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PHEREXA Trial in HER2+ Disease

Panelists:Adam M. Brufsky, MD, PhD, University of Pittsburgh Cancer Institute;Carlos L. Arteaga, MD, Vanderbilt University;Kimberly L. Blackwell, MD, Duke University Medical Center;Joyce A. O’Shaughnessy, MD, Baylor Charles A. Sammons Cancer Center;Sunil Verma, MD, MSEd, FRCPC, University of Calgary
Published: Friday, Aug 05, 2016


Transcript:

Adam M. Brufsky, MD, PhD:
Let’s move on to a few more HER2 topics before we get to tyrosine kinase inhibitors in HER2. The first one is there was a trial that was presented at ASCO, PHEREXA. Sunil, I think, actually, you are the discussant of PHEREXA at this year’s meeting. So, can you comment on that?

Sunil Verma, MD, MSEd, FRCPC: PHEREXA, I think, is an important study. It was done pre-integration of T-DM1, in the context of metastatic breast cancer. These were patients who had prior metastatic trastuzumab for advanced breast cancer and then were randomized to either capecitabine/trastuzumab or capecitabine/trastuzumab plus pertuzumab; initially a phase II trial that was then expanded to a phase III setting. And what it showed was that there was a difference in PFS; however, it’s not statistically significant. It went from 9 months to 11 months. The 9 months with capecitabine/trastuzumab is pretty good, much better than what we have seen traditionally. And then the overall survival, there was an 8-month difference. But because it was a hierarchical statistical design—because the P value was not significant for PFS—they can’t really look at the P value for overall survival.

So, where does that leave us? And, basically, my discussion is going to be that this is a negative trial; it was an underpowered study. Yes, pertuzumab does appear to have activity in this trastuzumab pretreated patient population; we have seen that. However, we cannot justify the use of this based on this negative trial and especially when we have other options, like T-DM1, now for those patients who have had trastuzumab. Would this study have been meaningful maybe a couple of years ago because we had some patients who never got a chance to receive pertuzumab in the first-line? Sure, but now the majority of patients would have gotten pertuzumab now that we have T-DM1 in the second line. Really, the clinical meaningfulness of this study is much limited as a result and, at the end of the day, is a negative trial.

Joyce A. O’Shaughnessy, MD: I completely agree with everything you said. From a practical standpoint for patients who have not had pertuzumab, to me, the 8-month improvement in survival—which was a little hampered by the fact that you couldn’t put a P value on it—still is very impressive and shows what we already know about pertuzumab from the frontline CLEOPATRA trial. And I think it justifies the use of getting one line of pertuzumab in the metastatic setting. Because I hope the trial is not used to saying that, “Gee, you have to get it in the frontline, or you don’t get it at all,” basically, because I don’t agree with that from the interpretation of that study.

Sunil Verma, MD, MSEd, FRCPC: The challenge there, Joyce, is, why did the PFS not improve to the same magnitude? Because if you look at the hazard ratios, the hazard ratio for CLEOPATRA is like 0.68 for PFS and 0.68 for overall survival—very consistent. Here, the hazard ratio was around 0.68 for overall survival, but the hazard ratio was around 0.8 for PFS. So, it didn’t quite… I think if we had seen the same magnitude of effect in PFS and it was a negative study, then I would say, sure, likely this is just an underpowered trial and there is a role. But here, there wasn’t the same magnitude of benefit in PFS as one would expect and one has seen through CLEOPATRA.

Joyce A. O’Shaughnessy, MD: Two points. Of course, survival is more important, again, so without the PFS. Secondly, it’s interesting. I wonder how long they got the capecitabine for. Was it continued through the whole thing? Because, obviously, in CLEOPATRA, patients stopped after six or eight cycles—so, I wonder. But, anyway, survival is so important. Pertuzumab certainly rings in a level of important non–cross-resistant therapy to patients who have had trastuzumab. At any rate, as somebody who makes sure that everybody gets a line of pertuzumab today—at least in the United States—I think the data support that therapy.

Kimberly L. Blackwell, MD: I think one day we’re going to have a capecitabine backbone, HER2 doublet. We have lapatinib/capecitabine. I think this would justify—for someone who is pertuzumab-naïve—utilizing it. It’s an equivalent study, not a negative study. And then I think we have other drugs that Adam might be getting to, but we have other small molecule inhibitors that are being studied in combination with capecitabine. We have an HER2-specific drug, ONT-380; the Oncothyreon drug. So, one day, especially because of capecitabine’s activity in the brain, I think we’re going to get an ideal capecitabine backbone combination.

Transcript Edited for Clarity
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Transcript:

Adam M. Brufsky, MD, PhD:
Let’s move on to a few more HER2 topics before we get to tyrosine kinase inhibitors in HER2. The first one is there was a trial that was presented at ASCO, PHEREXA. Sunil, I think, actually, you are the discussant of PHEREXA at this year’s meeting. So, can you comment on that?

Sunil Verma, MD, MSEd, FRCPC: PHEREXA, I think, is an important study. It was done pre-integration of T-DM1, in the context of metastatic breast cancer. These were patients who had prior metastatic trastuzumab for advanced breast cancer and then were randomized to either capecitabine/trastuzumab or capecitabine/trastuzumab plus pertuzumab; initially a phase II trial that was then expanded to a phase III setting. And what it showed was that there was a difference in PFS; however, it’s not statistically significant. It went from 9 months to 11 months. The 9 months with capecitabine/trastuzumab is pretty good, much better than what we have seen traditionally. And then the overall survival, there was an 8-month difference. But because it was a hierarchical statistical design—because the P value was not significant for PFS—they can’t really look at the P value for overall survival.

So, where does that leave us? And, basically, my discussion is going to be that this is a negative trial; it was an underpowered study. Yes, pertuzumab does appear to have activity in this trastuzumab pretreated patient population; we have seen that. However, we cannot justify the use of this based on this negative trial and especially when we have other options, like T-DM1, now for those patients who have had trastuzumab. Would this study have been meaningful maybe a couple of years ago because we had some patients who never got a chance to receive pertuzumab in the first-line? Sure, but now the majority of patients would have gotten pertuzumab now that we have T-DM1 in the second line. Really, the clinical meaningfulness of this study is much limited as a result and, at the end of the day, is a negative trial.

Joyce A. O’Shaughnessy, MD: I completely agree with everything you said. From a practical standpoint for patients who have not had pertuzumab, to me, the 8-month improvement in survival—which was a little hampered by the fact that you couldn’t put a P value on it—still is very impressive and shows what we already know about pertuzumab from the frontline CLEOPATRA trial. And I think it justifies the use of getting one line of pertuzumab in the metastatic setting. Because I hope the trial is not used to saying that, “Gee, you have to get it in the frontline, or you don’t get it at all,” basically, because I don’t agree with that from the interpretation of that study.

Sunil Verma, MD, MSEd, FRCPC: The challenge there, Joyce, is, why did the PFS not improve to the same magnitude? Because if you look at the hazard ratios, the hazard ratio for CLEOPATRA is like 0.68 for PFS and 0.68 for overall survival—very consistent. Here, the hazard ratio was around 0.68 for overall survival, but the hazard ratio was around 0.8 for PFS. So, it didn’t quite… I think if we had seen the same magnitude of effect in PFS and it was a negative study, then I would say, sure, likely this is just an underpowered trial and there is a role. But here, there wasn’t the same magnitude of benefit in PFS as one would expect and one has seen through CLEOPATRA.

Joyce A. O’Shaughnessy, MD: Two points. Of course, survival is more important, again, so without the PFS. Secondly, it’s interesting. I wonder how long they got the capecitabine for. Was it continued through the whole thing? Because, obviously, in CLEOPATRA, patients stopped after six or eight cycles—so, I wonder. But, anyway, survival is so important. Pertuzumab certainly rings in a level of important non–cross-resistant therapy to patients who have had trastuzumab. At any rate, as somebody who makes sure that everybody gets a line of pertuzumab today—at least in the United States—I think the data support that therapy.

Kimberly L. Blackwell, MD: I think one day we’re going to have a capecitabine backbone, HER2 doublet. We have lapatinib/capecitabine. I think this would justify—for someone who is pertuzumab-naïve—utilizing it. It’s an equivalent study, not a negative study. And then I think we have other drugs that Adam might be getting to, but we have other small molecule inhibitors that are being studied in combination with capecitabine. We have an HER2-specific drug, ONT-380; the Oncothyreon drug. So, one day, especially because of capecitabine’s activity in the brain, I think we’re going to get an ideal capecitabine backbone combination.

Transcript Edited for Clarity
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