judge whether this is similar or better than Ifosfamide. But it’s still, it’s difficult to compare studies in that way because the patient population is different and the study design is different.

So, I think we’re all eagerly awaiting the results from this study. The palifosfamide study was not significant in outcome in addition to doxorubicin. So, we’ll see what this one shows. But it still raises the question of, is it the right comparison?

Brian A. Van Tine, MD, PhD: So, I’d like to challenge my MD Anderson colleagues because they’re married to ifosfamide so much, to ask: if this becomes approved, how will it be used in soft tissue sarcoma?

Shreyaskumar R. Patel, MD: So, the available data is quite clear that this is a kinder, gentler ifosfamide, right? I think the toxicity profile is significantly better; the convenience and ease of administration is clearly better. I think, as Andy alluded to, the efficacy comparisons between ifosfamide and evofosfamide are truly unknown.

It will be very hard to draw cross-trial comparisons. But this would absolutely be a welcome addition to the therapeutic armamentarium. I think there are clearly candidates or patients who are not candidates for ifosfamide. There are our community oncology friends who may not feel comfortable with ifosfamide and probably shouldn’t be using it. For them, this might be a good addition for the patient population that they are treating. So, it will clearly have a place.

I think where on the landscape it falls will depend on the actual data from the trial as it comes out. And then, in many ways, I think we learn a lot about a new drug after its approval anyways, right? It’s the postmarketing, postapproval trials that will then determine how this changes the overall landscape of management for soft tissue sarcomas. It could completely bump ifosfamide off or it could be reserved for some select situations where ifosfamide would be appropriate, but not deliverable, because of toxicity or convenience or other reasons.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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