Expert Recaps Recent Developments in HER2+ Breast Cancer

Chau T. Dang, MD

The treatment of patients with HER2-positive breast cancer has evolved quite a bit in recent years; however, there is still more than can be achieved, explains Chau T. Dang, MD.

“HER2-positive breast cancer was a very difficult disease to treat and now we have so many options, including taxane with trastuzumab and pertuzumab in the first-line and T-DM1 in the second-line setting,” says Dang, a medical oncologist at Memorial Sloan Kettering Cancer Center. “But, what about beyond that?”

In an interview with OncLive, Dang discusses several recent trials investigating novel treatment approaches for patients with HER2-positive breast cancer. These include the PHEREXA trial, which explored the combination of trastuzumab and pertuzumab (Perjeta) in the second-line setting, and the ongoing NALA study, which is investigating neratinib plus capecitabine compared with lapatinib (Tykerb) and capecitabine in metastatic disease.

MYL-1401O, a biosimilar version of trastuzumab, also has potential to make a difference for patients with HER2-positive disease who may not have access to trastuzumab, adds Dang.

The drug recently demonstrated an overall response rate (ORR) of 69.6% among women who received MYL-1401O in combination with a taxane compared with a 64% ORR at 24 weeks for patients who received trastuzumab plus a taxane, demonstrating equivalency between the biosimilar and trastuzumab.

OncLive: What did we learn from the PHEREXA trial?

In the interview, Dang also explains the biggest challenges with HER2-positive breast cancer that need to be addressed and what she hopes to see achieved in the future.Dang: The PHEREXA trial looked at the combination of trastuzumab and pertuzumab in the second-line setting. We know that dual-antibody therapy with chemotherapy is indicated for first-line, but we did not know if it had potential in second-line.

The PHEREXA study was for patients who were being treated in the second-line setting and progressed after a taxane- and trastuzumab-based treatment. The patients were randomized to receive capecitabine and trastuzumab or capecitabine, trastuzumab, and pertuzumab.

The primary endpoint of the study was progression-free survival (PFS) by independent assessment and a secondary endpoint included overall survival. Although it did show a numerical increase in PFS, it was not statistically significant; in essence, it was a negative study.

Interestingly, in terms of OS, there was a difference of 8 months for survival in favor of pertuzumab. However, I want to say this carefully because this trial was not powered to look at survival—but it did make us think that these antibodies have a greater effect on survival than PFS. We have seen that with trastuzumab and pertuzumab in the CLEOPATRA study where the benefit in OS was better than seen with PFS.

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Please discuss the significance of the emergence of trastuzumab biosimilars.

What we should take away from this study is that it was a valiant effort by investigators to look at that activity of capecitabine, trastuzumab, and pertuzumab in the second-line setting. However, because it was negative, T-DM1 remains to be the standard second-line option. We work very hard as patients to try and find better treatments. Certainly, though, T-DM1 is a still an excellent option.At the 2016 ASCO Annual Meeting, Dr Hope Rugo reported a study looking at [the biosimilar] MYL-1401O with a taxane versus trastuzumab with a taxane as first-line treatment for patients with HER2-positive metastatic breast cancer. It is, essentially, an equivalency trial, and she did show that this proposed biosimilar was equivalent to trastuzumab when both biologics were added to chemotherapy.

What other emerging therapies for HER2-breast cancer are you excited about?

That is important to note because trastuzumab is not widely available worldwide. One of the main reasons is because of the cost. If we start seeing data of this biosimilar and hopefully others that may be available going forward, we will be able to treat more patients worldwide.Neratinib is being studied right now in a large phase III trial known as the NALA study, which is looking at neratinib plus capecitabine compared to lapatinib and capecitabine. This trial will allow us to see if neratinib, along with the standard chemotherapy, will beat its control and offer another option for our patients.

What are some of the biggest challenges that remain in this field?

What do you envision for the future of HER2-positive breast cancer?

Certainly, neratinib has shown activity in the adjuvant setting, so we should look out for this particular TKI. However, we are aware that the incidence of grade 3 diarrhea is not insignificant, but if patients are initially treated with antidiarrheal agents, the side effects can be managed.Our patients with HER2-positive breast cancer are doing so well and living a long time, which is great news. Unfortunately, about 40% of them or even more may experience brain metastases during the course of their disease. A lot of work is being done now to find effective agents for these patients.Pertuzumab was approved with trastuzumab with standard chemotherapy in the neoadjuvant setting in 2013 for patients with stage II/III breast cancer. The NCCN has endorsed its use, as well, in patients with the same burden of disease in the adjuvant setting.

However, we are waiting for the results of the definitive randomized phase III study looking at the dual-antibody therapy trastuzumab/pertuzumab versus trastuzumab combined with standard chemotherapy to look for improvement in invasive disease-free survival.

I hope that we will see positive results with trastuzumab/pertuzumab. That is my hope and, if it is, that will be wonderful news for our patients. Hopefully, they will continue to do quite well, because they are doing quite well already with adjuvant trastuzumab. We hope to see that data in the next year or so.

As far as the metastatic setting, again, our patients are doing well. There are many patients in our practice who have no evidence of disease who once had distant disease. What is interesting is that, for the most part, they are on maintenance antibody therapy. What is unclear to me is how long we should keep them on antibody therapy. More work will be done to sort out which patients can have their therapy aborted or deescalated.

We are going to see a lot of exciting data on small-molecule agents to treat patients with brain metastases and these agents are also systemically effective.