Expert Discusses Treatment Trends in HER2+ Breast Cancer

Sunil Verma, MD

Significant treatment advances are transforming the landscape of HER2-positive breast cancer, including the neoadjuvant setting.

One of the studies that has had critical implications across HER2-positive settings is the phase III MA.31 trial,¹ says Sunil Verma, MD. The study was a head-to-head analysis of lapatinib (Tykerb) and trastuzumab (Herceptin) in HER2-positive patients with metastatic breast cancer. In the trial, 537 patients were randomized 1:1 to receive lapatinib in combination with a taxane followed by lapatinib or trastuzumab in combination with a taxane followed by trastuzumab.

Lapatinib treatment was not only associated with inferior progression-free survival (PFS; HR, 1.37; 95% CI, 1.13-1.65; P = .001), it also produced worse overall survival (OS) outcomes compared with trastuzumab (HR, 1.47; 95% CI, 1.03-2.09; P = .03).

The findings from this study “can be applied in the early-stage setting,” as well, says Verma, medical director of the Tom Baker Cancer Centre and professor and head of the Department of Oncology at the University of Calgary.

Also in the early-stage setting, the neoadjuvant combination of pertuzumab (Perjeta), trastuzumab, and chemotherapy was granted an accelerated approval by the FDA in September 2013 for patients at high risk for metastases or death with locally advanced, inflammatory, or early-stage HER2-positive disease.

In addition to the proper integration of new therapies, another challenge in the neoadjuvant setting is determining when therapy should be escalated or de-escalated in select patients, adds Verma.

OncLive: What are some recent advances in the field of HER2-positive breast cancer?

In an interview with OncLive, Verma discusses the current landscape in HER2-positive breast cancer and his views on neoadjuvant treatment options.Verma: In this space, we have seen some tremendous advances over the past 5 years. The pivotal one is that we understand that advanced HER2-positive disease requires ongoing suppression of the HER2 receptor. We know that continued blockade of the HER2 receptor with an antibody through tyrosine kinase inhibition is needed.

The second biggest advance has been pertuzumab in the second-line setting, based on the CLEOPATRA results, which have shown improvements in PFS and OS. Along with that, we have also learned that we can use the antibody-drug conjugate T-DM1 in the second-line setting and beyond, as it significantly improves PFS and OS.

When we start collecting all the evidence and putting it into clinical practice, we can expect a median OS for patients with HER2-positive breast cancer to now exceed 5 years. We have seen a pretty dramatic improvement.

There are still some critical issues that we need to address. One is how to target and address patients with brain metastases in metastatic breast cancer; that is a common yet challenging concern that we have.

How have these advances impacted the neoadjuvant setting?

Secondly, how long do we need to have patients treated for with these expensive therapies? Currently, we give therapy until patients progress. However, there are some who do very well with complete responses, and we are not sure if we still need to give them these agents until progression.What we have learned in the metastatic setting, at least the principles, can be applied in the early-stage setting, as well. One of the pivotal studies, the MA.31 trial, showed that taxanes plus trastuzumab were better than taxanes plus lapatinib; we saw something very similar in the neoadjuvant and adjuvant setting. It shows that we can translate some of this evidence into the early breast cancer setting, as well.

For the current neoadjuvant treatment for early HER2-positive breast cancer, we give chemotherapy plus anti-HER2 treatments. Now, the FDA has approved pertuzumab for 3 to 6 cycles in the neoadjuvant setting, so that has been incorporated in the United States.

We have also learned that, in certain patients, we can de-escalate chemotherapy when giving weekly paclitaxel and trastuzumab therapy. Right now, where we are sitting in the neoadjuvant setting, is trying to balance who we can de-escalate therapy for and which patients need to receive all of the therapies. That’s where we’re looking in the next 5 years.

What are some emerging regimens in development for HER2-positive disease?

We are trying to be better at risk stratifying individuals. Some patients might just require minimal chemotherapy—whether it is weekly paclitaxel or, maybe in the future, T-DM1. On the other hand, we need some patients for whom we need to cycle through pertuzumab, trastuzumab, and maybe other novel therapies. The issue of how to de-escalate versus how to escalate treatment for these patients is going to be critical.The next couple of years are going to be key in the HER2-positive setting. There is a lot of interest in looking at immunotherapies in combination with anti-HER2 drugs. There is a lot of interest in looking at novel HER2 agents, such as neratinib. This is a potent TKI; we have data from the ExteNET trial that showed a modest improvement in disease-free survival, though it comes with a lot of toxicity.

There is a lot of interest to see if we can give patients, who have not had a complete pathological complete response, T-DM1 compared with trastuzumab. That is a pivotal trial—the KATHERINE study, which we will get the results of in the next couple years.

What do you envision as the future of HER2-positive breast cancer in the next 5 to 10 years?

Can we combine this antibody-drug conjugate concept with liposomal anthracyclines? One of the compounds is MM-302. There are a lot of new agents and approaches that one has to consider. By no means, is our work done. Patients are still suffering from this disease.We owe it to our patients to make sure that we can need to individualize therapy and de-escalate our treatment. I foresee that we will be using a combination of targeted therapies in the neoadjuvant setting, and only those patients who are not having complete pCRs would receive salvage chemotherapy in that setting. We need to consider a more targeted approach and only use chemotherapy in those who are not getting a great response at the time of surgery.

1. Gelmon KA, Boyle FM, Kaufman B, et al. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2—positive advanced breast cancer: Final results of NCIC CTG MA.31 [published online March 16, 2015]. J Clin Oncol. doi: 10.1200/JCO.2014.56.9590.