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Eribulin Mesylate 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: Friday, Sep 23, 2016



Transcript:

William D. Tap, MD:
What’s interesting is we’ve also been talking about this drug with our familiarity to it, right? We’ve chased it down, we’ve followed it, we fought for it. But I think, in the community, it’s not something yet that most doctors will be familiar with. Now, slightly different, is eribulin. Because eribulin has been FDA-approved in breast cancer, I imagine a lot of community doctors work with that. And there was a very similar study and a very similar approval. Shreyas, you were very prominent and influential in that study. I’ve seen you’re an author on the paper that got it approved. Why don’t you tell us a little bit about eribulin?

Shreyaskumar Patel, MD: So, this is another old-new drug. Not as old as trabectedin probably, certainly new for the sarcoma field, but older, relatively speaking, in the context of community oncologists having experience with it for the breast cancer population. The mechanism of action is interesting. I think, generally, or drilling it down to the very basics, it’s an antimitotic activity agent. But it exerts its antimitotic activity in a novel or a unique way, where it just binds to the positive end of the tubulin that then rises and doesn’t cause any adverse effects, if you will. More interesting, though, about the mechanism of action is, or may well may be, its effects on the tumor microenvironment. I think there is some evidence to suggest that it prevents invasion and migration of tumor cells, it prevents the epithelial mesenchymal transition (EMT), if you will, and maybe even some anti-angiogenic effect. It may be the effects on the tumor microenvironment. That’s what we were alluding to even with trabectedin, that they may be the more interesting effects, if you will, that explain some of the results.

The trial was designed very similarly. It shows you that the same culprits were designing the trials. It’s, again, based on the European phase II data, where what they call an episodic cycle of sarcomas—we’ll call them liposarcomas for our conversation—were the subsets where there was known activity or prominent activity. Those were chosen for the eligible population. Patients were randomized 1:1 between eribulin and dacarbazine, or DTIC, and were treated until maximum response. The drug is given intravenously on day 1 and day 8. Generally, it’s a very well-tolerated drug.

I think there are certain toxicities from the drug’s standpoint that one needs to keep in mind. One of the unique toxicities is peripheral neuropathy. Maybe approaching 20% of patients may see some degree of peripheral neuropathy; serious peripheral neuropathy is much less common. But if somebody was a diabetic, for example, and had preexisting neuropathy or had a preexisting neuropathy for other reasons like vincristine or something, one needs to be careful in using the drug. Neutropenia and neutropenic fever was not a major issue. Thrombocytopenia is much less common compared to dacarbazine, for example. So, the myelosuppressive effects are not that big a concern. Martee brought up the issue of alopecia in a patient population early on, and this is clearly a drug that does not cause alopecia. That can be a helpful issue. It’s less than other agents.

From an efficacy standpoint, I think the primary endpoint of the trial was overall survival. And it did improve overall survival by 2 or more months: 11 or 11.3 months versus 12.5 months or 10.3 months versus 12.5 months. And based on that endpoint, I think the drug got approved. But when you look at the Forest plots and look at the subsets, the leiomyosarcoma activity was identical or equivalent to the dacarbazine arm. The liposarcoma subset clearly did significantly better, where the median overall survivals were significantly different: 8 months versus 15 months. And because of that drastic difference, I think the FDA chose to approve this drug primarily for liposarcomas. You brought up the question of compare and contrast with trabectedin. Again, this may be one that’s the mirror image, if you will, of trabectedin, where the benefit seems to be far more profound in the well-differentiated liposarcoma subset compared with the myxoid liposarcoma. That probably was the reason why Damon said earlier that for the myxoid liposarcoma, he would put trabectedin to eribulin and vice versa for the well-differentiated liposarcoma.

I think this is a drug that has been around in the therapeutic armamentarium for oncologists who treat breast cancer a lot more often than they treat sarcomas. But certainly, from my personal standpoint, the approval is for liposarcoma. So, coverage can be an issue, but the way I would interpret the data is that it’s equally as effective for the leiomyosarcoma subset also. And in my personal experience, it’s generally been a well-tolerated drug that patients can take for the usual 6-month cycles and benefit from it.

William D. Tap, MD: I think that’s a great thing. In talking to Patrick Schöffski, who was one of those who also helped usher this drug through, there are nice responses in pleomorphic liposarcomas, which is something we haven’t spoken about either. But, liposarcoma disease, that was always thought to be chemotherapy-insensitive. Right now there are two drugs that are on the market. But I’m hearing there are these nuances of these studies, right? So, when we hear that drugs are FDA-approved, there are some nuances. And as experts, we’re hearing there may be a way that you’re positioning drugs when you look at patients. Liposarcoma, Mark, is the same thing? Do you have a way that you position them or would you position them?

Mark Agulnik, MD: I don’t think anything differently than what we’ve already discussed. And I think for the myxoid, the trabectedin is certainly higher, and eribulin is for the other subtypes traditionally.

George D. Demetri, MD: I think it also points out a problem with the way we design studies. Dacarbazine actually is more active than we want to give it credit for in leiomyosarcomas. So, the fact that eribulin was as active as dacarbazine, and it lost an FDA approval because of that, it’s a darn shame.

William D. Tap, MD: Correct.

George D. Demetri, MD: We weren’t trying to displace it. We were just trying to add a new agent to the armamentarium where we need more active agents.

William D. Tap, MD: That’s exactly right. And a lot of times, too, people will use dacarbazine with an anthracycline early on. So, it would have been nice to have another drug there. But, again, it’s still very impressive that some of these drugs are coming into the realm of what we can use.

Transcript Edited for Clarity

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Transcript:

William D. Tap, MD:
What’s interesting is we’ve also been talking about this drug with our familiarity to it, right? We’ve chased it down, we’ve followed it, we fought for it. But I think, in the community, it’s not something yet that most doctors will be familiar with. Now, slightly different, is eribulin. Because eribulin has been FDA-approved in breast cancer, I imagine a lot of community doctors work with that. And there was a very similar study and a very similar approval. Shreyas, you were very prominent and influential in that study. I’ve seen you’re an author on the paper that got it approved. Why don’t you tell us a little bit about eribulin?

Shreyaskumar Patel, MD: So, this is another old-new drug. Not as old as trabectedin probably, certainly new for the sarcoma field, but older, relatively speaking, in the context of community oncologists having experience with it for the breast cancer population. The mechanism of action is interesting. I think, generally, or drilling it down to the very basics, it’s an antimitotic activity agent. But it exerts its antimitotic activity in a novel or a unique way, where it just binds to the positive end of the tubulin that then rises and doesn’t cause any adverse effects, if you will. More interesting, though, about the mechanism of action is, or may well may be, its effects on the tumor microenvironment. I think there is some evidence to suggest that it prevents invasion and migration of tumor cells, it prevents the epithelial mesenchymal transition (EMT), if you will, and maybe even some anti-angiogenic effect. It may be the effects on the tumor microenvironment. That’s what we were alluding to even with trabectedin, that they may be the more interesting effects, if you will, that explain some of the results.

The trial was designed very similarly. It shows you that the same culprits were designing the trials. It’s, again, based on the European phase II data, where what they call an episodic cycle of sarcomas—we’ll call them liposarcomas for our conversation—were the subsets where there was known activity or prominent activity. Those were chosen for the eligible population. Patients were randomized 1:1 between eribulin and dacarbazine, or DTIC, and were treated until maximum response. The drug is given intravenously on day 1 and day 8. Generally, it’s a very well-tolerated drug.

I think there are certain toxicities from the drug’s standpoint that one needs to keep in mind. One of the unique toxicities is peripheral neuropathy. Maybe approaching 20% of patients may see some degree of peripheral neuropathy; serious peripheral neuropathy is much less common. But if somebody was a diabetic, for example, and had preexisting neuropathy or had a preexisting neuropathy for other reasons like vincristine or something, one needs to be careful in using the drug. Neutropenia and neutropenic fever was not a major issue. Thrombocytopenia is much less common compared to dacarbazine, for example. So, the myelosuppressive effects are not that big a concern. Martee brought up the issue of alopecia in a patient population early on, and this is clearly a drug that does not cause alopecia. That can be a helpful issue. It’s less than other agents.

From an efficacy standpoint, I think the primary endpoint of the trial was overall survival. And it did improve overall survival by 2 or more months: 11 or 11.3 months versus 12.5 months or 10.3 months versus 12.5 months. And based on that endpoint, I think the drug got approved. But when you look at the Forest plots and look at the subsets, the leiomyosarcoma activity was identical or equivalent to the dacarbazine arm. The liposarcoma subset clearly did significantly better, where the median overall survivals were significantly different: 8 months versus 15 months. And because of that drastic difference, I think the FDA chose to approve this drug primarily for liposarcomas. You brought up the question of compare and contrast with trabectedin. Again, this may be one that’s the mirror image, if you will, of trabectedin, where the benefit seems to be far more profound in the well-differentiated liposarcoma subset compared with the myxoid liposarcoma. That probably was the reason why Damon said earlier that for the myxoid liposarcoma, he would put trabectedin to eribulin and vice versa for the well-differentiated liposarcoma.

I think this is a drug that has been around in the therapeutic armamentarium for oncologists who treat breast cancer a lot more often than they treat sarcomas. But certainly, from my personal standpoint, the approval is for liposarcoma. So, coverage can be an issue, but the way I would interpret the data is that it’s equally as effective for the leiomyosarcoma subset also. And in my personal experience, it’s generally been a well-tolerated drug that patients can take for the usual 6-month cycles and benefit from it.

William D. Tap, MD: I think that’s a great thing. In talking to Patrick Schöffski, who was one of those who also helped usher this drug through, there are nice responses in pleomorphic liposarcomas, which is something we haven’t spoken about either. But, liposarcoma disease, that was always thought to be chemotherapy-insensitive. Right now there are two drugs that are on the market. But I’m hearing there are these nuances of these studies, right? So, when we hear that drugs are FDA-approved, there are some nuances. And as experts, we’re hearing there may be a way that you’re positioning drugs when you look at patients. Liposarcoma, Mark, is the same thing? Do you have a way that you position them or would you position them?

Mark Agulnik, MD: I don’t think anything differently than what we’ve already discussed. And I think for the myxoid, the trabectedin is certainly higher, and eribulin is for the other subtypes traditionally.

George D. Demetri, MD: I think it also points out a problem with the way we design studies. Dacarbazine actually is more active than we want to give it credit for in leiomyosarcomas. So, the fact that eribulin was as active as dacarbazine, and it lost an FDA approval because of that, it’s a darn shame.

William D. Tap, MD: Correct.

George D. Demetri, MD: We weren’t trying to displace it. We were just trying to add a new agent to the armamentarium where we need more active agents.

William D. Tap, MD: That’s exactly right. And a lot of times, too, people will use dacarbazine with an anthracycline early on. So, it would have been nice to have another drug there. But, again, it’s still very impressive that some of these drugs are coming into the realm of what we can use.

Transcript Edited for Clarity
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