 Dr O’Shaughnessy, Dr Chau Dang set the stage for this discussion by introducing the concept of dual 

 [human epidermal growth factor receptor 2]–targeted antibody therapies, both in the first-line metastatic setting in the case of the CLEOPATRA trial but also in the adjuvant setting for early stage for 

-positive breast cancer in the case of the APHINITY trial.

Can you drill down on those 2 studies in just a little more detail? Talk about the long-term follow-up from the CLEOPATRA study, for example, and talk a little about the safety data from this dual-antibody approach and how these have changed practice in terms of the landscape of therapy for both early and late-stage breast cancer.

 Sure, I’d be happy to. That was a great summary there, Chau—a really lovely, complete summary. The dual targeting with trastuzumab and pertuzumab, both of those antibodies were aimed at 

 can certainly be amplified and often is. It can heterodimerize but also homodimerize, but it can also heterodimerize and can be ligand-driven with heregulin, which binds to 

. The trastuzumab-pertuzumab combination with them binding to different domains of 

 with pertuzumab binding at the heterodimerization domain of 

, it stops not only homodimerization but also heterodimerization, which is very important in 

It made a great deal of sense to take this forward into the metastatic setting, as Chau said. In the CLEOPATRA trial, patients with first-line 

-positive metastatic breast cancer were randomized to docetaxel and trastuzumab with placebo vs. docetaxel, trastuzumab plus pertuzumab, and first-line metastatic. The results, as Chau said, were very striking in terms of very important improvement in progression-free survival but also a 15.7-month improvement long-term in overall survival. I don’t think we’ve really seen that kind of a survival delta really any time in 

-positive breast cancer, likely in any of our metastatic breast cancer settings. This was an amazingly large improvement in overall survival.

That really set the stage of course to bring this combination into the high-risk curative setting, as Chau said. Initially, in the preoperative setting with NeoSphere and TRYPHAENA, which led to pathologic complete response rates that were in the 45% range with ER-positive disease, they were in the 80% range when you gave the anthracycline preoperatively along with taxane, trastuzumab, and pertuzumab. There were very big improvements in pathologic complete rates. That led to the conditional accelerated approval of the combination preoperatively until the data from APHINITY were available, where the physicians had a choice of a taxane, carboplatin, trastuzumab plus-or-minus pertuzumab regimen, or an anthracycline regimen followed by taxane-trastuzumab with or without pertuzumab. There were a couple of different chemotherapies. About half of patients received anthracycline and half received nonanthracycline chemotherapy.

The trial was largely node-positive patients. There were a proportion of patients that were node negative, but then they closed that cohort down to enroll a much higher-risk population. We had recent data of a 6-year update, the mature data from APHINITY. Patients received either the trastuzumab chemotherapy with placebo or trastuzumab-pertuzumab with chemotherapy. The chemotherapy—when that was stopped, they finished then the year of the trastuzumab placebo or trastuzumab-pertuzumab. A year of therapy.

When you look at the intent-to-treat population at the 6-year follow-up, it was a 2.8% improvement in disease-free survival that was statistically significant. Interestingly, pretty much all the benefit was in the node-positive population. There was a 4.5% improvement in disease-free survival, which is certainly a clinically meaningful 4.5%. The toxicity, thankfully, with the addition of the pertuzumab both in the metastatic setting and in the curative setting, is highly manageable.

The main thing is diarrhea when the pertuzumab-trastuzumab is combined with chemotherapy. Once the patient stopped the chemotherapy, whether in the metastatic or neoadjuvant setting, then the diarrhea basically largely abates with the pertuzumab. It’s actually very manageable. I must say, these days of course, in practices for the higher-risk patients, we’re treating them preoperatively with chemotherapy, pertuzumab, and trastuzumab. If they have a pathologic complete response and they were high-risk to start off, we continue the pertuzumab and trastuzumab to finish the year. If they still have residual disease, they get the T-DM1 [trastuzumab emtansine] for the KATHERINE trial, as Chau told us.

Diarrhea is definitely an issue in some grade 3 diarrhea that can be running in 20% or more. Certainly with the proactive use of loperamide, what I do is 2 loperamide after the first loose stole of each day, and then 1 loperamide after each subsequent loose stool that day. Within a couple or 3 doses, it shuts down. Once the patients get a few days beyond that, usually the diarrhea abates. Then it usually goes away once they finish the chemotherapy, and they’re finishing their year of pertuzumab and trastuzumab if they had a pathologic complete response.

There was no additional cardiac toxicity in the CLEOPATA trial with the addition of the pertuzumab. There was a very small increment in cardiac toxicity in the APHINITY trial, with the addition of pertuzumab. Other than that, you can get some rash with pertuzumab, but it’s not usually very substantial. It’s mainly diarrhea, which we’re all very used to using it at this point. It’s basically to just take a proactive approach with antidiarrheal medicine.

Videos

Dual HER2-Targeted Approaches in Breast Cancer

® presentation. Today’s discussion will be focused on systemic therapy for early 

 [human epidermal growth factor receptor]–positive breast cancer.Joining me today in this discussion are my esteemed colleagues: Dr Chau Dang, chief of the medical oncology service at Memorial Sloan Kettering Cancer Center’s West Harrison Outpatient Center in West Harrison, New York; and Dr Joyce O’Shaughnessy, chair of breast cancer research and the celebrating women chair in breast cancer at Baylor Scott & White Charles A. Sammons Cancer Center in Dallas, Texas.

During the next 45 minutes or so we’re going to navigate through some data for a novel subcutaneous dual 

-directed treatment and the challenges and benefits of integrating this approach into clinical practice. Our program will be divided into 3 segments: segment 1, dual HER2-targeted therapy in breast cancer; segment 2, a data review on subcutaneous trastuzumab plus pertuzumab; and segment 3, practical challenges and strategies to integrate this new information into clinical practice.

Let’s get started on our first topic. Dr Dang, I’d like you to begin with segment 1. Can you please provide a historical perspective on the treatment of 

Thank you, Mark. Thank you so much for inviting me tonight. Over the last 2 decades I’ve seen a dramatic improvement in our patients with 

-positive breast cancer, in both the metastatic and early stage settings. Starting with the approval of trastuzumab in 1998 in combination with chemotherapy, namely paclitaxel for the frontline treatment of patients with 

-positive metastatic breast cancer. It was also approved as a single agent in patients who have been previously treated with chemotherapy.

For a long time, patients were given taxanes and trastuzumab, and we’ve seen a significant survival gain for about decade and a half until the publication of the APHINITY trial, which showed a significant improvement in progression-free survival and overall survival of docetaxel in combination with trastuzumab and pertuzumab over docetaxel and trastuzumab and placebo alone. This was a huge trial that led to a paradigm shift in treating our patients with metastatic 

-positive cancer in the frontline setting.

I also want to highlight that there were other trials in between that led to the approval of several other drugs—namely apatinib, T-DM1 [trastuzumab emtansine] in the metastatic treatment of patients, and more recently, fam-trastuzumab deruxtecan and neratinib, as well at tucatinib. These other targeted therapies need to be highlighted as well.

Moving on to early stage breast cancer, in 1998, when trastuzumab was approved in the metastatic setting, 4 large studies were launched: N9831, B-31, HERA, and BCRG006 testing trastuzumab in combination with chemotherapy for the treatment of patients with high-risk early stage breast cancer. We saw that at ASCO [American Society of Clinical Oncology Annual Meeting] 2005, that the combination of trastuzumab and chemotherapy led to a significant improvement in disease-free survival and overall survival. This was the first time we saw such a significant gain in combining agents together. With the median follow-up of about 10 years now, our patients are doing very well with a median survival of 85%.

Along the way, pertuzumab was combined with trastuzumab in the adjuvant setting in the APHINITY trial in patients with high-risk 

-positive breast cancer. We’re seeing that the combination of trastuzumab-pertuzumab-chemotherapy led to an improvement in disease-free survival, but most notably in patients with node-positive breast cancer. I also want to highlight the other key trials that are worth noting, namely the new adjuvant studies, NeoSphere, TRYPHAENA, and others testing the combination of trastuzumab-pertuzumab and chemotherapy, showing a significant improvement in pathologic complete response.

In 2013, pertuzumab-trastuzumab-chemotherapy was approved to be given to patients being treated in the neoadjuvant setting with high burden disease, namely stage II/III breast cancer with a tumor size of greater than 2 cm, or node-positive breast cancer, or inflammatory or locally advanced breast cancer. This is another indication for pertuzumab added to trastuzumab.

What’s also worth noting in the early setting is the KATHERINE study that was reported very recently showing that T-DM1, given in the adjuvant setting for patients with a residual disease after neoadjuvant treatment led to significant improvement in disease-free survival over trastuzumab. In the modern era, patients are given T-DM1after neoadjuvant treatment if they have residual disease.

Lastly, I also want to mention the neratinib story. Neratinib was also studied in the adjuvant setting from the ExteNET study, and this is a study that is also worth highlighting. This is a study where patients with high-risk breast cancer were given chemotherapy and trastuzumab. At the end of their trastuzumab treatment, they were randomized to neratinib or not. We’ve seen a significant improvement in disease-free survival in our patients, most notably in patients with hormone receptor–positive breast cancer. It’s noted here that we have a plethora of options for our patients for 

-positive breast cancer, both in the early stage in metastatic cancer settings, and they do so well.

Mark Pegram, MD, Stanford Women's Cancer Center

Articles

Dual HER2-Targeted Approaches in Breast Cancer

Historic Perspectives on HER2+ Breast Cancer