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Old 06-26-2015, 11:58 AM   #1
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ASCO 2015 Recap: Dr. Kimberly Blackwell Circles Back to HER2/ER Breast Cancer—Part 2

Dr. Kimberly Blackwell, Professor of Medicine and Assistant Professor in Radiation Oncology at Duke and member of the PracticeUpdate Oncology Advisory Board, speaks with Dr. Jarushka Naidoo, an advanced fellow in medical oncology at Memorial Sloan Kettering Cancer Center, about what she considers to be important papers on HER2/ER breast cancer presented at this year’s ASCO Annual Meeting.


Dr. Naidoo: Palbociclib is a relatively new agent that is in late-phase studies in breast cancer. Can you briefly outline the mode of action of this agent, the results we saw from PALOMA3,1 and where you think this agent may fit into the current treatment armamentarium for breast cancer?

Dr. Blackwell: Palbociclib is a very exciting agent for the treatment of ER-positive metastatic breast cancer. This is a drug that now has demonstrated improvement in PFS in a large phase II study when combined with letrozole, in endocrine therapy–naďve patients,2 and, as we saw this year at ASCO in PALOMA3, it doubled PFS when added to fulvestrant.1

Therefore, we have two randomized studies where adding a CDK inhibitor—and, in this case, palbociclib—significantly improved PFS with the expected toxicities of short-lived neutropenia and a very low incidence of febrile neutropenia. In fact, the incidence of febrile neutropenia was zero in PALOMA3.

Therefore, I think palbociclib is now a standard of care for patients being initiated on either letrozole or fulvestrant, and, at least in my own practice, I’ll be offering it as the standard of care for patients in whom I’m initiating either fulvestrant or an aromatase inhibitor. Finally, we actually have a positive study.

There’s a small population of practitioners who are going to be concerned about applying these data to the situation of, say, a 92-year-old patient who has a very slow–growing grade 1 breast cancer with two bone metastases. But, for the majority of patients, palbociclib will be the go-to agent in combination with endocrine therapy for first-line management of ER-positive metastatic disease.


Dr. Naidoo: Finally, in HER2-positive breast cancer we saw data in both the neoadjuvant and metastatic settings exploring the addition of TDM1. What is your opinion of these data?

Dr. Blackwell: I’ll start with my opinion about the HER2 agents in the metastatic arena from ASCO. We have the first-line results from the MARIANNE trial, which is a three-arm study looking at a taxane plus trastuzumab at standard dosing, versus TDM1 alone, versus TDM1 plus pertuzumab.3

My conclusions from the result of the study is that all three options were equivalent, and, just using common sense, we wouldn’t add pertuzumab to TDM1 if it didn’t add anything in terms of efficacy. It really didn’t add anything in terms of toxicity, but it certainly adds a cost.

So, the conclusions from the MARIANNE presentation are that TDM1 is equivalent therapy to taxane plus trastuzumab in terms of efficacy, and it’s certainly not inferior to taxane plus trastuzumab. Although we always want to see a positive study, even an equivalent study in this space represents a major breakthrough.

The reason being is that we know that antibody–drug conjugates in particular and, in this case, TDM1 are much better tolerated than taxane plus trastuzumab. I kind of view the MARIANNE study as a positive study in the context of how we employ TDM1 in the care of metastatic breast cancer patients. This is the first study really looking at metastatic HER2-positive breast cancer that actually demonstrated that a first-line drug, TDM1, worked as well as traditional chemotherapy plus trastuzumab, and has significantly fewer side effects. Although we took for granted that TDM1 would be as good, I think we did that on a very limited dataset.

We had phase II data comparing TDM1 with taxane plus trastuzumab in about 120 patients and it looked a lot better; but, other than those data, we really hadn’t examined TDM1 head-to-head with the old standard of taxane plus trastuzumab. So, I actually think that MARIANNE is a positive study in the sense that we now have an option that’s as good as, and certainly not worse than, traditional chemotherapy plus trastuzumab. I think that is a major breakthrough for women facing HER2-positive metastatic breast cancer who don’t want to lose their hair, who don’t want to have the nausea and vomiting. Most of the women in this situation have received adjuvant chemotherapy, so they know exactly what the side effects of taxane and trastuzumab are.

Although I think that most people were disappointed with the MARIANNE results, I would suggest that it actually was a very nice study to confirm the activity of TDM1 and also the absence of hypersensitive side effects. There are certainly side effects with both approaches, but they are significantly less with the use of TDM1. I think the outstanding question relative to MARIANNE is why didn’t the pertuzumab add anything? I have yet come up with a good answer for that.


In the neoadjuvant setting, we saw data from Nadia Harbeck in a study called the WSG-ADAPT study.4 This was a phase II study with a three-arm randomization comparing TDM1 alone (arm A), TDM1 plus endocrine therapy (arm B; premenopausal, tamoxifen; postmenopausal, aromatase inhibitor), and endocrine therapy plus trastuzumab (arm C), with a primary endpoint of complete pathologic response (pCR). The study showed the overall pCR rate was 30.8%: arm A, 40.5%; arm B, 45.8%; arm C, 6.7%. A 40% to 45% pCR rate in the neoadjuvant setting for HER2-positive breast cancer is one of the highest we’ve seen, and this certainly has changed my thinking about how we might incorporate TDM1 in the neoadjuvant setting.

Unfortunately, TDM1 is not approved in this setting in the US; its use in this space would remain experimental. But, again, the data suggest that in terms of a pCR rate TDM1 is as good as what we’ve seen with traditional taxane and trastuzumab–based therapy, and, hopefully, there will be additional studies exploring TDM1 as a neoadjuvant agent.

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