Enhertu Fulfills ‘Big Unmet Need’ for Patients with HER2-Low Metastatic Breast Cancer

Treatment with Enhertu (fam-trastuzumab deruxtecan-nxki) doubled progression-free survival (time during and after treatment when a patient lives without disease progression) in patients with HER2-low, hormone receptor–positive metastatic breast cancer, giving this patient population a new standard of care, according to recently published data.

Across all patients enrolled in the study, the median progression-free survival (time during and after treatment when a patient lives without disease progression) was 9.9 months with Enhertu compared with 5.1 months with chemotherapy. And the median overall survival was 23.4 months with Enhertu compared with 16.8 months for chemotherapy, representing a 6.6-month improvement in survival with the agent.

The results of the 3 DESTINY-Breast04 study — which were presented at the 2022 American Society of Clinical Oncology Annual Meeting and simultaneously published in the New England Journal of Medicine — demonstrated that the use of Enhertu was associated with a median progression-free survival of 10.1 months, compared with 5.4 months with physician choice of chemotherapy. Additionally, median overall survival (time from diagnosis or treatment start when patients are alive) was 23.9 months and 17.5 months, respectively. And there were fewer side effects reported with Enhertu compared to chemotherapy, 52.6% vs. 67.4%, respectively.

“(Enhertu) is the first HER2-targeted therapy to demonstrate statistically significant and clinically meaningful improvement in progression-free survival and overall survival compared (with) standard chemotherapy for patients with HER2-low metastatic breast cancer,” said lead study author Dr. Shanu Modi, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City. “With these results we have expanded of HER-2 targeted therapy to a new population of breast cancer patients and have established (Enhertu) as the new standard of care for patients with HER-2 low metastatic breast cancer.”

In the DESTINY-Breast04 study, 557 patients were randomly assigned to receive Enhertu (373 patients) or physician’s choice of chemotherapy (184 patients).

Low expression of HER2 was defined as an IHC score of 1+ or 2+ with a negative in situ hybridization (ISH) test, which represents approximately 65% of breast cancer diagnoses, Modi noted. Overall, 88.7% of patients were hormone receptor–positive and 11.3% were negative.

“Our currently available HER2-targeted therapies have not been effective for patients in this subgroup. We currently treat (patients with) HER2-low breast cancer as HER2-negative breast cancer, where therapy is really guided by hormone receptor status,” Modi said. “Ultimately, once we’ve exhausted endocrine therapy and a few lines of targeted agents, we have limited late-line options available for these patients, most commonly offering palliative single-agent chemotherapy, which has modest activity. We have a big unmet need for more effective therapies.”

Across all patients enrolled in the study, the median progression-free survival was 9.9 months with Enhertu compared with 5.1 months with chemotherapy. And the median overall survival was 23.4 months with Enhertu compared with 16.8 months for chemotherapy, representing a 6.6-month improvement in survival with the agent.

In those with hormone receptor–negative disease, the median progression-free survival was 8.5 months with Enhertu and 2.9 months for chemotherapy. The median overall survival in this group was 18.2 months and 8.3 months, respectively.

Across all patients, the overall response rate (a percentage of patients whose disease partially or completely responds to treatment) was 52.3% with Enhertu (331 patients) compared with 16.3% with chemotherapy (163 patients). In the hormone receptor–negative group, the overall response rates were 50% and 16.7% for Enhertu (40 patients) and chemotherapy (18 patients), respectively.

In those with hormone receptor–positive disease, the overall response rate was 52.6% Enhertu versus 16.3% for chemotherapy. The median duration of response (the time the disease responds to a treatment without growth or spread) was 10.7 months with Enhertu compared with 6.8 months for chemotherapy.

Enhertu demonstrated a consistent improvement in progression-free survival across subgroups. For patients with hormone receptor–positive disease, those with a HER2 IHC score of 1+ had a median progression-free survival of 10.3 months with Enhertu compared with 5.3 months with chemotherapy. Among individuals with hormone receptor–positive HER2 IHC 2+ and ISH-negative disease, the median progression-free survival was 10.1 months for Enhertu and 5.9 months for chemotherapy.

In patients with hormone receptor–positive disease who received prior treatment with a CDK4/6 inhibitor, the median progression-free survival was 10 months with Enhertu compared with 5.4 months for chemotherapy. For those with hormone receptor–positive disease who did not receive a CDK4/6 inhibitor, the median progression-free survival was 11.7 months with Enhertu compared with 5.9 months for chemotherapy.

“Overall, these results establish HER2-low metastatic breast cancer as a targetable population with Enhertu as a new standard of care in this setting,” Modi said.

At the time of data cutoff, the median treatment duration was 8.2 months for Enhertu and 3.5 months for chemotherapy. Side effects led to treatment discontinuation for 16.2% of patients in the Enhertu group compared with 8.1% for chemotherapy. Dose reductions were required due to side effects for 22.6% of patients in the Enhertu group compared with 38.4% for chemotherapy.

Treatment-emergent side effects were experienced by 99.5% of those in the Enhertu group compared with 98.3% of those treated with chemotherapy. Serious side effects occurred in 27.8% of patients treated with Enhertu and for 25% with physician’s choice.

The most frequently observed treatment-related side effects for Enhertu and chemotherapy, respectively, were nausea (73% vs 23.8%), fatigue (47.7% vs 42.4%), skin and subcutaneous tissue disorders, including alopecia (37.7% vs 32.6%), vomiting (34% vs 9.9%), neutropenia (33.2% vs 51.2%) and anemia (33.2% vs 22.7%).

There were 14 drug-related deaths with Enhertu (3.8%) compared with five for chemotherapy (2.9%). Adjudicated interstitial lung disease (ILD)/pneumonitis (which are conditions that cause scarring of the lungs) occurred in 45 patients treated with Enhertu (12.1%), with five patients having a severe event and three having a fatal event.

“The drug has been in use now for a couple years and I think we have all gotten a little more comfortable, first responding to pulmonary symptoms more quickly and also how to manage it,” said Dr. Julie R. Gralow, chief medical officer and executive vice president of ASCO, and previous director of Breast Medical Oncology at the Seattle Cancer Care Alliance, while commenting on the results. “I think it was much more of a concern a couple of years ago and now we have learned how to be more aware and to act quickly.”

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