Strategies Needed for Resistance to Targeted Agents in HER2+ Breast Cancer

Mothaffar F. Rimawi, MD

HER2-directed agents and chemotherapy have dramatically improved the outlook for patients with HER2-positive breast cancer, but researchers are still scratching the surface in understanding the biology of the disease and resistance mechanisms, said Mothaffar F. Rimawi, MD.

“When we look at the landscape of metastatic disease, we see that it evolves,” explained Rimawi. “Genomically, if we look at primary breast cancer and metastatic breast cancer, there are variations in the mutational profile; this would tell us there are pathways that get upregulated to create resistance. We need to be cognizant of that as we are developing these treatment strategies.”

The HER2-targeted agent pertuzumab (Perjeta) combined with trastuzumab (Herceptin) and chemotherapy or endocrine therapy is the well-established frontline option in the metastatic setting, but more agents are making headway in the adjuvant space, such as ado-trastuzumab emtansine (T-DM1; Kadcyla).

With the positive data from the KATHERINE trial presented at the 2018 San Antonio Breast Cancer Symposium, an adjuvant standard of care has emerged for patients with high-risk HER2-positive early breast cancer.

The open-label phase III trial showed that T-DM1 reduced the risk of invasive disease recurrence or death by 50% compared with trastuzumab. Adjuvant T-DM1 also demonstrated a statistically significant and clinically meaningful improvement in invasive disease-free survival (iDFS) versus trastuzumab; the 3-year iDFS rate was 88.3% with T-DM1 versus 77.0% with trastuzumab. The iDFS benefit with T-DM1 was upheld across key patient subgroups.

OncLive: Could you describe the metastatic HER2-positive breast cancer paradigm?

In an interview with OncLive, Rimawi, an associate professor and director of Clinical Research at the Lester and Sue Smith Breast Center at Baylor College of Medicine, discussed the current options in HER2-positive breast cancer and shed light on where future research is headed.Rimawi: The landscape of metastatic HER2-positive breast cancer is evolving very rapidly. It is evolving because of several factors. In the early-stage setting, [there are] increased reports from clinical trials showing benefits from anti-HER2 agents, such as pertuzumab and neratinib (Nerlynx) and, most recently, results from the KATHERINE study on T-DM1. [These agents] are improving patient outcomes in the early-stage setting, but they are also using them in the metastatic setting and moving them earlier. That is likely to affect how those agents are used, if they are used again in the metastatic setting.

Could you share any updates from the 2018 San Antonio Breast Cancer Symposium?

What are the biggest considerations in the field in terms of developing future agents?

The other aspect of it is that there are a number of new agents addressing a new mechanism of action as well as mechanisms of resistance. It is very important that we understand the biology of resistance and then try to develop strategies to overcome them. The combinations we design need to be rational and biologically informed. They need to be personalized to the particular patient and their individual tumor.The KATHERINE trial has been a major breakthrough in this field. It evaluated patients who received neoadjuvant chemotherapy plus anti-HER2 agents; about 80% of them received trastuzumab alone, while the 20% [were given] pertuzumab, too. If patients had residual disease, they moved on to a continuation of trastuzumab versus T-DM1. The study demonstrated quite a robust improvement in disease-free survival. We need to interpret these data with a lot of optimism. It is important to keep in mind that we personalize our approach for each individual patient. The patients who will do the best with this regimen are those similar to the ones enrolled in the trial, although all subgroups seemed to have similar benefit.As it stands today, pertuzumab is the frontline option in combination with trastuzumab and chemotherapy or endocrine therapy. Second-line treatment is T-DM1. With results from APHINITY and ExteNET, some proportion of patients are going to see these agents in the early-stage setting. If you want to use them again in the metastatic setting, enough time needs to pass, and we have data demonstrating that the efficacy will decrease.

We need to develop strategies to get around that. One idea that comes to mind is [the use of] TKIs. We have 2 in development. One is neratinib, which is approved in the extended adjuvant setting but not yet in the metastatic setting.

Tucatinib is another promising TKI and it seems to be very well tolerated. We will hopefully see more data with this agent in the next year or so. The reality is that these agents will be used in the third-line setting in combination with capecitabine. There is a lot of attention being paid to how these agents impact central nervous system (CNS) metastases. That seems to be one of the greatest challenges we face right now: about 50% of patients we treat will develop CNS progression before they succumb to their disease. Many ongoing studies are factoring in CNS penetration as a critical endpoint.

The other aspect is resistance due to other factors, such as heterogeneity of HER2-positive breast cancer. The T-DM1 strategy might be a way to use HER2 not only as a target, but also as an anchor to deliver the payload into the cells and increase efficacy. This approach seems to have an impact in patients with various levels of HER2 expression in their tumors.

A third approach is the immune response. The immuno-oncology approach is a very promising field and has been very efficacious in several cancers, most recently, in triple-negative breast cancer. One of the oldest immunotherapies, if you really think about it, has been trastuzumab.

One area where we can further understand the targeted therapies and mechanisms of resistance is in the estrogen receptor (ER). When the ER coexists with HER2, it is associated with lower response rates to chemotherapy and HER2-targeted therapy. There have been several studies looking at concurrently targeting the ER and HER2, and they have been successful. HER2-positive breast cancer is not just 1 disease; we can divide it into many subgroups. With a greater understanding of the biology, we can further dissect this disease.

von Minckwitz G, Huang C-S, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer [published online December 5, 2018]. N Eng J Med. doi: 10.1056/NEJMoa1814017.