Trastuzumab Deruxtecan Shows Promising Efficacy for Certain Patients With Breast Cancer

The use of trastuzumab deruxtecan (Enhertu) continued to show durable antitumor activity along with new promising efficacy results in previously treated patients with HER2-positive advanced breast cancer, according to an analysis of results from the DEBBRAH trial (NCT04420598) published in Neuro-Oncology.¹

Results from the ongoing, 5-cohort, phase 2 study met several end points in the first, second, and third cohorts of the study that separated patients with advanced breast cancer based on different baseline characteristics. In cohort 1, the end point was 16-week progression-free survival (PFS) defined as the rate of patients without progression or death for any cause. Then in cohorts 2 and 3, the primary end point was intracranial objective response rate (ORR-IC), which was determined locally by the investigator using RANO-BM criteria.

Overall, 21 patients received trastuzumab deruxtecan in the trial and of the 8 patients in cohort 1, 7 were alive at the time of data-cut off without progressive disease 16 weeks after initiating treatment, and the PFS rate was 87.5% (95% CI, 47.3-99.7; P < .001). Moreover, 3 patients experienced progressive disease, but of these 3 patients, one patient had intracranial disease progression, and 2 had extracranial disease progression.

In cohort 2, researchers observed an ORR-IC of 50% (95% CI, 6.7%-93.2%) as 2 of the 4 patients had partial intracranial responses. In cohort 3 there was an ORR-IC of 44.4% (95% CI, 13.7-78.8; P < .001) with 4 of the 9 patients showing an intracranial partial response. In cohort 3, 1 patient had stable disease that lasted more than 24 weeks, and 3 patients had stable disease that lasted for less than 24 weeks. One patient had progressive disease as their best response to treatment.

Overall, 4 patients experienced progressive disease at the time of data cutoff, but all patients experienced intracranial progressive disease. Additionally, 1 patient had extracranial progressive disease. The overall ORR-IC between patients with active brain metastases in cohorts 2 and 3 was 46.2% (95% CI, 19.2-74.9).

Similar efficacy results extended to patients who had measurable intracranial or extracranial lesions at baseline in the overall study group and in cohorts 1, 2, and 3, with an ORR of 66.7% (95% CI, 41.0-86.7), 80.0% (95% CI, 28.4-99.5), 50.0% (95% CI, 6.7-93.2), and 66.7% (95% CI, 29.9-92.5), respectively. However, all responders had partial responses, but most patients had a reduction in tumor size for both intracranial and extracranial lesions.

For patients with all measurable lesions, the median time to response with the study drug was 2.7 months (95% CI, 1.4-5.5), whereas median time to response for patients with intracranial lesions was 3.4 months (95% CI, 6.9-NA), and 1.5 months (95% CI, 1.3-NA) in patients with measurable extracranial lesions.

PFS and duration of response was immature at the time of analysis among all patients who received trastuzumab deruxtecan, but there was an events rate of 38.1% among all patients at 8.4 months of median follow-up. At 6 months, the PFS rate was 78.7% (95% CI, 52.7-91.5) and 61.4% at 9 months (95% CI, 31.0-81.6) for all patients on the trial with advanced breast cancer.

“Although efficacy outcomes are more easily measured, subjective symptoms and quality of life [QoL] of patients with [brain metastases] are increasingly recognized as a crucial end point of cancer care by patients as well as physicians and regulators,” the researchers wrote regarding their thoughts on the safety findings of the study. “In this study, the overall [general health survey]/QoL of most patients did not deteriorate from baseline at 6 months, suggesting that the trastuzumab deruxtecan regimen may have served to preserve the QoL of pretreated patients with stable or active HER2-positive [breast cancer brain metastases].”

The most common adverse events (AEs) included fatigue (52.4%), nausea (42.9%), neutropenia (28.6%), and constipation (28.6%). The most common reported grade 3-4 AEs were neutropenia (19.0%) and fatigue (4.8%), while AEs led to a dose interruption in 7 patients and a dose reduction in 3. Four patients discontinued treatment because of an AE, which were reported as interstitial lung disease/pneumonitis, fatigue, neutropenia, and SARS-CoV-2 infection with concomitant staphylococcal pneumonia.

In each cohort, the median relative dose intensity of the study drug was 99.2% (range, 81.0-101.0) in cohort 1, 98.9% (range, 91.5-101.0) in cohort 2, and 90.5% (range, 86.2-102.5) in cohort 3. In all 3 cohorts, the most common AE of any grade was fatigue while no patients in cohort 2 experienced a grade 3/4 AE. In comparison, 3 patients in cohort 3 experienced grade 3/4 neutropenia, 1 patient in cohort 1 had grade 3/4 neutropenia, and another had grade 3/4 fatigue.

Two deaths were observed during treatment due to intraventricular hemorrhage related to progressive disease and SARS-CoV-2 infection, but no deaths were associated with the treatment. Moreover, 6 patients had a serious AE but were still managed by treatments like corticosteroids.

“Our preliminary findings suggest that [trastuzumab deruxtecan] could be a valuable treatment option for HER2-positive patients with stable or active [breast cancer brain metastases],” the reserachers concluded. “Longer follow-up, along with data from cohorts 2, 4, and 5, will further guide the use of [trastuzumab deruxtecan] in HER2-positive or HER2-low patients [with advanced breast cancer] with [brain metastases] and/or leptomeningeal carcinomatosis.”

Reference

Pérez-García JM, Vaz Batista M, Cortez P, et al. Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: The DEBBRAH trial. Neuro Oncol. 2023 Jan 5;25(1):157-166. doi:10.1093/neuonc/noac144