Enhertu continues to show good results

Background

The most effective therapies for HER2-positive breast cancers are drugs that target the protein HER2. Newer drugs do this in more innovative ways. T-DXd is an antibody drug conjugate that combines the HER2-targeting drug trastuzumab, another anti-cancer drug, and a binding agent to deliver chemotherapy more directly.

T-DXd is the preferred second-line treatment for metastatic HR-positive, HER2-negative breast cancer. This approval was based on the results of the DESTINY-Breast03 randomized control trial presented last year at this meeting.

This same drug was also the source of excitement at the American Society of Clinical Oncology meeting in June 2022 when trial results revealed its effectiveness against breast cancers with low levels of HER2, a group of breast cancers not previously targeted with anti-HER2 drugs.

Results

The phase III randomized clinical trial DESTINY-Breast03 found that T-DXd was more effective in treating HER2-positive metastatic breast cancer than T-DM1/Kadcyla. Early results of this trial were presented last year. The updated findings confirm the benefit.

The global study included 524 people with metastatic HER2-positive breast cancer randomized to two groups: one that received T-DXd and another that received T-DM1. The characteristics of the two groups were very similar. Both groups were almost evenly split between people with hormone receptor-positive and hormone receptor-negative disease. People with brain metastases represented 16.5% of the T-DXd group and 14.8% of the T-DM1 group. More than half of participants in the trial were from Asia, followed by Europe, then North America, then the rest of the world. On average, participants had two prior lines of treatment.

On average, participants in the T-DXd group went 28.8 months (about two-and-a-half years) without cancer growth, as compared to 6.8 months for the T-DM1 group — a four-fold difference. Notably, 21% of people receiving T-DXd had a complete response compared to 9% receiving T-DM1. Although the study goal for median overall survival was not reached by either group, the T-DXd group fared better. At 24 months, overall survival was 77.4% for the T-DXd group compared to 69.9% for the T-DM1 group.

More than half of participants in both groups experienced serious side effects, described as adverse events of grade three or higher on a scale of one to five. The T-DXd group was slightly more affected.

T-DXd can cause serious lung side effects. Thirty-nine people (15.2%) in the T-DXd arm of the study developed interstitial lung disease. This compares with eight people or 3.1% in the T-DM1 group. Nausea, vomiting, and hair loss were more common side effects.

In a second report, DESTINY-Breast02 demonstrated that T-DXd is more effective than the doctor's choice of chemotherapy in people previously treated with T-DM1. Participants in this randomized trial who received T-DXd experienced on average nearly 18 months without cancer growth compared to nearly 7 months for the physician’s choice group. The results for overall survival favored T-DXd as well (39.2 versus 26.5 months). Overall, 69.7% of participants in the T-DXd group responded to the drug compared to 29.2% in the physician’s choice group, with complete responses by 14% of people receiving T-DXd and 5% of those receiving physician’s choice.

Most of the 608 people in the trial were on their third or fourth line of treatment. Approximately 18% had stable brain metastases. The same results were seen across clinical subgroups based on age, hormone status, brain metastases, and prior therapies. In all cases, T-DXd outperformed physician’s choice of treatment.

Side effects were similar to those reported in other studies. Slightly more than half of the participants in the T-DXd arm of the trial experienced an adverse event of grade three or higher. This compares to 44% in the physician choice’s group.

In this study, 10.4% of people receiving T-DXd developed interstitial lung disease. Most (88.1%) of the cases were mild (grade one or two). The most common mild side effects of T-DXd seen in this trial were nausea and vomiting. Approximately 37% of participants in the T-DXd group experienced some hair loss.

What these findings mean for you

These studies confirm what we have heard for the past year — that T-DXd may be more effective at stopping HER2-positive cancer growth than other treatments, including similar drugs.

T-DXd is typically given by infusion every three weeks. If you are receiving T-DXd or considering it, talk with your doctor about the potential side effects. This drug can cause serious lung problems in a percentage of people. Anyone receiving T-DXd should be monitored very closely for signs of lung disease, and the presenters at the symposium offered guidance for doctors to provide it. It's important to notify your doctor if you notice changes in your lung function. In some cases, you may need to take a break from the medicine or discontinue it. As doctors better understand this side effect, they can identify the people most at risk.

Today, T-DXd is available as a second-line therapy. A second-line therapy is given when a cancer fails to respond or stops responding to the first treatment. Talk with your doctor if you are interested in learning more about clinical trials testing T-DXd as a first-line therapy.