Enhertu Shows Promising Results in Treating HER2-Positive Metastatic Breast Cancer with Brain Metastases, Extending Progression-Free Survival

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Findings from the Phase IIIb/IV DESTINY-Breast12 trial (NCT04739761) show Enhertu (trastuzumab deruxtecan) led to significant overall and intracranial clinical activity, including prolonged progression-free survival (PFS), in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) with brain metastases who have not received more than two previous lines of therapy in the metastatic setting. Findings from the trial, published by Nature Medicine, support the potential use of Enhertu as a second-line treatment for this patient population.^1-3

“Up to 50% of patients with HER2-positive [mBC] experience the spread of disease to the brain during the course of their illness, which significantly impacts quality of life and outcomes,” principal trial investigator Nancy Lin, MD, associate chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Boston, MA, said in a press release. “These data help further characterize the clinical benefit and safety profile of Enhertu in these patients, which will help guide treatment decisions.”¹

Enhertu’s mechanism of action involves the humanized anti-HER2 IgG1 antibody trastuzumab attaching by a cleavable linker to the small molecule DXd. Trastuzumab then attaches to HER2 on tumor cells to halt growth, which causes the antibody to be internalized as lysosomal enzymes cleave off DXd. Subsequently, DXd causes DNA damage as it replicates and apoptotic cell death as a topoisomerase I inhibitor.^4,5

Enhertu has been FDA-approved for adults with unresectable or metastatic HER2-positive breast cancer previously administered an anti-HER2-based regimen; adults with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer; adults with unresectable or metastatic non-small cell lung cancer; and adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma.⁵

“Trastuzumab-based therapy has long been the mainstay of systemic therapy for patients with HER2+ mBC, and several additional HER2-directed therapies have been investigated for the treatment of HER2+ mBC with BMs, including tucatinib,” the study authors wrote. “Despite this, a large proportion of patients receiving treatment, including those with an initial response, eventually experience disease progression (commonly in the CNS).”³

The open-label, multicenter, two-cohort, non-comparative DESTINY-Breast12 clinical trial enrolled 504 patients to analyze the efficacy and safety of Enhertu at a dose of 5.4 mg/kg in patients with previously treated advanced/metastatic HER2-positive breast cancer. Cohort 1 of the trial included patients without brain metastases at baseline while cohort 2 had patients with brain metastases at baseline.

Both cohorts were comprised of patients who experienced disease progression following previous treatment with an anti-HER2-based regimen and who did not receive more than two previous lines of therapy in the metastatic setting. The primary endpoint of cohort 1 was objective response rate (ORR) as assessed by independent review while the primary endpoint of cohort 2 was PFS. Additional endpoints included central nervous system (CNS) PFS, CNS ORR, ORR in the brain metastases cohort, and safety.

Among patients with brain metastases at baseline, the 12-month PFS rate was 61.6% and the 12-month CNS PFS rate was 58.9%. These data were consistent among patients with stable and active brain metastases.

Those with stable brain metastases achieved a 12-month PFS rate of 62.9% and a 12-month CNS PFS rate of 57.8%. Patients with active brain metastases achieved a 12-month PFS rate of 59.6% and a 12-month CNS PFS rate of 60.1%. Among those without brain metastases at baseline, ORR was 62.7% with 23 complete responses and 128 partial responses.

“The results from DESTINY-Breast12 show substantial clinical activity for patients whose disease has spread to the brain,” said Sunil Verma, global head, Oncology Franchise, AstraZeneca, in a press release. “These data as well as the results in patients without brain metastases further build confidence in the clinical profile of Enhertu for the second-line treatment of HER2-positive metastatic breast cancer.”¹

A post-hoc analysis showed a CNS ORR of 82.6% (n=19/23) among patients with active brain metastases who were not previously administered local CNS therapy and 50.0% (n=19/38) among patients whose disease progressed after receiving local CNS therapy. In terms of safety, the profile of Enhertu was consistent with findings from prior breast cancer clinical trials and no new safety signals were identified. Safety findings for the drug were also generally consistent among patients with brain metastases and those without brain metastases.

“Treating brain metastases in patients with breast cancer is challenging as there are few effective treatment options,” said Mark Rutstein, global head, Oncology Development, Daiichi Sankyo, in a press release. “Building on previous studies, these results show Enhertu can provide strong overall and intracranial clinical activity and support its potential role in treating patients with active or stable brain metastases.”¹

References

1. Enhertu showed substantial clinical activity in patients with HER2-positive metastatic breast cancer and brain metastases. News release. AstraZeneca. September 13, 2024. Accessed September 17, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/enhertu-showed-substantial-clinical-activity-in-patients-with-her2-positive-metastatic-breast-cancer-and-brain-metastases.html#

2. A Study of T-DXd in Participants With or Without Brain Metastasis Who Have Previously Treated Advanced or Metastatic HER2 Positive Breast Cancer (DESTINY-B12). ClinicalTrials.gov. July 19, 2024. Accessed September 17, 2024. https://clinicaltrials.gov/study/NCT04739761

3. Harbeck, N., Ciruelos, E., Jerusalem, G. et al. Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Nat Med (2024). https://doi.org/10.1038/s41591-024-03261-7

4. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-option-patients-her2-positive-breast-cancer-who-have-progressed-available. Accessed September 17, 2024.

5. Enhertu. Prescribing information. Daiichi Sankyo, Inc.; 2022. Accessed September 17, 2024.