Burris Discusses T-DM1 Update, Neoadjuvant Care in HER2+ Breast Cancer

Howard A. “Skip” Burris, MD

Patients with advanced HER2-positive breast cancer who received treatment with trastuzumab emtanzssine (T-DM1; Kadcyla) were found to have a lower incidence of treatment-related adverse events, according to patient-reported outcomes (PRO) from the phase III MARIANNE trial.¹

In the overall study results, patients with locally advanced or untreated metastatic HER2-positive disease were randomized to receive T-DM1 plus pertuzumab (Perjeta), T-DM1 alone, or trastuzumab (Herceptin) plus a taxane-based agent. Phase III results of the trial showed that neither T-DM1 arm was associated with improved outcomes compared with the trastuzumab/taxane arm, painting a disappointing picture for T-DM1’s potential, as a phase II study had shown a statistically significant increase in progression-free survival.

The PRO analysis assessed quality of life; taxane-related symptoms; and rates of nausea, diarrhea, and alopecia. Findings from analysis presented at the 2016 ASCO Annual Meeting showed that patients in both T-DM1 arms reported a lower incidence of and a longer time to clinically important difference in neurotoxicity, as well as less alopecia versus patients receiving trastuzumab plus a taxane. Patients in the T-DM1—alone arm also reported less nausea and diarrhea than the other 2 arms.

“I think this was an important subject,” said Howard A. “Skip” Burris, MD, an author on the MARIANNE trial. “In this setting, if the therapy is comparable in its result and it is much better tolerated without cumulative side effects, it is certainly another reason to use it for a patient.”

OncLive: Please discuss the findings of the patient-reported outcomes analysis from the MARIANNE trial?

In an interview with OncLive, Burris, president of Clinical Operations and chief medical officer at Sarah Cannon Research Institute, offers insight on these findings and highlights exciting advancements in the neoadjuvant landscape of HER2-positive breast cancer.Burris: The MARIANNE trial was one that Sarah Cannon Research Institute gladly participated in. It was interesting, but there was some disappointment because the trial was statistically negative. To refresh, this looked at a baseline regimen of a taxane plus trastuzumab, and then looked at the addition of T-DM1 either alone or with pertuzumab. There was some disappointment that there was not a statistically positive result from the trial.

However, for the practicing oncologist, the much better tolerated antibody-drug conjugate T-DM1 did just as well, although it did not do better. Also, certainly, there were fewer side effects that were observed.

Switching the focus to neoadjuvant care, what are some of the challenges in this setting in HER2-positive breast cancer?

Last year, we saw comparative toxicities with regard to traditional neuropathy, blood counts, and gastrointestinal toxicities. This year, presented by Dr Carlos H. Barrios, was the patient-reported outcomes. Statistically looking at it, there is an improvement in that patients felt better taking T-DM1 than they did taking chemotherapy plus trastuzumab.HER2-positive breast cancer has been the great success story. I have been doing this for a while. When I was in fellowship, I remember that if you found out that a patient was HER2-positive, it was nothing but bad news. Then, trastuzumab came along, and then we found small molecules, such as lapatinib, and we found the antibody-drug conjugate pertuzumab. It has gotten us to a place where we really want to start thinking about whether this is one of those curable malignancies, such as testicular cancer or Hodgkin lymphoma.

However, one of the troublesome areas in HER2-positive breast cancer is the brain metastases that develop in patients with advanced disease, and they have to go through multiple therapies. Most of our therapies do not go through the brain very well. That just highlights back to the fact that we need to cure at the surgical end of the spectrum. We know that patients with HER2-positive breast cancer are going to get therapy, so it isn’t a question of “if,” it is a question of “when.”

That is the reason why, if we find out that a patient is HER2-positive, I try to give most of them their treatment in the neoadjuvant setting. This is working from the outside-in. If we put the best medicines into the bloodstream, clean up any cells that are in the bloodstream or in the lymph nodes, then let’s go ahead and shrink those tumors. We have seen some positive results with better pathological complete responses, and we know that, if we completely eradicate the tumor to be invisible to the eye prior to going into surgery, then those patients have better outcomes.

What neoadjuvant regimen do you tend to lean toward for your HER2-positive patients?

What advancements do you predict taking place in this specific setting?

I think this is a great example where we have these well-tolerated therapies in a setting where we know they are needed, so we should go ahead and give them before the operation and, therefore, we will get a better result.In the neoadjuvant setting, I give trastuzumab plus pertuzumab followed by a choice of what chemotherapy to give them. There is not great data to support this but, in general, if a patient is older or has much less disease, I might simply use a taxane. If the woman is younger than 60, or has node-positive disease or a larger tumor, I will often add the platinum-based therapy in with it. In that case, I will administer a platinum-based agent, a taxane, and trastuzumab combined with pertuzumab.In the area of HER2-positive breast cancer, where we will go in the next 5 to 10 years is to better understand how long we need to give therapy for. I do think neoadjuvant treatment will be a setting alone; patients can get less overall therapy if we give it to them earlier in their disease.

Additionally, I think we are going to have some drugs added to these regimens that will help cross the blood-brain barrier. That is a great sanctuary for cancer cells to hide out, so I think that will be very, very attractive.

Lastly, we are going to better understand where, in fact, we can simply use HER2-targeted therapy, endocrine therapy, and maybe leave off chemotherapy for some of these patients.

1. Barrios CH, Cella D, Martin M, et al. Patient-reported outcomes (PROs) from MARIANNE: A phase III study of trastuzumab emtansine (T-DM1) +/- pertuzumab (P) vs trastuzumab + taxane (HT) for HER2-positive advanced breast cancer. J Clin Oncol. 2016;34 (suppl; 593).