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Registration Trials for Olaratumab and Doxorubicin for STS

Insights From: Mark Agulnik, MD, Northwestern University Feinberg School of Medicine; Brian Van Tine, MD, PhD, Washington University; Richard F. Riedel, MD, Duke University Health System; Victor Villalobos, MD, PhD, University of Colorado Denver
Published: Friday, Dec 23, 2016


Transcript:

Brian Van Tine, MD, PhD:
Going back to the very beginning of this trial, this was designed as a phase I/II trial. And so, if you go back to the original investigator’s meeting where Gary Schwartz brought together a group of people, what he did was do a toxicity lead-in to a randomized phase II. This randomized phase II had one arm where patients got the combination of doxorubicin with olaratumab. In the other, they were randomized to get doxorubicin and upon failure, go on to olaratumab independently.

I think what comes out of this is a really striking, overall survival for the combination over monotherapy, which is 11.8 months. This is statistically significant. And it was a very striking observation because it was the first time we’ve really seen, in a randomized trial, a huge overall survival benefit of a drug. Whereas, eribulin was only in liposarcoma. This was across all the sarcomas because we found something that worked in combination with doxorubicin to make it work better. If you look at the progression-free survival, it was 6.6 months for the combination, but 4.1 months for monotherapy with just doxorubicin alone. Although this wasn’t statistically significant, it borderlined on it. But, what we see is that the addition of this monoclonal antibody has an effect that really does seem to change the overall survival and treatment course of a patient, which may actually, fundamentally alter the biology of sarcoma. This is leading to a lot of neat, new opportunities to develop this drug in our space.

Victor Villalobos, MD, PhD: The design of the phase Ib, phase II trial was a randomized design looking at doxorubicin alone versus doxorubicin plus olaratumab. There was a lead-in to look at safety within the first 15 patients. And so, the dosing scheme was the same for doxorubicin and there was no placebo control. So, it was an open-labeled design.

The primary endpoint was actually progression-free survival. And, even though the P-value for this study was 0.06, it still actually met the primary endpoint because they were looking for a P-value of 0.2 or less. It is a smaller study. So, the PFS benefit was a little over 2-1/2 months with the combination, which is similar to what we’ve seen actually with other combination drugs. But, what was most striking with this trial—and there was a secondary endpoint—was overall survival benefit. What we saw was that it was nearly 1 year of median overall survival benefit with a combination over doxorubicin alone. Looking at the prior EORTC studies where AIM, or Adriamycin/ifosfamide/mesna, had overall survival benefit, median overall survival of about 14-1/2 months versus doxorubicin alone having a survival benefit about 12-1/2 months. This one doxorubicin alone arm matched similarly to that. It was about 14 months or so for doxorubicin alone, but the combination had over 26-month median overall survival.

Also, importantly, the tail of the Kaplan-Meier Curves was higher with the combination arm, suggesting people are living a lot longer at the end. And so, the combination arm had about 40% long-term survivals, whereas the doxorubicin arm had about 20%. So, really ‘unexpected’ is what I would say that this trial is because of really the true overall benefit. But, that really has been dramatic, and I’m quite hopeful that it will continue and the phase III trial will confirm those results.

Richard F. Riedel, MD: In the phase II study, the primary outcome was progression-free survival, and that was assessed via radiographic assessments on their CT scan or MRI. Investigator assessment was used for the study primarily, and that’s using individual investigators at the individual sites where the study was being performed. An alternative way to look at progression-free survival is through an independent central review where you take all the CT scans from the individual sites, you send them to a central site, and have an individual or small group of individuals evaluate the CT scans. That’s a more attractive approach in the sense that there’s a standardization regarding how images are assessed and how the evaluation is performed. In this phase II study by investigator-assessed progression-free survival, the combination of olaratumab with doxorubicin revealed a progression-free survival of approximately 6.6 months compared to 4.1 months for doxorubicin alone. In the independent central review, the independent assessment, the progression-free survival for the combination was 8.2 months compared to 4.4 months for doxorubicin alone. So, you can see between those two assessments there can be some variability.

Victor Villalobos, MD, PhD: With regard to the investigator versus independent radiologic assessments, there were some minor differences. But, in general for the PFS, the progression-free survival, the hazard ratio was exactly the same. It was 0.67 for both. There were some minor differences in the doxorubicin arm as far as response rates, and the independent arms actually showed poor response rates for the doxorubicin arm. PFS is always a tricky endpoint because there’s always some inner-reader variation. You know a difference of 1 or 2 millimeters can make a difference as far as someone is responding or not. And so, there’s always some error to be found in PFS. That’s why perhaps overall survival is an unbiased approach because it’s a very hard endpoint there. So, overall, I think it matched relatively well, and it did not change the outcomes of the study.

Interestingly, the subgroup analysis for this study favored the combination over doxorubicin alone in pretty much all subsets. It was also very striking that PDGFRα expression had almost no effect on the benefit and actually people, even with negative expression of PDGFRα, had benefit over doxorubicin. Now, not all the benefits were statistically significant, but, in general, if you look at the graph, everything is to the left of that line there. And so, it was very consistent overall.

It’s oftentimes very difficult to actually compare different subtypes of sarcoma because they’re so rare, and they actually enrolled a quite diverse set of tumors. So, not every tumor had a paired tumor on both sides of the treatment protocol. But, the ones that were most common were leiomyosarcomas, and those, it made no difference whether it was leiomyosarcoma or not. They both had benefit with a combination in general. I think, overall, it’s clear that we should not segregate patients based on their subtype or PDGRFα expression. I think they would both benefit with the combination in general.

Brian Van Tine, MD, PhD: One of the things that’s ongoing right now is an accrued trial, which is actually a confirmatory phase III randomized, blinded trial. And, in this trial, what we’ve done is randomize people to getting doxorubicin with olaratumab or doxorubicin with placebo completely blinded to the investigators and to the patients. So, this would be the big confirmatory trial that will report out in the next couple of years. As you can see, there’s already 1-year overall survival of the combinations, so to get enough events, this will actually probably take a lot longer than just this contingent label that we have to actually report out and to confirm. This is just an exciting time to have a brand new molecule.

Transcript Edited for Clarity
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Transcript:

Brian Van Tine, MD, PhD:
Going back to the very beginning of this trial, this was designed as a phase I/II trial. And so, if you go back to the original investigator’s meeting where Gary Schwartz brought together a group of people, what he did was do a toxicity lead-in to a randomized phase II. This randomized phase II had one arm where patients got the combination of doxorubicin with olaratumab. In the other, they were randomized to get doxorubicin and upon failure, go on to olaratumab independently.

I think what comes out of this is a really striking, overall survival for the combination over monotherapy, which is 11.8 months. This is statistically significant. And it was a very striking observation because it was the first time we’ve really seen, in a randomized trial, a huge overall survival benefit of a drug. Whereas, eribulin was only in liposarcoma. This was across all the sarcomas because we found something that worked in combination with doxorubicin to make it work better. If you look at the progression-free survival, it was 6.6 months for the combination, but 4.1 months for monotherapy with just doxorubicin alone. Although this wasn’t statistically significant, it borderlined on it. But, what we see is that the addition of this monoclonal antibody has an effect that really does seem to change the overall survival and treatment course of a patient, which may actually, fundamentally alter the biology of sarcoma. This is leading to a lot of neat, new opportunities to develop this drug in our space.

Victor Villalobos, MD, PhD: The design of the phase Ib, phase II trial was a randomized design looking at doxorubicin alone versus doxorubicin plus olaratumab. There was a lead-in to look at safety within the first 15 patients. And so, the dosing scheme was the same for doxorubicin and there was no placebo control. So, it was an open-labeled design.

The primary endpoint was actually progression-free survival. And, even though the P-value for this study was 0.06, it still actually met the primary endpoint because they were looking for a P-value of 0.2 or less. It is a smaller study. So, the PFS benefit was a little over 2-1/2 months with the combination, which is similar to what we’ve seen actually with other combination drugs. But, what was most striking with this trial—and there was a secondary endpoint—was overall survival benefit. What we saw was that it was nearly 1 year of median overall survival benefit with a combination over doxorubicin alone. Looking at the prior EORTC studies where AIM, or Adriamycin/ifosfamide/mesna, had overall survival benefit, median overall survival of about 14-1/2 months versus doxorubicin alone having a survival benefit about 12-1/2 months. This one doxorubicin alone arm matched similarly to that. It was about 14 months or so for doxorubicin alone, but the combination had over 26-month median overall survival.

Also, importantly, the tail of the Kaplan-Meier Curves was higher with the combination arm, suggesting people are living a lot longer at the end. And so, the combination arm had about 40% long-term survivals, whereas the doxorubicin arm had about 20%. So, really ‘unexpected’ is what I would say that this trial is because of really the true overall benefit. But, that really has been dramatic, and I’m quite hopeful that it will continue and the phase III trial will confirm those results.

Richard F. Riedel, MD: In the phase II study, the primary outcome was progression-free survival, and that was assessed via radiographic assessments on their CT scan or MRI. Investigator assessment was used for the study primarily, and that’s using individual investigators at the individual sites where the study was being performed. An alternative way to look at progression-free survival is through an independent central review where you take all the CT scans from the individual sites, you send them to a central site, and have an individual or small group of individuals evaluate the CT scans. That’s a more attractive approach in the sense that there’s a standardization regarding how images are assessed and how the evaluation is performed. In this phase II study by investigator-assessed progression-free survival, the combination of olaratumab with doxorubicin revealed a progression-free survival of approximately 6.6 months compared to 4.1 months for doxorubicin alone. In the independent central review, the independent assessment, the progression-free survival for the combination was 8.2 months compared to 4.4 months for doxorubicin alone. So, you can see between those two assessments there can be some variability.

Victor Villalobos, MD, PhD: With regard to the investigator versus independent radiologic assessments, there were some minor differences. But, in general for the PFS, the progression-free survival, the hazard ratio was exactly the same. It was 0.67 for both. There were some minor differences in the doxorubicin arm as far as response rates, and the independent arms actually showed poor response rates for the doxorubicin arm. PFS is always a tricky endpoint because there’s always some inner-reader variation. You know a difference of 1 or 2 millimeters can make a difference as far as someone is responding or not. And so, there’s always some error to be found in PFS. That’s why perhaps overall survival is an unbiased approach because it’s a very hard endpoint there. So, overall, I think it matched relatively well, and it did not change the outcomes of the study.

Interestingly, the subgroup analysis for this study favored the combination over doxorubicin alone in pretty much all subsets. It was also very striking that PDGFRα expression had almost no effect on the benefit and actually people, even with negative expression of PDGFRα, had benefit over doxorubicin. Now, not all the benefits were statistically significant, but, in general, if you look at the graph, everything is to the left of that line there. And so, it was very consistent overall.

It’s oftentimes very difficult to actually compare different subtypes of sarcoma because they’re so rare, and they actually enrolled a quite diverse set of tumors. So, not every tumor had a paired tumor on both sides of the treatment protocol. But, the ones that were most common were leiomyosarcomas, and those, it made no difference whether it was leiomyosarcoma or not. They both had benefit with a combination in general. I think, overall, it’s clear that we should not segregate patients based on their subtype or PDGRFα expression. I think they would both benefit with the combination in general.

Brian Van Tine, MD, PhD: One of the things that’s ongoing right now is an accrued trial, which is actually a confirmatory phase III randomized, blinded trial. And, in this trial, what we’ve done is randomize people to getting doxorubicin with olaratumab or doxorubicin with placebo completely blinded to the investigators and to the patients. So, this would be the big confirmatory trial that will report out in the next couple of years. As you can see, there’s already 1-year overall survival of the combinations, so to get enough events, this will actually probably take a lot longer than just this contingent label that we have to actually report out and to confirm. This is just an exciting time to have a brand new molecule.

Transcript Edited for Clarity
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