T-DXd emerges as new standard second-line treatment for HER2+ MBC

The growing number of treatment options for HER2+ breast cancer raises questions about how and when to use different medicines. This new research, presented on December 9, identified a new standard second-line treatment for metastatic disease, a more effective tyrosine kinase inhibitor, and a cell pathway for further study.

Discussions also touched on themes of limited global access to anti-HER2 drugs, challenges, and signs of early progress for treating brain metastases, and hard-to-manage side effects.

Background

Treatment for breast cancer is based on subtypes. The HER2+ subtype describes cancers that test positive for a protein called HER2, which is found to promote cancer growth.

These cancers are treated with anti-HER2 medicines. Eight medicines are approved by the U.S. Food and Drug Administration to treat HER2+ breast cancer in the United States. Four were approved in the past two years. More are in development.

The first-line treatment for HER2+ metastatic breast cancer is trastuzumab, pertuzumab, and taxane. If this combination does not work, or stops working, trastuzumab emtansine (T-DM1) is often used next.

Recent attention focuses on two classes of medicine:

• Antibody-drug conjugates that combine the HER2-targeting medicine trastuzumab, another anti-cancer medicine, and a binding agent
• Tyrosine kinase inhibitors, small molecule medicines that target HER2

People with HER2 + MBC develop brain metastases more often than those with HER2– disease. Tucatinib (Tukysa), approved in 2020, is the first anti-HER2 medicine shown to be active on brain metastases.

Results

As reported earlier this year in Europe, the phase III randomized DESTINY-BREAST 03 trial found that trastuzumab deruxtecan (T-DXd/Enhertu) was more effective than the standard second-line treatment trastuzumab emtansine (T-DM1/Kadcyla) against HER2+ metastatic breast cancer.

Participants in this study were enrolled from Asia, Europe, and North America. Based on these findings, the U.S. Food and Drug Administration recently granted T-DXd breakthrough designation as a second-line therapy for HER2+ metastatic breast cancer.

New results looked at the data by subgroup, including hormone receptor status, prior treatments, and location of metastases. The study team found no differences by subgroup. T-DXd worked better than T-DM1, even in people with brain metastasis.

Participants tolerated the medicine well. There were no incidents of grade 4 or 5 interstitial lung disease, a prior concern.

These findings support the use of T-DXd as the new standard second-line treatment for HER2+ metastatic breast cancer.

Findings from a Chinese HER2 metastatic breast cancer trial was highlighted, as there are unmet needs for additional HER2-targeted therapies for people in countries where access to HER2 therapies is scarce. The phase III randomized trial PHOEBE compared two tyrosine kinase inhibitor medicines, pyrotinib and lapatinib. Twenty-nine centers in China offered the trial, recruiting 267 women with HER2+ metastatic breast cancer. Participants were randomized to the two medicines, each taken as a daily pill. Both groups also received capecitabine on a two-week on/one-week off schedule.

The study looked at progression-free survival (PFS), the length of time during and after treatment that a participant lives with the disease without it getting worse. Interim results presented last year showed a PFS of 12.5 months for pyrotinib versus 6.8 months for lapatinib. This led to the approval of pyrotinib as a second-line treatment in China. Final results were slightly better (12.5 months versus 5.6 months).

The study also looked at median overall survival (OS), the length of time from either the date of diagnosis or the start of treatment that half the participants are no longer alive. Pyrotinib did not reach the median goal for overall survival. People are living longer on pyrotinib. The median OS for the lapatinib group was 26.9 months.

A third study identified the MAPK pathway as a marker for future research to better understand cell activity in HER2+ metastatic breast cancer. As of now, the HER2+ subtype is defined solely by HER2+ status. Other markers might explain the limited success of these medicines against brain metastases or provide targets for new medicines.

What it means for people with HER2+ MBC

T-DXd is now favored as second-line treatment for HER2+ metastatic breast cancer. The potential positive effect on brain metastases is an exciting finding that hopefully will bear out over future studies. It will be interesting to see if this medicine can prevent brain metastases in high-risk, early-stage disease.

People considering treatments may still want to look at tucatinib combined with capecitabine and trastuzumab. The HER2CLIMB study, not described here, showed positive results in survival and brain metastases with this medicine combination. Advocates point out that HER2CLIMB included in its trial design people with active brain metastases, a harder to treat population, providing hope that additional trial designs will include participants with active and stable brain metastasis. The positive impact of the subgroup of participants with stable brain metastasis in the T-DXd trial is encouraging news for both researchers and patient advocates.

People with HER2+ metastatic breast cancer in other countries have more limited options. For example, fewer medicines are approved in China. In countries where T-DXd is not available, pyrotinib is a possible second-line treatment.

Side effects are an important consideration as well. In the PHOEBE trial, nearly one-third of trial participants in the pyrotinib study group reported serious diarrhea. Pyrotinib is not available in the United States.

Overall, the findings from SABCS show continued progress in treating HER2+ breast cancer and add clarity to the treatment landscape.