CLEOPATRA Reigns Supreme
Kathy D. Miller, MD: Hello. I am Kathy Miller, Associate Professor of Medicine at Indiana University School of Medicine, in Indianapolis. This is Medscape Oncology Insights on Breast Cancer, coming to you from the 2011 San Antonio Breast Cancer Symposium.
Joining me today is Dr. Sandra Swain, Professor of Medicine at Georgetown University, and Medical Director at the Washington Cancer Institute at the MedStar Washington Hospital Center, in Washington, DC. Thank you for coming in, Sandy.
Sandra M. Swain, MD: I am delighted to be here, Kathy.
Dr. Miller: Today I wanted to talk about the results of the CLEOPATRA study, a study for which I personally -- and much of our audience -- have been waiting many years. First we probably need to talk about pertuzumab, since that is the new agent being studied in this particular trial.
Dr. Swain: The trial design involves patients with metastatic breast cancer, first-line treatment, using a combination of chemotherapy with docetaxel, trastuzumab, and pertuzumab. Pertuzumab is another monoclonal antibody, very similar to trastuzumab, except it is a dimerization inhibitor. It binds to a different domain than does trastuzumab. Trastuzumab binds at domain 2, whereas pertuzumab binds at domain 4 and prevents the coupling or the dimerization of HER2 with HER3, preferentially, and any of the other HER2 partners. It has been shown in preclinical models and phase 2 studies to be very active.
Dr. Miller: This study had to be limited to women with HER2-positive disease because it was based on inhibiting HER2. These women were getting their first therapy for metastatic disease, but most of our patients are treated in the adjuvant setting beforehand. Had these women already received adjuvant chemotherapy or adjuvant trastuzumab?
Dr. Swain: In this setting, we had approximately 800 patients and only 10% had received adjuvant trastuzumab. The study was started in 2004, before adjuvant trastuzumab was approved, and it took place in many countries where adjuvant trastuzumab wasn'tavailable, so only 10% actually had previous adjuvant trastuzumab.
Dr. Miller: With the timing, a lot of those women probably would have received their adjuvant chemotherapy before trastuzumab was standard, even if they were in a country where it might have been available.
Dr. Swain: Right, and it is interesting that only about 50% of the patients actually did have adjuvant chemotherapy on the study, so it is a less pretreated population probably than we would see if we were doing this trial today.
Dr. Miller: So, this was a head-to-head comparison? We always have to think about sources of bias. Was there a placebo included in this trial?
Dr. Swain: Yes. It was an extremely well-designed trial in that it was placebo- controlled (an IV placebo) and the patients should have had a minimum of 6 cycles of docetaxel. The median number was 8 cycles in both arms, and then they could stop the chemotherapy if they wanted to and continue with just the pertuzumab or the placebo and the trastuzumab.
Dr. Miller: This is different from many trials in the United States where we might hope to continue all of the therapies, but with docetaxel on an every-3-week schedule toxicity starts to become limiting around that 6- to 8-cycle mark.
Dr. Swain: Right, it does, and it honestly is not a standard in the United States. Most of us don't use docetaxel in first-line metastatic settings. It was a big discussion when we designed this study because in the United States we would have preferred paclitaxel, and initially the accrual to this study was fairly slow, because only a couple of studies had been done. I had done a study and Jose Baselga had done a study that showed some modest activity.Our response rate was about 19%, and his was in the low 20% range. Initially there wasn't a huge push to get this study done. The accrual was low and it took quite a long time.
Dr. Miller: The initial studies that you mentioned, just to be clear for our audience, were studies with the combination of trastuzumab and pertuzumab (the 2 antibodies) but no chemotherapy, and in previously trastuzumab-treated patients. I am surprised to hear that people didn't find that exciting, because I thought those response rates in that population with no chemotherapy were actually really encouraging.
Dr. Swain: I did too, and that is why I participated in the study and wrote the protocol with several people. I thought it was very exciting, but just to give a little history on why it took so long, it was a slow uptake in the beginning, and in the United States especially because of the docetaxel backbone.
Dr. Miller: So the good news is that the study got done, because this is a really important question -- to look at the dual targeting of the same receptor with these 2 different agents. Is dual targeting better?
Dr. Swain: The results were absolutely spectacular. The median increase in progression-free survival was 6.1 months and the hazard ratio was 0.62, so there was almost a 40% reduction in progression on this study. These are excellent results in a double-blinded study where you don't have as much bias looking at the progression-free survival endpoint.
Dr. Miller: A 6-month improvement in progression-free survival is not something we have seen before. If I remember correctly, the original pivotal trial of trastuzumab didn't quite show a 6-month improvement in median progression-free survival. I think it was about 5 months.
Dr. Swain: It was, and the progression-free survival was much lower in both of the arms of that study. It was 5 or 6 months vs 12 months, or something like that. It is interesting how years ago the same kind of study was done, except without the addition of that second monoclonal antibody, and the progression-free survival was so much shorter.
Dr. Miller: One thing that has changed that makes this comparison difficult is the definition of HER2, because those original studies allowed 2+ patients to enroll without FISH confirmation, so that may have diluted the results. Although many of us thought this was going to be a positive study, I am not sure many people hoped for that degree of improvement just by looking at the dual targeting.
Dr. Swain: Right. I agree, and as supportive as I have been of this and having done a trial myself with about a 20% response rate, I was very excited about it, but I did not expect a 6-month median increase in progression-free survival. The survival was also increased, but it didn't cross the boundary of significance. We are hopeful that with longer follow-up and more events, we can see a survival benefit also.
Dr. Miller: We will stay tuned for survival, but what about response rates, particularly for symptomatic patients? That may be a key driver in reducing their symptoms in that acute setting.
Dr. Swain: The response rate was about 15% or so higher in the combination arm, so it clearly was better. And in a lot of these phase 3 studies, many patients don't have a lot of symptoms, so it is really hard to sort those kinds of things out. Clearly, however, the response rate was significantly higher.
Dr. Miller: Whenever we think about adding another drug, we have to think about the bad things that might come with it, and frequently when we are talking about chemotherapy, the combinations start running into toxicity difficulties. Was a major difference in toxicity seen with adding trastuzumab to pertuzumab in this setting?
Dr. Swain: There were some differences. Let's talk about the cardiac toxicity first. That was what everybody was worried about, because you have cardiac toxicity with trastuzumab, especially in patients who have had previous anthracyclines, and a fair number had on this study. The cardiac toxicity was actually higher in the placebo arm -- about twice as high. It was only, depending on how you look at it, 2% vs 6%, or 6% vs 3%. It was very minimal cardiac toxicity. It is very reassuring that we don't have to worry about it. The toxicities that were more frequent were febrile neutropenia, for example, with the dual-targeted antibody, and we have seen that with other monoclonal antibodies. There is some interaction, maybe with IgG, that produces more neutropenia, so that was greater. One caution for those viewers who have Asian patients: We had a large percentage of Asian patients on this study, and they had an even higher febrile neutropenia rate, so it is probably due to the docetaxel metabolism. Be really cautious about that.
Dr. Miller: That is an important caution, although I suspect it may vary much more with changes in the chemotherapy regimen that might not have quite so much associated myelosuppression.
Dr. Swain: Right, I absolutely agree. The physicians were allowed to escalate docetaxel to 100 mg/m if they wanted to, but not too many did that. I can't remember the exact number, but it was not very high.
Dr. Miller: These really are amazing results in an area where many people were a little bit skeptical that there might not be a whole lot of room for improvement beyond what we get with chemotherapy and trastuzumab. I have to ask where you are going to go with these results; what do you do with these results now?
Dr. Swain: It is very exciting. They are going into the adjuvant setting -- that has been planned for the last year or so -- and the AFFINITY trial is looking at the dual-targeted antibody. We haven't opened it yet at our institution, but we have 2 patients who have actually been enrolled in that study.
Dr. Miller: In that adjuvant trial, will it be limited to the HER2-positive population, and are there other key eligibility criteria?
Dr. Swain: The main thing is HER2 positivity. The other thing I didn't mention on the CLEOPATRA study is that the HER2 was all centrally reviewed, so these patients were clearly HER2 positive. The same will be true with AFFINITY to make sure that the patients really do have HER2-positive disease.
Dr. Miller: Sandy, thank you for coming in and sharing these amazing results with us.
And thanks to you, our audience, for joining us for this edition of Medscape Oncology Insights. This is Kathy Miller coming to you from the 2011 San Antonio Breast Cancer Symposium in San Antonio.
Introduction
Kathy D. Miller, MD: Hello. I am Kathy Miller, Associate Professor of Medicine at Indiana University School of Medicine, in Indianapolis. This is Medscape Oncology Insights on Breast Cancer, coming to you from the 2011 San Antonio Breast Cancer Symposium.
Joining me today is Dr. Sandra Swain, Professor of Medicine at Georgetown University, and Medical Director at the Washington Cancer Institute at the MedStar Washington Hospital Center, in Washington, DC. Thank you for coming in, Sandy.
Sandra M. Swain, MD: I am delighted to be here, Kathy.
At Long Last, CLEOPATRA
Dr. Miller: Today I wanted to talk about the results of the CLEOPATRA study, a study for which I personally -- and much of our audience -- have been waiting many years. First we probably need to talk about pertuzumab, since that is the new agent being studied in this particular trial.
Dr. Swain: The trial design involves patients with metastatic breast cancer, first-line treatment, using a combination of chemotherapy with docetaxel, trastuzumab, and pertuzumab. Pertuzumab is another monoclonal antibody, very similar to trastuzumab, except it is a dimerization inhibitor. It binds to a different domain than does trastuzumab. Trastuzumab binds at domain 2, whereas pertuzumab binds at domain 4 and prevents the coupling or the dimerization of HER2 with HER3, preferentially, and any of the other HER2 partners. It has been shown in preclinical models and phase 2 studies to be very active.
Dr. Miller: This study had to be limited to women with HER2-positive disease because it was based on inhibiting HER2. These women were getting their first therapy for metastatic disease, but most of our patients are treated in the adjuvant setting beforehand. Had these women already received adjuvant chemotherapy or adjuvant trastuzumab?
Dr. Swain: In this setting, we had approximately 800 patients and only 10% had received adjuvant trastuzumab. The study was started in 2004, before adjuvant trastuzumab was approved, and it took place in many countries where adjuvant trastuzumab wasn'tavailable, so only 10% actually had previous adjuvant trastuzumab.
Dr. Miller: With the timing, a lot of those women probably would have received their adjuvant chemotherapy before trastuzumab was standard, even if they were in a country where it might have been available.
Dr. Swain: Right, and it is interesting that only about 50% of the patients actually did have adjuvant chemotherapy on the study, so it is a less pretreated population probably than we would see if we were doing this trial today.
Dr. Miller: So, this was a head-to-head comparison? We always have to think about sources of bias. Was there a placebo included in this trial?
Dr. Swain: Yes. It was an extremely well-designed trial in that it was placebo- controlled (an IV placebo) and the patients should have had a minimum of 6 cycles of docetaxel. The median number was 8 cycles in both arms, and then they could stop the chemotherapy if they wanted to and continue with just the pertuzumab or the placebo and the trastuzumab.
Dr. Miller: This is different from many trials in the United States where we might hope to continue all of the therapies, but with docetaxel on an every-3-week schedule toxicity starts to become limiting around that 6- to 8-cycle mark.
Dr. Swain: Right, it does, and it honestly is not a standard in the United States. Most of us don't use docetaxel in first-line metastatic settings. It was a big discussion when we designed this study because in the United States we would have preferred paclitaxel, and initially the accrual to this study was fairly slow, because only a couple of studies had been done. I had done a study and Jose Baselga had done a study that showed some modest activity.Our response rate was about 19%, and his was in the low 20% range. Initially there wasn't a huge push to get this study done. The accrual was low and it took quite a long time.
Dr. Miller: The initial studies that you mentioned, just to be clear for our audience, were studies with the combination of trastuzumab and pertuzumab (the 2 antibodies) but no chemotherapy, and in previously trastuzumab-treated patients. I am surprised to hear that people didn't find that exciting, because I thought those response rates in that population with no chemotherapy were actually really encouraging.
Dr. Swain: I did too, and that is why I participated in the study and wrote the protocol with several people. I thought it was very exciting, but just to give a little history on why it took so long, it was a slow uptake in the beginning, and in the United States especially because of the docetaxel backbone.
Targeting the Same Receptor Twice
Dr. Miller: So the good news is that the study got done, because this is a really important question -- to look at the dual targeting of the same receptor with these 2 different agents. Is dual targeting better?
Dr. Swain: The results were absolutely spectacular. The median increase in progression-free survival was 6.1 months and the hazard ratio was 0.62, so there was almost a 40% reduction in progression on this study. These are excellent results in a double-blinded study where you don't have as much bias looking at the progression-free survival endpoint.
Dr. Miller: A 6-month improvement in progression-free survival is not something we have seen before. If I remember correctly, the original pivotal trial of trastuzumab didn't quite show a 6-month improvement in median progression-free survival. I think it was about 5 months.
Dr. Swain: It was, and the progression-free survival was much lower in both of the arms of that study. It was 5 or 6 months vs 12 months, or something like that. It is interesting how years ago the same kind of study was done, except without the addition of that second monoclonal antibody, and the progression-free survival was so much shorter.
Dr. Miller: One thing that has changed that makes this comparison difficult is the definition of HER2, because those original studies allowed 2+ patients to enroll without FISH confirmation, so that may have diluted the results. Although many of us thought this was going to be a positive study, I am not sure many people hoped for that degree of improvement just by looking at the dual targeting.
Dr. Swain: Right. I agree, and as supportive as I have been of this and having done a trial myself with about a 20% response rate, I was very excited about it, but I did not expect a 6-month median increase in progression-free survival. The survival was also increased, but it didn't cross the boundary of significance. We are hopeful that with longer follow-up and more events, we can see a survival benefit also.
Dr. Miller: We will stay tuned for survival, but what about response rates, particularly for symptomatic patients? That may be a key driver in reducing their symptoms in that acute setting.
Dr. Swain: The response rate was about 15% or so higher in the combination arm, so it clearly was better. And in a lot of these phase 3 studies, many patients don't have a lot of symptoms, so it is really hard to sort those kinds of things out. Clearly, however, the response rate was significantly higher.
Reassuring News About Toxicity
Dr. Miller: Whenever we think about adding another drug, we have to think about the bad things that might come with it, and frequently when we are talking about chemotherapy, the combinations start running into toxicity difficulties. Was a major difference in toxicity seen with adding trastuzumab to pertuzumab in this setting?
Dr. Swain: There were some differences. Let's talk about the cardiac toxicity first. That was what everybody was worried about, because you have cardiac toxicity with trastuzumab, especially in patients who have had previous anthracyclines, and a fair number had on this study. The cardiac toxicity was actually higher in the placebo arm -- about twice as high. It was only, depending on how you look at it, 2% vs 6%, or 6% vs 3%. It was very minimal cardiac toxicity. It is very reassuring that we don't have to worry about it. The toxicities that were more frequent were febrile neutropenia, for example, with the dual-targeted antibody, and we have seen that with other monoclonal antibodies. There is some interaction, maybe with IgG, that produces more neutropenia, so that was greater. One caution for those viewers who have Asian patients: We had a large percentage of Asian patients on this study, and they had an even higher febrile neutropenia rate, so it is probably due to the docetaxel metabolism. Be really cautious about that.
Dr. Miller: That is an important caution, although I suspect it may vary much more with changes in the chemotherapy regimen that might not have quite so much associated myelosuppression.
Dr. Swain: Right, I absolutely agree. The physicians were allowed to escalate docetaxel to 100 mg/m if they wanted to, but not too many did that. I can't remember the exact number, but it was not very high.
Dual Targeting as Adjuvant Therapy?
Dr. Miller: These really are amazing results in an area where many people were a little bit skeptical that there might not be a whole lot of room for improvement beyond what we get with chemotherapy and trastuzumab. I have to ask where you are going to go with these results; what do you do with these results now?
Dr. Swain: It is very exciting. They are going into the adjuvant setting -- that has been planned for the last year or so -- and the AFFINITY trial is looking at the dual-targeted antibody. We haven't opened it yet at our institution, but we have 2 patients who have actually been enrolled in that study.
Dr. Miller: In that adjuvant trial, will it be limited to the HER2-positive population, and are there other key eligibility criteria?
Dr. Swain: The main thing is HER2 positivity. The other thing I didn't mention on the CLEOPATRA study is that the HER2 was all centrally reviewed, so these patients were clearly HER2 positive. The same will be true with AFFINITY to make sure that the patients really do have HER2-positive disease.
Conclusion
Dr. Miller: Sandy, thank you for coming in and sharing these amazing results with us.
And thanks to you, our audience, for joining us for this edition of Medscape Oncology Insights. This is Kathy Miller coming to you from the 2011 San Antonio Breast Cancer Symposium in San Antonio.