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Early Data With Olaratumab 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: Tuesday, Jan 12, 2016



Transcript:

Brian A. Van Tine, MD, PhD:
I’d like to transition to another molecule that I grew up using. I seem to have shown up in the field at the right times.

Shreyaskumar R. Patel, MD: That’s assuming you’re grown up already.

Brian A. Van Tine, MD, PhD: That is actually a very bad assumption. So, there was a wonderful molecule called IMC-3G3, which was an ImClone compound that was wonderfully developed initially by Gary Schwartz and Lilly in a phase I/II clinical trial which was the first investigator meeting I ever got to go to.

It now has a name, and this name of this compound is olaratumab, which is a bit of a tongue-twister. Robin, since you have actually used a lot of this also, what is this?

Robin L. Jones, MD, MRCP: So, this is a monoclonal antibody to PDGFR-alpha, platelet-derived growth factor receptor-alpha. Again, this is given intravenously on days 1 and 8 of a 3-week cycle. Dr. Gary Schwartz has done a fair bit of preclinical work assessing the use of this compound in sarcoma, and there’s some very interesting data suggesting a good effect in combination with doxorubicin in sarcoma models. And this basically led to the phase I/II trial in advanced and metastatic soft tissue sarcoma.

Brian A. Van Tine, MD, PhD: Jonathan, this is a very interesting phase I/II trial that had kind of a spectacular overall survival, which was seen not in a phase III trial, but in a phase II. But it made a lot of people stand up and notice. What do you think the significance of that is?

Jonathan C. Trent, MD: Cautious optimism. But seriously, the trial did show a substantially superior overall survival compared to the control arm. I think that what really should be expected of this drug is additional investigation, such as a phase III trial, showing that olaratumab plus doxorubicin is superior to doxorubicin alone in terms of overall survival in the study. It really needs to be looked at in a phase III study, in my opinion.

Then the question will also arise is single agent doxorubicin the appropriate comparator arm? That will also have to be revisited. However, I am optimistic that this promising activity, in terms of the combination, will hopefully one day give us additional therapeutic options.

Andrew J. Wagner, MD, PhD: Jon, for this study I actually think this is the right comparison because it’s not “replacement,” if you will, of a type of drug like ifosfamide. If this is positive, or even if it’s negative, I think it would be a great comparison to look at doxorubicin and ifosfamide with or without olaratumab, for example.

Jonathan C. Trent, MD: Yeah. The only criticism is then, if you prove that this combination is superior to doxorubicin, then you’re saying that this is the new regimen for those patients whom you think single-agent doxorubicin is appropriate. That’s certainly a good indication, but that may be limiting the population that you could help with an additional therapy. So, showing that this regimen is superior to doxorubicin/ifosfamide or a doublet would then allow you to help more people with a more active regimen.

Andrew J. Wagner, MD, PhD: I think what’s striking, though, about the phase II study, and it’s making us scratch our heads, is a dramatic improvement in overall survival, but no improvement in progression-free survival. That’s in contrast to the PALETTE study and the trabectedin study, which both showed PFS but no overall survival.

And I think I agree, Jon, that cautious optimism is really important. I think it’s dramatic, but it’s a small study, 60 patients in each arm, 60-some patients in each arm, not designed to look at overall survival as a primary endpoint. I think we just need the phase III study to really define this because the potential is there that the arms were imbalanced in some way that we can’t detect.

Jonathan C. Trent, MD: And back to your point about continuing therapy, such as with trabectedin, such as we do with tyrosine kinase inhibitors and GIST. Patients that were randomized and treated with olaratumab plus doxorubicin were able to stop doxorubicin and continue the anti-PDGF-receptor inhibitor therapy, which may play a role in extending overall survival.

Brian A. Van Tine, MD, PhD: The other thing that’s really interesting is if you get into PDGF biology, this may be the first drug we’re using that alters the mesenchymal microenvironment, which alters the mesenchymal tumor biology in a way where we’re not really truly understanding, but we may be actually growing something out that’s different than what we started.

Robin L. Jones, MD, MRCP: And that may account for this discrepancy in terms of the progression-free survival and overall survival results of the trial.

Andrew J. Wagner, MD, PhD: It certainly could.

Robin L. Jones, MD, MRCP: I take your point regarding the number of patients in the study and, the heterogeneity, basically, of sarcomas, but the trial was powered for overall survival.

Andrew J. Wagner, MD, PhD: So, I guess my point is that there are other characteristics that could play a role in the 60 patients in each arm, which could be, for example, one group had bulkier disease than another and so they had fewer, a shorter survival after progression than another group.

Robin L. Jones, MD, MRCP: Point taken. Yeah.

Andrew J. Wagner, MD, PhD: And so that’s where we need a larger study to look at that.

Robin L. Jones, MD, MRCP: Yes. Agreed.

Brian A. Van Tine, MD, PhD: So, you know, kind of looking in the tea leaves, I’m beginning to see a chalk regimen kind of come together where we have an Adria/ifosfamide with a monoclonal antibody eventually evolving. Dr. Patel, do you think there are any conclusions that can be drawn at this point about these two novel agents in terms of safety, efficacy, patient selection? Or do you think it’s too early?

Shreyaskumar R. Patel, MD: Well, I think the conclusions that can be drawn are what we’ve already talked about: that they’re clearly drugs of interest and absolutely deserve further development. I think we have a short list of drugs. We’re clearly looking for additional therapeutic modalities to help our patients, and there’s clearly promise. Will it be delivered as promised and will it hold up over a period of time I think are questions that only time will answer.

But clearly, I think evofosfamide and olaratumab, and I think one of the critical things here is, up until now we’ve always tested drugs with some maybe possibly additive effects at the expense of toxicities. Here is one where there may well be some synergy, and that’s exactly what will get us some logarithmic benefit and get to the next level. So, both drugs are clearly exciting. I think if they fulfill the promise and get approved and hold up, I think the landscape of therapy for sarcoma patients will clearly change.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity

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Transcript:

Brian A. Van Tine, MD, PhD:
I’d like to transition to another molecule that I grew up using. I seem to have shown up in the field at the right times.

Shreyaskumar R. Patel, MD: That’s assuming you’re grown up already.

Brian A. Van Tine, MD, PhD: That is actually a very bad assumption. So, there was a wonderful molecule called IMC-3G3, which was an ImClone compound that was wonderfully developed initially by Gary Schwartz and Lilly in a phase I/II clinical trial which was the first investigator meeting I ever got to go to.

It now has a name, and this name of this compound is olaratumab, which is a bit of a tongue-twister. Robin, since you have actually used a lot of this also, what is this?

Robin L. Jones, MD, MRCP: So, this is a monoclonal antibody to PDGFR-alpha, platelet-derived growth factor receptor-alpha. Again, this is given intravenously on days 1 and 8 of a 3-week cycle. Dr. Gary Schwartz has done a fair bit of preclinical work assessing the use of this compound in sarcoma, and there’s some very interesting data suggesting a good effect in combination with doxorubicin in sarcoma models. And this basically led to the phase I/II trial in advanced and metastatic soft tissue sarcoma.

Brian A. Van Tine, MD, PhD: Jonathan, this is a very interesting phase I/II trial that had kind of a spectacular overall survival, which was seen not in a phase III trial, but in a phase II. But it made a lot of people stand up and notice. What do you think the significance of that is?

Jonathan C. Trent, MD: Cautious optimism. But seriously, the trial did show a substantially superior overall survival compared to the control arm. I think that what really should be expected of this drug is additional investigation, such as a phase III trial, showing that olaratumab plus doxorubicin is superior to doxorubicin alone in terms of overall survival in the study. It really needs to be looked at in a phase III study, in my opinion.

Then the question will also arise is single agent doxorubicin the appropriate comparator arm? That will also have to be revisited. However, I am optimistic that this promising activity, in terms of the combination, will hopefully one day give us additional therapeutic options.

Andrew J. Wagner, MD, PhD: Jon, for this study I actually think this is the right comparison because it’s not “replacement,” if you will, of a type of drug like ifosfamide. If this is positive, or even if it’s negative, I think it would be a great comparison to look at doxorubicin and ifosfamide with or without olaratumab, for example.

Jonathan C. Trent, MD: Yeah. The only criticism is then, if you prove that this combination is superior to doxorubicin, then you’re saying that this is the new regimen for those patients whom you think single-agent doxorubicin is appropriate. That’s certainly a good indication, but that may be limiting the population that you could help with an additional therapy. So, showing that this regimen is superior to doxorubicin/ifosfamide or a doublet would then allow you to help more people with a more active regimen.

Andrew J. Wagner, MD, PhD: I think what’s striking, though, about the phase II study, and it’s making us scratch our heads, is a dramatic improvement in overall survival, but no improvement in progression-free survival. That’s in contrast to the PALETTE study and the trabectedin study, which both showed PFS but no overall survival.

And I think I agree, Jon, that cautious optimism is really important. I think it’s dramatic, but it’s a small study, 60 patients in each arm, 60-some patients in each arm, not designed to look at overall survival as a primary endpoint. I think we just need the phase III study to really define this because the potential is there that the arms were imbalanced in some way that we can’t detect.

Jonathan C. Trent, MD: And back to your point about continuing therapy, such as with trabectedin, such as we do with tyrosine kinase inhibitors and GIST. Patients that were randomized and treated with olaratumab plus doxorubicin were able to stop doxorubicin and continue the anti-PDGF-receptor inhibitor therapy, which may play a role in extending overall survival.

Brian A. Van Tine, MD, PhD: The other thing that’s really interesting is if you get into PDGF biology, this may be the first drug we’re using that alters the mesenchymal microenvironment, which alters the mesenchymal tumor biology in a way where we’re not really truly understanding, but we may be actually growing something out that’s different than what we started.

Robin L. Jones, MD, MRCP: And that may account for this discrepancy in terms of the progression-free survival and overall survival results of the trial.

Andrew J. Wagner, MD, PhD: It certainly could.

Robin L. Jones, MD, MRCP: I take your point regarding the number of patients in the study and, the heterogeneity, basically, of sarcomas, but the trial was powered for overall survival.

Andrew J. Wagner, MD, PhD: So, I guess my point is that there are other characteristics that could play a role in the 60 patients in each arm, which could be, for example, one group had bulkier disease than another and so they had fewer, a shorter survival after progression than another group.

Robin L. Jones, MD, MRCP: Point taken. Yeah.

Andrew J. Wagner, MD, PhD: And so that’s where we need a larger study to look at that.

Robin L. Jones, MD, MRCP: Yes. Agreed.

Brian A. Van Tine, MD, PhD: So, you know, kind of looking in the tea leaves, I’m beginning to see a chalk regimen kind of come together where we have an Adria/ifosfamide with a monoclonal antibody eventually evolving. Dr. Patel, do you think there are any conclusions that can be drawn at this point about these two novel agents in terms of safety, efficacy, patient selection? Or do you think it’s too early?

Shreyaskumar R. Patel, MD: Well, I think the conclusions that can be drawn are what we’ve already talked about: that they’re clearly drugs of interest and absolutely deserve further development. I think we have a short list of drugs. We’re clearly looking for additional therapeutic modalities to help our patients, and there’s clearly promise. Will it be delivered as promised and will it hold up over a period of time I think are questions that only time will answer.

But clearly, I think evofosfamide and olaratumab, and I think one of the critical things here is, up until now we’ve always tested drugs with some maybe possibly additive effects at the expense of toxicities. Here is one where there may well be some synergy, and that’s exactly what will get us some logarithmic benefit and get to the next level. So, both drugs are clearly exciting. I think if they fulfill the promise and get approved and hold up, I think the landscape of therapy for sarcoma patients will clearly change.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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