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Phase III Data on Eribulin in Advanced STS

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: Wednesday, Jan 27, 2016



Transcript:

Brian A. Van Tine, MD, PhD:
So, I’d like to move on to one last drug before we conclude. And I think Dr. Schöffski did a wonderful job this year presenting our phase III data on another drug called eribulin. Jonathan, do you want to talk a little bit, not only about what eribulin is, but actually this trial?

Jonathan C. Trent, MD: Yeah. Eribulin is a dynamic microtubule inhibitor, so its mechanism of action is similar to other agents that we use in the sarcoma world in terms of inhibiting microtubules. It showed some promising activity in sarcoma in the original phase I trial. This was followed up by a phase II, and then this phase III trial of 452 patients were randomized equally to either eribulin day 1, day 8, or dacarbazine, which is a common comparator arm that you’re seeing in our trials.

In this study, the eribulin arm provided a superior overall survival of 13.5 months versus 11.5 with dacarbazine. So again, a superior overall survival. Interestingly, there was no progression-free survival benefit either in this study. And so it does show promise in terms of overall survival, which was the, in this study, the primary end point. So, this phase III study certainly should be considered for approval by the agencies I would think for, or at least discussed for, metastatic soft tissue sarcomas.

Back to the issue of overall survival benefit, in terms of a lack of progression-free survival, it could have to do with a number of different things: the biology of these drugs may be acting differently in terms of post-progression efficacy or there could be cross-over in this study, as well as the other studies.

Brian A. Van Tine, MD, PhD: I think it’s interesting that the NCCN panel has already actually included this on the guidelines. Andy, where do you see this actually fitting into where you are treating patients?

Andrew J. Wagner, MD, PhD: I think this is an unusual situation for sarcomas when we’re on the verge of potentially having many drugs to choose from without defined positioning in terms of clinical trial design, to say, for a second-, third-, fourth-, fifth-line treatment. Again, the study was restricted to leiomyosarcomas and liposarcomas, and I would still look at those subgroups as potential treatment options.

And coming back to the comments we’ve made before, which is, let’s look at our patients, let’s look at what toxicity profile is most important for that patient in terms of choosing the drugs. We could have these options of the same different drugs. It could be Adriamycin/ifosfamide. It could be Adriamycin/olaratumab. It could be trabectedin. It could be eribulin. It’s going to be a dealer’s choice, I think, for a lot of these things looking at, again, the features of the patient.

What’s the patient’s performance status like? What’s their need for cytoreductive therapy and shrinkage of the tumor? What’s their need for their tolerance for different toxicities?

Brian A. Van Tine, MD, PhD: I think that’s well put. There was a brief abstract presented this year on regorafenib. Do you have any thoughts on that, Shreyas?

Shreyaskumar R. Patel, MD: I think a simple, short comment would be that this is, from a kinase inhibition spectrum standpoint, relatively or close enough to pazopanib. And the activity that they saw in the three cohorts that they tested was fairly comparable to what they saw in pazopanib.

There is an ongoing SARC trial looking at regorafenib in a few different subsets, so I think it’s in keeping with what would be expected given how much you can extrapolate from their kinase inhibition spectrum.

Brian A. Van Tine, MD, PhD: I think this is exciting and only says we need more clinical trials. I think that’s the one thing I’m hoping we can all agree on. But one final question, Robin, with this and if you throw in a drug we haven’t talked about which is a reformulation of albumin and bound Adriamycin, and called aldoxorubicin. We really have this huge flux in our front-line therapy.

What do you think the future of combination therapy, if you were to actually be able to go 5 years in the future and look back, where do you think we’re going to go?

Robin L. Jones, MD, MRCP: In response, I think there’s definitely a future for combination therapy. I think the optimal schedule and sequence, as you allude, really remains to be defined by ongoing clinical trials and future clinical trials. I think this is an evolving field, a rapidly evolving field.

I’m not going to give a definitive answer in terms of the optimal schedule. But I think in terms of combination therapy, yes, for sure, there’s a future and it’s good to have a choice of different drugs that are showing promise in these rare diseases.

Brian A. Van Tine, MD, PhD: Dr. Randall, one of the privileges of sitting around at the multidisciplinary tumor board not giving chemo is you get to watch. And what are your feelings about when we should transition patients from active to true conservative, palliative, hospice-type treatments?

R. Lor Randall, MD, FACS: It’s an issue that’s near and dear to my heart. We all know that as oncologists, whether we be medical, pediatric, radiation, or surgical, our mission is to prolong life. But as we’ve all resonated again today, maintaining quality of life is very important and it becomes a personal decision you make with, not for, a patient and their family. And that trigger point is different for everyone, and that’s why the communication is so important and gets back to our opening comments about the social workers, survivorship issues.

Some people, unfortunately, have a lot of pressure also to keep fighting because they feel their family will be disappointed in them if they don’t keep fighting, but they’re actually exhausted. And it’s a hard discussion when to say enough is enough and let’s emphasize on today and your quality of life today and not worry about the future so much. But let’s make you happy now so that you can enjoy the time you have. That’s a hard thing. I don’t think any of us has a pet answer for that. But it’s something that we all need to carry with us every single day with our, with our families.

Brian A. Van Tine, MD, PhD: I think that’s well said, and I think that it’s one of the—it makes the treatment of sarcoma, now that we have so many more drugs, even more complicated.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity

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Transcript:

Brian A. Van Tine, MD, PhD:
So, I’d like to move on to one last drug before we conclude. And I think Dr. Schöffski did a wonderful job this year presenting our phase III data on another drug called eribulin. Jonathan, do you want to talk a little bit, not only about what eribulin is, but actually this trial?

Jonathan C. Trent, MD: Yeah. Eribulin is a dynamic microtubule inhibitor, so its mechanism of action is similar to other agents that we use in the sarcoma world in terms of inhibiting microtubules. It showed some promising activity in sarcoma in the original phase I trial. This was followed up by a phase II, and then this phase III trial of 452 patients were randomized equally to either eribulin day 1, day 8, or dacarbazine, which is a common comparator arm that you’re seeing in our trials.

In this study, the eribulin arm provided a superior overall survival of 13.5 months versus 11.5 with dacarbazine. So again, a superior overall survival. Interestingly, there was no progression-free survival benefit either in this study. And so it does show promise in terms of overall survival, which was the, in this study, the primary end point. So, this phase III study certainly should be considered for approval by the agencies I would think for, or at least discussed for, metastatic soft tissue sarcomas.

Back to the issue of overall survival benefit, in terms of a lack of progression-free survival, it could have to do with a number of different things: the biology of these drugs may be acting differently in terms of post-progression efficacy or there could be cross-over in this study, as well as the other studies.

Brian A. Van Tine, MD, PhD: I think it’s interesting that the NCCN panel has already actually included this on the guidelines. Andy, where do you see this actually fitting into where you are treating patients?

Andrew J. Wagner, MD, PhD: I think this is an unusual situation for sarcomas when we’re on the verge of potentially having many drugs to choose from without defined positioning in terms of clinical trial design, to say, for a second-, third-, fourth-, fifth-line treatment. Again, the study was restricted to leiomyosarcomas and liposarcomas, and I would still look at those subgroups as potential treatment options.

And coming back to the comments we’ve made before, which is, let’s look at our patients, let’s look at what toxicity profile is most important for that patient in terms of choosing the drugs. We could have these options of the same different drugs. It could be Adriamycin/ifosfamide. It could be Adriamycin/olaratumab. It could be trabectedin. It could be eribulin. It’s going to be a dealer’s choice, I think, for a lot of these things looking at, again, the features of the patient.

What’s the patient’s performance status like? What’s their need for cytoreductive therapy and shrinkage of the tumor? What’s their need for their tolerance for different toxicities?

Brian A. Van Tine, MD, PhD: I think that’s well put. There was a brief abstract presented this year on regorafenib. Do you have any thoughts on that, Shreyas?

Shreyaskumar R. Patel, MD: I think a simple, short comment would be that this is, from a kinase inhibition spectrum standpoint, relatively or close enough to pazopanib. And the activity that they saw in the three cohorts that they tested was fairly comparable to what they saw in pazopanib.

There is an ongoing SARC trial looking at regorafenib in a few different subsets, so I think it’s in keeping with what would be expected given how much you can extrapolate from their kinase inhibition spectrum.

Brian A. Van Tine, MD, PhD: I think this is exciting and only says we need more clinical trials. I think that’s the one thing I’m hoping we can all agree on. But one final question, Robin, with this and if you throw in a drug we haven’t talked about which is a reformulation of albumin and bound Adriamycin, and called aldoxorubicin. We really have this huge flux in our front-line therapy.

What do you think the future of combination therapy, if you were to actually be able to go 5 years in the future and look back, where do you think we’re going to go?

Robin L. Jones, MD, MRCP: In response, I think there’s definitely a future for combination therapy. I think the optimal schedule and sequence, as you allude, really remains to be defined by ongoing clinical trials and future clinical trials. I think this is an evolving field, a rapidly evolving field.

I’m not going to give a definitive answer in terms of the optimal schedule. But I think in terms of combination therapy, yes, for sure, there’s a future and it’s good to have a choice of different drugs that are showing promise in these rare diseases.

Brian A. Van Tine, MD, PhD: Dr. Randall, one of the privileges of sitting around at the multidisciplinary tumor board not giving chemo is you get to watch. And what are your feelings about when we should transition patients from active to true conservative, palliative, hospice-type treatments?

R. Lor Randall, MD, FACS: It’s an issue that’s near and dear to my heart. We all know that as oncologists, whether we be medical, pediatric, radiation, or surgical, our mission is to prolong life. But as we’ve all resonated again today, maintaining quality of life is very important and it becomes a personal decision you make with, not for, a patient and their family. And that trigger point is different for everyone, and that’s why the communication is so important and gets back to our opening comments about the social workers, survivorship issues.

Some people, unfortunately, have a lot of pressure also to keep fighting because they feel their family will be disappointed in them if they don’t keep fighting, but they’re actually exhausted. And it’s a hard discussion when to say enough is enough and let’s emphasize on today and your quality of life today and not worry about the future so much. But let’s make you happy now so that you can enjoy the time you have. That’s a hard thing. I don’t think any of us has a pet answer for that. But it’s something that we all need to carry with us every single day with our, with our families.

Brian A. Van Tine, MD, PhD: I think that’s well said, and I think that it’s one of the—it makes the treatment of sarcoma, now that we have so many more drugs, even more complicated.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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